Textbook of Psychiatry [7 ed.]

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Kaplan & Sadock's Comprehensive Textbook of Psychiatry (2 Volume Set) by Benjamin J. Sadock (Editor), Virginia A. Sadock (Editor) Lippincott Williams & Wilkins Publishers; 7th edition (January 15, 2000)

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Kaplan & Sadock’s Comprehensive Textbook of Psychiatry TABLE OF CONTENTS Tribute to Harold I. Kaplan, M.D. About the Editors Contributors Editors Preface Introduction John C. Nemiah, M.D. Drugs Used in Psychiatry Color Plates

VOLUME I CHAPTER 1. NEURAL SCIENCES Section 1.1 Neural Sciences: Introduction and Overview Jack A. Grebb, M.D. Section 1.2 Functional Neuroanatomy David A. Lewis, M.D. Section 1.3 Developmental Neurobiology Kathryn J. Kotrla, M.D., Daniel R. Weinberger, M.D. Section 1.4 Monoamine Neurotransmitters Laurence H. Tecott, M.D., Ph.D. Section 1.5 Amino Acid Neurotransmitters Richard P. Shank, Ph.D., Virginia L. Smith-Swintosky, Ph.D. and Roy E. Twyman, M.D. Section 1.6 Neuropeptides: Biology and Regulation Michael J. Owens, Ph.D., Charles B. Nemeroff, M.D., Ph.D. and Garth Bissette, Ph.D. Section 1.7 Neurotrophic Factors Eric Stephen Levine, Ph.D. and Ira B. Black, M.D. Section 1.8 Intraneuronal Signaling Pathways Jay M. Baraban, M.D., Ph.D. Section 1.9 Basic Electrophysiology Charles F. Zorumski, M.D. and Keith E. Isenberg, M.D. Section 1.10 Basic Molecular Neurobiology Steven E. Hyman, M.D. and Eric J. Nestler, M.D., Ph.D. Section 1.11 Psychoneuroendocrinology Victor I. Reus, M.D. and Sydney Frederick-Osborne, Ph.D. Section 1.12 Immune System and Central Nervous System Interactions Andrew H. Miller, M.D., Bradley D. Pearce, Ph.D. and Carmine M. Pariante, M.D. Section 1.13 Chronobiology Thomas A. Wehr, M.D. Section 1.14 Applied Electrophysiology Edward L. Reilly, M.D. Section 1.15 Principles of Neuroimaging: Radiotracer Techniques Robert T. Malison, M.D. and Robert B. Innis, M.D., Ph.D. Section 1.16 Principles of Neuroimaging: Magnetic Resonance Techniques Craig N. Karson, M.D. and Perry F. Renshaw, M.D., Ph.D. Section 1.17 Population Genetic Methods in Psychiatry Steven O. Moldin, Ph.D. and Irving I. Gottesman, Ph.D., F.R.C. Psych. (Hon.) Section 1.18 Genetic Linkage Analysis of the Psychiatric Disorders Carol A. Mathews, M.D. and Nelson B. Freimer, M.D. Section 1.19 Basic Science of Sleep J. Christian Gillin, M.D., Erich Seifritz, M.D., Rebecca Zoltoski, Ph.D. and Rafael J. Salin-Pascual, M.D., Ph.D. Section 1.20 Appetite Nori Geary, Ph.D. and Gerard P. Smith, M.D. Section 1.21 Future Directions in Neuroscience and Psychiatry Solomon H. Snyder, M.D. CHAPTER 2. NEUROPSYCHIATRY AND BEHAVIORAL NEUROLOGY Section 2.1 Neuropsychiatry: Clinical Assessment and Approach to Diagnosis Tiffany W. Chow, M.D. and Jeffrey L. Cummings, M.D. Section 2.2 Neuropsychiatric Aspects of Cerebrovascular Disorders Robert G. Robinson, M.D. and Sergio E. Starkstein, M.D., Ph.D. Section 2.3 Neuropsychiatric Aspects of Brain Tumors Facundo F. Manes, M.D. and Robert G. Robinson, M.D. Section 2.4 Neuropsychiatric Aspects of Epilepsy Mario F. Mendez, M.D., Ph.D. Section 2.5 Neuropsychiatric Aspects of Traumatic Brain Injury Ricardo E. Jorge, M.D., Jeffrey E. Max, M.B.B.Ch. and Robert G. Robinson, M.D. Section 2.6 Neuropsychiatric Aspects of Movement Disorders

David Gordon Daniel, M.D., Michael F. Egan, M.D. and Steven S. Wolf, M.D. Section 2.7 Neuropsychiatric Aspects of Multiple Sclerosis and Other Demyelinating Disorders William W. Beatty, Ph.D. and Robert H. Paul, Ph.D. Section 2.8 Neuropsychiatric Aspects of HIV Infection and AIDS Igor Grant, M.D., F.R.C.P.(C)and J. Hampton Atkinson, Jr., M.D. Section 2.9 Neuropsychiatric Aspects of Other Infectious Diseases Brian Anthony Fallon, M.D., M.P.H. Section 2.10 Neuropsychiatric Aspects of Headache Kathleen Ries Merikangas, Ph.D. and James R. Merikangas, M.D. Section 2.11 Neuropsychiatric Aspects of Neuromuscular Disease James C. Edmondson, M.D., Ph.D. Section 2.12 Neuropsychiatric Aspects of Child Neurology James C. Edmondson, M.D., Ph.D. Section 2.13 Neuroimaging in Clinical Practice Joseph C. Wu, M.D., Daniel G. Amen, M.D. and H. Stefan Bracha, M.D. CHAPTER 3. CONTRIBUTIONS OF THE PSYCHOLOGICAL SCIENCES Section 3.1 Perception and Cognition Daniel J. Siegel, M.D. Section 3.2 Extending Piagets Approach to Intellectual Functioning Stanley I. Greenspan, M.D. and John F. Curry, Ph.D. Section 3.3 Learning Theory W. Stewart Agras, M.D., F.R.C.P.(C) and G. Terence Wilson, Ph.D. Section 3.4 Biology of Memory Larry R. Squire, Ph.D. and Ken A. Paller, Ph.D. Section 3.5 Brain Models of Mind Karl H. Pribram, M.D., Ph.D. 3.6 Emotional Intelligence Daniel Goleman, PhD. CHAPTER 4. CONTRIBUTIONS OF THE SOCIOCULTURAL SCIENCES Section 4.1 Anthropology and Psychiatry Anne E. Becker, M.D., Ph.D. and Arthur Kleinman, M.D. Section 4.2 Sociology and Psychiatry Ronald C. Kessler, Ph.D. Section 4.3 Evolutionary Biology and Psychiatry Michael T. McGuire, M.D. and Alfonso Troisi, M.D. Section 4.4 Cultural Psychiatry Manuel Trujillo, M.D. CHAPTER 5. QUANTITATIVE AND EXPERIMENTAL METHODS IN PSYCHIATRY Section 5.1 Epidemiology Darrel A. Regier, M.D., M.P.H. and Jack D. Burke, Jr., M.D., M.P.H. Section 5.2 Statistics and Experimental Design Robert M. Kaplan, Ph.D. and Igor Grant, M.D., F.R.C.P.(C) Section 5.3 Mental Health Services Research Mark Olfson, M.D., M.P.H. Section 5.4 Animal Research and Its Relevance to Psychiatry William T. McKinney, Jr., M.D. CHAPTER 6. THEORIES OF PERSONALITY AND PSYCHOPATHOLOGY Section 6.1 Psychoanalysis Glen O. Gabbard, M.D. Section 6.2 Erik H. Erikson Dorian S. Newton, Ph.D. and Peter M. Newton, Ph.D. Section 6.3 Other Psychodynamic Schools Paul C. Mohl, M.D. and Myron F. Weiner, M.D. Section 6.4 Approaches Derived From Philosophy and Psychology Paul T. Costa, Jr., Ph.D. and Robert R. McCrae, Ph.D. CHAPTER 7. DIAGNOSIS AND PSYCHIATRY: EXAMINATION OF THE PSYCHIATRIC PATIENT Section 7.1 Psychiatric Interview, History, and Mental Status Examination Myrl R. S. Manley, M.D. Section 7.2 Psychiatric Report and Medical Record Benjamin J. Sadock, M.D. Section 7.3 Signs and Symptoms in Psychiatry Benjamin J. Sadock, M.D. Section 7.4 Clinical Neuropsychology and Intellectual Assessment of Adults Rex M. Swanda, Ph.D., Kathleen Y. Haaland, Ph.D. and Asenath LaRue, Ph.D. Section 7.5 Personality Assessment: Adults and Children Russell L. Adams, Ph.D. and Jan L. Culbertson, Ph.D. Section 7.6 Neuropsychological and Intellectual Assessment of Children Ida Sue Baron, Ph.D. and Eileen B. Fennell, Ph.D. Section 7.7 Medical Assessment and Laboratory Testing in Psychiatry Richard B. Rosse, M.D., Lynn H. Deutsch, D.O. and Stephen I. Deutsch, M.D., Ph.D Section 7.8 Psychiatric Rating Scales Deborah Blacker, M.D., Sc.D. Section 7.9 Computer-Based Testing of the Psychiatric Patient Marvin J. Miller, M.D. CHAPTER 8. CLINICAL MANIFESTATIONS OF PSYCHIATRIC DISORDERS

Joel Yager, M.D. and Michael J. Gitlin, M.D. CHAPTER 9. CLASSIFICATION OF MENTAL DISORDERS Section 9.1 Classification of Mental Disorders Michael P. Bogenschutz, M.D. and H. George Nurnberg, M.D. Section 9.2 International Psychiatric Diagnosis Juan E. Mezzich, M.D., Ph.D., Angel A. Otero-Ojeda, M.D. and Sing Lee, M.D. CHAPTER 10. DELIRIUM, DEMENTIA, AND AMNESTIC AND OTHER COGNITIVE DISORDERS Eric D. Caine, M.D. and Jeffrey M. Lyness, M.D. CHAPTER 11. SUBSTANCE-RELATED DISORDERS Section 11.1 Introduction and Overview Jerome H. Jaffe, M.D. Section 11.2 Alcohol-Related Disorders Marc A. Schuckit, M.D. Section 11.3 Amphetamine (or Amphetamine-like)-Related Disorders Jerome H. Jaffe, M.D. Section 11.4 Caffeine-Related Disorders Eric C. Strain, M.D. and Roland R. Griffiths, Ph.D. Section 11.5 Cannabis-Related Disorders Wayne Macfadden, M.D. and George E. Woody, M.D. Section 11.6 Cocaine-Related Disorders Jerome H. Jaffe, M.D. Section 11.7 Hallucinogen-Related Disorders Henry David Abraham, M.D. Section 11.8 Inhalant-Related Disorders Thomas J. Crowley, M.D. Section 11.9 Nicotine-Related Disorders John R. Hughes, M.D. Section 11.10 Opioid-Related Disorders Jerome H. Jaffe, M.D. and Ari B. Jaffe, M.D. Section 11.11 Phencyclidine (or Phencyclidine-like)-Related Disorders Stephen R. Zukin, M.D. Section 11.12 Sedative-, Hypnotic-, or Anxiolytic-Related Abuse Domenic A. Ciraulo, M.D. and Ofra Sarid-Segal, M.D. Section 11.13 Anabolic-Androgenic Steroid Abuse Harrison G. Pope, Jr., M.D. and Kirk J. Brower, M.D. CHAPTER 12. SCHIZOPHRENIA Section 12.1 Schizophrenia: Introduction and Overview Robert W. Buchanan, M.D. and William T. Carpenter, Jr., M.D. Section 12.2 Schizophrenia: Epidemiology Grayson S. Norquist, M.D., M.S.P.H. and William E. Narrow, M.D., M.P.H. Section 12.3 Schizophrenia: Brain Structure and Function Raquel E. Gur, M.D., Ph.D. and Ruben C. Gur, Ph.D. Section 12.4 Schizophrenia: Neurobiology Michael F. Egan, M.D. and Thomas M. Hyde, M.D., Ph.D. Section 12.5 Schizophrenia: Genetics Kenneth S. Kendler, M.D. Section 12.6 Schizophrenia: Psychodynamic to Neurodynamic Theories Thomas H. McGlashan, M.D. and Ralph E. Hoffman, M.D. Section 12.7 Schizophrenia: Clinical Features Robert Cancro, M.D., Med.D.Sc. and Heinz E. Lehmann, M.D. Section 12.8 Schizophrenia: Somatic Treatment Stephen R. Marder, M.D. Section 12.9 Schizophrenia: Psychosocial Treatment Juan Bustillo, M.D., Samuel J. Keith, M.D. and John Lauriello, M.D. Section 12.10 Schizophrenia: Individual Psychotherapy Wayne S. Fenton, M.D. and Thomas H. McGlashan, M.D. CHAPTER 13. OTHER PSYCHOTIC DISORDERS Section 13.1 Schizoaffective Disorder, Schizophreniform Disorder, and Brief Psychotic Disorder John Lauriello, M.D., Brenda R. Erickson, M.D. and Samuel J. Keith, M.D. Section 13.2 Delusional Disorder and Shared Psychotic Disorder Theo C. Manschreck, M.D., M.P.H. Section 13.3 Acute and Transient Psychotic Disorders and Culture-Bound Syndromes Juan E. Mezzich, M.D., Ph.D., Keh-Ming Lin, M.D., M.P.H. and Charles Campbell Hughes, Ph.D. Section 13.4 Postpartum Psychiatric Syndromes Ruta Nonacs, M.D., Ph.D. and Lee S. Cohen, M.D. CHAPTER 14. MOOD DISORDERS Section 14.1 Mood Disorders: Introduction and Overview Hagop S. Akiskal, M.D. Section 14.2 Mood Disorders: Epidemiology Dan G. Blazer, II, M.D., Ph.D. Section 14.3 Mood Disorders: Genetics John R. Kelsoe, M.D. Section 14.4 Mood Disorders: Neurobiology Michael E. Thase, M.D. Section 14.5 Mood Disorders: Psychodynamic Aspects

Glen O. Gabbard, M.D. Section 14.6 Mood Disorders: Clinical Features Hagop S. Akiskal, M.D. Section 14.7 Mood Disorders: Treatment of Depression A. John Rush, M.D. Section 14.8 Mood Disorders: Treatment of Bipolar Disorders Robert M. Post, M.D. Section 14.9 Mood Disorders: Psychotherapy Robert M. A. Hirschfeld, M.D. and M. Tracie Shea, Ph.D. CHAPTER 15. ANXIETY DISORDERS Section 15.1 Anxiety Disorders: Introduction and Overview Jack M. Gorman, M.D. Section 15.2 Anxiety Disorders: Epidemiology Ewald Horwath, M.D., M.Sc. and Myrna M. Weissman, Ph.D. Section 15.3 Anxiety Disorders: Biochemical Aspects Gregory M. Sullivan, M.D. and Jeremy David Coplan, M.D. Section 15.4 Anxiety Disorders: Genetics Abby J. Fyer, M.D. Section 15.5 Anxiety Disorders: Psychodynamic Aspects Glen O. Gabbard, M.D. Section 15.6 Anxiety Disorders: Clinical Features Daniel S. Pine, M.D. Section 15.7 Anxiety Disorders: Somatic Treatment Laszlo A. Papp, M.D. Section 15.8 Anxiety Disorders: Psychological Treatments Lawrence A. Welkowitz, Ph.D. CHAPTER 16. SOMATOFORM DISORDERS Frederick G. Guggenheim, M.D. CHAPTER 17. FACTITIOUS DISORDERS Marc D. Feldman, M.D. and Charles V. Ford, M.D. CHAPTER 18. DISSOCIATIVE DISORDERS Section 18.1 Dissociative Amnesia Marlene Steinberg, M.D. Section 18.2 Dissociative Fugue Philip M. Coons, M.D. Section 18.3 Dissociative Identity Disorder Frank W. Putnam, M.D. and Richard J. Loewenstein, M.D. Section 18.4 Depersonalization Disorder Marlene Steinberg, M.D. Section 18.5 Dissociative Disorders Not Otherwise Specified Daphne Simeon, M.D. and Eric Hollander, M.D. CHAPTER 19. NORMAL HUMAN SEXUALITY AND SEXUAL AND GENDER IDENTITY DISORDERS Section 19.1 Normal Human Sexuality Section 19.1a Normal Human Sexuality and Sexual Dysfunctions Virginia A. Sadock, M.D. Section 19.1b Homosexuality and Homosexual Behavior Terry S. Stein, M.D. Section 19.2 Paraphilias Stephen B. Levine, M.D. Section 19.3 Gender Identity Disorders Richard Green, M.D., J.D. and Ray Blanchard, Ph.D.

VOLUME II CHAPTER 20. EATING DISORDERS Katherine A. Halmi, M.D. CHAPTER 21. SLEEP DISORDERS Constance A. Moore, M.D., Robert L. Williams, M.D. and Max Hirshkowitz, Ph.D. CHAPTER 22. IMPULSE-CONTROL DISORDERS NOT ELSEWHERE CLASSIFIED Vivien K. Burt, Ph.D. and Jeffrey William Katzman, M.D. CHAPTER 23. ADJUSTMENT DISORDERS Jeffrey H. Newcorn, M.D., James J. Strain, M.D. and Juan E. Mezzich, M.D., Ph.D. CHAPTER 24. PERSONALITY DISORDERS C. Robert Cloninger, M.D. and Dragan M. Svrakic, M.D., Ph.D. CHAPTER 25. PSYCHOLOGICAL FACTORS AFFECTING MEDICAL CONDITIONS Section 25.1 History, Classification, and Current Trends in Psychosomatic Medicine Alan Stoudemire, M.D. and John Stephen McDaniel, M.D. Section 25.2 Gastrointestinal Disorders William R. Yates, M.D. Section 25.3 Obesity Kelly D. Brownell, Ph.D. and Thomas A. Wadden, Ph.D. Section 25.4 Cardiovascular Disorders Peter A. Shapiro, M.D. Section 25.5 Respiratory Disorders Michael G. Moran, M.D.

Section 25.6 Endocrine and Metabolic Disorders Victoria C. Hendrick, M.D. and Thomas R. Garrick, M.D. Section 25.7 Psychocutaneous Disorders Lesley M. Arnold, M.D. Section 25.8 Musculoskeletal Disorders Teresa A. Rummans, M.D., Kemuel L. Philbrick, M.D. and M. Kevin O’Connor, M.D. Section 25.9 Stress and Psychiatry Joel E. Dimsdale, M.D., Francis J. Keefe, Ph.D. and Murray B. Stein, M.D. Section 25.10 Behavior and Immunity John M. Petitto, M.D. and Dwight L. Evans, M.D. Section 25.11 Psycho-Oncology Marguerite S. Lederberg, M.D. and Jimmie C. Holland, M.D. Section 25.12 Consultation-Liaison Psychiatry James J. Strain, M.D. CHAPTER 26. RELATIONAL PROBLEMS Johan M. F. Verhulst, M.D. CHAPTER 27. ADDITIONAL CONDITIONS THAT MAY BE A FOCUS OF CLINICAL ATTENTION Section 27.1 Treatment Compliance Barry Blackwell, M.D., F.R.C.Psych. Section 27.2 Malingering Mark S. Lipian, M.D., Ph.D. and Mark J. Mills, J.D., M.D. Section 27.3 Adult Antisocial Behavior and Criminality Kenneth Tardiff, M.D., M.P.H. Section 27.4 Borderline Intellectual Functioning and Academic Problem James J. Mcgough, M.D. Section 27.5 Other Additional Conditions That May Be a Focus of Clinical Attention Leah J. Dickstein, M.D. CHAPTER 28. SPECIAL AREAS OF INTEREST Section 28.1 Primary Care and Psychiatry Mack Lipkin, Jr., M.D. Section 28.2 Psychiatry and Reproductive Medicine Sarah L. Berga, M.D. and Barbara L. Parry, M.D. Section 28.3 Premenstrual Dysphoric Disorder Kimberly A. Yonkers, M.D. and Lori L. Davis, M.D. Section 28.4 Genetic Counseling Kate A. Berg, Ph.D. and Darrell G. Kirch, M.D. Section 28.5 Death, Dying, and Bereavement Sidney Zisook, M.D. and Nancy S. Downs, M.D. Section 28.6 Chronic Pain and the Placebo Effect James C. Edmondson, M.D., Ph.D. Section 28.7 Physical and Sexual Abuse of Adults Bessel A. van der Kolk, M.D. Section 28.8 Alternative and Complementary Health Practices Thomas J. Kiresuk, Ph.D. and Alan Trachtenberg, M.D., M.P.H. Section 28.9 Nonprofessional Therapies, Quacks and Cults Louis J. West, M.D. CHAPTER 29. PSYCHIATRIC EMERGENCIES Section 29.1 Suicide Alec Roy, M.D. Section 29.2 Other Psychiatric Emergencies Beverly J. Fauman, M.D. CHAPTER 30. PSYCHOTHERAPIES Section 30.1 Psychoanalysis and Psychoanalytic Psychotherapy Glen O. Gabbard, M.D. Section 30.2 Behavior Therapy Rolf G. Jacob, M.D. and William H. Pelham, Ph.D. Section 30.3 Hypnosis Herbert Spiegel, M.D., Marcia Greenleaf, Ph.D. and David Spiegel, M.D. Section 30.4 Group Psychotherapy, Combined Individual and Group Psychotherapy Anne Alonso, Ph.D. Section 30.5 Family Therapy and Couple Therapy Alan S. Gurman, Ph.D. and Jay L. Lebow, Ph.D. Section 30.6 Cognitive Therapy A. John Rush, M.D. and Aaron T. Beck, M.D. Section 30.7 Interpersonal Psychotherapy Myrna M. Weissman, Ph.D. and John C. Markowitz, M.D. Section 30.8 Brief Psychotherapy Robert J. Ursano, M.D. and Ann E. Norwood, M.D. Section 30.9 Eriksonian Clinical Theory and Psychiatric Treatment Edward R. Shapiro, M.D. and M. Gerard Fromm, Ph.D. Section 30.10 Other Methods of Psychotherapy Kenneth Z. Altshuler, M.D. Section 30.11 Evaluation of Psychotherapy Kenneth I. Howard, Ph.D., Ronald F. Krasner, M.D. and Stephen M. Saunders, Ph.D. Section 30.12 Combined Psychotherapy and Pharmacotherapy

Glen O. Gabbard, M.D. CHAPTER 31. BIOLOGICAL THERAPIES Section 31.1 General Principles of Psychopharmacology Jack A. Grebb, M.D. Section 31.2 Pharmacokinetics and Drug Interactions Philip G. Janicak, M.D. and John M. Davis, M.D. Section 31.3 Drug Development and Approval Process in the United States Paul Leber, M.D. Section 31.4 Medication-Induced Movement Disorders Edmond Hsin-tung Pi, M.D. and George M. Simpson, M.D. Section 31.5 b-Adrenergic Receptor Antagonists George M. Simpson, M.D. and Calvin J. Flowers, M.D. Section 31.6 Anticholinergics and Amantadine Jonathan M. Meyer, M.D. and George M. Simpson, M.D. Section 31.7 Anticonvulsants Section 31.7a Carbamazepine Carlos A. Zarate, Jr., M.D. and Mauricio Tohen, M.D., Dr.P.H. Section 31.7b Valproate Susan L. McElroy, M.D., Harrison G. Pope, Jr., M.D. and Paul E. Keck, Jr., M.D. Section 31.7c Other Anticonvulsants Norman Sussman, M.D. Section 31.8 Antihistamines Lawrence S. Gross, M.D. and George M. Simpson, M.D. Section 31.9 Barbiturates and Similarly Acting Substances Lawrence A. Labbate, M.D., George W. Arana, M.D. and James C. Ballenger, M.D. Section 31.10 Benzodiazepine Receptor Agonists and Antagonists James C. Ballenger, M.D. Section 31.11 Bupropion Robert N. Golden, M.D. and Linda M. Nicholas, M.D. Section 31.12 Buspirone Olga Brawman-Mintzer, M.D., R. Bruce Lydiard, Ph.D., M.D., James C. Ballenger, M.D. Section 31.13 Calcium Channel Inhibitors Robert M. Post, M.D. Section 31.14 Chloral Hydrate Lawrence A. Labbate, M.D., George W. Arana, M.D. and James C. Ballenger, M.D. Section 31.15 Cholinesterase Inhibitors Steven C. Samuels, M.D. and Kenneth L. Davis, M.D. Section 31.16 Clonidine Norman Sussman, M.D. Section 31.17 Dopamine Receptor Antagonist (Typical Antipsychotics) Stephen R. Marder, M.D. and Daniel P. van Kammen, M.D., Ph.D. Section 31.18 Lithium James W. Jefferson, M.D. and John H. Greist, M.D. Section 31.19 Mirtazapine James L. Claghorn, M.D. Section 31.20 Monoamine Oxidase Inhibitors Sidney H. Kennedy, M.D., Kevin F. McKenna, M.D., Ph.D. and Glen B. Baker, Ph.D. Section 31.21 Naltrexone Stephanie S. O’Malley, Ph.D., Suchitra Krishnan-Sarin, Ph.D. and Bruce J. Rounsaville, M.D. Section 31.22 Nefazodone Steven J. Garlow, M.D., Ph.D., Michael J. Owens, Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.23 Opioid Agonists Richard S. Schottenfeld, M.D. and Herbert D. Kleber, M.D. Section 31.24 Selective Serotonin-Noradrenaline Reuptake Inhibitors Linda Beauclair, M.D., Denisa Radoi-Andraous, M.D. and Guy Chouinard, M.D., M.Sc. Section 31.25 Selective Serotonin Reuptake Inhibitors Section 31.25a Introduction and Overview Jeffrey E. Kelsey, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.25b Citalopram Jeffrey E. Kelsey, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.25c Fluoxetine Jeffrey E. Kelsey, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.25d Fluvoxamine Jeffrey E. Kelsey, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.25e Paroxetine Jeffrey E. Kelsey, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.25f Sertraline Jeffrey E. Kelsey, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.26 Serotonin-Dopamine Antagonists Daniel P. van Kammen, M.D., Ph.D. and Stephen R. Marder, M.D. Section 31.27 Sympathomimetics Jan Fawcett, M.D. Section 31.28 Thyroid Hormones Russell T. Joffe, M.D. Section 31.29 Trazodone

Steven J. Garlow, M.D., Ph.D. and Charles B. Nemeroff, M.D., Ph.D. Section 31.30 Tricyclics and Tetracyclics J. Craig Nelson, M.D. Section 31.31 Electroconvulsive Therapy Keith E. Isenberg, M.D. and Charles F. Zorumski, M.D. Section 31.32 Neurosurgical Treatments Scott L. Rauch, M.D. and G. Rees Cosgrove, M.D., F.R.C.S.(C) Section 31.33 Other Pharmacological and Biological Therapies Charles DeBattista, M.D., D.M.H. and Alan F. Schatzberg, M.D. CHAPTER 32. CHILD PSYCHIATRY Section 32.1 Introduction and Overview Caroly S. Pataki, M.D. Section 32.2 Normal Child Development Maureen Fulchiero Gordon, M.D. Section 32.3 Normal Adolescence Nancy S. Cotton, Ph.D. CHAPTER 33. PSYCHIATRIC EXAMINATION OF THE INFANT, CHILD, AND ADOLESCENT Robert A. King, M.D., Mary E. Schwab-Stone, M.D., Bradley S. Peterson, M.D. and Armin Paul Thies, Ph.D. CHAPTER 34. MENTAL RETARDATION Bryan H. King, M.D., Robert M. Hodapp, Ph.D. and Elisabeth M. Dykens, Ph.D. CHAPTER 35. LEARNING DISORDERS Section 35.1 Reading Disorders Michael E. Spagna, Ph.D., Dennis P. Cantwell, M.D. and Lorian Baker, Ph.D. Section 35.2 Mathematics Disorder Michael E. Spagna, Ph.D., Dennis P. Cantwell, M.D. and Lorian Baker, Ph.D. Section 35.3 Disorder of Written Expression and Learning Disorder Not Otherwise Specified Michael E. Spagna, Ph.D., Dennis P. Cantwell, M.D. and Lorian Baker, Ph.D. CHAPTER 36. MOTOR SKILLS DISORDER: DEVELOPMENTAL COORDINATION DISORDER Michael E. Spagna, Ph.D., Dennis P. Cantwell, M.D. and Lorian Baker, Ph.D. CHAPTER 37. COMMUNICATION DISORDERS Section 37.1 Expressive Language Disorder Carla J. Johnson, Ph.D. and Joseph H. Beitchman, M.D. Section 37.2 Mixed Receptive-Expressive Language Disorder Carla J. Johnson, Ph.D. and Joseph H. Beitchman, M.D. Section 37.3 Phonological Disorder Carla J. Johnson, Ph.D. and Joseph H. Beitchman, M.D. Section 37.4 Stuttering Robert Kroll, Ph.D. and Joseph H. Beitchman, M.D. Section 37.5 Communication Disorder Not Otherwise Specified Rebecca F. Detweiler, Ph.D. and Joseph H. Beitchman, M.D. CHAPTER 38. PERVASIVE DEVELOPMENTAL DISORDERS Fred R. Volkmar, M.D. and Ami Klin, Ph.D. CHAPTER 39. ATTENTION-DEFICIT DISORDERS Section 39.1 Attention-Deficit Disorders James T. McCracken, M.D. Section 39.2 Adult Manifestations of Attention-Deficit/Hyperactivity Disorder Paul H. Wender, M.D. CHAPTER 40. DISRUPTIVE BEHAVIOR DISORDERS Hans Steiner, M.D. CHAPTER 41. FEEDING AND EATING DISORDERS OF INFANCY AND EARLY CHILDHOOD Irene Chatoor, M.D. CHAPTER 42. TIC DISORDERS James T. McCracken, M.D. CHAPTER 43. ELIMINATION DISORDERS Edwin J. Mikkelsen, M.D. CHAPTER 44. OTHER DISORDERS OF INFANCY, CHILDHOOD, AND ADOLESCENCE Section 44.1 Reactive Attachment Disorder of Infancy and Early Childhood Neil W. Boris, M.D. and Charles H. Zeanah, M.D. Section 44.2 Stereotypic Movement Disorder of Infancy and Disorders of Infancy and Early Childhood Not Otherwise Specified Joan L. Luby, M.D. CHAPTER 45. MOOD DISORDERS AND SUICIDE IN CHILDREN AND ADOLESCENTS Caroly S. Pataki, M.D. CHAPTER 46. ANXIETY DISORDERS IN CHILDREN Section 46.1 Obsessive-Compulsive Disorder in Children John Piacentini, Ph.D. and R. Lindsey Bergman, Ph.D. Section 46.2 Posttraumatic Stress Disorder in Children and Adolescents Lisa Amaya-Jackson, M.D. Section 46.3 Separation Anxiety Disorder and Other Anxiety Disorders Carrie Sylvester, M.D., M.P.H. Section 46.4 Selective Mutism Henrietta L. Leonard, M.D. CHAPTER 47. EARLY-ONSET SCHIZOPHRENIA Jon M. McClellan, M.D.

CHAPTER 48. CHILD PSYCHIATRY: PSYCHIATRIC TREATMENT Section 48.1 Individual Psychodynamic Psychotherapy Owen Lewis, M.D. Section 48.2 Short-Term Psychotherapy Euthymia D. Hibbs, Ph.D. Section 48.3 Cognitive-Behavioral Psychotherapy John S. March, M.D., M.P.H. Section 48.4 Group Psychotherapy Alberto C. Serrano, M.D. Section 48.5 Family Therapy Allan M. Josephson, M.D. Section 48.6 Pediatric Psychopharmacology Barbara J. Coffey, M.D. Section 48.7 Partial Hospital and Ambulatory Behavioral Health Services Laurel J. Kiser, Ph.D., M.B.A., Jerry D. Heston, M.D. and David B. Pruitt, M.D. Section 48.8 Residential and Inpatient Treatment Mark DeAntonio, M.D. Section 48.9 Community-Based Treatment Andres J. Pumariega, M.D. Section 48.10 Psychiatric Treatment of Adolescents Cynthia R. Pfeffer, M.D. CHAPTER 49. CHILD PSYCHIATRY: SPECIAL AREAS OF INTEREST Section 49.1 Psychiatric Aspects of Day Care Klaus Minde, M.D., F.R.C.P.(C) Section 49.2 Adoption Steven L. Nickman, M.D. Section 49.3 Foster Care Marilyn B. Benoit, M.D. Section 49.4 Child Maltreatment William Bernet, M.D. Section 49.5 Childrens Reaction to Illness and Hospitalization Martin J. Drell, M.D. and Tonya Jo Hanson White, M.D. Section 49.6 Psychiatric Sequelae of HIV and AIDS Jennifer F. Havens, M.D., Sheila Ryan, C.S.W. and Claude Mellins, Ph.D. Section 49.7 Childhood or Adolescent Antisocial Behavior Hans Steiner, M.D. and S. Shirley Feldman, Ph.D. Section 49.8 Dissociative Disorders in Children and Adolescents Nancy L. Hornstein, M.D. Section 49.9 Gender Identity and Sexual Issues Alayne Yates, M.D. Section 49.10 Identity Problem and Borderline Disorders Victor M. Fornari, M.D. and David Pelcovitz, Ph.D. Section 49.11 Adolescent Substance Abuse Oscar G. Bukstein, M.D., M.P.H. Section 49.12 Forensic Child and Adolescent Psychiatry Stephen P. Herman, M.D. Section 49.13 Ethical Issues in Child and Adolescent Psychiatry Diane H. Schetky, M.D. Section 49.14 School Consultation Richard E. Mattison, M.D. Section 49.15 Psychiatric Prevention in Children and Adolescents Norbert B. Enzer, M.D. and Stephanie L. Heard, M.D. CHAPTER 50. ADULTHOOD Calvin A. Colarusso, M.D. CHAPTER 51. GERIATRIC PSYCHIATRY Section 51.1 Overview Section 51.1a Geriatric Psychiatry: Introduction Lissy F. Jarvik, M.D., Ph.D. and Gary W. Small, M.D. Section 51.1b Epidemiology of Psychiatric Disorders A. Scott Henderson, M.D., D.Sc., F.R.A.C.P., F.R.A.N.Z.C.P., F.R.C.P., F.R.C.Psych. Section 51.2 Assessment Section 51.2a Psychiatric Examination of the Older Patient Eleanor P. Lavretsky, M.D., Ph.D. and Lissy F. Jarvik, M.D., Ph.D. Section 51.2b Central Nervous System Changes With Normal Aging Jeff Victoroff, M.D. Section 51.2c Psychological Changes With Normal Aging Jennifer J. Dunkin, Ph.D. and Julia E. Kasl-Godley, Ph.D. Section 51.2d Neuropsychological Evaluation Kyle Brauer Boone, Ph.D. Section 51.2e Neuroimaging: Overview Eric M. Reiman, M.D. Section 51.2f Neuroimaging: Special Issues Anand Kumar, M.D.

Section 51.3 Psychiatric Disorders of Late Life Section 51.3a Psychiatric Problems in the Medically Ill Soo Borson, M.D. and Jurgen Unützer, M.D., M.P.H. Section 51.3b Sleep Disorders Patricia N. Prinz, Ph.D., Michael V. Vitiello, Ph.D. and Soo Borson, M.D. Section 51.3c Anxiety Disorders Ira M. Lesser, M.D. Section 51.3d Mood Disorders George S. Alexopoulos, M.D. Section 51.3e Alzheimers Disease and Other Dementias Gary W. Small, M.D. Section 51.3f Schizophrenia and Delusional Disorders M. Jackuelyn Harris, M.D. and Dilip V. Jeste, M.D. Section 51.3g Personality Disorders Robert M. Rohrbaugh, M.D. Section 51.3h Drug and Alcohol Abuse Eve J. Wiseman, M.D. Section 51.4 Treatment of Psychiatric Disorders Section 51.4a Introduction and Overview Lissy F. Jarvik, M.D., Ph.D. and Fredda L. Leiter, M.D. Section 51.4b Psychopharmacology: General Principles Bruce G. Pollock, M.D., Ph.D. Section 51.4c Psychopharmacology: Antidepressants and Mood Stabilizers Charles F. Reynolds, III, M.D. Section 51.4d Psychopharmacology: Antianxiety Drugs Javaid I. Sheikh, M.D., M.B.A. and Cynthia T. M. H. Nguyen, M.D. Section 51.4e Psychopharmacology: Antipsychotic Drugs David L. Sultzer, M.D. and Helen Lavretsky, M.D. Section 51.4f Psychopharmacology: Antidementia Drugs Lon S. Schneider, M.D. Section 51.4g Electroconvulsive Therapy Donald P. Hay, M.D., Elsa M. Zayas, M.D. and George T. Grossberg, M.D. Section 51.4h Psychosocial Treatments: General Principles Joel Sadavoy, M.D., F.R.C.P.(C) Section 51.4i Individual Psychotherapy Joel Sadavoy, M.D., F.R.C.P.(C) and Lawrence W. Lazarus, M.D. Section 51.4j Cognitive-Behavioral Therapy Garrett C. Daum, M.D. Section 51.4k Interventions and Consultation With Families of Older Adults Deborah A. King, Ph.D., Cleveland G. Shields, Ph.D. and Lyman C. Wynne, M.D., Ph.D. Section 51.4l Group Therapy Molyn Leszcz, M.D., F.R.C.P.(C) Section 51.5 Health Care Delivery Systems Section 51.5a Financial Issues Gary L. Gottlieb, M.D., M.B.A. Section 51.5b Managed Care Jerome V. Vaccaro, M.D. and S. Alan Savitz, M.D. Section 51.5c Veterans Affairs Medical Centers and Psychogeriatric Services William W. Van Stone, M.D. and Thomas B. Horvath, M.D., F.R.A.C.P. Section 51.5d Community Services for the Elderly Psychiatric Patient Barry D. Lebowitz, Ph.D. Section 51.6 Special Areas of Interest Section 51.6a Psychiatric Aspects of Long-Term Care Ira R. Katz, M.D., Ph.D., Joel E. Streim, M.D. and Buster D. Smith, M.D. Section 51.6b Forensic Issues Bennett Blum, M.D. and Spencer Eth, M.D. Section 51.6c Ethical Issues Deborah B. Marin, M.D. and Christine K. Cassel, M.D. Section 51.6d Sociocultural Issues Hugh C. Hendrie, M.B., Ch.B. Section 51.6e Minority Issues ZF. M. Baker, M.D., M.P.H. Section 51.6f Gender Issues Marion Zucker Goldstein, M.D. Section 51.6g Elder Abuse, Neglect, and Exploitation Marion Zucker Goldstein, M.D. CHAPTER 52. HOSPITAL AND COMMUNITY PSYCHIATRY Section 52.1 Public Psychiatry John Richard Elpers, M.D. Section 52.2 Managed Care Robert Jean Campbell, III, M.D. Section 52.3 Role of the Psychiatric Hospital in the Treatment of Mental Illness W. Walter Menninger, M.D. Section 52.4 Psychiatric Rehabilitation

Robert Paul Liberman, M.D., Alex Kopelowicz, M.D. and Thomas E. Smith, M.D. CHAPTER 53. PSYCHIATRIC EDUCATION Section 53.1 Graduate Psychiatric Education Stephen C. Scheiber, M.D. Section 53.2 Examining Psychiatrists and Other Trainees James Morrison, M.D. and Rodrigo A. Muñoz, M.D. CHAPTER 54. ETHICS AND FORENSIC PSYCHIATRY Section 54.1 Legal Issues in Psychiatry Robert I. Simon, M.D. Section 54.2 Ethics in Psychiatry Peter B. Gruenberg, M.D. CHAPTER 55. PSYCHIATRY: PAST AND FUTURE Section 55.1 History of Psychiatry Ralph Colp, Jr., M.D. Section 55.2 World Aspects of Psychiatry Jorge Alberto Costa e Silva, M.D. Section 55.3 The Future of Psychiatry Peter D. Kramer, M.D.

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ABOUT THE EDITORS BENJAMIN J. SADOCK, M.D.

Benjamin James Sadock, M.D., is the Menas S. Gregory Professor of Psychiatry and Vice Chairman of the Department of Psychiatry at the New York University (NYU) School of Medicine. He was graduated from Union College, received his Doctor of Medicine degree from New York Medical College, and did his internship at Albany Hospital. He completed his residency at Bellevue Psychiatric Hospital and then entered military service where he served as assistant chief and acting chief of neuropsychiatry at Sheppard Air Force Base, Texas. He has held faculty and teaching appointments at Southwestern Medical School and Parkland Hospital in Dallas, and at New York Medical College, St. Luke’s Hospital, the New York State Psychiatric Institute, and Metropolitan Hospital in New York City. He joined the faculty of the NYU School of Medicine in 1980 and served in various positions: director of medical student education in psychiatry, co-director of the Residency Training Program in Psychiatry, and director of Graduate Medical Education. Currently, Dr. Sadock is director of Student Mental Health Services, psychiatric consultant to the Admissions Committee and co-director of Continuing Education in Psychiatry at the NYU School of Medicine. He is on the staff of Bellevue Hospital and Tisch Hospital and is consultant psychiatrist at Lenox Hill Hospital. Dr. Sadock is a diplomate of the American Board of Psychiatry and Neurology and served as an assistant and associate examiner for the board for over a decade. He is a Fellow of the American Psychiatric Association, a Fellow of the American College of Physicians, a Fellow of the New York Academy of Medicine, and a member of Alpha Omega Alpha Honor Society. He is active in numerous psychiatric organizations and is president and founder of the NYU-Bellevue Psychiatric Society. Dr. Sadock was a member of the National Committee in Continuing Education in Psychiatry of the American Psychiatric Association, served on the Ad Hoc Committee on Sex Therapy Clinics of the American Medical Asso ciation, was delegate to the Conference on Recertification of the American Board of Medical Specialists, and was a representative of the American Psychiatric Association’s Task Force on the National Board of Medical Examiners and the American Board of Psychiatry and Neurology. In 1985 he received the Academic Achievement Award from New York Medical College. He is author or editor of over 100 publications, a book reviewer for psychiatric journals, and lectures on a broad range of topics in general psychiatry. Dr. Sadock maintains a private practice for diagnostic consultations, psychotherapy, and pharmacotherapy. He has been married to Virginia Alcott Sadock, M.D., clinical professor of psychiatry at NYU School of Medicine, since completing his residency. Dr. Sadock enjoys opera, skiing, and traveling, and is an avid fly-fisherman. VIRGINIA A. SADOCK, M.D.

Virginia Alcott Sadock, M.D., joined the faculty of the New York University (NYU) School of Medicine in 1980 where she is currently clinical professor of psychiatry and attending psychiatrist at Tisch Hospital and Bellevue Hospital. She is director of the Program in Human Sexuality and Sex Therapy at the NYU Medical Center, one of the largest treatment and training programs of its kind in the United States. She is the author of over 50 articles and chapters on sexual behavior and was the developmental editor of The Sexual Experience, published by Williams & Wilkins—one of the first major textbooks on human sexuality. She serves as referee and book reviewer for several medical journals including the American Journal of Psychiatry and the Journal of the American Medical Association. She has had a long-standing interest in the role of women in medicine and psychiatry and was a founder of the Committee on Women in Psychiatry of the New York County District Branch of the American Psychiatric Association. She is active in academic matters, has served as an assistant and associate examiner for the American Board of Psychiatry and Neurology for over 15 years, and was also a member of the test committee in psychiatry for both the American Board of Psychiatry and the Psychiatric Knowledge and Self-Assessment Program (PKSAP) of the American Psychiatric Association. She served as chairperson of the Committee on Public Relations. New York County District Branch of the American Psychiatric Association and also participated in the National Medical Television Network series Women in Medicine and the PBS television documentary Women and Depression. She has been vice-president of the Society of Sex Therapy and Research, a regional council member of the American Association of Sex Education Counselors and Therapists, and is president of the Alumni Association of Sex Therapists. She lectures extensively both in this country and abroad on sexual dysfunction, relational problems, and dep ression and anxiety disorders. She is a Fellow of the American Psychiatric Association, a Fellow of the New York Academy of Medicine and a diplomate of the American Board of Psychiatry and Neurology. Dr. Sadock was graduated from Bennington College, received her M.D. from New York Medical College, and trained in psychiatry at Metropolitan Hospital. She lives in Manhattan with her husband, Dr. Benjamin Sadock, where she maintains an active psychiatric practice that includes individual psychotherapy, couples and marital therapy, sex therapy, psychiatric consultation, and pharmacotherapy. They have two children, James and Victoria, both physicians. In her leisure time Dr. Sadock enjoys theater, film, reading fiction, and travel.

CONTRIBUTORS Henry David Abraham, M.D. Clinical Associate Professor of Psychiatry, Brown University School of Medicine; Chief of Alcohol and Drug Treatment Services, Butler Hospital, Providence, Rhode Island; Lecturer in Psychiatry, Harvard Medical School; Consultant in Psychiatry, Massachusetts General Hospital, Boston, Massachusetts. 11.7. Hallucinogen-Related Disorders Russell L. Adams, Ph.D. Professor of Psychiatry and Behavioral Science, University of Oklahoma College of Medicine; Director of University Hospital Neuropsychology Assessment Laboratory; Director of Psychology Internship and Post Doctoral Neuropsychology Training Program, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 7.5. Personality Assessment: Adults and Children W. Stewart Agras, M.D., F.R.C.P.(C) Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine; Director of Stanford University Psychiatric Clinics, Stanford, California. 3.3. Learning Theory Hagop S. Akiskal, M.D. Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Director of Outpatient Psychiatric Services, San Diego Veterans Affairs Healthcare System, San Diego, California. 14.1. Mood Disorders: Introduction and Overview 14.6. Mood Disorders: Clinical Features George S. Alexopoulos, M.D. Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University, New York, New York; Director of Cornell Institute of Geriatric Psychiatry, New York Hospital-Cornell Medical Center, Westchester Division, White Plains, New York. 51.3d. Geriatric Psychiatry: Mood Disorders Anne Alonso, Ph.D. Clinical Professor of Psychology, Harvard Medical School; Director of Center for Psychoanalytic Studies at the Massachusetts General Hospital, Boston, Massachusetts; Professor, The Fielding Institute, Santa Barbara, California. 30.4. Group Psychotherapy, Combined Individual and Group Psychotherapy Kenneth Z. Altshuler, M.D. Stanton Sharp Professor of Psychiatry and Chairman, Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, Texas. 30.10. Other Methods of Psychotherapy Lisa Amaya-Jackson, M.D. Assistant Professor of Psychiatry and the Behavioral Sciences, Duke University School of Medicine; Director of Trauma Evaluation, Treatment and Research Program, Center for Child and Family Health, Durham, North Carolina. 46.2. Posttraumatic Stress Disorder in Children and Adolescents Daniel G. Amen, M.D. Director of Amen Clinic for Behavioral Medicines, Fairfield, California. 2.13. Neuroimaging in Clinical Practice George W. Arana, M.D. Professor of Psychiatry and Behavioral Sciences, Associate Dean of College of Medicine, Medical University of South Carolina; Director of Mental Health Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina. 31.9. Barbiturates and Similarly Acting Substances 31.14. Chloral Hydrate Lesley M. Arnold, M.D. Assistant Professor of Psychiatry, Director of Division of Psychosomatic Research, University of Cincinnati College of Medicine, Cincinnati, Ohio. 25.7. Psychocutaneous Disorders J. Hampton Atkinson, Jr., M.D. Adjunct Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Staff Psychiatrist, San Diego Veterans Affairs Healthcare System, San Diego, California. 2.8. Neuropsychiatric Aspects of HIV Infection and AIDS F. M. Baker, M.D., M.P.H. Professor of Psychiatry, University of Hawaii John A. Burns School of Medicine; Chief of Inpatient Psychiatry, Hawaii State Hospital, Kaneohe, Hawaii. 51.6e. Geriatric Psychiatry: Minority Issues Glen B. Baker, Ph.D. Professor of Psychiatry, Co-Director of Neurochemical Research Unit, University of Alberta Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada. 31.20. Monoamine Oxidase Inhibitors Lorian Baker, Ph.D. Former Research Professor of Child Psychiatry, University of California at Los Angeles School of Medicine, Los Angeles, California. 35.1. Reading Disorder 35.2. Mathematics Disorder 35.3. Disorder of Written Expression and Learning Disorder Not Otherwise Specified 36. Motor Skills Disorder: Developmental Coordination Disorder James C. Ballenger, M.D. Professor of Psychiatry and Chairman, Department of Psychiatry and Behavioral Sciences, Director of Institute of Psychiatry, Medical University of South Carolina, Charleston, South Carolina. 31.9. Barbiturates and Similarly Acting Substances 31.10. Benzodiazepine Receptor Agonists and Antagonists 31.12. Buspirone 31.14. Chloral Hydrate Jay M. Baraban, M.D., Ph.D. Associate Professor of Neuroscience Psychiatry, and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. 1.8. Intraneuronal Signaling Pathways Ida Sue Baron, Ph.D. Clinical Associate Professor of Pediatrics, Georgetown University School of Medicine and Health Sciences, Washington, D.C.

7.6. Neuropsychological and Intellectual Assessment of Children William W. Beatty, Ph.D. Professor of Psychiatry and Behavioral Science, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma. 2.7. Neuropsychiatric Aspects of Multiple Sclerosis and Other Demyelinating Disorders Linda Beauclair, M.D. Assistant Professor of Psychiatry McGill University Faculty of Medicine, Montreal, Quebec, Canada. 31.24. Selective Serotonin-Noradrenaline Reuptake Inhibitors Aaron T. Beck, M.D. Professor Emeritus of Psychiatry and Director of Psychopathology Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. 30.6. Cognitive Therapy Anne E. Becker, M.D., Ph.D. Assistant Professor of Medical Anthropology and Psychiatry Harvard Medical School, Boston, Massachusetts. 4.1. Anthropology and Psychiatry Joseph H. Beitchman, M.D. Professor of Psychiatry and Public Health Science, University of Toronto Faculty of Medicine; Head of Child and Family Studies Centre, Clarke Institute of Psychiatry, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 37.1. Expressive Language Disorder 37.2. Mixed Receptive-Expressive Language Disorder 37.3. Phonological Disorder 37.4. Stuttering 37.5. Communication Disorder Not Otherwise Specified Marilyn B. Benoit, M.D. Clinical Associate Professor of Psychiatry, Georgetown University School of Medicine and Health Sciences, Washington, D.C. 49.3. Foster Care Kate A. Berg, Ph.D. Co-Director of Office of Bioethics and Special Populations Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 28.4. Genetic Counseling Sarah L. Berga, M.D. Associate Professor of Obstetrics, Gynecology, Reproductive Sciences, and Psychiatry, University of Pittsburgh School of Medicine; Attending Physician, Magee-Women’s Hospital, Pittsburgh, Pennsylvania. 28.2. Psychiatry and Reproductive Medicine R. Lindsey Bergman, Ph.D. Clinical Instructor of Psychiatry and Biobehavioral Science, University of California at Los Angeles School of Medicine; Associate Director of Child and Adolescent Obsessive-Compulsive Disorder and Anxiety Program, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 46.1. Obsessive-Compulsive Disorder in Children William Bernet, M.D. Associate Professor of Psychiatry, Vanderbilt University School of Medicine; Medical Director of Psychiatric Hospital at Vanderbilt, Nashville, Tennessee. 49.4. Child Maltreatment Garth Bissette, Ph.D. Professor of Psychiatry, University of Mississippi School of Medicine, Jackson, Mississippi. 1.6. Neuropeptides: Biology and Regulation Ira B. Black, M.D. Professor and Chair, Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, Piscataway, New Jersey. 1.7. Neurotrophic Factors Deborah Blacker, M.D., Sc.D. Assistant Professor of Psychiatry, Harvard Medical School; Assistant Professor of Epidemiology, Harvard School of Public Health; Clinical Staff, Massachusetts General Hospital; Boston, Massachusetts. 7.8. Psychiatric Rating Scales Barry Blackwell, M.D., F.R.C.Psych. Clinical Professor of Psychiatry, University of Wisconsin Medical School, Milwaukee Campus, Milwaukee, Wisconsin. 27.1. Treatment Compliance Ray Blanchard, Ph.D. Associate Professor of Psychiatry, University of Toronto Faculty of Medicine; Head of Clinical Sexology Program, Clarke Institute of Psychiatry, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 19.3. Gender Identity Disorders Dan G. Blazer, II, M.D., Ph.D. J.P. Gibbons Professor of Psychiatry and Behavioral Sciences, Professor of Community and Family Medicine and Dean of Medical Education, Duke University School of Medicine, and Durham, North Carolina. 14.2. Mood Disorders: Epidemiology Bennett Blum, M.D. Clinical Instructor of Geriatric Psychiatry, University of California at Los Angeles School of Medicine; Director of Forensic Gero-Psychiatry Division, Park Dietz and Associates, Newport Beach, California. 51.6b. Geriatric Psychiatry: Forensic Issues Michael P. Bogenschutz, M.D. Assistant Professor of Psychiatry, University of New Mexico School of Medicine; Clinical Director of Dual Diagnosis Treatment Program, Mental Health Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. 9.1. Classification of Mental Disorders Kyle Brauer Boone, Ph.D. Associate Professor-in-Residence, University of California at Los Angeles School of Medicine, Los Angeles, California; Director of Neuropsychological Services,

Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California. 51.2d. Geriatric Psychiatry: Neuropsychological Evaluation Neil W. Boris, M.D. Assistant Professor of Community Health Sciences, Tulane University School of Public Health and Tropical Medicine; Assistant Professor of Pediatrics, Psychiatry, and Neurology, Tulane University School of Medicine, New Orleans, Louisiana. 44.1. Reactive Attachment Disorder of Infancy and Early Childhood Soo Borson, M.D. Professor of Psychiatry and Behavioral Sciences, University of Washington School of Medicine; Director of Geropsychiatry Services and Director of University of Washington Medical Center Alzheimer’s Disease Research Center, Seattle, Washington. 51.3a. Geriatric Psychiatry: Psychiatric Problems in the Medically Ill; 51.3b. Geriatric Psychiatry: Sleep Disorders H. Stefan Bracha, M.D. Research Physician, National Center for Posttraumatic Stress Disorder, Honolulu Veterans Affairs Medical and Regional Office Center, Honolulu, Hawaii. 2.13. Neuroimaging in Clinical Practice Olga Brawman-Mintzer, M.D. Assistant Professor of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina. 31.12. Buspirone Kirk J. Brower, M.D. Associate Professor of Psychiatry, Director of Alcohol Research Center, University of Michigan Medical School, Ann Arbor, Michigan. 11.13. Anabolic-Androgenic Steroid Abuse Kelly D. Brownell, Ph.D. Professor of Psychology, Master of Silliman College, Yale University; Professor of Epidemiology and Public Health and Director of Clinical Training, Director of Yale Center for Eating and Weight Disorders, Yale University School of Medicine, New Haven, Connecticut. 25.3. Obesity Robert W. Buchanan, M.D. Associate Professor of Psychiatry University of Maryland School of Medicine, Baltimore, Maryland; Chief of Outpatient Research Program, Maryland Psychiatric Research Center, Catonsville, Maryland. 12.1. Schizophrenia: Introduction and Overview Oscar G. Bukstein, M.D., M.P.H. Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 49.11. Adolescent Substance Abuse Jack D. Burke, Jr., M.D., M.P.H. Professor of Psychiatry and Head, Department of Psychiatry and Behavioral Science, Texas A & M University College of Medicine; Chairman, Department of Psychiatry, Scott and White Memorial Hospital and Clinic, Temple, Texas. 5.1. Epidemiology Vivien K. Burt, M.D., Ph.D. Associate Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Women’s Life Center, UCLA Neuropsychiatric Institute and Hospital; Medical Director, Mental Health Clinic, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 22. Impulse-Control Disorders Not Elsewhere Classified Juan Bustillo, M.D. Assistant Professor of Psychiatry, University of New Mexico School of Medicine, Albuquerque, New Mexico. 12.9. Schizophrenia: Psychosocial Treatment Eric D. Caine, M.D. John Romano Professor of Psychiatry and Chair, Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York. 10. Delirium, Dementia, and Amnestic and Other Cognitive Disorders Robert Jean Campbell, III, M.D. Clinical Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University; Medical Director, New York Gracie Square Hospital; Attending Psychiatrist, New York Hospital, New York, New York. 52.2. Managed Care Robert Cancro, M.D., Med.D.Sc. Lucius N. Littauer Professor of Psychiatry and Chairman, Department of Psychiatry, New York University School of Medicine; Director of Department of Psychiatry, Tisch Hospital, New York, New York; Director of Nathan Kline Institute for Psychiatric Research, Orangeburg, New York. 12.7. Schizophrenia: Clinical Features Dennis P. Cantwell, M.D.* Joseph Campbell Professor of Child Psychiatry, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California. 35.1. Reading Disorder; 35.2. Mathematics Disorder; 35.3. Disorder of Written Expression and Learning Disorder Not Otherwise Specified 36. Motor Skills Disorder: Developmental Coordination Disorder William T. Carpenter, Jr., M.D. Professor of Psychiatry and Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland; Director of Maryland Psychiatric Research Center, Catonsville, Maryland. 12.1. Schizophrenia: Introduction and Overview Christine K. Cassel, M.D. Professor of Psychiatry and Chairman, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York. 51.6c. Geriatric Psychiatry: Ethical Issues Irene Chatoor, M.D. Professor of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences; Interim Chair and Director of Infant Psychiatry, Children’s National Medical Center, Washington, D.C. 41. Feeding and Eating Disorders of Infancy and Early Childhood

Guy Chouinard, M.D., M.Sc. Professor of Psychiatry, McGill University Faculty of Medicine; Professor of Psychiatry, University of Montreal Faculty of Medicine; Director of Clinical Psychopharmacology Unit, Allan Memorial Institute; Head of Clinical Psychopharmacology Inpatient Unit, Fernand-Seguin Research Centre, Louis-H. Lafontaine Hospital, Montreal, Quebec, Canada. 31.24. Selective Serotonin-Noradrenaline Reuptake Inhibitors Tiffany W. Chow, M.D. Clinical Instructor of Neurology, University of California at Los Angeles School of Medicine; Director of Frontotemporal Dementia Clinic, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 2.1. Neuropsychiatry: Clinical Assessment and Approach to Diagnosis Domenic A. Ciraulo, M.D. Professor of Psychiatry and Chairman, Boston University School of Medicine; Psychiatrist-in-Chief, Boston Medical Center; Chief of Psychiatry Service, Veterans Affairs Boston Clinic, Boston, Massachusetts. 11.12. Sedative-, Hypnotic-, or Anxiolytic-Related Abuse James L. Claghorn, M.D. Clinical Associate Professor of Psychiatry, University of Texas Medical School at Houston, Houston, Texas. 31.19. Mirtazapine C. Robert Cloninger, M.D. Wallace Renard Professor of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri. 24. Personality Disorders Barbara J. Coffey, M.D. Assistant Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts; Director of Tourette’s Clinic, Director of Pediatric Psychopharmacology Clinic, McLean Hospital, Belmont, Massachusetts. 48.6. Pediatric Psychopharmacology Lee S. Cohen, M.D. Associate Professor of Psychiatry, Harvard Medical School; Director of Perinatal and Reproductive Psychiatry, Clinical Research Program, Clinical Psychopharmacology Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts. 13.4. Postpartum Psychiatric Syndromes Calvin A. Colarusso, M.D. Clinical Professor of Psychiatry and Director of Child Psychiatry Residency Training Program, University of California at San Diego School of Medicine, La Jolla, California; Training and Supervising Analyst, San Diego Psychoanalytic Institute, San Diego, California. 50. Adulthood Ralph Colp, Jr., M.D. Assistant Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Senior Attending Psychiatrist, St. Luke’s-Roosevelt Hospital Center, New York, New York. 55.1. History of Psychiatry Philip M. Coons, M.D. Professor of Psychiatry, Indiana University School of Medicine; Attending Psychiatrist, Indiana University Hospitals, Indianapolis, Indiana. 18.2. Dissociative Fugue Jeremy D. Coplan, M.D. Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Associate Director of Biological Studies Unit, New York State Psychiatric Institute, New York, New York. 15.3. Anxiety Disorders: Biochemical Aspects G. Rees Cosgrove, M.D., F.R.C.S.(C) Associate Professor of Surgery, Harvard Medical School, Boston, Massachusetts. 31.32. Neurosurgical Treatments Jorge Alberto Costa e Silva, M.D. Professor of Psychiatry and Director of International Center for Mental Health Policy and Research, New York University School of Medicine; Director of Division of Mental Health and Prevention of Substance Abuse, World Health Organization, Geneva, Switzerland. 55.2. World Aspects of Psychiatry Paul T. Costa, Jr., Ph.D. Clinical Professor of Psychiatry, Georgetown University School of Medicine and Health Sciences, Washington, D.C.; Associate Professor of Medical Psychology, Johns Hopkins University School of Medicine; Chief of Laboratory of Personality and Cognition, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 6.4. Approaches Derived From Philosophy and Psychology Nancy S. Cotton, Ph.D. Instructor of Psychology, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. 32.3. Normal Adolescence Thomas J. Crowley, M.D. Professor of Psychiatry, University of Colorado School of Medicine; Director of Division of Substance Dependence, University of Colorado Health Sciences Center, Denver, Colorado. 11.8. Inhalant-Related Disorders Jan L. Culbertson, Ph.D. Associate Professor of Pediatrics and Clinical Associate Professor of Psychiatry and Behavioral Sciences, University of Oklahoma College of Medicine; Director of Neuropsychology Services, Child Study Center, Children’s Hospital of Oklahoma, Oklahoma City, Oklahoma. 7.5. Personality Assessment: Adults and Children Jeffrey L. Cummings, M.D. Augustus S. Rose Professor of Neurology and Professor of Psychiatry and Biobehavioral Science, University of California at Los Angeles School of Medicine, Los Angeles, California. 2.1. Neuropsychiatry: Clinical Assessment and Approach to Diagnosis John F. Curry, Ph.D. Associate Professor of Psychiatry and Behavioral Sciences, Duke University School of Medicine; Associate Professor of Psychology, Duke University, Durham, North Carolina.

3.2. Extending Piaget’s Approach to Intellectual Functioning David Gordon Daniel, M.D. Clinical Professor of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, D.C. 2.6. Neuropsychiatric Aspects of Movement Disorders Garrett C. Daum, M.D. Assistant Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Medical Director of Outpatient Geriatric Psychiatry Programs, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 51.4j. Geriatric Psychiatry: Cognitive-Behavioral Therapy John M. Davis, M.D. Gilman Professor of Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, Illinois. 31.2. Pharmacokinetics and Drug Interactions Kenneth L. Davis, M.D. Esther and Joseph Klingenstein Professor of Psychiatry and Chairman, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York. 31.15. Cholinesterase Inhibitors Lori L. Davis, M.D. Assistant Professor of Psychiatry, University of Alabama School of Medicine, Birmingham, Alabama. 28.3. Premenstrual Dysphoric Disorder Mark DeAntonio, M.D. Assistant Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Inpatient Adolescent Service, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 48.8. Child Psychiatry: Residential and Inpatient Treatment Charles DeBattista, M.D., D.M.H. Clinical Fellow in Affective Disorders, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. 31.33. Other Pharmacological and Biological Therapies Rebecca F. Detweiler, Ph.D. Assistant Professor of Speech-Language Pathology, University of Toronto, Toronto, Ontario, Canada. 37.5. Communication Disorder Not Otherwise Specified Lynn H. Deutsch, D.O. Clinical Assistant Professor of Psychiatry, Georgetown University School of Medicine and Health Sciences; Medical Officer, District of Columbia Commission on Mental Health Services, Saint Elizabeth’s Campus, Washington, D.C. 7.7. Medical Assessment and Laboratory Testing in Psychiatry Stephen I. Deutsch, M.D., Ph.D. Professor and Associate Chairman of Clinical Neurosciences, Department of Psychiatry, Georgetown University School of Medicine and Health Sciences; Chief of Psychiatry Service, Veterans Affairs Medical Center, Washington, D.C. 7.7. Medical Assessment and Laboratory Testing in Psychiatry Leah J. Dickstein, M.D. Professor of Psychiatry and Associate Chair for Academic Affairs, Director of Division of Attitudinal and Behavioral Medicine, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine; Staff Psychiatrist, University of Louisville Hospital, Louisville, Kentucky. 27.5. Other Additional Conditions That May Be a Focus of Clinical Attention Joel E. Dimsdale, M.D. Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California. 25.9. Stress and Psychiatry Nancy S. Downs, M.D. Assistant Clinical Professor of Psychiatry, Associate Director of Residency Training, University of California at San Diego School of Medicine, La Jolla, California. 28.5. Death, Dying, and Bereavement Martin J. Drell, M.D. Professor of Clinical Psychiatry and Head of Infant, Child, and Adolescent Psychiatry, Louisiana State University Medical School; Clinical Director of New Orleans Adolescent Hospital, New Orleans, Louisiana. 49.5. Children’s Reaction to Illness and Hospitalization Jennifer J. Dunkin, Ph.D. Assistant Professor of Psychiatry and Director of Geriatric Psychology and Biobehavioral Sciences Fellowship Program, University of California at Los Angeles School of Medicine, Los Angeles, California. 51.2c. Psychological Changes with Normal Aging Elisabeth M. Dykens, Ph.D. Associate Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Attending Psychiatrist, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 34. Mental Retardation James C. Edmondson, M.D., Ph.D. Clinical Assistant Professor of Neurology, State University of New York at Brooklyn College of Medicine; Assistant Attending, Department of Neurology, Brooklyn Hospital Center; Assistant Attending, Department of Neurology, Long Island College Hospital, Brooklyn, New York. 2.11. Neuropsychiatric Aspects of Neuromuscular Disease; 2.12. Neuropsychiatric Aspects of Child Neurology 28.6. Chronic Pain and the Placebo Effect Michael F. Egan, M.D. Director of Clinical Research, Neuroscience Research Center at Saint Elizabeth’s Hospital, and Acting Branch Chief of Clinical Research Services Branch, National Institute of Mental Health, National Institutes of Health, Washington, D.C. 2.6. Neuropsychiatric Aspects of Movement Disorders; 12.4. Schizophrenia: Neurobiology John Richard Elpers, M.D. Professor of Clinical Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California; Vice Chairman, Department of Psychiatry for Planning and Development, and Director of Ambulatory Psychiatric Services, Harbor-UCLA Medical Center, Torrance, California.

52.1. Public Psychiatry Norbert B. Enzer, M.D. Professor of Psychiatry and Interim Associate Dean for Community Programs and Graduate Medical Education, Michigan State University College of Human Medicine, East Lansing, Michigan. 49.15. Psychiatric Prevention in Children and Adolescents Brenda R. Erickson, M.D. Former Assistant Professor of Psychiatry, University of Nevada School of Medicine, Reno, Nevada. 13.1. Schizoaffective Disorder, Schizophreniform Disorder, and Brief Psychotic Disorder Spencer Eth, M.D. Professor of Psychiatry, New York Medical College; Vice Chairman and Clinical Director, Department of Psychiatry, St. Vincents Hospital, New York, New York. 51.6b. Geriatric Psychiatry: Forensic Issues Dwight L. Evans, M.D. Professor of Psychiatry, Chair of Department of Psychiatry, Professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. 25.10. Behavior and Immunity Brian Anthony Fallon, M.D., M.P.H. Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Attending Psychiatrist, New York State Psychiatric Institute, New York, New York. 2.9. Neuropsychiatric Aspects of Other Infectious Diseases Beverly J. Fauman, M.D. Associate Professor of Psychiatry, University of Maryland School of Medicine; Senior Psychiatrist, Walter P. Carter Center, University of Maryland Medical System, Baltimore, Maryland. 29.2. Other Psychiatric Emergencies Jan Fawcett, M.D. Stanley G. Harris, Sr., Professor of Psychiatry and Chairman, Department of Psychiatry, Rush Medical College; Director, Rush Institute for Mental Well-Being, Chicago, Illinois. 31.27. Sympathomimetics Marc D. Feldman, M.D. Associate Professor of Psychiatry, Vice Chairman for Clinical Services, Medical Director of Center for Psychiatric Medicine, and Director of Division of Adult Psychiatry, Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, Birmingham, Alabama. 17. Factitious Disorders S. Shirley Feldman, Ph.D. Senior Research Scientist, Division of Child Psychiatry and Child Development, Stanford University School of Medicine; Associate Director of Human Biology Program at Stanford University, Stanford, California. 49.7. Childhood or Adolescent Antisocial Behavior Eileen B Fennell, Ph.D. Professor of Clinical and Health Psychology, University of Florida; Professor of Neurology, University of Florida College of Medicine, Gainesville, Florida. 7.6. Neuropsychological and Intellectual Assessment of Children Wayne S. Fenton, M.D. Associate Clinical Professor of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, D.C.; Director of Research, Chestnut Lodge Hospital, Rockville, Maryland. 12.10. Schizophrenia: Individual Psychotherapy Calvin J. Flowers, M.D. Research Fellow, Department of Psychiatry and the Behavioral Sciences, University of Southern California School of Medicine, Los Angeles County and USC Medical Center, Los Angeles, California. 31.5. b-Adrenergic Receptor Antagonists Charles V. Ford, M.D. Professor of Psychiatry, Director of Neuropsychiatry Clinic, Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, Birmingham, Alabama. 17. Factitious Disorders Victor M. Fornari, M.D. Associate Professor of Clinical Psychiatry, New York University School of Medicine, New York, New York; Associate Chairman for Education and Training, Department of Psychiatry, North Shore University Hospital, Manhasset, New York. 49.10. Child Psychiatry: Identity Problem and Borderline Disorders Sydney Frederick-Osborne, Ph.D. Postdoctoral Fellow, Department of Psychiatry, University of California at San Francisco School of Medicine, San Francisco, California. 1.11. Psychoneuroendocrinology Nelson B. Freimer, M.D. Associate Professor of Psychiatry, University of California at San Francisco School of Medicine, San Francisco, California. 1.18. Genetic Linkage Analysis of the Psychiatric Disorders M. Gerard Fromm, Ph.D. Director of Therapeutic Community Program, Austen Riggs Center, Stockbridge, Massachusetts; Faculty, Massachusetts Institute for Psychoanalysis, Cambridge, Massachusetts. 30.9. Eriksonian Clinical Theory and Psychiatric Treatment Abby J. Fyer, M.D. Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Attending Psychiatrist, New York State Psychiatric Institute, New York, New York. 15.4. Anxiety Disorders: Genetics Glen O. Gabbard, M.D. Bessie Walker Callaway Distinguished Professor of Psychoanalysis and Education, Karl Menninger School of Psychiatry, The Menninger Clinic; Clinical Professor of Psychiatry, University of Kansas School of Medicine, Wichita, Kansas; Director of Topeka Institute for Psychoanalysis, Topeka, Kansas. 6.1. Psychoanalysis 14.5. Mood Disorders: Psychodynamic Aspects;

15.5. Anxiety Disorders: Psychodynamic Aspects; 30.1. Psychoanalysis and Psychoanalytic Psychotherapy; 30.12. Combined Psychotherapy and Pharmacotherapy Steven J. Garlow, M.D., Ph.D. Assistant Professor of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 31.22. Nefazodone 31.29. Trazodone Thomas R. Garrick, M.D. Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Staff Psychiatrist, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 25.6. Endocrine and Metabolic Disorders Nori Geary, Ph.D. Associate Research Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University, New York, New York; Research Professor, E. W. Bourne Behavioral Research Laboratory, New York Hospital-Cornell Medical Center, Westchester Division, White Plains, New York. 1.20. Appetite J. Christian Gillin, M.D. Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Director of Mental Health Clinical Research Center, San Diego Veterans Affairs Healthcare System, San Diego, California. 1.19. Basic Science of Sleep Michael J. Gitlin, M.D. Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Mood Disorders Program and Medical Director of Schizophrenia Aftercare Clinic, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 8. Clinical Manifestations of Psychiatric Disorders Robert N. Golden, M.D. Professor of Psychiatry and Chair, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 31.11. Bupropion Marion Zucker Goldstein, M.D. Associate Professor of Psychiatry, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Director of Division of Geriatric Psychiatry, University Psychiatry Practice, Erie County Medical Center, Buffalo, New York. 51.6f. Geriatric Psychiatry: Gender Issues; 51.6g. Geriatric Psychiatry: Elder Abuse, Neglect, and Exploitation Daniel Goleman, Ph.D. Former Science Editor, New York Times, New York, New York. 3.6. Emotional Intelligence Maureen Fulchiero Gordon, M.D. Assistant Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California. 32.2. Normal Child Development Jack M. Gorman, M.D. Professor of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York. 15.1. Anxiety Disorders: Introduction and Overview Irving I. Gottesman, Ph.D., F.R.C.Psych.(Hon) Sherell J. Aston Professor, Departments of Psychology and Pediatrics (Medical Genetics), University of Virginia School of Medicine, Charlottesville, Virginia. 1.17. Population Genetic Methods in Psychiatry Gary L. Gottlieb, M.D., M.B.A. Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts. 51.5a. Geriatric Psychiatry: Financial Issues Igor Grant, M.D., F.R.C.P.(C) Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Chief of Ambulatory Care for Psychiatry and Staff Psychiatrist, San Diego Veterans Affairs Healthcare System, San Diego, California. 2.8. Neuropsychiatric Aspects of HIV Infection and AIDS; 5.2. Statistics and Experimental Design Jack A. Grebb, M.D. Clinical Professor of Psychiatry, New York University School of Medicine, New York, New York. 1.1. Neural Sciences: Introduction and Overview; 31.1. General Principles of Psychopharmacology Richard Green, M.D., J.D. Visiting Professor of Psychiatry, Imperial College School of Medicine; Head of Gender Identity Clinic, Charing Cross Hospital, London, England; Professor of Psychiatry Emeritus, University of California at Los Angeles School of Medicine, Los Angeles, California; Senior Research Fellow, Institute of Criminology, and Affiliated Lecturer, Faculty of Law, University of Cambridge, Cambridge, England. 19.3. Gender Identity Disorders Marcia Greenleaf, Ph.D. Assistant Professor of Psychology, Department of Psychiatry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. 30.3. Hypnosis Stanley I. Greenspan, M.D. Clinical Professor of Psychiatry and Behavioral Sciences and Pediatrics, George Washington University School of Medicine and Health Sciences; Supervising Child Psychoanalyst, Washington Psychoanalytic Institute, Washington, D.C. 3.2. Extending Piaget’s Approach to Intellectual Functioning John H. Greist, M.D. Clinical Professor of Psychiatry, University of Wisconsin Medical School; Distinguished Senior Scientist. Co-Director of Lithium Information Center, Madison Institute of Medicine, Madison, Wisconsin. 31.18. Lithium Roland R. Griffiths, Ph.D.

Professor of Psychiatry and Behavioral Sciences, Department of Neurosciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. 11.4. Caffeine-Related Disorders Lawrence S. Gross, M.D. Associate Professor of Clinical Psychiatry and Behavioral Sciences, University of Southern California School of Medicine; Director of Outpatient Psychiatry, Cedars-Sinai Medical Center, Los Angeles, California. 31.8. Antihistamines George T. Grossberg, M.D. Samuel W. Fordyce Professor of Psychiatry and Chairman, Department of Psychiatry, Saint Louis University School of Medicine, Saint Louis, Missouri. 51.4g. Geriatric Psychiatry: Electroconvulsive Therapy Peter B. Gruenberg, M.D. Associate Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California. 54.2. Ethics in Psychiatry Frederick G. Guggenheim, M.D. Marie Wilson Howells Professor of Psychiatry and Chair, Department of Psychiatry and Behavioral Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas. 16. Somatoform Disorders Raquel E. Gur, M.D., Ph.D. Professor of Psychiatry and Director of Neurospsychiatry, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. 12.3. Schizophrenia: Brain Structure and Function Ruben C. Gur, Ph.D. Professor of Psychiatry and Director of Neuropsychology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. 12.3. Schizophrenia: Brain Structure and Function Alan S. Gurman, Ph.D. Professor of Psychiatry, Director of Couple-Family Clinic, Chief Psychologist, University of Wisconsin Medical School, Madison, Wisconsin. 30.5. Family Therapy and Couple Therapy Kathleen Y. Haaland, Ph.D. Professor of Psychiatry, University of New Mexico School of Medicine; Staff Psychologist, Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico. 7.4. Clinical Neuropsychology and Intellectual Assessment of Adults Katherine A. Halmi, M.D. Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University, New York, New York; Director of Eating Disorders Program, New York Hospital-Cornell Medical Center, Westchester Division, White Plains, New York. 20. Eating Disorders M. Jackuelyn Harris, M.D. Associate Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Co-Director of Geriatric Psychiatry Program, San Diego Veterans Affairs Healthcare System, San Diego, California. 51.3f. Geriatric Psychiatry: Schizophrenia and Delusional Disorders Jennifer F. Havens, M.D. Assistant Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Director of Special Needs Clinic, Pediatric Psychiatry, Columbia-Presbyterian Medical Center, New York, New York. 49.6. Child Psychiatry: Psychiatric Sequelae of HIV and AIDS Donald P. Hay, M.D. Associate Professor of Psychiatry, Director of Geriatric Pscychiatry Programs, University of Colorado Health Sciences Center, Denver, Colorado. 51.4g. Geriatric Psychiatry: Electroconvulsive Therapy Stephaine L. Heard, M.D. Clinical Assistant Professor of Psychiatry, Michigan State University College of Human Medicine, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan. 49.15. Psychiatric Prevention in Children and Adolescents A. Scott Henderson, M.D., D.Sc., F.R.A.C.P., F.R.A.N.Z.C.P., F.R.C.P., F.R.C.Psych. Professor, Australian National University; Director of National Health and Medical Research Council, Psychiatric Epidemiology Research Centre, Canberra, Capital Territory, Australia. 51.1b. Geriatric Psychiatry: Epidemiology of Psychiatric Disorders Victoria C. Hendrick, M.D. Assistant Professor of Psychiatry and Biobehavioral Sciences, Director of Pregnancy and Postpartum Mood Disorders Program, University of California at Los Angeles School of Medicine, Los Angeles, California. 25.6. Endocrine and Metabolic Disorders Hugh C. Hendrie, M.B., Ch.B. Albert E. Sterne Professor of Psychiatry and Chairman, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana. 51.6d. Geriatric Psychiatry: Sociocultural Issues Stephen P. Herman, M.D. Associate Clinical Professor of Psychiatry, Mount Sinai School of Medicine, New York, New York. 49.12. Forensic Child and Adolescent Psychiatry Jerry D. Heston, M.D. Associate Professor of Psychiatry, University of Tennessee at Memphis College of Medicine; Medical Director of Child and Adolescent Day Treatment Services, University of Tennessee Medical Center, Memphis, Tennessee. 48.7. Child Psychiatry: Partial Hospital and Ambulatory Behavioral Health Services Euthymia D. Hibbs, Ph.D. Chief of Child and Adolescent Psychosocial Treatment Research, Child and Adolescent Treatment and Preventive Intervention Research Branch, Division of Services and Intervention Research, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland; Adjunct Associate Professor of Psychiatry; George Washington University School of Medicine and Health Sciences, Washington, D.C. 48.2. Child Psychiatry, Short-Term Psychotherapy Robert M. A. Hirschfeld, M.D. Titus H. Harris Distinguished Professor of Psychiatry and Chair, Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Galveston,

Galveston, Texas. 14.9. Mood Disorders: Psychotherapy Max Hirshkowitz, Ph.D. Associate Professor of Psychiatry, Associate Director of Sleep Disorders Center, Baylor College of Medicine; Director of Sleep Research Center, Houston Veterans Affairs Medical Center, Houston, Texas. 21. Sleep Disorders Robert M. Hodapp, Ph.D. Associate Professor of Education and Psychological Studies in Education, University of California at Los Angeles, Los Angeles, California. 34. Mental Retardation Ralph E. Hoffman, M.D. Associate Professor of Psychiatry, Yale University School of Medicine; Medical Director, Yale Psychiatric Institute, New Haven, Connecticut. 12.6. Schizophrenia: Psychodynamic to Neurodynamic Theories Jimmie C. Holland, M.D. Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University; Chief of Psychiatry Services and Wayne E. Chapman Chair in Psychiatric Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York. 25.11. Psycho-Oncology Eric Hollander, M.D. Professor of Psychiatry, Director of Psychopharmacology Mount Sinai School of Medicine, New York, New York. 18.5. Dissociative Disorders Not Otherwise Specified Nancy L. Hornstein, M.D. Attending Staff, Condell Medical Center, Libertyville, Illinois; Attending Staff, Victory Memorial Hospital, Waukegan, Illinois. 49.8. Dissociative Disorders in Children and Adolescents Thomas B. Horvath, M.D., F.R.A.C.P. Professor of Psychiatry, Baylor College of Medicine; Chief of Staff, Houston Veterans Affairs Medical Center, Houston, Texas. 51.5c. Geriatric Psychiatry: Veterans Affairs Medical Centers and Psychogeriatric Services Ewald Horwath, M.D., M.Sc. Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons; Director of Intensive Care Unit, Washington Heights Community Service, New York State Psychiatric Institute, New York, New York. 15.2. Anxiety Disorders: Epidemiology Kenneth I. Howard, Ph.D. Professor of Psychology, Northwestern University, Evanston, Illinois; Professor of Psychiatry, Northwestern University Medical School, Chicago, Illinois. 30.11. Evaluation of Psychotherapy Charles Campbell Hughes, Ph.D.* Professor of Anthropology, University of Utah; Professor of Family and Preventative Medicine, University of Utah School of Medicine, Salt Lake City, Utah. 13.3. Acute and Transient Psychotic Disorders and Culture-Bound Syndromes John R. Hughes, M.D. Professor of Psychiatry, Psychology, and Family Practice, University of Vermont School of Medicine, Burlington, Vermont. 11.9. Nicotine-Related Disorders Thomas M. Hyde, M.D., Ph.D. Special Expert in Neurology, Neurology Consultation Service, Clinical Brain Disorders Branch, National Institute of Mental Health Neuroscience Center at Saint Elizabeth’s Hospital, National Institutes of Health, Washington, D.C. 12.4. Schizophrenia: Neurobiology Steven E. Hyman, M.D. Director of National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. 1.10. Basic Molecular Neurobiology Robert B. Innis, M.D., Ph.D. Professor of Psychiatry and Pharmacology, Director of Neurochemical Brain Imaging Program, Yale University School of Medicine, New Haven, Connecticut. 1.15. Principles of Neuroimaging: Radiotracer Techniques Keith E. Isenberg, M.D. Associate Professor of Psychiatry, Washington University School of Medicine; Research Associate Professor, Saint Louis College of Pharmacy; Director of Electroconvulsive Therapy (ECT) Service, Barnes-Jewish Hospital, Saint Louis, Missouri. 1.9. Basic Electrophysiology 31.31. Electroconvulsive Therapy Rolf G. Jacob, M.D. Associate Professor of Psychiatry and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 30.2. Behavior Therapy Ari B. Jaffe, M.D. Clinical Instructor of Psychiatry, New York University School of Medicine, New York, New York. 11.10. Opioid-Related Disorders Jerome H. Jaffe, M.D. Clinical Professor of Psychiatry University of Maryland School of Medicine, Baltimore, Maryland. 11.1. Substance-Related Disorders: Introduction and Overview; 11.3. Amphetamine (or Amphetamine-like)-Related Disorders; 11.6. Cocaine-Related Disorders; 11.10. Opioid-Related Disorders Philip G. Janicak, M.D. Professor of Psychiatry Medical Director of the Psychiatric Clinical Research Center, University of Illinois at Chicago College of Medicine, Chicago, Illinois. 31.2. Pharmacokinetics and Drug Interactions

Lissy F. Jarvik, M.D., Ph.D. Professor Emeritus of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Distinguished Physician (Emeritus), UCLA Neuropsychiatric Institute and Hospital, Staff Psychiatrist, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 51.1a. Geriatric Psychiatry: Introduction; 51.2a. Psychiatric Examination of the Older Patient; 51.4a. Geriatric Psychiatry: Treatment of Psychiatric Disorders: Introduction and Overview James W. Jefferson, M.D. Clinical Professor of Psychiatry, University of Wisconsin Medical School; Distinguished Senior Scientist, Co-Director of Lithium Information Center, Madison Institute of Medicine, Madison, Wisconsin. 31.18. Lithium Dilip V. Jeste, M.D. Professor of Psychiatry and Neuroscience, University of California at San Diego School of Medicine, La Jolla, California; Director of Geriatric Psychiatry Clinical Research Center, San Diego Veterans Affairs Healthcare System, San Diego, California. 51.3f. Geriatric Psychiatry: Schizophrenia and Delusional Disorders Russell T. Joffe, M.D. Professor of Psychiatry and Chair, Department of Psychiatry, McMaster University Faculty of Health Sciences; Psychiatrist-in-Chief, Hamilton Psychiatric Hospital, Hamilton, Ontario, Canada. 31.28. Thyroid Hormones Carla J. Johnson, Ph.D. Associate Professor of Speech-Language Pathology, University of Toronto, Toronto, Ontario, Canada. 37.1. Expressive Language Disorder; 37.2. Mixed Receptive-Expressive Language Disorder; 37.3. Phonological Disorder Ricardo E. Jorge, M.D. Associate Research Scientist, Department of Psychiatry, University of Iowa College of Medicine; Attending Psychiatrist, University of Iowa Hospitals and Clinics, Iowa City, Iowa. 2.5. Neuropsychiatric Aspects of Traumatic Brain Injury Allan M. Josephson, M.D. Professor of Psychiatry and Chief of Psychiatry and Health Behavior, Section of Child, Adolescent, and Family Psychiatry, Medical College of Georgia; Director of Clinical Services for Psychiatry, Medical College of Georgia Hospital and Clinics, Augusta, Georgia. 48.5. Child Psychiatry: Family Therapy Robert M. Kaplan, Ph.D. Professor of Family and Preventive Medicine and Chief of Division of Health Care Sciences, University of California at San Diego School of Medicine, La Jolla, California. 5.2. Statistics and Experimental Design Craig N. Karson, M.D. Professor of Psychiatry and Pathology, University of Arkansas for Medical Sciences; Chief of Staff, John L. McClellan Memorial Hospital, Little Rock, Arkansas. 1.16. Principles of Neuroimaging: Magnetic Resonance Techniques Julia E. Kasl-Godley, Ph.D. Research Associate, Department of Psychiatry, University of California at Los Angeles School of Medicine, Los Angeles, California. 51.2c. Psychological Changes With Normal Aging Ira R. Katz, M.D., Ph.D. Professor of Psychiatry, University of Pennsylvania School of Medicine; Director of Section of Geriatric Psychiatry, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania. 51.6a. Geriatric Psychiatry: Psychiatric Aspects of Long-Term Care Jeffrey William Katzman, M.D. Assistant Clinical Professor of Psychiatry, University of New Mexico School of Medicine; Acting Chief of Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico. 22. Impulse-Control Disorders Not Elsewhere Classified Paul E. Keck, Jr., M.D. Professor of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio. 31.7b. Valproate Francis J. Keefe, Ph.D. Adjunct Professor of Psychiatry and Biobehavioral Sciences, Duke University School of Medicine, Durham, North Carolina. 25.9. Stress and Psychiatry Samuel J. Keith, M.D. Professor of Psychiatry and Chairman, Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, New Mexico. 12.9. Schizophrenia: Psychosocial Treatment; 13.1. Schizoaffective Disorder, Schizophreniform Disorder, and Brief Psychotic Disorder Jeffrey E. Kelsey, M.D., Ph.D. Assistant Professor of Psychiatry and Behavioral Sciences, Director of Mood and Anxiety Disorders Clinical Trials Program, Emory University School of Medicine, Atlanta, Georgia. 31.25a. Selective Serotonin Reuptake Inhibitors: Introduction and Overview; 31.25b. Citalopram; 31.25c. Fluoxetine; 31.25d. Fluvoxamine; 31.25e. Paroxetine; 31.25f. Sertraline John R. Kelsoe, M.D. Associate Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California. 14.3. Mood Disorders: Genetics Kenneth S. Kendler, M.D. Professor of Psychiatry and Human Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Medical College of Virginia at Virginia Commonwealth

University, Richmond, Virginia. 12.5. Schizophrenia: Genetics Sidney H. Kennedy, M.D. Professor of Psychiatry, University of Toronto Faculty of Medicine; Head of Mood and Anxiety Disorders Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 31.20. Monoamine Oxidase Inhibitors Ronald C. Kessler, Ph.D. Professor of Sociology, Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts. 4.2. Sociology and Psychiatry Bryan H. King, M.D. Professor of Psychiatry and Pediatrics, Dartmouth Medical School, Hanover, New Hampshire; Director of Child and Adolescent Psychiatry, Children’s Hospital at Dartmouth, Dartmouth Hitchock Medical Center, Lebanon, New Hampshire. 34. Mental Retardation Deborah A. King, Ph.D. Associate Professor of Psychiatry (Psychology), University of Rochester School of Medicine and Dentistry; Staff Psychologist and Director of Geriatric Psychiatry Services, Strong Memorial Hospital, Rochester, New York. 51.4k. Interventions and Consultation With Families of Older Adults Robert A. King, M.D. Professor of Child Psychiatry, Medical Director of Tic Disorder/Obsessive-Compulsive Disorder Specialty Clinic, Yale Child Study Center, Yale University School of Medicine; Associate Director of Child Psychiatry Consultation-Liaison Service in Pediatrics, Yale-New Haven Hospital, New Haven, Connecticut. 33. Psychiatric Examination of the Infant, Child, and Adolescent Darrell G. Kirch, M.D. Professor of Psychiatry and Health Behavior and Dean, Schools of Medicine and Graduate Studies, Medical College of Georgia, Augusta, Georgia. 28.4. Genetic Counseling Thomas J. Kiresuk, Ph.D. Professor of Health Psychology, Department of Psychiatry, University of Minnesota Medical School; Chief Clinical Psychologist, Hennepin County Medical Center; Director of Center for Addiction and Alternative Medicine Research, Minneapolis Medical Research Foundation, Minneapolis, Minnesota. 28.8. Alternative and Complimentary Health Practices Laurel J. Kiser, Ph.D., M.B.A. Professor of Psychiatry, University of Tennessee at Memphis College of Medicine; Executive Director of Child and Adolescent Day Treatment Services, University of Tennessee Medical Center, Memphis, Tennessee. 48.7. Child Psychiatry: Partial Hospital and Ambulatory Behavioral Health Services Herbert D. Kleber, M.D. Professor of Psychiatry, Director of Division on Substance Abuse, Department of Psychiatry, Columbia University College of Physicians and Surgeons; Executive Vice President and Medical Director, National Center on Addiction and Substance Abuse at Columbia University, New York, New York. 31.23. Opioid Agonists Arthur Kleinman, M.D. Presley Professor of Medical Anthropology and Psychiatry, Chairman, Department of Social Medicine, Harvard Medical School, Boston, Massachusetts; Professor of Social Anthropology, Harvard University, Cambridge, Massachusetts. 4.1. Anthropology and Psychiatry Ami Klin, Ph.D. Harris Associate Professor of Child Psychology and Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 38. Pervasive Developmental Disorders Alex Kopelowicz, M.D. Assistant Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California; Director of San Fernando Mental Health Center, Mission Hills, California. 52.4. Psychiatric Rehabilitation Kathryn J. Kotrla, M.D. Assistant Professor of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Chief of Psychiatry, Ben Taub General Hospital, Houston, Texas. 1.3. Developmental Neurobiology Peter D. Kramer, M.D. Clinical Professor of Psychiatry, Brown University School of Medicine, Providence, Rhode Island. 55.3. The Future of Psychiatry Ronald F. Krasner, M.D. Assistant Professor of Psychiatry, Director of Psychiatric Education, and Vice Chairman, Department of Psychiatry and Behavioral Sciences, Northwestern University Medical School, Chicago, Illinois. 30.11. Evaluation of Psychotherapy Suchitra Krishnan-Sarin, Ph.D. Assistant Professor of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 31.21. Naltrexone Robert Kroll, Ph.D. Assistant Professor of Speech-Language Pathology, University of Toronto; Assistant Professor of Psychiatry, University of Toronto Faculty of Medicine; Director of Speech Foundation of Ontario Stuttering Centre; Toronto, Ontario, Canada. 37.4. Stuttering Anand Kumar, M.D. Associate Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Attending Psychiatrist, Geriatric Service, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 51.2f. Geriatric Psychiatry: Neuroimaging: Special Issues Lawrence A. Labbate, M.D. Associate Professor of Psychiatry and Behavioral Sciences, Medical University of South Carolina; Director of Outpatient Mental Health Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; Associate Professor of Clinical Psychiatry, Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine, Bethesda, Maryland.

31.9. Barbiturates and Similarly Acting Substances 31.14. Chloral Hydrate Asenath LaRue, Ph.D. Professor of Psychiatry, University of New Mexico School of Medicine, Albuquerque, New Mexico. 7.4. Clinical Neurology and Intellectual Assessment of Adults John Lauriello, M.D. Assistant Professor of Psychiatry, University of New Mexico School of Medicine, Albuquerque, New Mexico. 12.9. Schizophrenia: Psychosocial Treatment; 13.1. Schizoaffective Disorder, Schizophreniform Disorder, and Brief Psychotic Disorder Eleanor P. Lavretsky, M.D., Ph.D. Research Psychopharmacologist, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 51.2a. Psychiatric Examination of the Older Patient Helen Lavretsky, M.D. Assistant Professor of Psychiatry, University of California at Los Angeles School of Medicine, Los Angeles, California. 51.4e. Geriatric Psychiatry: Psychopharmacology: Antipsychotic Drugs Lawrence W. Lazarus, M.D. Assistant Professor of Psychiatry, Director of Geropsychiatry Fellowship Program, Rush Medical College, Chicago, Illinois. 51.4i. Geriatric Psychiatry: Individual Psychotherapy Paul Leber, M.D. Associate Clinical Professor of Psychiatry and Behavioral Science, George Washington University School of Medicine and Health Sciences, Washington, D.C.; Former Director, Division of Neuropharmacological Drug Product, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland. 31.3. Drug Development and Approval Process in the United States Jay L. Lebow, Ph.D. Senior Therapist and Research Consultant, Family Institute, Northwestern University, Evanston, Illinois. 30.5. Family Therapy and Couple Therapy Barry D. Lebowitz, Ph.D. Chief of Adult and Geriatric Treatment and Preventive Intervention, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland; Adjunct Faculty, Department of Psychiatry, Georgetown University School of Medicine and Health Sciences, Washington, D.C. 51.5d. Community Services for the Elderly Psychiatric Patient Marguerite S. Lederberg, M.D. Clinical Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University; Attending Psychiatrist, Memorial Sloan-Kettering Cancer Center, New York, New York. 25.11. Psycho-Oncology Sing Lee, M.D. Associate Professor of Psychiatry, Chinese University of Hong Kong, Hong Kong, China; Lecturer of Social Medicine, Harvard Medical School, Boston, Massachusetts. 9.2. International Psychiatric Diagnosis Heinz E. Lehmann, M.D.* Professor Emeritus of Psychiatry, McGill University Faculty of Medicine, Montreal, Quebec, Canada; Deputy Commissioner for Research, Office of Mental Health, Albany, New York. 12.7. Schizophrenia: Clinical Features Fredda L. Leiter, M.D. Clinical Instructor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Attending Psychiatrist, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 51.4a. Geriatric Psychiatry: Treatment of Psychiatric Disorders: Introduction and Overview Henrietta L. Leonard, M.D. Professor of Psychiatry and Human Behavior, Brown University School of Medicine; Director of Training, Child and Adolescent Psychiatry Residency Program and Combined Pediatrics-Psychiatry-Child Psychiatry Residency Program, Rhode Island Hospital, Providence, Rhode Island. 46.4. Selective Mutism Ira M. Lesser, M.D. Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California; Director of Residency Training, Vice Chair for Academic Affairs, Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California. 51.3c. Geriatric Psychiatry: Anxiety Disorders Molyn Leszcz, M.D., F.R.C.P.(C) Assistant Professor of Psychiatry, Head of Psychotherapy Program, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada. 51.4l. Geriatric Psychiatry: Group Therapy Eric S. Levine, Ph.D. Assistant Professor of Pharmacology, University of Connecticut School of Medicine, Farmington, Connecticut. 1.7. Neurotrophic Factors Stephen B. Levine, M.D. Clinical Professor of Psychiatry Case Western Reserve University School of Medicine, Clinical Staff, University Hospitals of Cleveland, Cleveland, Ohio; Co-Director of The Center for Marital and Sexual Health, Beachwood, Ohio. 19.2. Paraphilias David A. Lewis, M.D. Professor of Psychiatry and Neuroscience, University of Pittsburgh School of Medicine; Associate Director for Basic Research, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. 1.2. Functional Neuroanatomy Owen Lewis, M.D. Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons; Director of Residency Education in Child Psychiatry, New York State Psychiatric Institute, New York, New York.

48.1. Child Psychiatry: Individual Psychodynamic Psychotherapy Robert Paul Liberman, M.D. Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Clinical Research Center for Serious Mental Illnesses, Los Angeles, California. 52.4. Psychiatric Rehabilitation Keh-Ming Lin, M.D., M.P.H. Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California. 13.3. Acute and Transient Psychotic Disorders and Culture-Bound Syndromes Mark S. Lipian, M.D., Ph.D. Assistant Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California; Associate Clinical Professor of Psychiatry and Human Behavior, University of California at Irvine College of Medicine, Irvine, California; Medical Director of Conditional Release Program of Orange County, Santa Ana, California. 27.2. Malingering Mack Lipkin, Jr., M.D. Professor of Clinical Medicine and Director of Division of Primary Care, New York University School of Medicine, New York, New York. 28.1. Primary Care and Psychiatry Richard J. Loewenstein, M.D. Medical Director, Trauma Disorders, Sheppard Pratt Health System, Baltimore, Maryland. 18.3. Dissociative Identity Disorder Joan L. Luby, M.D. Assistant Professor of Psychiatry (Child), Director of Preschool and Infant Clinic, Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri. 44.2. Stereotypic Movement Disorder of Infancy and Disorders of Infancy and Early Childhood Not Otherwise Specified R. Bruce Lydiard, Ph.D., M.D. Professor of Psychiatry and Behavioral Sciences, Director of Psychopharmacology Unit and Clinical Psychopharmacology Research Division, Medical University of South Carolina, Charleston, South Carolina. 31.12. Buspirone Jeffrey M. Lyness, M.D. Assistant Professor of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York. 10. Delirium, Dementia, and Amnestic and Other Cognitive Disorders Wayne Macfadden, M.D. Clinical Assistant Professor of Psychiatry, University of Pennsylvania School of Medicine; Chief of Inpatient Dual Diagnosis Unit, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania. 11.5. Cannabis-Related Disorders Robert T. Malison, M.D. Assistant Professor of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 1.15. Principles of Neuroimaging: Radiotracer Techniques Facundo F. Manes, M.D. Research Fellow, Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa. 2.3. Neuropsychiatric Aspects of Brain Tumors Myrl R. S. Manley, M.D. Associate Professor of Clinical Psychiatry, Director of Medical Student Education in Psychiatry New York University School of Medicine, New York, New York. 7.1. Psychiatric Interview, History, and Mental Status Examination Theo C. Manschreck, M.D., M.P.H. Professor of Psychiatry and Human Behavior, Director of Laboratory for Clinical and Experimental Psychopathology, Director of Division of Public Psychiatry, Director of Schizophrenia and Related Psychosis Research, Brown University School of Medicine, Providence, Rhode Island. 13.2. Delusional Disorder and Shared Psychotic Disorder John S. March, M.D., M.P.H. Associate Professor of Psychiatry and Director of Programs in Pediatric Anxiety Disorders and Psychopharmacology, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Duke University School of Medicine; Associate Professor of Psychology: Social and Health Sciences, Duke University, Durham, North Carolina. 48.3. Child Psychiatry: Cognitive-Behavioral Psychotherapy Stephen R. Marder, M.D. Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Mental Health Services and Chief of Psychiatry, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 12.8. Schizophrenia: Somatic Treatment; 31.17. Dopamine Receptor Antagonists (Typical Antipsychotics); 31.26. Serotonin-Dopamine Antagonists Deborah B. Marin, M.D. Assistant Professor of Psychiatry and Geriatrics, Mount Sinai School of Medicine; Director of Division of Geriatric Psychiatry, Mount Sinai Medical Center, New York, New York. 51.6c. Geriatric Psychiatry: Ethical Issues John C. Markowitz, M.D. Associate Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University, New York, New York. 30.7. Interpersonal Psychotherapy Carol A. Mathews, M.D. Research Fellow, Department of Psychiatry, University of California at San Francisco School of Medicine, San Francisco, California. 1.18. Genetic Linkage Analysis of the Psychiatric Disorders Richard E. Mattison, M.D. Clinical Professor of Psychiatry and Director of School Consultation, Department of Psychiatry and Behavioral Science, State University of New York at Stony Brook School of Medicine, Stony Brook, New York.

49.14. School Consultation Jeffrey E. Max, M.B.B.Ch. Associate Professor-In-Residence, University of California at San Diego School of Medicine, La Jolla, California; Director of Neuropsychiatric Research, Children’s Hospital and Health Center, San Diego, California. 2.5. Neuropsychiatric Aspects of Traumatic Brain Injury Jon M. McClellan, M.D. Assistant Professor of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington; Medical Director, Child Study and Treatment Center, Lakewood, Washington. 47. Early-Onset Schizophrenia James T. McCracken, M.D. Professor-in-Residence of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Division of Child and Adolescent Psychiatry, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 39.1. Attention-Deficit Disorders 42. Tic Disorders Robert R. McCrae, Ph.D. Research Psychologist, Personality, Stress and Coping Section, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 6.4. Approaches Derived From Philosophy and Psychology John Stephen McDaniel, M.D. Associate Professor of Psychiatry and Behavioral Sciences, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 25.1. History, Classification, and Current Trends in Psychosomatic Medicine Susan L. McElroy, M.D. Professor of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio. 31.7b. Valproate Thomas H. McGlashan, M.D. Professor of Psychiatry, Yale University School of Medicine; Executive Director, Yale Psychiatric Institute, New Haven, Connecticut. 12.6. Schizophrenia: Psychodynamic to Neurodynamic Theories; 12.10. Schizophrenia: Individual Psychotherapy James J. McGough, M.D. Associate Clinical Professor of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, University of California at Los Angeles School of Medicine; Associate Director of Outpatient Service, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 27.4. Borderline Intellectual Functioning and Academic Problem Michael T. McGuire, M.D. Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Attending Psychiatrist, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 4.3. Evolutionary Biology and Psychiatry Kevin F. McKenna, M.D., Ph.D. Clinical Associate Professor of Psychiatry, University of Alberta Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada. 31.20. Monoamine Oxidase Inhibitors William T. McKinney, Jr., M.D. Helen and Norman Asher Professor of Psychiatry and Behavioral Sciences, Northwestern University Medical School; Director of The Asher Center for the Study and Treatment of Depressive Disorders; Clinical Staff, Northwestern Memorial Hospital, Chicago, Illinois. 5.4. Animal Research and Its Relevance to Psychiatry Claude Mellins, Ph.D. Assistant Professor of Clinical Psychology in Psychiatry, Columbia University College of Physicians and Surgeons; Research Scientist, HIV Center for Clinical and Behavioral Studies, New York State Psychiatric Institute; Co-Director of Speech Needs Clinic, Pediatric Psychiatry, Columbia-Presbyterian Medical Center, New York, New York. 49.6. Child Psychiatry: Psychiatric Sequelae of HIV and AIDS Mario F. Mendez, M.D., Ph.D. Associate Professor of Neurology, Psychiatry, and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Neurobehavioral Unit, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 2.4. Neuropsychiatric Aspects of Epilepsy W. Walter Menninger, M.D. J. Cotter Hirschberg Professor and Former Dean, Karl Menninger School of Psychiatry and Mental Health Sciences, Chief Executive Officer of The Menninger Foundation and Clinic; Clinical Professor of Psychiatry, University of Kansas School of Medicine, Kansas City, Kansas; Instructor, Topeka Institute for Psychoanalysis, Topeka, Kansas. 52.3. Role of the Psychiatric Hospital in the Treatment of Mental Illness James R. Merikangas, M.D. Lecturer of Psychiatry, Yale University School of Medicine; Attending in Neurology, Yale-New Haven Hospital, New Haven, Connecticut. 2.10. Neuropsychiatric Aspects of Headache Kathleen Ries Merikangas, Ph.D. Professor of Epidemiology and Psychiatry and Director of Geriatric Epidemiology Research Unit, Yale University School of Medicine, New Haven, Connecticut. 2.10. Neuropsychiatric Aspects of Headache Jonathan M. Meyer, M.D. Adjunct Assistant Professor of Psychiatry, Oregon Health Sciences University School of Medicine, Portland, Oregon. 31.6. Anticholinergics and Amantadine Juan E. Mezzich, M.D., Ph.D. Professor of Psychiatry, Mount Sinai School of Medicine; Director of Division of Psychiatric Epidemiology and International Center for Mental Health, Mount Sinai Medical Center, New York, New York. 9.2. International Psychiatric Diagnosis; 13.3. Acute and Transient Psychotic Disorders and Culture-Bound Syndromes;

23. Adjustment Disorders Edwin J. Mikkelson, M.D. Associate Professor of Psychiatry, Harvard Medical School; Medical Director, Mentor Clinical Care; Consultant, Massachusetts Department of Mental Retardation, Boston, Massachusetts. 43. Elimination Disorders Andrew H. Miller, M.D. Associate Professor of Psychiatry and Behavioral Sciences and Emory University School of Medicine, Atlanta, Georgia. 1.12. Immune System and Central Nervous System Interactions Marvin J. Miller, M.D. Assistant Professor of Psychiatry, Indiana University School of Medicine; Staff Psychiatrist, Larue Carter Memorial Hospital, Indianapolis, Indiana. 7.9. Computer-Based Testing of the Psychiatric Patient Mark J. Mills, J.D., M.D. Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California. 27.2. Malingering Klaus Minde, M.D., F.R.C.P.(C) Professor of Psychiatry and Pediatrics and Chairman, Division of Child Psychiatry, McGill University Faculty of Medicine; Director of Department of Psychiatry, Montreal Children’s Hospital, Montreal, Quebec, Canada. 49.1. Psychiatric Aspects of Day Care Paul C. Mohl, M.D. Professor of Psychiatry, University of Texas Southwestern Medical School; Director of Psychiatric Residency Training, University of Texas Southwestern Medical Center, Dallas, Texas. 6.3. Other Psychodynamic Schools Steven O. Moldin, Ph.D. Chief of Genetics Research Branch, Division of Basic and Clinical Neuroscience Research, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland. 1.17. Population Genetic Methods in Psychiatry Constance A. Moore, M.D. Associate Professor of Psychiatry and Director of Sleep Disorders Center, Baylor College of Medicine; Director of Sleep Diagnostic Center, Houston Veterans Affairs Medical Center, Houston, Texas. 21. Sleep Disorders Michael G. Moran, M.D. Associate Professor of Psychiatry, University of Colorado School of Medicine; Director of Adult Psychosocial Medicine, National Jewish Medical and Research Center, Denver, Colorado. 25.5. Respiratory Disorders James Morrison, M.D. Clinical Professor of Psychiatry, Temple University School of Medicine, Philadelphia, Pennsylvania; Chief of Staff, Coatesville Veterans Affairs Medical Center, Coatesville, Pennsylvania. 53.2. Examining Psychiatrists and Other Trainees Rodrigo A. Muñoz, M.D. Clinical Professor of Psychiatry, University of California at San Diego; Attending Psychiatrist, UCSD Medical Center; Attending Psychiatrist, Scripps Memorial Hospital, La Jolla, California; Attending Psychiatrist, Mercy Hospital and Medical Center, San Diego, California. 53.2. Examining Psychiatrists and Other Trainees William E. Narrow, M.D., M.P.H. Senior Advisor for Epidemiology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. 12.2. Schizophrenia: Epidemiology J. Craig Nelson, M.D. Professor of Psychiatry, Yale University School of Medicine; Director of Inpatient Psychiatry Service and Geriatric Psychiatry Programs, Yale-New Haven Hospital, New Haven, Connecticut. 31.30. Tricyclics and Tetracyclics Charles B. Nemeroff, M.D., Ph.D. Reunette W. Harris Professor of Psychiatry and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 1.6. Neuropeptides: Biology and Regulation; 31.22. Nefazodone; 31.25a. Selective Serotonin Reuptake Inhibitors: Introduction and Overview; 31.25b. Citalopram; 31.25c. Fluoxetine; 31.25d. Fluvoxamine; 31.25e. Paroxetine; 31.25f. Sertraline; 31.29. Trazodone John C. Nemiah, M.D. Professor of Psychiatry, Dartmouth Medical School, Hanover, New Hampshire; Clinical Staff, Mary Hitchcock Memorial Hospital, Lebanon, New Hampshire; Professor of Psychiatry Emeritus, Harvard Medical School, Boston, Massachusetts. Introduction Eric J. Nestler, M.D., Ph.D. Jameson Professor of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 1.10. Basic Molecular Neurobiology Jeffrey H. Newcorn, M.D. Associate Professor of Psychiatry and Pediatrics, Mount Sinai School of Medicine; Director of Child and Adolescent Psychiatry, Mount Sinai Medical Center, New York, New York. 23. Adjustment Disorders Dorian S. Newton, Ph.D.

Affiliate Member, San Francisco Psychoanalytic Institute, San Francisco, California; Director of Mills College Counseling and Psychological Services, Oakland, California. 6.2. Erik H. Erikson Peter M. Newton, Ph.D. Professor of Psychology, Wright Institute, Berkeley, California. 6.2. Erik H. Erikson Cynthia T. M. H. Nguyen, M.D. Postdoctoral Research Fellow, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. 51.4d. Geriatric Psychiatry: Psychopharmacology: Antianxiety Drugs Linda M. Nicholas, M.D. Assistant Professor of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 31.11. Bupropion Steven L. Nickman, M.D. Clinical Assistant Professor of Psychiatry, Harvard Medical School; Assistant in Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Assistant in Psychiatry, McLean Hospital, Belmont, Massachusetts. 49.2. Adoption Ruta Nonacs, M.D., Ph.D. Instructor of Psychiatry, Harvard Medical School, Boston, Massachusetts. 13.4. Postpartum Psychiatric Syndromes Grayson S. Norquist, M.D., M.S.P.H. Director of Division of Services and Intervention Research, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland. 12.2. Schizophrenia: Epidemiology Ann E. Norwood, M.D. Associate Professor of Psychiatry and Associate Chairman, Department of Psychiatry, Uniformed Services University of the Health Sciences F. Herbert School of Medicine, Bethesda, Maryland. 30.8. Brief Psychotherapy H. George Nurnberg, M.D. Professor of Psychiatry and Vice Chair for Clinical Programs, Department of Psychiatry, University of New Mexico School of Medicine; Medical Director, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. 9.1. Classification of Mental Disorders M. Kevin O’Connor, M.D. Assistant Professor of Psychiatry, Mayo Foundation, Rochester, Minnesota. 25.8. Musculoskeletal Disorders Stephanie S. O’Malley, Ph.D. Associate Professor of Psychiatry, Director of Division of Substance Abuse Research, Yale University School of Medicine, New Haven, Connecticut. 31.21. Naltrexone Mark Olfson, M.D., M.P.H. Associate Professor of Clinical Psychiatry, College of Physicians and Surgeons of Columbia University; Attending Psychiatrist, New York State Psychiatric Institute, New York, New York. 5.3. Mental Health Services Research Angel A. Otero-Ojeda, M.D. Professor of Psychiatry, Havana University; Chairman, Executive Committee, Cuban Glossary of Psychiatry, Havana, Cuba. 9.2. International Psychiatric Diagnosis Michael J. Owens, Ph.D. Associate Professor of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 1.6. Neuropeptides: Biology and Regulation; 31.22. Nefazodone Ken A. Paller, Ph.D. Assistant Professor of Psychology, Northwestern University, Evanston, Illinois. 3.4. Biology of Memory Laszlo A. Papp, M.D. Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Director of Biological Studies Unit, New York State Psychiatric Institute, New York, New York; Director of Anxiety Disorders Program, Long Island Jewish-Hillside Medical Center, Queens, New York. 15.7. Anxiety Disorders: Somatic Treatment Carmine M. Pariante, M.D. Medical Research Council Clinical Training Fellow, Section of Clinical Neuropharmacology, Institute of Psychiatry, London, United Kingdom. 1.12. Immune System and Central Nervous System Interactions Barbara L. Parry, M.D. Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Director of Psychiatric Emergency Room, UCSD Medical Center, San Diego, California. 28.2. Psychiatry and Reproductive Medicine Caroly S. Pataki, M.D. Associate Clinical Professor of Psychiatry and Biobehavioral Sciences and Associate Director of Training and Education for Child and Adolescent Psychiatry, University of California at Los Angeles School of Medicine; Attending Psychiatrist, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 32.1. Child Psychiatry: Introduction and Overview; 45. Mood Disorders and Suicide in Children and Adolescents Robert H. Paul, Ph.D. Fellow, Department of Psychiatry and Behavioral Sciences, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma. 2.7. Neuropsychiatric Aspects of Multiple Sclerosis and Other Demyelinating Disorders Bradley D. Pearce, Ph.D. Assistant Professor of Psychiatry and Behavioral Sciences, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta,

Georgia. 1.12. Immune System and Central Nervous System Interactions David Pelcovitz, Ph.D. Clinical Associate Professor of Psychology in Psychiatry, New York University School of Medicine, New York, New York; Chief Psychologist, Division of Child and Adolescent Psychiatry, North Shore University Hospital, Manhasset, New York. 49.10. Child Psychiatry: Identity Problem and Borderline Disorders William H. Pelham, Ph.D. Professor of Psychology and Director of Clinical Training, State University of New York at Buffalo, Buffalo, New York. 30.2. Behavior Therapy Bradley S. Peterson, M.D. House Jameson Assistant Professor in Child Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 33. Psychiatric Examination of the Infant, Child, and Adolescent John M. Petitto, M.D. Associate Professor of Psychiatry, Neuroscience, and Pharmacology, University of Florida College of Medicine, Gainesville, Florida. 25.10. Behavior and Immunity Cynthia R. Pfeffer, M.D. Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell University, New York, New York. 48.10. Psychiatric Treatment of Adolescents Kemuel L. Philbrick, M.D. Assistant Professor of Psychiatry, Mayo Foundation, Rochester, Minnesota. 25.8. Musculoskeletal Disorders Edmond Hsin-tung Pi, M.D. Executive Vice Chair, Department of Psychiatry, King/Drew University of Medicine and Science, Los Angeles, California. 31.4. Medication-Induced Movement Disorders John Piacentini, Ph.D. Assistant Professor-in-Residence of Psychiatry and Biobehavioral Science, University of California at Los Angeles School of Medicine; Director of Child and Adolescent Obsessive-Compulsive Disorder and Anxiety Program, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California. 46.1. Obsessive-Compulsive Disorder in Children Daniel S. Pine, M.D. Associate Professor of Clinical Psychiatry, Division of Child and Adolescent Psychiatry, College of Physicians and Surgeons of Columbia University; Attending Psychiatrist, New York State Psychiatric Institute, New York, New York. 15.6. Anxiety Disorders: Clinical Features Bruce G. Pollock, M.D., Ph.D. Professor of Psychiatry and Pharmacology, University of Pittsburgh School of Medicine; Director of Geriatric Psychopharmacology Program, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. 51.4b. Geriatric Psychiatry: Psychopharmacology: General Principles Harrison G. Pope, Jr., M.D. Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts; Chief of Biological Psychiatry Laboratory, McLean Hospital, Belmont, Massachusetts. 11.13. Anabolic-Androgenic Steroid Abuse; 31.7b. Valproate Robert M. Post, M.D. Chief of Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. 14.8. Mood Disorders: Treatment of Bipolar Disorders; 31.13. Calcium Channel Inhibitors Karl H. Pribram, M.D., Ph.D. Director of Center for Brain Research and Informational Sciences, Radford University, Radford, Virginia; Professor Emeritus, Stanford University, Stanford, California. 3.5. Brain Models of Mind Patricia N. Prinz, Ph.D. Professor of Biobehavioral Nursing and Health Systems, University of Washington School of Nursing; Adjunct Professor of Psychiatry, University of Washington School of Medicine, Seattle, Washington. 51.3b. Geriatric Psychiatry: Sleep Disorders David B. Pruitt, M.D. Professor of Psychiatry and Vice Chairman, Department of Psychiatry, University of Tennessee at Memphis College of Medicine, Memphis, Tennessee. 48.7. Child Psychiatry: Partial Hospital and Ambulatory Behavioral Health Services Andres J. Pumariega, M.D. Professor of Psychiatry and Chair, Department of Psychiatry and Behavioral Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. 48.9. Child Psychiatry: Community-Based Treatments Frank W. Putnam, M.D. Chief of Unit on Developmental Traumatology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; Professor of Pediatrics, Ohio State University College of Medicine and Public Health; Professor of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio. 18.3. Dissociative Identity Disorder Denisa Radoi-Andraous, M.D. Assistant Professor of Psychiatry, University of Montreal Faculty of Medicine, Montreal, Quebec, Canada. 31.24. Selective Serotonin-Noradrenaline Reuptake Inhibitors Scott L. Rauch, M.D. Associate Professor of Psychiatry, Harvard Medical School; Associate Chief of Psychiatry for Neuroscience Research, Massachusetts General Hospital, Boston, Massachusetts. 31.32. Neurosurgical Treatments Darrel A. Regier, M.D., M.P.H. Associate Director for Epidemiology and Health Policy Research, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; Clinical

Professor of Psychiatry, Georgetown University School of Medicine and Health Sciences, Washington, D.C. 5.1. Epidemiology Edward L. Reilly, M.D. Professor of Psychiatry and Director of Residency Training, University of Texas Medical School at Houston; Director of Mental Sciences Institute, University of Texas-Houston Health Science Center, Houston, Texas. 1.14. Applied Electrophysiology Eric M. Reiman, M.D. Professor, Associate Head of Psychiatry University of Arizona College of Medicine, Tucson, Arizona; Scientific Director of Positron Emission Tomography Center, Good Samaritan Regional Medical Center; Director of Arizona Alzheimer’s Disease Research Center, Phoenix, Arizona. 51.2e. Geriatric Psychiatry: Neuroimaging: Overview Perry F. Renshaw, M.D., Ph.D. Research Director, Brain Imaging Center, McLean Hospital, Boston, Massachusetts. 1.16. Principles of Neuroimaging: Magnetic Resonance Techniques Victor I. Reus, M.D. Professor of Psychiatry, University of California at San Francisco School of Medicine; Director of Psychiatry, Langley Porter Psychiatric Institute, San Francisco, California. 1.11. Psychoneuroendocrinology Charles F. Reynolds, III, M.D. Professor of Psychiatry, University of Pittsburgh School of Medicine; Director of Mental Health Clinical Research Center for the Study of Late-Life Mood Disorders, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. 51.4c. Geriatric Psychiatry: Psychopharmacology: Antidepressants and Mood Stabilizers Robert G. Robinson, M.D. The Paul W. Penningroth Professor of Psychiatry and Head, Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa. 2.2. Neuropsychiatric Aspects of Cerebrovascular Disorders; 2.3. Neuropsychiatric Aspects of Brain Tumors; 2.5. Neuropsychiatric Aspects of Traumatic Brain Injury Robert M. Rohrbaugh, M.D. Assistant Clinical Professor of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Director of Education in Psychiatry, Connecticut Veterans Affairs Healthcare System, West Haven, Connecticut. 51.3g. Geriatric Psychiatry: Personality Disorders Richard B. Rosse, M.D. Associate Professor of Psychiatry, Georgetown University School of Medicine and Health Sciences; Chief of Georgetown University Teaching Unit, Veterans Affairs Medical Center, Washington, D.C. 7.7. Medical Assessment and Laboratory Testing in Psychiatry Bruce J. Rounsaville, M.D. Professor of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 31.21. Naltrexone Alec Roy, M.D. Professor of Psychiatry, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; Assistant Chief of Psychiatry for Substance Abuse, East Orange Campus of the Veterans Affairs New Jersey Health Care System, East Orange, New Jersey. 29.1. Suicide Teresa A. Rummans, M.D. Associate Professor of Psychiatry, Mayo Foundation, Rochester, Minnesota. 25.8. Musculoskeletal Disorders A. John Rush, M.D. Professor of Psychiatry, Betty Jo Hay Distinguished Chair in Mental Health, and Rosewood Corporation Chair in Biomedical Science, University of Texas Southwestern Medical School, Dallas, Texas. 14.7. Mood Disorders: Treatment of Depression; 30.6. Cognitive Therapy Sheila Ryan, C.S.W. Program Director of Special Needs Clinic, Pediatric Psychiatry, Columbia-Presbyterian Medical Center, New York, New York. 49.6. Child Psychiatry: Psychiatric Sequelae of HIV and AIDS Joel Sadavoy, M.D., F.R.C.P.(C) Associate Professor of Psychiatry and Head, Division of General Psychiatry, University of Toronto Faculty of Medicine; Psychiatrist-in-Chief, Mount Sinai Hospital; Clinical Director, Joint General Psychiatry Program, Mount Sinai Hospital and Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 51.4h. Geriatric Psychiatry: Psychosocial Treatments: General Principles 51.4i. Geriatric Psychiatry: Individual Psychotherapy Benjamin J. Sadock, M.D. Menas S. Gregory Professor of Psychiatry and Vice Chairman, Department of Psychiatry, New York University School of Medicine; Attending Psychiatrist, Tisch Hospital; Attending Psychiatrist, Bellevue Hospital Center; Consultant Psychiatrist, Lenox Hill Hospital, New York, New York. 7.2. Psychiatric Report and Medical Record; 7.3. Signs and Symptoms in Psychiatry Virginia A. Sadock, M.D. Clinical Professor of Psychiatry and Director of Program in Human Sexuality and Sex Therapy, New York University School of Medicine; Attending Psychiatrist, Tisch Hospital; Attending Psychiatrist, Bellevue Hospital Center, New York, New York. 19.1a. Normal Human Sexuality and Sexual Dysfunctions Rafael J. Salin-Pascual, M.D., Ph.D. Professor of Psychiatry and Physiology, Department of Physiology, Universidad Nacional Autonomona de Mexico, Mexico City, Mexico. 1.19. Basic Science of Sleep Steven C. Samuels, M.D. Assistant Professor of Psychiatry, Mount Sinai School of Medicine; Director of Outpatient Geriatric Psychiatry Program, Department of Psychiatry, Mount Sinai Medical Center, New York, New York.

31.15. Cholinesterase Inhibitors Ofra Sarid-Segal, M.D. Assistant Professor of Psychiatry, Boston University School of Medicine; Staff Psychiatrist, Department of Veterans Affairs Outpatient Clinic, Boston, Massachusetts. 11.12. Sedative-, Hypnotic-, or Anxiolytic-Related Abuse Stephen M. Saunders, Ph.D. Assistant Professor of Psychology, Marquette University, Milwaukee, Wisconsin. 30.11. Evaluation of Psychotherapy S. Alan Savitz, M.D. President and Chief Executive Officer, PacifiCare Behavioral Health, Laguna Hills, California. 51.5b. Geriatric Psychiatry: Managed Care Alan F. Schatzberg, M.D. Kenneth T. Norris Jr., Professor of Psychiatry and Chairman, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. 31.33. Other Pharmacological and Biological Therapies Stephen C. Scheiber, M.D. Adjunct Professor of Psychiatry, Northwestern University Medical School, Chicago, Illinois; Adjunct Professor of Psychiatry, Medical College of Wisconsin, Milwaukee, Wisconsin; Executive Vice President American Board of Psychiatry and Neurology, Deerfield, Illinois; Senior Attending Physician, Evanston Hospital, Evanston, Illinois. 53.1. Graduate Psychiatric Education Diane H. Schetky, M.D. Associate Clinical Professor of Psychiatry, University of Vermont College of Medicine, Burlington, Vermont; Attending Psychiatrist, Maine Medical Center, Portland, Maine. 49.13. Ethical Issues in Child and Adolescent Psychiatry Lon S. Schneider, M.D. Professor of Psychiatry, Neurology, and Gerontology, University of Southern California School of Medicine, Los Angeles, California. 51.4f. Geriatric Psychiatry: Psychophamacology: Antidementia Drugs Richard S. Schottenfeld, M.D. Professor of Psychiatry, Director of Substance Abuse Residency Training Yale University School of Medicine; Director of Substance Abuse Treatment Unit and Associate Clinical Director of Addiction Services, Connecticut Mental Health Center, New Haven, Connecticut. 31.23. Opioid Agonists Marc A. Schuckit, M.D. Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California; Director of Alcohol Research Center, San Diego Veterans Affairs Healthcare System, San Diego, California. 11.2. Alcohol-Related Disorders Mary E. Schwab-Stone, M.D. Associate Professor of Child Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 33. Psychiatric Examination of the Infant, Child, and Adolescent Erich Seifritz, M.D. Professor of Psychiatry, Psychiatric University Hospital, Basel, Switzerland. 1.19. Basic Science of Sleep Alberto C. Serrano, M.D. Professor of Psychiatry, University of Hawaii John A. Burns School of Medicine; Director of Consortium of Education and Training, Kapi’olani Medical Center for Women and Children, Honolulu, Hawaii. 48.4. Child Psychiatry: Group Psychotherapy Richard P. Shank, Ph.D. Senior Research Fellow, CNS Drug Discovery, Robert Wood Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania. 1.5. Amino Acid Neurotransmitters Edward R. Shapiro, M.D. Medical Director and Chief Executive Officer, Austen Riggs Center, Stockbridge, Massachusetts; Director of Erik H. Erikson Institute for Education and Research of the Austen Riggs Center; Associate Clinical Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts. 30.9. Eriksonian Clinical Theory and Psychiatric Treatment Peter A. Shapiro, M.D. Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Assistant Director, Consultation-Liaison Psychiatry Service, Columbia-Presbyterian Medical Center, New York, New York. 25.4. Cardiovascular Disorders M. Tracie Shea, Ph.D. Associate Professor of Psychiatry and Human Behavior and Director of Clinical Assessment and Training Unit, Brown University School of Medicine; Staff Psychologist, Providence Veterans Affairs Medical Center, Providence, Rhode Island. 14.9. Mood Disorders: Psychotherapy Javaid I. Sheikh, M.D., M.B.A. Associate Professor of Psychiatry, Stanford University School of Medicine, Stanford, California; Chief of Psychiatry, Palo Alto Veterans Affairs Health Care System, Palo Alto, California. 51.4d. Geriatric Psychiatry: Antianxiety Drugs Cleveland G. Shields, Ph.D. Associate Professor of Family Medicine and Psychiatry, University of Rochester School of Medicine and Dentistry; Family Therapist, Highland Hospital; Family Therapist, Strong Memorial Hospital, Rochester, New York. 51.4k. Interventions and Consultation With Families of Older Adults Daniel J. Siegel, M.D. Associate Professor of Clinical Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Medical Director of Infant and Preschool Service, UCLA Neuropsychiatric Institute and Hospital, Los Angeles, California.

3.1. Perception and Cognition Daphine Simeon, M.D. Assistant Professor of Psychiatry and Director of Medical Student Education in Psychiatry, Mount Sinai School of Medicine, New York, New York. 18.5. Dissociative Disorders Not Otherwise Specified Robert I. Simon, M.D. Clinical Professor of Psychiatry and Director of Program in Psychiatry and Law, Georgetown University School of Medicine, Washington, D.C. 54.1. Legal Issues in Psychiatry George M. Simpson, M.D. Professor of Research Psychiatry and Director of Clinical Research, Department of Psychiatry and the Behavioral Sciences, University of Southern California School of Medicine, Los Angeles County and USC Medical Center, Los Angeles, California. 31.4. Medication-Induced Movement Disorders; 31.5. b-Adrenergic Receptor Antagonists; 31.6. Anticholinergics and Amantadine; 31.8. Antihistamines Gary W. Small, M.D. Professor of Psychiatry and Biobehavioral Sciences, Director of Geriatric Psychiatry and Psychology Fellowship Program, Director of Center on Aging, University of California at Los Angeles School of Medicine, Los Angeles, California. 51.1a. Geriatric Psychiatry: Introduction; 51.3e. Geriatric Psychiatry: Alzheimer’s Disease and Other Dementias Buster D. Smith, M.D. Clinical Associate in Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. 51.6a. Geriatric Psychiatry: Psychiatric Aspects of Long-Term Care Gerard P. Smith, M.D. Professor of Psychiatry, The Joan and Sanford I. Weill Medical College of Cornell Univerity; Attending Psychiatrist (Behavioral Science), New York Hospital, New York, New York. 1.20. Appetite Thomas E. Smith, M.D. Assistant Professor of Psychiatry, New York, New York. 52.4. Psychiatric Rehabilitation Virginia L. Smith-Swintosky, Ph.D. Senior Scientist, CNS Drug Discovery, Robert Wood Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania. 1.5. Amino Acid Neurotransmitters Solomon H. Snyder, M.D. Distinguished Service Professor of Neuroscience, Pharmacology, Molecular Sciences, and Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland. 1.21. Future Directions in Neuroscience and Psychiatry Michael E. Spagna, Ph.D. Associate Professor of Special Education, California State University at Northridge, Northridge, California. 35.1. Reading Disorder; 35.2. Mathematics Disorder; 35.3. Disorder of Written Expression and Learning Disorder Not Otherwise Specified; 36. Motor Skills Disorder: Developmental Coordination Disorder David Spiegel, M.D. Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. 30.3. Hypnosis Herbert Spiegel, M.D. Special Lecturer in Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York. 30.3. Hypnosis Larry R. Squire, Ph.D. Professor of Psychiatry and Neurosciences, University of California at San Diego School of Medicine; Professor of Psychology, University of California at San Diego, La Jolla, California; Research Career Scientist, San Diego Veterans Affairs Healthcare System, San Diego, California. 3.4. Biology of Memory Sergio E. Starkstein, M.D., Ph.D. Director of Neuropsychiatry, FLENI, Buenos Aires, Argentina. 2.2. Neuropsychiatric Aspects of Cerebrovascular Disorders Murray B. Stein, M.D. Associate Professor of Psychiatry, University of California at San Diego School of Medicine, La Jolla, California. 25.9. Stress and Psychiatry Terry S. Stein, M.D. Professor of Psychiatry, Michigan State University College of Human Medicine, East Lansing, Michigan. 19.1b. Homosexuality and Homosexual Behavior Marlene Steinberg, M.D. Associate Professor of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts; Research Affiliate, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 18.1. Dissociate Amnesia; 18.4. Depersonalization Disorder Hans Steiner, M.D. Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine; Director of Training, Division of Child Psychiatry and Human Development, Stanford, California. 40. Disruptive Behavior Disorders; 49.7. Childhood or Adolescent Antisocial Behavior Alan Stoudemire, M.D.

Professor of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. 25.1. History, Classification, and Current Trends in Psychosomatic Medicine Eric C. Strain, M.D. Associate Professor of Psychiatry and Behavioral Science, Johns Hopkins School of Medicine, Baltimore, Maryland. 11.4. Caffeine-Related Disorders James J. Strain, M.D. Professor of Psychiatry, Mount Sinai School of Medicine; Director of Division of Behavioral Medicine and Consultation-Psychiatry, Mount Sinai Medical Center, New York, New York. 23. Adjustment Disorders; 25.12. Consultation-Liaison Psychiatry Joel E. Streim, M.D. Associate Professor of Psychiatry, University of Pennsylvania School of Medicine; Director of Geriatric Psychiatry Fellowship Program, Ralston-Penn Center, Philadelphia, Pennsylvania. 51.6a. Geriatric Psychiatry: Psychiatric Aspects of Long-Term Care Gregory M. Sullivan, M.D. Postdoctoral Fellow, Department of Psychiatry, Columbia University College of Physicians and Surgeons; Clinical Assistant in Psychiatry, Columbia-Presbyterian Medical Center, New York, New York. 15.3. Anxiety Disorders: Biochemical Aspects David L. Sultzer, M.D. Associate Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine; Director of Gero-Neuropsychiatry Division, West Los Angeles Veterans Affairs Ambulatory Care Center, Los Angeles, California. 51.4e. Geriatric Psychiatry: Psychopharmacology: Antipsychotic Drugs Norman Sussman, M.D. Clinical Professor of Psychiatry, New York University School of Medicine; Director of Psychopharmacology Research and Consultation Service, Bellevue Hospital Center, New York, New York. 31.7c. Other Anticonvulsants; 31.16. Clonidine Dragan M. Svrakic, M.D., Ph.D. Assistant Professor of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri. 24. Personality Disorders Rex M. Swanda, Ph.D. Adjunct Assistant Professor of Psychiatry, University of New Mexico School of Medicine; Staff Psychologist, Veterans Affairs Medical Center, Albuquerque, New Mexico. 7.4. Clinical Neuropsychology and Intellectual Assessment of Adults Carrie Sylvester, M.D., M.P.H. Associate Professor of Psychiatry, Behavioral Sciences, and Pediatrics and Director of Education in Child and Adolescent Psychiatry, Northwestern University School of Medicine; Attending Psychiatrist, Children’s Memorial Hospital; Attending Psychiatrist, Northwestern Memorial Hospital, Chicago, Illinois. 46.3. Separation Anxiety Disorder and Other Anxiety Disorders Kenneth Tardiff, M.D., M.P.H. Professor of Psychiatry and Public Health, The Joan and Sanford I. Weill Medical College of Cornell University; Attending Psychiatrist and Medical Director of Payne Whitney Clinic, New York Hospital, New York, New York. 27.3. Adult Antisocial Behavior and Criminality Laurence H. Tecott, M.D., Ph.D. Assistant Professor of Psychiatry, University of California at San Francisco School of Medicine, San Francisco, California. 1.4. Monoamine Neurotransmitters Michael E. Thase, M.D. Professor of Psychiatry, University of Pittsburgh School of Medicine; Research Director of Division of General Adult Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. 14.4. Mood Disorders: Neurobiology Armin Paul Thies, Ph.D. Associate Clinical Professor of Psychology, Yale University School of Medicine, New Haven, Connecticut. 33. Psychiatric Examination of the Infant, Child, and Adolescent Mauricio Tohen, M.D., Dr.P.H. Associate Clinical Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts. 31.7a. Carbamazepine Alan Trachtenberg, M.D., M.P.H. Adjunct Associate Professor of Community Medicine and Health Care Sciences, George Washington University School of Medicine and Health Sciences, Washington, D.C.; Medical Director, Office of Pharmacologic and Alternative Therapies, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, United State Public Health Service, Rockville, Maryland. 28.8. Alternative and Complimentary Health Practices Alfonso Troisi, M.D. Professor of Psychopathology, University of Rome Tor Vergata, Rome, Italy. 4.3. Evolutionary Biology and Psychiatry Manuel Trujillo, M.D. Professor of Clinical Psychiatry and Vice Chairman of Psychiatry, New York University School of Medicine; Director of Psychiatry, Director of Division of Cultural Psychiatry, Bellevue Hospital Center, New York, New York. 4.4. Cultural Psychiatry Roy E. Twyman, M.D. Associate Professor of Neurology and Pharmacology, University of Utah School of Medicine, Salt Lake City; Director, Global CNS Research and Development, Robert Wood Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania. 1.5. Amino Acid Neurotransmitters Jurgen Unützer, M.D., M.P.H.

Assistant Professor-in-Residence, University of California at Los Angeles School of Medicine, Los Angeles, California. 51.3a. Geriatric Psychiatry: Psychiatric Problems in the Medically Ill Robert J. Ursano, M.D. Professor of Psychiatry and Neuroscience and Chairman, Department of Psychiatry, Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine, Bethesda, Maryland. 30.8. Brief Psychotherapy Jerome V. Vaccaro, M.D. Associate Clinical Professor Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California. 51.5b. Geriatric Psychiatry: Managed Care Bessel A. van der Kolk, M.D. Professor of Psychiatry, Boston University School of Medicine, Boston, Massachusetts; Chief of Trauma Center, HRI Hospital, Brookline, Massachusetts. 28.7. Physical and Sexual Abuse of Adults Daniel P. van Kammen, M.D., Ph.D. Professor of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Director of Global Clinical Research and Development, Robert Wood Johnson Pharmaceutical Research Institute, Springhouse, New Jersey. 31.17. Dopamine Receptor Antagonists (Typical Antipsychotics); 31.26. Serotonin-Dopamine Antagonists William W. Van Stone, M.D. Emeritus Clinical Associate Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Chief of Treatment Services, Mental Health and Behavioral Sciences Services, Veterans Affairs Medical Center, Washington, D.C. 51.5c. Geriatric Psychiatry: Veterans Affairs Medical Centers and Psychogeriatric Services Johan M. F. Verhulst, M.D. Associate Professor of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington. 26. Relational Problems Jeff Victoroff, M.D. Associate Professor of Clinical Neurology, University of Southern California School of Medicine, Los Angeles, California; Director of Neurobehavior, Co-Director of Geriatric Neurology Clinic, Director Near Medicine Clinic, Rancho Los Amigos Medical Center, Downey, California. 51.2b. Central Nervous System Changes With Normal Aging Michael V. Vitiello, Ph.D. Professor of Psychiatry and Behavioral Sciences, University of Washington School of Medicine; Adjunct Professor of Psychology, and Biobehavioral Nursing and Health Systems, University of Washington School of Nursing, Seattle, Washington. 51.3b. Geriatric Psychiatry: Sleep Disorders Fred R. Volkmar, M.D. Harris Associate Professor of Child Psychiatry, Pediatrics, and Psychology, Yale University School of Medicine, New Haven, Connecticut. 38. Pervasive Developmental Disorders Thomas A. Wadden, Ph.D. Professor of Psychology and Director of Weight and Eating Disorders Program, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. 25.3. Obesity Thomas A. Wehr, M.D. Chief of Clinical Psychobiology Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. 1.13. Chronobiology Daniel R. Weinberger, M.D. Chief of Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. 1.3. Developmental Neurobiology Myron F. Weiner, M.D. Professor of Psychiatry and Vice Chair, Department of Psychiatry, University of Texas Southwestern Medical School; Chief of Geropsychiatry, University of Texas Southwestern Medical Center, Dallas, Texas. 6.3. Other Psychodynamic Schools Myrna M. Weissman, Ph.D. Professor of Epidemiology in Psychiatry, Columbia University College of Physicians and Surgeons; Chief of Division of Clinical and Genetic Epidemiology, New York State Psychiatric Institute, New York, New York. 15.2. Anxiety Disorders: Epidemiology; 30.7. Interpersonal Psychotherapy Lawrence A. Welkowitz, Ph.D. Assistant Professor of Psychology, Keene State College, Keene, New Hampshire. 15.8. Anxiety Disorders: Psychological Treatments Paul H. Wender, M.D. Distinguished Professor of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah. 39.2. Adult Manifestations of Attention-Deficit Disorders Louis J. West, M.D.* Professor of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California 28.9. Nonprofessional Therapies, Quacks, and Cults Tonya Jo Hanson White, M.D. Assistant Professor of Psychiatry, University of Iowa College of Medicine; Attending Psychiatrist, Eating Disorders Clinic, University of Iowa Hospital and Clinics, Iowa City, Iowa. 49.5. Children’s Reaction to Illness and Hospitalization Robert L. Williams, M.D. Professor Emeritus of Psychiatry, Baylor College of Medicine, Houston, Texas.

21. Sleep Disorders G. Terence Wilson, Ph.D. Professor of Psychology, Rutgers University, Piscataway, New Jersey. 3.3. Learning Theory Eve J. Wiseman, M.D. Associate Professor of Psychiatry and Behavioral Sciences, University of Arkansas for Medical Sciences; Chief of Special Treatment Section, John L. McClellan Memorial Hospital, Little Rock, Arkansas. 51.3h. Geriatric Psychiatry: Drug and Alcohol Abuse Steven S. Wolf, M.D. Co-Director of Neurology Consultation Service, National Institute of Mental Health Neuroscience Center at Saint Elizabeth’s Hospital, National Institutes of Health; Director of Neurology Service, District of Columbia Commission on Mental Health Services, Washington, D.C. 2.6. Neuropsychiatric Aspects of Movement Disorders George E. Woody, M.D. Clinical Professor of Psychiatry, University of Pennsylvania School of Medicine; Chief of Substance Abuse Treatment Unit, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania. 11.5. Cannabis-Related Disorders Joseph C. Wu, M.D. Associate Professor of Psychiatry, Clinical Director of Brain Imaging Center, University of California at Irvine College of Medicine, Irvine, California. 2.13. Neuroimaging in Clinical Practice Lyman C. Wynne, M.D., Ph.D. Professor of Psychiatry Emeritus, University of Rochester School of Medicine and Dentistry, Rochester, New York. 51.4k. Interventions and Consultation With Families of Older Adults Joel Yager, M.D. Professor of Psychiatry and Vice Chair for Education, Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, New Mexico. 8. Clinical Manifestations of Psychiatric Disorders Alayne Yates, M.D. Professor of Child and Adolescent Psychiatry, University of Hawaii John A. Burns School of Medicine; Director of Division of Child and Adolescent Psychiatry, Kapi’olani Medical Center for Women and Children, Honolulu, Hawaii. 49.9. Child Psychiatry: Gender Identity and Sexual Issues William R. Yates, M.D. Professor of Psychiatry and Family Medicine, Chairman of Department of Psychiatry, University of Oklahoma College of Medicine-Tulsa, Tulsa, Oklahoma. 25.2. Gastrointestinal Disorders Kimberly A. Yonkers, M.D. Associate Professor of Psychiatry, Obstetrics, and Gynecology, University of Texas Southwestern Medical School, Dallas, Texas. 28.3. Premenstrual Dysphoric Disorder Carlos A. Zarate, Jr., M.D. Assistant Professor of Psychiatry, University of Massachusetts Medical School; Director of Bipolar and Psychotic Disorders Program, University of Massachusetts Medical Center, Worcester, Massachusetts. 31.7a. Carbamazepine Elsa M. Zayas, M.D. Instructor, Director of Geriatric Consultation, Department of Psychiatry, Director of Partial Hospitalization Program, Saint Louis University School of Medicine, Saint Louis, Missouri. 51.4g. Geriatric Psychiatry: Electroconvulsive Therapy Charles H. Zeanah, M.D. Professor of Psychiatry and Chair of Division of Child and Adolescent Psychiatry, Tulane University School of Medicine, New Orleans, Louisiana. 44.1. Reactive Attachment Disorder of Infancy and Early Childhood Sidney Zisook, M.D. Professor of Psychiatry and Director of Residency Training, University of California at San Diego School of Medicine, La Jolla, California; Attending Psychiatrist, San Diego Veterans Affairs Healthcare System, San Diego, California. 28.5. Death, Dying, and Bereavement Rebecca K. Zoltoski, Ph.D. Assistant Professor of Biological Sciences, Illinois College of Optometry, Chicago, Illinois. 1.19. Basic Science of Sleep Charles F. Zorumski, M.D. Professor of Psychiatry and Neurobiology, Washington University School of Medicine; Attending Psychiatrist, Barnes-Jewish Hospital, Saint Louis, Missouri. 1.9. Basic Electrophysiology; 31.31. Electroconvulsive Therapy Stephen R. Zukin, M.D. Director of Division of Clinical and Services Research, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland; Clinical Professor of Psychiatry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. 11.11. Phencyclidine (or Phencyclidine-like)-Related Disorders *deceased

EDITORS Benjamin J. Sadock, M.D. Menas S. Gregory Professor of Psychiatry and Vice Chairman Department of Psychiatry New York University School of Medicine Attending Psychiatrist, Tisch Hospital Attending Psychiatrist, Bellevue Hospital Center Consultant Psychiatrist, Lenox Hill Hospital New York, New York Virginia A. Sadock, M.D. Clinical Professor of Psychiatry Department of Psychiatry New York University School of Medicine Attending Psychiatrist, Tisch Hospital Attending Psychiatrist, Bellevue Hospital Center New York, New York

SENIOR CONTRIBUTING EDITOR Robert, Cancro, M.D., Med.D.Sc. Lucius N. Littauer Professor of Psychiatry and Chairman, Department of Psychiatry New York University School of Medicine Director of Department of Psychiatry, Tisch Hospital New York, New York Director of Nathan S. Kline Institute for Psychiatric Research Orangeburg, New York

CONTRIBUTING EDITORS Dennis P. Cantwell, M.D.* Joseph Campbell Professor of Child Psychiatry Department of Psychiatry and Biobehavioral Sciences University of California at Los Angeles School of Medicine Los Angeles, California Glen O. Gabbard, M.D. Bessie Walker Callaway Distinguished Professor of Psychoanalysis and Education Karl Menninger School of Psychiatry The Menninger Clinic Clinical Professor of Psychiatry University of Kansas School of Medicine Wichita, Kansas Director of Topeka Institute for Psychoanalysis Topeka, Kansas Jack A. Grebb, M.D. Clinical Professor of Psychiatry New York University School of Medicine New York, New York Lissy F. Jarvik, M.D., Ph.D. Professor Emeritus of Psychiatry and Biobehavioral Sciences University of California at Los Angeles School of Medicine Distinguished Physician (Emeritus) UCLA Neuropsychiatric Institute and Hospital Staff Psychiatrist West Los Angeles Veterans Affairs Medical Center Los Angeles, California. Joel, Yager, M.D. Professor of Psychiatry and Vice Chair for Education Department of Psychiatry University of New Mexico School of Medicine Albuquerque, New Mexico

SECTION EDITORS Hagop S. Akiskal, M.D. Professor of Psychiatry University of California at San Diego School of Medicine Director of Outpatient Psychiatric Services San Diego Veterans Affairs Healthcare System San Diego, California Jack M. Gorman, M.D. Professor of Psychiatry Columbia University College of Physicians and Surgeons New York, New York Kathleen Y. Haaland, Ph.D. Professor of Psychiatry University of New Mexico School of Medicine Staff Psychologist Veterans Affairs Medical Center Albuquerque, New Mexico Jerome H. Jaffe, M.D.

Clinical Professor of Psychiatry University of Maryland School of Medicine Baltimore, Maryland Samuel J. Keith, M.D. Professor of Psychiatry and Chairman Department of Psychiatry, University of New Mexico School of Medicine Health Sciences Center Albuquerque, New Mexico Caroly S. Pataki, M.D. Associate Clinical Professor of Psychiatry and Biobehavioral Sciences Associate Director of Training and Education for Child and Adolescent Psychiatry, University of California at Los Angeles School of Medicine Attending Psychiatrist UCLA Neuropsychiatric Institute and Hospital Los Angeles, California Gary W. Small, M.D. Professor of Psychiatry and Biobehavioral Sciences Director of Geriatric Psychiatry and Psychology Fellowship Program Director of Center on Aging University of California at Los Angeles School of Medicine Los Angeles, California Alan, Stoudemire, M.D. Professor of Psychiatry and Behavioral Sciences Emory University School of Medicine Atlanta, Georgia *deceased

PREFACE This seventh edition of Kaplan and Sadock’s Comprehensive Textbook of Psychiatry is being published on the threshold of the twenty-first century. For over 30 years it has helped educate generations of psychiatrists, other physicians, and mental health professionals from all fields—psychology, social work, and nursing, among others. Its goal has always been to foster professional competence and ensure the highest quality of care based upon humanistic and scientific principles. The textbook has earned a reputation both in the United States and around the world, as a reliable, consistent, and accurate compendium of psychiatric knowledge. We believe this millennium edition meets the high standards set by its predecessors.

EDITORSHIP The task of continuing the Comprehensive Textbook of Psychiatry without the collaboration of Harold I. Kaplan, M.D. (1927–1998), was made possible with the able assistance of Virginia A. Sadock, M.D., who was often referred to as the “unsung heroine” of this and other Kaplan and Sadock books. Her role was described in the preface of the last edition of the textbook as follows: We especially want to thank Virginia Alcott Sadock. M.D., Clinical Professor of Psychiatry and Director of Graduate Education in Human Sexuality at New York University School of Medicine. As in all our previous books, she has served as an assistant to the editors and actively participated in every editorial decision. Her enthusiasm, sensitivity, comprehension, and depth of psychiatric knowledge were of immeasurable importance to the editors. She has ably represented not only the viewpoint of women in medicine and psychiatry but has also made many contributions to the content of this textbook. We are deeply appreciative of her outstanding help and assistance. She now joins as coeditor of the Comprehensive Textbook of Psychiatry for this edition and those to follow.

TEACHING SYSTEM This textbook forms one part of a comprehensive system developed to facilitate the teaching of psychiatry and the behavioral sciences. At the head of the system is Comprehensive Textbook of Psychiatry, which is global in depth and scope. It is designed for and used by psychiatrists, behavioral scientists, and all workers in the mental health field. Kaplan and Sadock’s Synopsis of Psychiatry is a relatively brief, highly modified, original, and current version useful for medical students, psychiatric residents, practicing psychiatrists, and mental health professionals. The Concise Textbook of Clinical Psychiatry, derived from the Synopsis, emphasizes clinical psychiatry and includes extensive case studies useful for students and clinical practitioners from all fields. Another part of the system is Study Guide and Self-Examination Review for Kaplan and Sadock’s Synopsis of Psychiatry, which consists of over 1600 multiple-choice questions and answers including detailed case histories. It is designed for students of psychiatry and for clinical psychiatrists who require a review of the behavioral sciences and general psychiatry in preparation for a variety of examinations. The questions are modeled after and consistent with the format used by the United States Medical Licensing Examination. Other parts of the system are the pocket handbooks: Pocket Handbook of Clinical Psychiatry, Pocket Handbook of Psychiatric Drug Treatment, Pocket Handbook of Emergency Psychiatric Medicine, and Pocket Handbook of Primary Care Psychiatry. These books cover the diagnosis and treatment of psychiatric disorders, psychopharmacology, psychiatric emergencies, and primary care psychiatry, respectively, and are compactly designed and concisely written to be carried in the pocket of clinical clerks and practicing physicians, whatever their specialty, to provide a quick reference. Finally, Comprehensive Glossary of Psychiatry and Psychology provides simply written definitions for psychiatrists and other physicians, psychologists, students, other mental health professionals, and the general public. Taken together, these books create a multiple approach to the teaching, study, and learning of psychiatry.

CHANGES IN THIS EDITION New Contributors A tradition of inviting a certain number of new authors to write sections written by prior authors began with the second edition of the textbook. That was done for the same reasons as in other great textbooks of medicine—to ensure a fresh approach to each topic and to keep the Comprehensive Textbook of Psychiatry vital and current. Over 60 percent of the contributors to this edition are new. The editors are deeply grateful to the more than 1500 psychiatrists and behavioral scientists who contributed to previous editions, all of whom maintained the highest standards of scholarship. Many of their sections remain classics in the field and are accessible to the interested reader. We especially wish to thank John Nemiah, M.D., editor emeritus of the American Journal of Psychiatry, for agreeing to write the Introduction. He has contributed to every edition of this book since its beginning. Major Changes in This Edition Almost every chapter in this edition has been completely rewritten or revised, and many new sections have been added. Some of the major additions to the text-book and other highlights are listed below. Neural Science, Neuropsychiatry, and Behavioral Neurology A major expansion in the chapters covering neural science, neuropsychiatry, and behavioral neurology reflects the rapid advances in these fields. New sections include Developmental Neurobiology, Neurotrophic Factors, Appetite, and expanded sections on radiotracing imaging and magnetic resonance imaging. Also added to this edition are sections on Neuropsychiatric Aspects of Neuromuscular Diseases, Neuropsychiatric Aspects of Traumatic Brain Injury, Neuropsychiatric Aspects of Brain Tumors, and a special section on Psychiatric Aspects of Child Neurology. Recent advances are included in Genetic Linkage Analysis of Psychiatric Disorders, Neuropsychiatric Aspects of HIV and AIDs, and Neuropsychiatric Aspects of Other Infectious Diseases. These sections chapters were completely revised and updated. Psychological, Sociocultural, and Experimental Sciences The sections Perception and Cognition, Learning Theory, and Brain Models of Mind were extensively revised. Recent advances are included in Biology of Memory and a new section Emotional Intelligence has been added. Evolutionary Biology and Psychiatry is included in a separate section for the first time. Health Services Research and Outcomes Research in Psychiatry was added to the chapter on experimental methods, and the section Epidemiology is thoroughly updated. The chapter Theories of Personality and Psychopathology has been revised, and the section Psychoanalysis is updated to reflect changing theories in the field. Clinical Psychiatry A newly written version of Psychiatric Interview, History, and Mental Status was prepared for this edition. The section Psychiatric Report was expanded to include the medical record and third-party documentation requirements. Signs and Symptoms in Psychiatry was revised to include a glossary of psychiatric terms. A new section, Computer-Based Testing of the Psychiatric Patient, is included in this edition. Anxiety Disorders is greatly expanded with newly written sections that include Introduction and Overview, Epidemiology, Biochemical Aspects, Genetics, Psychodynamic Aspects, Clinical Features, Somatic Treatment, and Psychological Treatments. The chapter Substance-Related Disorders was expanded to include the separate sections Caffeine-Related Disorders and Nicotine-Related Disorders and a new section Anabolic-Androgenic Steroid Abuse. The treatment of depressive disorders has been enlarged to include the separate sections Psychotherapy, Treatment of Bipolar Disorders, and Treatment of Depressive Disorders. The dissociative disorders are now covered in five new sections: Dissociative Amnesia, Dissociative Fugue. Dissociative Identity Disorder (formerly called multiple personality disorder), Depersonalization Disorder, and Dissociative Disorders Not Otherwise Specified. The coverage of attention-deficit/hyperactivity disorder now includes a new section. Adult Manifestations of Attention-Deficit/Hyperactivity Disorder. Other new sections include Primary Care Psychiatry and Cults, Quacks, and Nonprofessional Therapies. A new section, Alternative and Complementary Health Practices, is included for the first time in a major psychiatric textbook. All sections dealing with clinical disorders have been thoroughly updated and follow a similar outline, which includes an introduction and definition of the disorder; a history of the disorder including comparative nosology, epidemiology, and etiology; diagnosis and clinical features; pathology and laboratory examination; differential diagnosis; and course and prognosis. Treatment strategies for all clinical disorders are presented eclectically to include biological, pharmacological, psychosocial, and psychotherapeutic approaches. The area of psychiatric treatment has been expanded with the addition of three new sections: Interpersonal Therapy. Eriksonian Clinical Theory and Psychiatric Treatment, and Combined Psychotherapy and Psychopharmacotherapy. Because of the increased importance of certification and qualifications of physicians generally, the editors included a new section. Examining Psychiatrists and Other Trainees. The chapter Ethics and Forensic Psychiatry is completely updated and a new section, World Aspects of Psychiatry, was written to reflect the fact that mental

illness is a worldwide problem that requires global solutions. A new section on Chronic Pain and the Placebo Effect is included to reflect the editors’ belief that psychiatrists be involved in the emerging clinical specialties of palliative care and pain control. In the Spring of 1999, the American Board of Psychiatry and Neurology (ABPN) and the American Board of Physical Medicine and Rehabilitation (ABPMR) joined the American Board of Anesthesiology (ABA) in recognition of pain management as an interdisciplinary subspecialty. The respective Boards have agreed on a single standard of certification. Geriatric Psychiatry The chapters on geriatric psychiatry continue to expand in each edition, and we thank Lissy Jarvik, M.D., for her extraordinary help over the years as contributing editor of this section. With the assistance of Gary Small, M.D., she helped coordinate the content of this important subspecialty. Both the editors and the field of psychiatry owe her a debt of gratitude. We especially wish to thank Dr. Small for integrating the many sections in this chapter into a coherent whole. New sections written by new contributors in geriatric psychiatry for this edition include Special Issues in Neuroimaging, Psychopharmacology: General Principles, Antidepressants and Mood Stabilizers, Antianxiety Drugs, Antipsychotic Drugs, and Antidementia Drugs. Other new sections include Psychosocial Treatment: General Principles, Cognitive Behavior Therapy, Gender Issues, and the section Health Care Delivery Systems, which includes the separate subsections Medicare and Medicaid and Managed Care. All the geropsychiatry sections were revised and updated. Child and Adolescent Psychiatry The editors owe a great debt to Dennis Cantwell, M.D. (1939–1997), who served as contributing editor to the child and adolescent psychiatry section. He was responsible for organizing and inviting the contributors to this chapter—all of whom he valued as experts in their respective fields. The editors wish to dedicate this area of the Comprehensive Textbook of Psychiatry to his memory and as a testimonial to this outstanding and much admired child psychiatrist. Dr. Cantwell had been assisted by Caroly Pataki, M.D., who was able to step into the breach to complete the work he had begun. We thank her deeply for her efforts. Many new sections covering child and adolescent psychiatry were added to this edition. New sections written by new contributors include Obsessive-Compulsive Disorder in Children, Posttraumatic Stress Disorder in Children, Short-term Psychotherapy, Cognitive and Behavioral Therapy, Family Therapy, Psychiatric Sequela of HIV and AIDS, Dissociative Disorders, Gender Identity and Sexual Issues, Adolescent Substance Abuse, Forensic Child and Adolescent Psychiatry, Ethical Issues in Child and Adolescent Psychiatry, School Consultation, Community-Based Treatments, and Psychiatric Prevention. Psychopharmacology The editors continue to use the unique format of discussing drugs used in the treatment of mental disorders on a pharmacological basis rather than under the rubric of antidepressant, antipsychotic, and the like. Thus the clinician can use a psychotherapeutic drug on the basis of its pharmacological activity, which may make it equally effective in depression, anxiety, and other disorders as well as being specific for a particular condition. A thoroughly updated section General Principles of Psychopharmacology was written for this edition, and two new sections, Drug Development and Approval and Pharmacokinetics and Drug Interactions, were added. New sections on classes of drugs with unique pharmacological properties were written, including Cholinesterase Inhibitors and Other Anticonvulsants. The most recently developed drugs are covered in detail, and all discussions of other drugs have been thoroughly updated. New Format This seventh edition uses color for the first time to highlight figures, tables, and case studies and to help differentiate the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) and fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnostic criteria. Like all Kaplan and Sadock books, this edition includes color plates of major psychiatric drugs and their various dosage forms including those recently released. This edition is heavily illustrated; photographs enhance the learning experience and keep the reader from being lost in a sea of type. Following the style of other major medical textbooks, internal literature citations were eliminated, and the number of references at the end of each section reduced. Contributors were asked to limit themselves to 30 to 40 major books, monographs, and review articles and to include current references where possible; thus some citation lists are not as long as some of the authors would have wished. In addition, 1999 references were added by the editors to alert the reader to the most current literature. Contributors were also asked to note the five most important references with an asterisk. Case histories are cited extensively to add clarity to the clinical disorders. They are derived from the DSM-IV and ICD-10 casebooks and the clinical and research experience of the contributors. We wish to thank the American Psychiatric Association (APA) and the World Health Organization (WHO) for permission to use some of their material.

DSM-IV AND ICD-10 In 1994 DSM-IV was published by the APA. DSM-IV contains the official nomenclature used by psychiatrists and other mental health professionals; thus DSM-IV terminology is used throughout the Comprehensive Textbook. In the year 2000, according to treaties between the United States and WHO, DSM-IV classifications must be identical with those used by ICD-10. Accordingly, this is the first U.S. textbook to include the definitions and diagnostic criteria of mental disorders used in ICD-10. Readers can find tables comparing the DSM-IV and ICD-10 diagnostic criteria in Chapter 10. The psychiatric disorders discussed in this textbook are consistent with the nosology in DSM-IV; however, some of our contributors maintain reservations about the changes introduced into the various editions of DSM. In several sections of the book the reader will find these objections clearly stated. DSM-IV is a diagnostic and statistical manual; it is not and never claimed to be a textbook. Unfortunately, it is used as a text by some groups, including insurance companies who believe it to be a comprehensive source of information about mental illness. As future editions of DSM appear—and the editors believe they are in the offing—the Comprehensive Textbook of Psychiatry will continue to allow room for dissent, before and especially after every new edition of the manual appears. It will continue to provide a forum for discussion, evaluation, criticism, and disagreement, while duly acknowledging the official nomenclature.

THE CONTINUING CRISIS IN THE FUTURE OF PSYCHIATRY The last edition of the Comprehensive Textbook of Psychiatry, published in 1995, included the following commentary on the crisis of the future of psychiatry. This crisis continues and is far from resolution. The introduction of the American Health Security Bill (the Clinton plan) in 1993 served as a catalyst for dramatic change in the delivery of health care in the United States even though the bill was not enacted into law. In the vanguard of change were the insurance companies and the health maintenance organizations (HMOs), which are, in the main, managed care programs run by large profit-seeking corporations. Managed care has had serious and adverse effects on the practice of psychiatry. For example, most managed mental health care (MMHC) plans restrict the number of outpatient visits for psychotherapy to a small and unpredictable number of sessions, usually 5 to 20 a year. Although some types of psychotherapy can be conducted within that framework, other types (insight oriented) require frequent visits over an extended period. Before a patient can be referred to a psychiatrist, many HMOs require that the patient see a primary care physician (the so-called gatekeeper), sometimes for several weeks; during that time, the doctor may prescribe pharmacotherapy about which he or she may have limited knowledge. Drugs, rather than psychotherapy, become the treatment of choice even though many studies have found the superior efficacy of psychotherapy used in conjunction with drugs in the treatment of most mental disorders, particularly depressive disorders and schizophrenia. Persons who are emotionally well make fewer general medical visits than do persons with emotional disorders. Providing timely psychotherapy results in savings in the overall cost of general medical care. Many HMOs require preauthorization by a panel of so-called behavioral health experts. This panel requires information about the intimate and private details of a person’s life to authorize therapy. If the patient or doctor refuses to comply, permission for psychiatric treatment is usually denied. And even if the patient is permitted to enter therapy, the psychiatrist must send frequent written reports to the HMO about the treatment, which breaches the confidentiality and trust of the doctor-patient relationship. Patients usually must be treated by psychiatrists who are enrolled in their particular HMO. They forfeit the right to see a doctor of their own choosing. In the traditional fee-for-service system patients can seek treatment from any psychiatrist they choose and can seek a second or even a third opinion if they so desire. In an HMO the patient does not have these options. Capitation, another method of payment used by HMOs, is untested in psychiatry and may mean “de-capitation” of the field. HMOs use from 15 to 30 percent of their revenues to pay for marketing, administration, and the distribution of profits to owners and investors—money that

would otherwise be available for clinical care, research, and medical education. Health care in America is being “corporatized,” and HMOs reap profits by often eliminating laboratory tests, referrals to specialists, and reducing length of hospital stay to questionable and dangerous proportions. For example, patients with major psychiatric disorders are being forced out of the hospital, often against their will and against the recommendation of their psychiatrists. HMOs also increase their profit margin by paying lower fees to doctors, and since the HMOs control the supply of patients, price control rules the system. The issue of financial liability is another area of danger to doctors who work for HMOs. Psychiatrists (and other physicians) who sign contracts with HMOs must agree to accept complete liability if any adverse effects to the patient occur during the course of treatment. Consider this example: A psychiatrist wants to hospitalize a potentially suicidal patient, but the HMO refuses to pay for hospitalization or limits the number of days allowed in the hospital to fewer than the psychiatrist deems necessary. The psychiatrist can be sued for malpractice if the patient ultimately commits suicide because of premature hospital discharge mandated by the HMO. The HMO accepts no liability for any adverse outcome based on their decisions. The only alternative is for the psychiatrist to treat the patient for no fee or for the patient to pay for treatment out-of-pocket. Neither option is satisfactory. Currently, the future of psychiatric treatment is of concern. Unfortunately, prejudice toward mental illness still exists in many quarters—political policy makers, insurance companies, the general public, and, sadly, the medical profession itself. Psychiatry and medicine are at a crossroad. It would be tragic to take the path that discards and negates the humanism that psychiatry has brought to medicine and the great advances that have been made over the past hundred years by Sigmund Freud and other great psychiatric clinicians and researchers. A new concept of medical services as market driven now dominates the health care industry and will do so for the foreseeable future. Paradoxically, the role of government must increase to regulate this new industry whose preoccupation is the cost of health care. For example, some states recently passed legislation allowing patients to sue health maintenance organizations (HMOs). Ultimately the U.S. Congress will become the arbiter between the consumers of health care (patients), the providers (physicians and other health professionals), and the payers (insurance companies and HMOs). In this sense, society and the body politic will determine the nature and quality of health care in the United States. Physicians, especially psychiatrists, have a special obligation to be informed about sociopolitical issues affecting the physical and psychological well-being of their patients. The spirit of the Hippocratic oath written over 2000 years ago continues to inspire the ethics of the medical profession: To act for the good of my patients according to my ability and my judgment. As medicine changes, physicians (and other health care professionals) are the last stronghold for humanitarian and compassionate care that stresses the inherent dignity and worth of each person.

CONTRIBUTING AND SECTION EDITORS In the preparation of this textbook we have been helped immensely by our distinguished section and contributing editors. The section editors worked closely with the authors and suggested modifications when necessary. We are deeply appreciative of their efforts. They include Hagop S. Akiskal, M.D., who covered the area of mood disorders; Jack M. Gorman, M.D., who covered anxiety disorders; Katherine A. Haaland, Ph.D., who covered neuropsychological assessment; Jerome Jaffe, M.D., who covered substance-related disorders; Samuel Keith, M.D., who covered schizophrenia and other psychotic disorders; Caroly Pataki, M.D., who covered child and adolescent disorders; Gary W. Small, M.D., who covered geriatric psychiatry; and Alan Stoudemire, M.D., who covered psychosomatic medicine. The contributing editors kept us apprised of new advances in the field and helped obtain contributors with expertise in their respective areas. We thank them for their help and cooperation. They include Glen Gabbard, M.D., who contributed to the areas of psychodynamics and psychoanalysis; Lissy Jarvik, M.D., who contributed to geriatric psychiatry; Joel Yager, M.D., who contributed to clinical psychiatric disorders; and the late Dennis Cantwell, M.D., who contributed to child and adolescent psychiatry. Our special thanks are extended to Jack Grebb, M.D., a past coauthor of Kaplan and Sadock’s Synopsis of Psychiatry who, as contributing editor, assisted us in many editorial decisions, particularly in the area of biological psychiatry. Together this admirable and distinguished group of men and women helped integrate an immense amount of material into a balanced and consistently styled work. The editors and the field of psychiatry owe them a debt of gratitude for their outstanding help.

ACKNOWLEDGMENTS In addition to our contributing and section editors mentioned above, we want to extend our appreciation to Justin Hollingsworth, who served as project editor in New York and helped us immensely. He was ably assisted by Linda Kenevich. Margaret Cuzzolino, David Abramson, and Angela Barbuscia, all of whom worked with alacrity. Our editors Anne Schwartz and Radhika Rao Gupta provided invaluable assistance. We especially want to thank our dear friend Nancy Barrett Kaplan, who gave us her complete support throughout this project. Over the years she has been an invaluable source of encouragement and understanding. Others who helped us were Norman Sussman, M.D., Victoria Sadock, M.D., James Sadock, M.D., Chris Marra, D.O., and Ben Hammer, M.D. We take this opportunity to acknowledge those who have translated this and other Kaplan and Sadock books into foreign languages. Current translations include Croatian, French, German, Greek, Indonesian, Italian, Japanese, Polish, Portuguese, Russian, Spanish, and Turkish, in addition to a special Asian and international student edition. The staff at Lippincott Williams & Wilkins was most efficient. We especially wish to thank Katey Millet, developmental editor, who was extraordinarily helpful and who has been an inspiration to us all. We also thank Susan Gay, former vice-president and publisher of Williams & Wilkins, for her encouragement and support over the years and we want to welcome Charley Mitchell. Robert Cancro, M.D., Professor and Chairman of the Department of Psychiatry at New York University School of Medicine, participated as Senior Contributing Editor of this edition. Dr. Cancro’s commitment to psychiatric education and psychiatric research is recognized throughout the world. He has been a source of great inspiration to the editors and contributed immeasurably to this and previous editions. He is a much valued and highly esteemed colleague, and it is very special privilege to work closely with him. Dr. Cancro has developed a department that represents the very best in American psychiatry. Our collaboration and association with this outstanding American educator has contributed immeasurably to the ideas and directions shaping this textbook. Finally, we want to express our deepest thanks to our contributors who were extraordinarily cooperative in every aspect of this textbook. NYU School of Medicine, New York, New York Benjamin James Sadock, M.D. Virginia Alcott Sadock, M.D.

INTRODUCTION: TWO FACES OF PSYCHIATRY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

INTRODUCTION: TWO FACES OF PSYCHIATRY JOHN C. NEMIAH, M.D.

Over 30 years have elapsed since the publication of the first edition of Comprehensive Textbook of Psychiatry (CTP-I). In comparison with its successors, it was a modest work of only some 1600 pages contained within the covers of a single volume. Equally striking is the difference in its contents from what the modern reader will find in this seventh edition of this now classic text. CTP-I, in line with the standard diagnostic manual of its day, referred to “psychiatric reactions” rather than to “disorders” and construed their causes and treatment in psychological terms. Twelve pages, for example, ere devoted to the “psychological treatment” of schizophrenia in contrast to a mere two-and-a-half to its “organic treatment.” “Serotonin” had but a single entry in the index, “dopamine” was not listed at all, and only a handful of pages were allotted to the budding clinical experience with the use of chloropromazine and the antidepressants. It needs only the most cursory glance at the pages of the latest edition to discover what dramatic changes 30 years have wrought. “Psychiatric reactions” are now full-fledged illnesses, their cause and treatment are seen as being primarily biological in nature, and psychological factors are minor actors on the clinical stage. A shift of outlook of such magnitude occurs, of course, for many reasons. It is notable, however, that similar shifts have happened before in the development of psychiatric theory and practice, and the brief account that follows of a curious chapter of psychiatric history may, therefore, give us useful insights into the nature and implications of the changes that have taken place in our own era. “The 11th of August,” wrote Frank Podmore in From Mesmer to Christian Science, should be observed as a day of humiliation in the civilised world, for on that date in 1784 a Commission, consisting of the most distinguished representatives of Science in the most distinguished capital in Europe, pronounced the rejection of a pregnant scientific discovery—a discovery possibly rivaling in permanent significance all the contributions to the physical sciences made by the two most famous members of the Commission—Lavoisier and Benjamin Franklin. The oft-told events to which Podmore alludes may be quickly recounted. In the early 1770s the Viennese physician Franz-Anton Mesmer had developed a remarkable treatment for human illness that became a highly popular therapeutic procedure among the citizens of Paris after he established a clinical practice in that ity in 1778. Indeed, so thronged was Mesmer's clinic with patients from all levels of society that a commission of inquiry was established by the authorities to examine his procedures and their results. Mesmer's explanation of the pathogenesis of human discases was based on his concept of the nature and function of what be called “animal magnetism.” There exists, he proposed, an invisble fluid spread throughout the universe with properties similar to mineral magnetism whose steady flow through the bodies of living beings sustains their healthy physiological functioning. However, as the result of a pathological blockage of that flow, a localized organ dysfunction occurs that is manifested in the symptoms of a specific bodily disease. Treatment was aimed at restoring the normal flow of the fluid by overcoming the blockage. That was accomplished by the production of a powerful surge of fluid in the patient's body by a magnetic therapist, who induced the flow of magnetic fluid by repetitious passes of his hands over the patient's thorax and abdomen. The same therapeutic effect could be produced in several patients at once by placing them in contact with the baquet, a large, circular wooden tub filled with “magnetized” water. The high drama of such a group treatment is evident in the commissioners' description of a typical clinical session in their final report. The patients are arranged in large numbers in several rows around the baquet and are exposed to the therapeutic flow of the magnetic fluid over several channels at once—by its transmission over the iron rods protruding from the baquet, by a long cord entwined around their bodies connecting the patients to one another, through the fluid's transmission to their neighbors by the mutual contact of their thumbs, and by the sounds of a piano or a pleasing voice that spreads it through the atmosphere. Patients are also magnetized directly when the magnetist passes his fingers or an iron wand over their faces, over the back or top of their heads, or over the diseased parts of their bodies. It is particularly to be noted that magnetization is produced by contact with the magnetist's hands as be applies pressure to the upper and lower abdomen for a long stretch of time, often several hours in duration. The patients present a spectacle of wide-ranging conditions and behavior. Some are calm and tranquil and have no untoward sensations. Other are coughing and spitting, or suffer from mild pains and complain of localized or generalized burning accompanied by bouts of sweating. Yet others are agitated and wracked by convulsions that are notable for their frequency, duration, and violence. Moreover, when one patient has a convulsion, many others follow suit. The Commissioners have witnessed some seizures that lasted more than three hours and were accompanied by the violent expectoration of a foul, viscous fluid, sometimes flecked with blood. The convulsions are further characterized by precipitous involuntary movements of all the limbs and the entire body, by a construction of the throat, by spasmodic jerks in the hypochondrium and the epigastric region, by a dimming and clouding of vision, by piercing shrieks, tears and hiccoughs, and by immoderate laughter. All of these events are preceded or followed by a state of languor, dreaminess, and prostration, and even by drowsiness. After extensive observations of these remarkable phenomena the commissioners proceeded to investigate the nature of the animal magnetism alleged to be their cause. In a series of clever experiments, whose design might well be admired by modern investigators, they determined conclusively that there was no evidence whatsoever for the existence of a magnetic fluid, and that the dramatic, often wildly violent behavior attributed to it was entirely due to the effect of imagination and imitation on suggestible patients in a group setting. The commissioners in the concluding paragraph of their report wrote. We have determined that the magnetic fluid cannot be detected by any of the five senses and that it has no effect whatsoever either on the Commissioners themselves or on the patients they exposed to it. They have ascertained that the practice of compressing or touching the body brings about changes that are rarely favorable and arouses excitations of the imagination that are invariably vexatious. Finally, they have demonstrated by definitive experiments that imagination without magnetism produces convulsions and that magnetism without imagination produces nothing. Therefore, the Commissioners have unanimously concluded regarding the question of the existence and the effectiveness of animal magnetism that there is no evidence whatsoever of a magnetic fluid and that such a non-existent fluid is consequently without useful effect. They have further determined that the observable violent results of public treatment are the product of touching, of an aroused imagination, and of an instinctive tendency automatically to imitate whatever strongly impresses the senses. At the same time, the Commissioners feel obliged to add the important observation that the practice of touching and the repetitious arousal of the imagination designed to bring on the magnetic crisis can be injurious. Furthermore, the public spectacle of these crises is equally dangerous because of that element of imitativeness that nature appears to have designed as a basic law. As a consequence, public treatment employing magnetism can in the long run have only disastrous effects. Such, then, were the commissioners' conclusions and recommendations to which Podmore took such vigorous objection. It was not so much their denial of the existence of Mesmer's magnetic fluid that troubled him as the fact that having recognized the central importance of imagination and suggestion in producing the therapeutic convulsions (and the cures that frequently followed them), the commissioners then proceeded to dismiss magnetic phenomena as being the result of mere imagination and to condemn treatment as harmful. Mesmer's magnetic fluid, Podmore agreed, was a chimera and Mesmer . . . perhaps three parts a charlatan, [but] his claim to our remembrance lies in this—that he wrested the privilege of healing from the Churches and gave it to mankind as a universal possession. In rejecting that gift for themselves and their successors to the third and fourth generation, Bailly and his colleagues rejected more than they knew. If Podmore's charges against the commissioners are perhaps a bit overblown, he does point to an arresting fact: Having skillfully demonstrated the fallacy of Mesmer's hypothesis of a physical magnetic fluid, the commissioners perceptively recognized the psychological basis for the patients' dramatic response to magnetic procedures and for the significant number of genuine cures that resulted from their application. But having made that discovery, far from being intrigued by such a remarkable finding and advising its further exploration, they dismissed it as not only being nugatory but as resulting in dangerous clinical practices that should be

curtailed. The conclusions of the commissioners' report seem to have had little or no effect on the continued development of animal magnetism. Indeed, although the French Revolution temporarily slowed its progress, it became a vigorous movement throughout France in the early decades of the nineteenth century, spread beyond French borders to the rest of the Continent, crossed the Channel to England, and ultimately reached the United States. The large number of individuals engaged in the clinical application of animal magnetism (or “mesmerism,” as it came to be called) ignored the commissioners' evidence against the existence of a magnetic fluid and held fast to Mesmer's mechanistic view that it was the active agent in the response to magnetic treatment. The discovery in 1785 by the Marquis de Puységur of the phenomenon of somnambulistic trance (which thereafter replaced seizures as the primary response to magnetic passes) did not alter adherence to the fluidic hypothesis. Nor was it in any way modified by the proposal of Alexandre Bertrand in the 1820s that the magnetic fluid was indeed nonexistent and that the effects of mesmeric treatment were entirely due to the psychological agency of suggestion. Not until the 1840s did the first serious challenge to the fluidic hypothesis arise. In the late autumn of 1841 James Braid, an English surgeon in Manchester, attended a public demonstration of magnetism by the traveling French mesmerist, Charles Lafontaine. Impressed, despite his initial skepticism, by what he observed, Braid embarked upon a series of mesmeric experiments of his own. In the course of these he ultimately discovered that he could produce all the phenomena of mesmeric trance by merely arousing the idea of them in his subjects' minds. Hypnosis (as Braid termed it) was, he proposed, a process arising entirely within the hypnotic subject and set in motion by the hypnotist's verbal instructions. Braid's procedures made it clear that neither a magnetic fluid nor any other external physical agency was responsible for the observed phenomena, but that they resulted from those very psychological agencies of suggestion and imagination that had been so vigorously belittled and rejected by the French commission a half-century earlier. Although Braid's studies made no immediate impact on his English colleagues, by a curious turn of fate his ideas returned across the Channel to France where they caught the attention of the French physician Eugene Azam. Azam is perhaps best remembered for his description of the phenomenon of “double consciousness” in his famous patient, Félida X, but he was also notable for the fact that, as Charcot wrote, “he was the first person in France to verify Braid's findings by his own experiments.” Indeed, Azam's publication in 1860 of a description of Braid's hypnotic experiments helped set the stage for three important developments in France during the ensuing decade. 1. Charcot's major interest in the nature and clinical application of hypnosis, which led to its extensive use at the Salpêtriàre in Paris, gave the subject a legitimacy it had not had before. From being a phenomenon viewed by most of the orthodox scientific and medical world as mere quackery, if not outrightly fraudulent, with the blessing of a person of Charcot's academic and scientific reputation it became for the first time in its history a sanctioned procedure worthy of clinical application and serious study. The major thrust of Charcot's research was aimed at the clinical application of hypnosis to patients with major hysterical disorders. In this context, he came to the conclusion that hypnosis and hysteria were closely related phenomena whose manifestations were the result of poorly defined pathological processes in the central nervous system. Charcot, that is, held to a physical rather than a psychological view of the hypnotic process. 2. At the same time that Charcot's studies were under way in Paris, Hippolyte Bernheim in Nancy had joined with Ambroise Liábeault, a general practitioner in the neighboring countryside, in a study of the medical uses of therapeutic hypnotism. Influence by their reading of Bertrand and Braid. Liábeault and Bernheim advanced the hypothesis that the basic factor in the production of hypnotic phenomena was the subject's psychological state of suggestibility. Suggestibility, they held, was an entirely normal trait that was to be found to a greater or lesser degree in the vast majority of human beings; and it was, furthermore, the primary agency in affecting cures by hypnotic therapy. It is evident from the nature of their views that Liábeault and Bernheim, and the so-called Nancy School that gathered around them, were completely at odds with Charcot and the “Salpêtriàre School” with regard to every aspect of therapeutic hypnosis. Nor is it surprising that a protracted controversy raged between them, ultimately to be settled in favor of Bernheim and his colleagues. 3. Although Pierre Janet came from a background of philosophical rather than medical studies, it is evident that he was thoroughly familiar with the literature of clinical hypnosis. “M. Despine,” he wrote in 1889 in his first major publication. L'Automatisma Psychologioue, has maintained that psychology has no application whatsoever to somnambulism and that it can be explained only by physiology. In fact, far from explaining it, it cannot even be defined in physiological terms. Many authors, such as Bertrand and Braid, and more recently Gurney and Bernheim, have distinguished themselves by having recognized that somnambulism is a psychological phenomenon and can be defined only by its uniquely psychological characteristics. It was with this intellectual background and predilection for psychological concepts that in the early 1880s Janet embarked on the hypnotic investigation of hysterical patients that led to his important discovery of psychological dissociation and psychological automatism—a discovery that led him to formulate the psychological explanation of hysterical symptoms as originating from dissociated traumatic memories and to his use of hypnotic suggestion in their treatment. Almost simultaneously with Janet, Sigmund Freud, stimulated by his observations of Charcot's work at the Salpêtriàre and Bernheim's practice in Nancy, began his own investigation of hysterical patients in conjunction with Josef Breuer. Like Janet (with whose early studies he was familiar) Freud focused his attention on the role of unconscious traumatic memories in the production of hysterical symptoms. He went beyond Janet, however, in pointing to the important psychogenic role of the unconscious painful feelings associated with the traumatic memories and the necessity for their conscious expression in the course of therapy. With these original formulations Freud laid the groundwork for the concepts of psychological conflict and psychic structure that became the hallmark of psychoanalytic theory and practice. While Janet and Freud were thus pursuing the medical aspects of dissociation and hypnosis, a less well known group of lay investigators, working in London under the aegis of the recently created Society for Psychical Research, were studying the nature and extent of hypnotic and dissociative phenomena in normal subjects. Particularly prominent among these investigators was Frederic W. H. Myers, one of the first of their contemporaries to recognize and publicize the significance of Freud's and Janet's early findings. Myers's own investigations led him to a demonstration of the presence of dissociative elements in a variety of unusual but not necessarily pathological phenomena, such as artistic creation, nonpsychotic hallucinations, automatic writing, medium trance-states, and spirit possession. His postulate of a “subliminal mind” expanded the scope and meaning of the process of dissociation far beyond the narrower pathological concept of clinical investigators. So impressed was William James by Myers's contributions that (as he wrote in a eulogy published after Myers's death in 1901) he “was disposed to think it a probability that Frederic Myers will always be remembered in psychology as the pioneer who staked out a vast tract of mental wilderness and planted the flag of genuine science upon it.” James himself, of course, was a major player in the explorations of the reaches of the mind, and his The Varieties of Religious Experience remains a classic contribution to the psychology of religion. His profound interest in and commitment to the development of depth-psychology is evident throughout his writings. As he commented in the volume just mentioned, I cannot but think that the most important step forward that has occurred in psychology since I have been a student of that science is the discovery . . . that, in certain subjects at least, there is not only the consciousness of the ordinary field . . . but an addition thereto in the shape of a set of memories, thoughts, and feelings which are extra-marginal and outside of the primary consciousness altogether. . . . I call this the most important step forward because, unlike the other advances which psychology has made, this discovery has revealed to us an entirely unsuspected peculiarity in the constitution of human nature. It is evident that as it evolved 100 years ago the study of psychology, both normal and abnormal, was satisfying, rewarding, and stimulating for those engaged in it. Moreover, they were optimistic about its future and looked forward confidently to further explorations and major discoveries in the still uncharted land of the unconscious. As the philosopher Henri Bergson wrote at the dawn of the twentieth century, To explore the most sacred depths of the unconscious, to labor in . . . the subsoil of consciousness, that will be the principal task of psychology in the century which is opening. I do not doubt that wonderful discoveries await it, as important perhaps as have been in the preceding centuries the discoveries of the physical and natural sciences. Brave words! Bold predictions! And yet how widely off the mark they appear in the face of modern developments in psychiatry, especially on the North American continent as it approaches the new millennium. Our current major emphasis on the biological, neurological, and phenomenological aspects of psychiatric disorders is a far cry from the prominent concern with their psychological attributes among investigators 100 years ago. The briefest perusal of our contemporary psychiatric literature will readily indicate the extent of that difference. The space current major psychiatric publications allot to the elucidation of the unconscious, of psychological conflict, and of psychodynamic processes is miniscule compared with that devoted to the description of psychiatric syndromes and their neurobiological underpinnings. It is clear that there have been major changes in the conception of psychiatric illness over the course of the century now ending—changes whose

details are within the memory of many living psychiatrists and need be only briefly reviewed. From the earlist years of the twentieth century. American psychiatry was significantly guided by two major influences—the psychobiological concepts of Adolf Meyer and the psychoanalytic theories of Freud. Both strongly underscored the vital importance of including psychosocial factors in the clinical understanding and treatment of psychiatric illnesses. The intellectual stimulation and the therapeutic optimism aroused by that humanistic approach brought psychiatrists away from their isolation in asylums for the insane back into the mainstream of medicine. By midcentury, the number of physicians choosing the practice of psychiatry was beginning to swell; general hospitals throughout the country were opening psychiatric inpatient units and outpatient clinics, and under the banners of “psychosomatic medicine” and “consultation-liaison psychiatry,” psychiatric clinicians and investigators were applying their psychological knowledge and procedures beyond the realm of psychiatric disorders to an exploration of the psychosocial aspects of the conventional medical and surgical illnesses as well. At the height of this movement. Carl Binger, for many years the editor-in-chief of the journal Psychosomatic Medicine, wrote in The Two Face of Medicine, The principal contribution of psychiatry to medicine lies in its humanizing influence. It has kept man himself as the center of its concern rather than his enzymes or the chains of proteins of which he is composed. It has thus far managed to escape the automation that threatens to swallow up clinical medicine. . . . Our view is the holistic view. . . . We are less preoccupied with machine processed data than are those in other medical disciplines. The unprocessed reality of our world is . . . the human animal in his [inner] environment . . . which we approach through a study of personality. This latter has become of paramount importance not only for psychiatry but in the management of all sick people. Binger's comments should make starkly clear the magnitude of the revolution that has occurred in the three decades since their utterance. The scientific advances in the knowledge of brain structure and function that have been achieved since that time, the development of effective psychopharmacotherapeutic agents, and the radical revision of the concept of psychiatric disorders and their diagnosis have now to a large degree supplanted attention to the clinical applications of psychodynamic understanding. However, no matter how strongly the biological view of psychiatric disease dominates the current scene, it constitutes only a cross-sectional view of a more extended historical process. A look backward over the past 200 years reveals an interesting pattern in the evolution of ideas about mind and body and their role in the production of illness. Mesmer, of course, was not aware that his animal magnetism and the conditions he treated with it would evolve into the modern discipline of psychiatry. Indeed, he viewed his procedure as a contribution to the general practice of medicine and ascribed the therapeutic effect of his magnetic treatment to the direct mechanical action of a physical magnetic fluid on the patient's bodily organs. His materialistic hypothesis persisted as the accepted view for some 70 years until it was at last superseded by the psychological hypothesis of suggestion that emerged from the experiments and writings of James Braid. As the discipline of psychiatry gradually crystallized from those early clinical studies, it was dominated by psychological theories in one form or another for nearly a century until they were replaced by the biological hypotheses now in the ascendancy. A historical perspective, in other words, reveals a curious alternation between psychological and biological explanations of illness. History, moreover, makes evident the fact that although one outlook may be dominant, it is not necessarily exclusive. On the contrary, its obverse is always to be found in a small but devoted minority. Indeed, throughout the two centuries that began with Mesmer, whatever the prevailing theoretical view of psychiatric illness, there has been, as Stanley Jackson has demonstrated, a constant demand for psychological understanding and treatment, while at the same time the quest for biological knowledge has continued at a steady pace. History shows as well that there has always been a degree of antagonism between the proponents of the psychological and the biological view of psychiatric phenomena. The reasons for this seeming incompatibility are not entirely clear, but perhaps it has something to do with differences in human temperament. As Samuel Taylor Coleridge long ago suggested, each of us is born either an Aristotelian or a Platonist—each of us, that is, inherently prefers either to limit knowledge to what is ascertainable by the five senses alone or to include within its compass the psychological insights derived from introspection, intuition, and inspiration. Thus, among psychiatrists, there are those who would restrict the understanding of psychiatric disease to their biological aspects alone and those who would include their intangible, but no less real, psychological components as well. The inherent tendency toward misunderstanding and antagonism between the proponents of these separate views hardly gives logical grounds for concluding that the concepts and practical clinical procedures associated with each are mutually exclusive, or even incompatible. On the contrary, biological and psychological knowledge each have vital contributions to make to the understanding and treatment of psychiatric disease. To borrow Binger's metaphor, they are the two faces of psychiatry, and both are essential for the fullest development of psychiatry as a discipline. That is not to say, however, that any one individual can become completely familiar with both of these basic pathways to knowledge. A mere glance at the overwhelming wealth of information contained in this new edition of CTP demonstrates the impossibility of that feat. Instead of straining after the unattainable, each of us must choose that portion of the whole that is of most interest and master that more limited domain. At the same time, we must move outside our own parochial perceptions and predilections to a genuine understanding and appreciation of the pursuits of those who are following different pathways from our own. It is a major virtue of the volumes in hand that they greatly facilitate that task. The various contributors to their pages have delineated aspects of one or the other of the two faces of psychiatry with a clarity and precision that will enable their readers to achieve a broader vision of the nature and treatment of psychiatric disorders. Therein lies the basis for the ultimate integration of our knowledge of body and mind.

SUGGESTED CROSS-REFERENCES The neural sciences are discussed in Chapter 1, neuropsychiatry in Chapter 2, and biological therapies in Chapter 3. Psychoanalytic theories and other psychological theories are covered in Chapter 6, and psychological therapies are covered in Chapter 30. The history and future of psychiatry is discussed in Chapter 55. CHAPTER REFERENCES Azam E: Hypnotisme at Double Conscience. Félix Alcan, Paris. 1893. Bailly J: Rapport des commissaires chargés par le roi de l'examen du magnétisme animal. Imprimerie Royale, Paris, 1784. Bergson H: Dreams. Huebsch, New York, 1914. Bertrand A: Du Magnétisme Animal en France. Bailliàre. Paris. 1826. *Binger C: The Two Faces of Medicine. Norton. New York, 1967. Coleridge S: Table Talk. Oxford University Press, London, 1917. *Jackson S: Care of the Psyche. Yale University Press, New Haven, 1999. James W: Frederic Myers's service to psychology. Proc Soc Psychical Res 17:13, 1901–1903. *James W: The Varieties of Religious Experience. Longmans, Green, New York, 1903. Janet P: L'Automatisme Psychologique. Félix Alcan, Paris. 1889. Mesmer F-A: Le Magnétisme Animal (R Amadou, editor). Payot, Paris, 1971. *Myers W: Human Personality. Longmans, Green, London, 1903. *Podmore F: From Mesmer to Christian Science. University Books, New Hyde Park, NY, 1963.

Textbook of Psychiatry

DRUGS USED IN PSYCHIATRY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

DRUGS USED IN PSYCHIATRY This guide contains color reproductions of some commonly prescribed major psychotherapeutic drugs. This guide mainly illustrates tablets and capsules. A † symbol preceding the name of the drug indicates that other doses are available. Check directly with the manufacturer. ( Although the photos are intended as accurate reproductions of the drug, this guide should be used only as a quick identification aid.)

Textbook of Psychiatry

COLOR PLATES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

COLOR PLATES

FIGURE 1.15–4 SPECT images of the distribution of [ 123I]b-CIT (cocaine-iodo-tropane) in a healthy subject and a patient with Parkinson's disease. [ 123I]b-CIT is a radiolabeled cocaine analogue and is a probe of dopamine transporters in the striatum. These transporters are located presynaptically on terminals of dopamine neurons projecting from the substantia nigra to the striatum. These transverse images show a high density of dopamine transporters in striatum and a marked reduction of these sites in an age- and sex-matched patient with idiopathic Parkinson's disease. The transporters are lost because the entire dopaminergic neuron, including its terminal projections in the striatum, degenerate in this disorder. (Courtesy of John Seibyl, Yale University.)

FIGURE 1.16–6 fMRI studies of photic stimulation. A, Change in image signal intensity in a single pixel during four alternating, 30-second epochs of flash photic stimulation. B, Activation maps demonstrating statistically significant increases in image signal intensity in primary visual cortex. Image data is acquired with a surface coil placed at the back of the head, thus explaining the decrease in image intensity with increasing distance from the occipital pole of the head. (Courtesy of Jonathan M. Levin, M.D., and Luis C. Maas.)

FIGURE 2.6–2 Regional cerebral blood flow, visualized with Technetium-99m HMPAO ( left panel), and dopamine D2-receptor binding, visualized with 123I-iodobenzamide (I-123 BZM) (right panel), in a patient with hemiparkinsonism. Individuals with Parkinson's disease may present with markedly asymmetric symptoms. In this case, I-123 BZM uptake is markedly increased in the basal ganglia contralateral to the affected limb, whereas blood flow is unaffected. The increased uptake reflects increased D 2-receptor availability, either because of receptor upregulation or depletion of competing dopamine for the D 2 sites. (Courtesy of Michael Knable, D.O., and Daniel R. Weinberger, M.D.)

FIGURE 2.9–1 Transverse views obtained with Technetium-99m HMPAO SPECT. The two views on the left are of the brain of an adolescent with Lyme encephalopathy and demonstrate moderate heterogeneous hypoperfusion. The views on the right are of the brain of an adolescent without encephalopathy and demonstrate a normally perfused scan. The color spectrum scale, from purple to white, represents low to normal perfusion.

FIGURE 2.13–2 Three-dimensional PET FDG images demonstrate markedly lower glucose metabolism in temporoparietal region in patient with Alzheimer's disease than in normal control.

FIGURE 2.13–3 Transaxial section of PET FDG demonstrates hypermetabolism in striatum in patient with Parkinson's disease compared with normal control average image.

FIGURE 2.13–4 Stroke. Left side surface view shows marked decreased left frontal, temporal, and parietal lobe. (Note: SPECT cortical surface images are rendered by setting the threshold at 55%, looking at most active 45% of brain activity; SPECT active images are rendered by setting blue color threshold set at 55%, looking at average brain activity in the brain compared to red [or white] threshold set at 85%, looking at the most active 15% of brain activity.)

FIGURE 2.13–5 Two right hemisphere strokes with depression as presenting symptom. Top-down surface view shows marked decreased right frontal, temporal, and parietal lobe.

FIGURE 2.13–6 Three-dimensional PET FDG images demonstrate lower orbitofrontal metabolism in orbital frontal lobe syndrome in patient secondary to traumatic brain injury than in normal control.

FIGURE 2.13–7 Three-dimensional PET FDG image demonstrate hypermetabolism in region of brain tumor in frontal cortex and decreased metabolism in parietal cortex secondary to postradiation injury.

FIGURE 3.4–2 A schematic diagram of the circuitry of the mammalian cerebellum (top). In the classically conditioned blink response, input from the air-puff unconditioned stimulus and input from the auditory conditioned stimulus comes in through parallel pathways to the cerebellar cortex and to the deep cerebellar nucleus, and plasticity occurs in both pathways ( bottom). (Reprinted with permission from Raymond JL, Lisberger SG, Mauk MD: The cerebellum: A neuronal learning machine? Science 272:1126, 1996. ©1996 American Association for the Advancement of Science.)

FIGURE 3.4–5 PET and MRI scans in a patient with Korsakoff's syndrome. Neural dysfunction was evident as reduced glucose utilization in multiple cortical regions in the frontal and parietal lobes, and in the cingulate. Functional neuroimaging can reveal brain dysfunction that might otherwise not be evident if limited to structural neuroimaging results. In Korsakoff's syndrome, the memory impairment probably reflects a disruption of thalamocortical circuitry. (Reprinted with permission from Paller KA, Acharya A, Richardson BC, Plaisant O, Shimamura AP, Reed BR, Jagust WJ: Functional neuroimaging of cortical dysfunction in alcoholic Korsakoff's syndrome. J Cogn Neurosci 9:277, 1997.)

FIGURE 3.4–9 PET activations superimposed over averaged transverse MRI scans with the distance shown representing the distance from the line connecting the anterior and posterior commissure. Words were studied under strong or weak learning conditions (high recall or low recall) and then both declarative memory (cued recall) and nondeclarative memory (priming) were tested. The Baseline minus Priming subtraction showed an area of decreased blood flow (green) in right visual association cortex thought to be related to the greater ease of processing primed words. The Low Recall minus Baseline subtraction showed an area of increased blood flow (yellow) in secondary visual cortex and left prefrontal cortex thought to be related to the effort involved in deliberate, effortful retrieval. The High Recall minus Baseline subtraction showed a region of increased blood flow (red) in bilateral hippocampal regions thought to be related to successful retrieval of recently acquired information. (Reprinted with permission from Schacter DL, Alpert NM, Savage CR, Rauch SL, Albert MS: Conscious recollection and the human hippocampal formation: Evidence from positron emission tomography. Proc Natl Acad Sci USA 93:321, 1996. ©1996 National Academy of Sciences, U.S.A.)

FIGURE 3.4–10 Brain potentials showing a differential response based on the extent to which subjects engaged in recollection following word presentations. Potentials shown at the left were recorded from a frontal scalp electrode. Measurements from multiple electrodes over the 400- to 800-ms latency range were used to

generate the topographical map at the right, showing that the neural correlate of recollection was broadly distributed across the scalp, with largest responses over frontal cortex. (Adapted with permission from Paller KA, Kutas M: Brain potentials during memory retrieval provide neurophysiological support for the distinction between conscious recollection and priming. J Cogn Neurosci 4:375, 1992.)

FIGURE 11.7–3 Illustrative cases of quantitative EEG abnormalities in hallucinogen persisting perception disorder (flashback). Patient 1: A 26-year-old computer programmer used LSD at the age of 18 on 15 occasions; 31 months later the patient experienced the abrupt onset of intense, LSD-like set of visual and affective disturbances lasting all night. At 25 he suffered the spontaneous onset of hourly flashing white lights centrally and black dots in his peripheral fields, which have continued for the past 10 years. Topographic brain maps are shown during the 380–420 msec epoch of the visually evoked potential in row A. The upper left map represents the subject's data. The upper middle map shows control subjects for the same poststimulus latency epoch. The right upper image is a significance probability map (SPM) showing Z-scores resulting from a comparison of the data from the left and middle upper maps. The patient shows an enhancement in the visually evoked signal involving both temporal regions of the cerebrum. Patient 2: A 23-year-old musician used LSD on 16 occasions over a 4-month period at the age of 20. Within 2 months he began to notice a progressive, continuous visual disorder characterized by flashes of color, persisting afterimages, haloes around objects, a grainy texture to the sky, and the lingering trails of objects as they passed through his visual field. The graininess in the visual field interfered with night vision. Topographic brain mapping is illustrated during the 260–300 msec epoch of auditory evoked potentials in row B. Note the region of reduced electrical activity in the left posterior temporal region in the lower right map. (Reprinted with permission from Abraham HD, Duffy FH: Stable quantitative EEG difference in post-LSD visual disorder by split-half analysis: Evidence for disinhibition. Psychiatry Res 67:173, 1996.)

FIGURE 12.1–1 Axial sections demonstrating brain areas with significantly increased activity during auditory verbal hallucinations in the group study. Functional PET results (threshold at Z > 3.09, P < 0.001, by reference to the unit normal distribution) are displayed in color, superimposed upon a single structural T1-weighted magnetic resonance imaging (MRI) scan that has been transformed into the Talairach space for anatomical reference. Section numbers refer to the distance from the anterior commissure-posterior commissure line, with positive numbers being superior to the line. The areas of activation extend into the amygdala bilaterally, and into the right orbitofrontal cortex. Although these regions of extension are consistent with the limbic paralimbic component of activity during hallucinations, and may contribute to drive and affect in this context, definitive statements cannot be made in the absence of discrete maxima. (Reprinted with permission from Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, et al: A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:1769, 1995.)

FIGURE 12.1–2 There is a significant difference in O 15 activity in the prefrontal and parietal cortex during the performance of an auditory discrimination task in deficit and nondeficit patients, with deficit patients having decreased activity in these regions. (Courtesy of A. Lahti, Maryland Psychiatric Research Center, Baltimore, MD.)

FIGURE 12.3–6 Illustration of functional imaging data obtained in healthy people: A, sex differences in local glucose metabolism; B, activation with verbal and spatial tasks as seen by functional MRI.

FIGURE 12.4–2 PET scans using H 2O15 of two monozygotic twins, one with (right) and one without (left) schizophrenia. Top and bottom scans show two levels through the dorsolateral prefrontal cortex. At the time of scanning, subjects are performing a cognitive task that typically requires prefrontal cortical function. The affected twin blood flow to the dorsolateral prefrontal cortex is markedly reduced compared to the unaffected twin. (Courtesy of R. Berman and D. Weinberger.)

FIGURE 25.8–2 Woman with lupus erythematosus malar rash. (Courtesy of M. Kevin O'Connor, M.D.)

FIGURE 30.3–1 Model of the shift from normal to hypnotic attention. Hypnosis involves narrowing the focus of attention, with concomitant increases in dissociation of thoughts, perceptions, and feelings at the periphery and increased suggestibility.

FIGURE 30.3–2 Brain electrical activity mapping of visual event-related potentials comparing the effects of selective inattention to a visual stimulus (attending to the other visual hemifield) and hypnotically hallucinating an obstruction to that stimulus. Selective inattention involves increased amplitude anteriorly, while hypnotic hallucination produces decreased amplitude in the occipital cortex.

FIGURE 49.4–1 Child maltreatment is frequently manifested by bruises, burns, and other skin lesions. The diagnostic problem is that abusive injuries may be mistaken for medical conditions and vice versa. A, Physical abuse, a cigarette burn on the sole of the foot of a 5-month-old infant. B, A swimming pool granuloma overlying an interphalangeal joint. C, Tinea corporis. D, Clark's nevus, a benign, common acquired nevus. [Reprinted with permission from Reece RM: Child Abuse: Medical Diagnosis and Management. Lea & Febiger, Philadelphia, 1994 (A); Caputo R: Pediatric Dermatology and Dermatopathology, vol 4. Williams & Wilkins, Baltimore, 1996 (B); Caputo R: Pediatric Dermatology and Dermatopathology, vol 2. Lea & Febiger, Philadelphia, 1993 (C); Caputo R: Pediatric Dermatology and Dermatopathology, Lea & Febiger, Philadelphia, 1990 (D).]

FIGURE 49.4–2 These linear skin lesions illustrate both child maltreatment and other conditions not related to abuse. A, Physical abuse, superficial ulcers caused by applying sandpaper to a child's skin. B, A series of insect bites distributed in a linear fashion, indicating that a single insect took bites in sequence. C, Common warts that are linear because lesions are induced when old lesions are scratched. [Reprinted with permission from Caputo R: Pediatric Dermatology and Dermatopathology, vol 2. Lea & Febiger, Philadelphia, 1993 (A); Caputo R: Pediatric Dermatology and Dermatopathology, vol 4. Williams & Wilkins, Baltimore, 1996 ( B and C).]

Textbook of Psychiatry

1.1 NEURAL SCIENCES: INTRODUCTION AND OVERVIEW Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.1 NEURAL SCIENCES: INTRODUCTION AND OVERVIEW JACK A. GREBB, M.D. Neuroanatomy Neurotransmitters Signal Transduction and Molecular Genetics Integration and Time Imaging Brain Function Applied Genetics Sleep and Appetite Suggested Cross-References

The first two chapters of this textbook—Neural Sciences and Neuropsychiatry and Behavioral Neurology—provide the reader a very complete primer and reference resource on the biological basis of normal behaviors and mental illnesses. Both chapters focus on the human brain, which is the biological substrate for all of our emotions, cognitive abilities, and behaviors—that is, everything we feel, think, and do. This chapter describes the basic biology of the brain and presents information on the interactive systems within the brain, the imaging of brain function, and the genetics of mental illnesses. Chapter 2, Neuropsychiatry and Behavioral Neurology, focuses on the neuropsychiatric aspects of the more classical neurological diseases, the study of which provides valuable information regarding how identified lesions in the nervous system are associated with disorders of affect, cognition, and behavior.

NEUROANATOMY Functional neuroanatomy (discussed in Section 1.2) is the study of interacting and interdependent neurons, groups of neurons (e.g., nuclei), and brain regions. The three neural systems of most interest in psychiatry are the thalamocortical system, the basal ganglia, and the limbic system. In the 1970s, the thalamus was a focus of psychiatric research; however, the thalamus and its interactions with the cerebral cortex have primary importance in the sensory, motor, and associative functions of the brain. Moreover, the thalamus and its interactions with the cerebellar cortex are now known to be involved in cognition. The basal ganglia, once thought of only as part of the motor system, is now known to be a complex system within itself, and plays a key role in the cognitive functions of the brain. In contrast to the thalamus and basal ganglia, the limbic system has long been associated with psychiatric symptoms because of its clear involvement in the experience and expression of emotions. The rapidly expanding understanding of the adult human brain in recent years has allowed more questions to be asked about the developing human brain ( Section 1.3). Because psychiatric disorders that become symptomatic only in adulthood may be caused by genetic or environmental events that occur during conception or early in development, the study of human brain development has the potential to provide neurobehavioral scientists with a breakthrough in understanding mental illnesses.

NEUROTRANSMITTERS There are four broad classes of neurotransmitter and neuromodulator substances in the brain: monoamines, amino acids, peptide neurotransmitters, and the much more recently discovered neurotrophins (also known as neurotrophic factors). Two additional neurotransmitters that do not fit into these four major classes are the gas nitric oxide and the purine-related neurotransmitters adenosine and adenosine triphosphate (ATP). Any single neuron can release multiple different types of neurotransmitters or neuromodulators, and also have receptors for multiple different receptor types and subtypes, thus making each individual neuron capable of exquisite integration and modulation of incoming and outgoing signals. There are five classic monoamine neurotransmitters, which are serotonin, the three catecholamines (epinephrine, norepinephrine, and dopamine), acetylcholine, and histamine ( Section 1.4). The monoamine neurotransmitters, although present in only a small percentage of neurons localized in small nuclei of the brain, have enormous impact on total brain functioning because the diffuse projections of axons from these monoaminergic neurons can affect virtually every brain region. In contrast to the monoamine neurotransmitters, the amino acid neurotransmitters are widely distributed in the brain, and it is possible to conceptualize the brain as reflecting the balance between the excitatory amino acid glutamate, and the inhibitory amino acid g-aminobutyric acid (GABA) (Section 1.5). In contrast to the relatively small number of different monoamine and amino acid neurotransmitters, over one hundred different neuropeptide neurotransmitters have already been identified ( Section 1.6). Because virtually all existing drugs for psychiatric conditions act through monoamine or amino acid neurotransmitter systems, the development of drugs that would have specific agonist or antagonist properties on neuropeptide systems offers great hopes for the development of new pharmacological treatments. The first neurotrophic factor, nerve growth factor (NGF), was discovered by the Nobel Prize laureate, Rita Levi-Montalcini. The neurotrophic factors are polypeptides (i.e., proteins), and thus have the same basic structure as the neuropeptide neurotransmitters. Less is known about neurotrophic factors than about the more classic neurotransmitter substances, but neurotrophic factors can be conceptualized as differing from neuropeptide neurotransmitters in having longer-term regulatory functions (Section 1.7). The identification of additional neurotrophic factors and neurotrophic factor receptors provides researchers with many new hypotheses for disease etiologies and new hopes for disease interventions. Clinical trials of specific neurotrophic factors (e.g., brain-derived neurotrophic factor [BDNF], ciliary neurotrophic factor [CNTF]) in neurological diseases have already been conducted on neurodegenerative diseases such as amyotrophic lateral sclerosis. Nitric Oxide Nitric oxide (NO) acts in the brain as both an intraneuronal second messenger and as a neurotransmitter. NO is formed from the amino acid arginine by the actions of NO synthase. NO and NOS synthase have been described in the brain. NO synthase is present in discrete regions of the brain, particularly the striatum, hypothalamus, basal forebrain, and cerebellum. The best understood pathway resulting in the generation of NO begins with activation of the N-methyl-D aspartate (NMDA) subtype of the glutamate receptor. Activation of the NMDA receptor results in the influx of calcium into the neuron, and the calcium-mediated activation of NO synthase, which generates NO from arginine. Intraneuronal NO then acts on the iron molecule contained in guanylyl cyclase and results in the formation of cyclic guanylyl monophosphate (cGMP), a potent second-messenger molecule. Because of its gaseous properties, NO can also diffuse to adjacent neurons, in which it can also result in the formation of cGMP. Unlike other neurotransmitters, NO is not stored in synaptic vesicles and is not necessarily released only on depolarization. Its receptors are iron and possibly other reactive metals, and not the conventional protein neurotransmitter receptors. Currently available data suggest that NO may be involved in some aspects of learning and memory. In addition, inhibitors of NO synthase may be effective in reducing ischemic damage after cerebrovascular events. Adenosine and ATP Adenosine is a purine and ATP is synthesized from adenosine. P 1 receptors, which have a high affinity for adenosine, and P 2 receptors, which have a high affinity for ATP, have been found in the brain. The P 1 receptors are blocked by xanthines, such as caffeine and theophylline. Three subtypes of the P 1 receptor are the adenosine A 1, A 2 and A3 receptors, all of which are G protein-linked receptors. Adenosine is concentrated in discrete regions of the brain and appears to have the general effect of inhibiting the release of most other neurotransmitters. This property has led to research activities to study adenosine analogues for use as anticonvulsants or sedatives. ATP is stored along with catecholamines in synaptic vesicles, and is released when the catecholamines are released. ATP preferentially acts on P 2 receptors, and data show that at least one function of ATP is the excitatory activation of sodium-potassium and calcium ion channels. A small body of evidence suggests that nucleotides and nucleosides may have trophic actions on glial and neuronal cells. s-Receptors Another molecule that does not fit easily into the general scheme is the s-receptor, for which a natural ligand has not been identified, although in the past the sigma receptor was erroneously thought to be the primary receptor for phencyclidine (PCP, also known as “angel dust”). The previous association between s-receptors and PCP and the discovery that a number of antipsychotic drugs bind with high affinities to the s-receptors have caused researchers and pharmaceutical companies to develop sigma antagonists as potential antipsychotic compounds. So far, however, clinical trials with these compounds have not been successful.

SIGNAL TRANSDUCTION AND MOLECULAR GENETICS The process of chemical neurotransmission refers strictly to the release of a neurotransmitter by a presynaptic neuron, the travel of that neurotransmitter across some space (e.g., the synaptic cleft), and the binding of that neurotransmitter to its specific receptor on a postsynaptic neuron (or an autoreceptor on a presynaptic neuron). The process of signal transduction, however, refers to the process by which an electrical signal (e.g., the action potential) in the presynaptic neuron is translated into a chemical signal (e.g., the release of a neurotransmitter), and the process by which the chemical signal (e.g., the interaction of a neurotransmitter and its receptor) is translated back into an electrical signal in the postsynaptic neuron. The study of intraneuronal signaling pathways and the regulation of neuronal ion channels

provides the basics for understanding signal transduction. The initial step in intraneuronal signaling is most often the generation of second-messenger molecules (e.g., ATP) following the activation of a neurotransmitter receptor by its specific neurotransmitter ( Section 1.8). In this schema, the first messenger is considered to be the neurotransmitter, peptide, or hormone that activated the receptor. The generation of the second messenger, however, can lead to a cascade of intraneuronal third, fourth, and more messenger molecules. One example of this cascade is the process of protein phosphorylation, which is a reversible, posttranslational modification of a protein. The deletion or the addition of one or more phosphate groups to a protein results in a change in the function of that protein. Thus, protein phosphorylation can serve as a type of molecular on-off switch for protein function. Protein phosphorylation more often modulates the function of a protein than it turns a specific function completely on or off. The identification of multiple biochemical steps, such as protein phosphorylation, offers researchers novel opportunities to identify pathophysiological processes as well as to develop therapeutic approaches. Although psychiatrists and other mental health professionals may be more familiar with neurotransmitters and intraneuronal messengers than with ion channels, it is the balance between external and internal concentrations of ions that actually fuels the activities of the brain ( Section 1.9). This balance is achieved by a wide array of ion channels, some of which are regulated by neurotransmitters and others by voltage gradients directly. Many of the drugs of interest in psychiatry act directly on ion channels. The benzodiazepines act on GABA type A (GABA A) receptors that are chloride ion channels. Phencyclidine acts on the NMDA subtype of glutamate receptors that are calcium ion channels. Nicotine, the active ingredient in tobacco, acts on nicotinic acetylcholine receptors that are sodium and potassium ion channels. As with the neurotransmitter receptors, the delineation of ion channel subtypes and the modulation of ion channel function by processes such as protein phosphorylation are among the most active areas of neuropsychiatric and neuropharmacological research. Driving the development of the brain as well as the daily maintenance and regulation of brain function is the process of genetic expression ( Section 1.10). The basic process of genetics involves the transcription of deoxyribonucleic acid (DNA) into ribonucleic acid (RNA) and the translation of RNA into a protein. A complex system of regulation exists for transcription and translation, and the newly discovered molecules and pathways for this regulation are sites of investigation for discoveries in the etiology, pathophysiology, and treatment of mental disorders. Alterations in gene expression occur both during development and in adulthood and may be the bases for abnormal and normal development, and for abnormal and normal adaptation to stress. Psychiatric research in the twenty-first century is likely to investigate neurotrophic factors and molecular genetics.

INTEGRATION AND TIME In addition to the central nervous system, the human body contains two other systems that have complex, internal communicative networks—the endocrine system and the immune system. Mostly because of the discoveries of the involved molecular signals, it is now known that these three systems are integrated with each other, which has given birth to the sciences of psychoneuroendocrinology ( Section 1.11) and psychoneuroimmunology (Section 1.12). The interactions between the neuroendocrine and central nervous systems can most easily be seen in the psychiatric symptoms that can accompany some hormonal disorders (e.g., depression in Cushing's syndrome), and also in the identification of disorders of neuroendocrine regulation as potential markers for state or trait variables in psychiatric conditions. In addition to the property of internal communication, another property shared by the neuroendocrine, immune, and central nervous systems is that they undergo regular changes with time. The study of these changes with time and disorders of time regulation are encompassed in the field of chronobiology ( Section 1.13).

IMAGING BRAIN FUNCTION Although X-rays and computed tomography (CT) can provide images of the skull, these are often of more interest to neurologists and neurosurgeons than to psychiatrists because psychiatry is more focused on the function of the brain itself. The first approach to be developed for measuring and imaging brain function was the field of applied electrophysiology, using the tools of electroencephalography (EEG) and evoked potentials (EPs) ( Section 1.14). More recently, computerized approaches to these data have yielded more sophisticated analyses and presentations of information. The recent development of magnetoencephalography may expand the ability of this field to measure the activity of deeper brain structures. Of most value in psychiatric research today for the visualization of brain function are the modalities of positron emission tomography (PET) and single photon emission computed tomography (SPECT), utilizing either radiotracer techniques ( Section 1.15) or the differing magnetic resonance properties of the molecules in the brain (Section 1.16). These techniques can measure and visualize brain function during increasingly shorter time periods, allowing researchers to ask increasingly specific questions about specific brain regions and neural networks and their relationship to specific emotional, cognitive, and behavioral states and activities.

APPLIED GENETICS The application of the techniques of population genetics to the study of mental illness provided some of the first objective data that mental illnesses were biological illnesses, thereby helping to destigmatize these human conditions. The use of population genetic methods in psychiatric research continues to yield important data and insights into mental illnesses ( Section 1.17). The tools of population genetics have been more recently supplemented by the application of molecular neurobiological tools to this discipline, and the ability to study specific genetic linkages among individuals and groups of individuals ( Section 1.18). The application of these techniques can lead to the identification of a specific gene or genes as causative agents for specific mental disorders. The example of the discovery of the gene for Huntington's disease is described in a subsequent chapter ( Section 1.21).

SLEEP AND APPETITE Sleep and appetite are just two examples of complex behaviors that are the observable results of the summations of neural processes. Sleep ( Section 1.19) and appetite (Section 1.20) are regulated by specific brain regions and specific neurotransmitters, modulated by intraneuronal signals and ion channels, affected by the immune and neuroendocrine systems, altered with time, visualizable through brain-imaging techniques, subject to genetic regulation, and often affected by neurological or psychiatric disorders. Other complex brain activities such as perception, cognition, and memory are described elsewhere in this textbook.

SUGGESTED CROSS-REFERENCES Neuropsychiatry and behavioral neurology are discussed in Chapter 2; the neuropsychological and psychiatric aspect of AIDS are discussed in Section 2.8; the neurochemical, viral, and immunological studies of schizophrenia are discussed in Section 12.4; the biochemical aspects of mood disorders are discussed in Section 14.3; biological therapies are discussed in Chapter 31; and Alzheimer's disease is discussed in Section 51.3. The future of psychiatry is discussed in Section 55.3. SECTION REFERENCES Barnard EA, Burnstock G, Webb TE: G protein-coupled receptors for ATP and other nucleosides: A new receptor family. Trends Pharmacol Sci 15:67, 1994. Erfurth A: Adenosine and neuropsychiatric disorders. Implications for treatment. CNS Drugs 2:184, 1994. *Iadecola C: Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 20:132, 1997. Kandel ER: A new intellectual framework for psychiatry. Am J Psychiatry 155:457, 1998. *Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 329:2002, 1993. Neary JT, Rathbone MP, Cattabeni F, Abbracchio MP, Burnstock G: Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells. Trends Neurosci 19:13, 1996. *Nelson RJ, Demas GE, Huang PL, Fishman MC, Dawson VL, Dawson TM, Snyder SH: Behavioral abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 378:383, 1995. *Porka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW: Adenosine: A mediator of the sleep-inducing effects of prolonged wakefulness. Science 276:1265, 1997. *Shihabuddin LS, Ray J, Gage FH: Stem cell technology for basic science and clinical applications. Arch Neurol 56:29, 1999.

*Vile RG, Sunassee K, Diaz RM: Strategies for achieving multiple layers of selectivity in gene therapy. Mol Med Today 4:84, 1998. *Weinberger DR: Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry 45:395, 1999. *Young GB, Pigott SE: Neurobiological basis of consciousness. Arch Neurol 56:153, 1999. *Zigmond MJ, Bloom FE, Landis SC, Roberts JL, Squire LR, editors: Fundamental Neuroscience. Academic Press, San Diego, 1999.

Textbook of Psychiatry

1.2 FUNCTIONAL NEUROANATOMY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.2 FUNCTIONAL NEUROANATOMY DAVID A. LEWIS, M.D. Principles of Brain Organization Structural Components Functional Brain Systems Suggested Cross-References

The normal affective, cognitive, and behavioral processes that are disturbed in different psychiatric disorders arise because of specific patterns of activation in networks of neurons that are distributed through the central nervous system. These patterns of activation are mediated by the connections among specific brain structures. Consequently, understanding the neurobiological bases for psychiatric disorders requires an appreciation of the major principles governing the functional organization of these structures and connections in the human brain. The thalamocortical, basal ganglia, and limbic systems are of particular relevance to neuropsychiatric disorders. Those systems are formed by extensive and highly specific connections among certain anatomical structures, and the activation of those multiple connections gives rise to distinct behaviors, cognitive abilities, and emotional states. Thus, knowledge of the anatomical organization of the functional systems is crucial for the development and testing of hypotheses regarding the biological bases of the signs and symptoms of neuropsychiatric disorders.

PRINCIPLES OF BRAIN ORGANIZATION Cells The human brain contains approximately 10 11 nerve cells or neurons. In general, neurons are composed of four morphologically identified regions ( Fig. 1.2-1): (1) the cell body or soma, which contains the nucleus and can be considered the metabolic center of the neuron; (2) the dendrites, processes that arise from the cell body, branch extensively, and serve as the major recipient zones of input from other neurons; (3) the axon, a single process that arises from a specialized portion of the cell body (the axon hillock) and conveys information to other neurons; and (4) the axon terminals, fine branches near the end of the axon that form contacts (synapses) generally with the dendrites or the cell bodies of other neurons, release neurotransmitters, and thereby provide a mechanism for interneuronal communication.

FIGURE 1.2-1 Drawing of the major features of a typical neuron. (Adapted from Kandel ER: Nerve cells and behavior. In Principles of Neural Science, ed 3, E Kandel, J Schwartz, T Jessell, editors. Elsevier, New York, 1991.)

The majority of neurons in the human brain are considered to be multipolar in that they give rise to a single axon and several dendritic processes. Although there are a number of classification schemes for neurons in different brain regions, almost all neurons can be considered either projection or local circuit neurons. Projection neurons have long axons and convey information from the periphery to the brain (sensory neurons), from one brain region to another, or from the brain to effector organs (motor neurons). In contrast, local circuit neurons or interneurons have short axons and process information within distinct regions of the brain. Neurons can also be classified according to the neurotransmitters they contain (e.g., the dopamine neurons of the substantia nigra). Identification of neurons by their neurotransmitter content in anatomical studies provides a means for correlating the structure of a neuron with certain aspects of its function. However, neurotransmitters have defined effects on the activity of neurons, whereas complex brain functions, such as those disturbed in psychiatric disorders, are mediated by the coordinated activity of ensembles of neurons. Thus, the effects of neurotransmitters (or of pharmacological agents that mimic or antagonize the action of neurotransmitters) on behavioral, emotional, or cognitive states must be viewed within the context of the neural circuits that they influence. In addition to neurons, the brain also contains several types of glial cells, which are at least ten times more numerous than the neurons. Although glial cells are not directly involved in information processing, they play several important roles in the nervous system. Oligodendrocytes and Schwann cells, found in the central and peripheral nervous systems, respectively, are relatively small cells that wrap their membranous processes around axons in a tight spiral. The resulting myelin sheath facilitates the conduction of action potentials along the axon. Astrocytes, the most numerous class of glial cells, appear to serve a number of functions, including participation in the formation of the blood-brain barrier, removal of certain neurotransmitters from the synaptic cleft, buffering of the extracellular potassium (K +) concentration, and, given their close contact with both neurons and blood vessels, possibly a nutritive function as well. The third class of glial cells, the microglia, are actually derived from macrophages and function as scavengers, eliminating the debris resulting from neuronal death and injury. Architecture Neurons and their processes form groupings in a number of different ways, and those patterns of organization can be evaluated by several approaches. The pattern of distribution of the neurons, called cytoarchitecture, is revealed by aniline dyes that stain ribonucleotides, Nissl substance, in the nucleus and the cytoplasm of neuronal cell bodies. The Nissl stains demonstrate the relative size and packing density of the neurons and consequently reveal, for example, the organization of the neurons into the different layers of the cerebral cortex. In certain pathological states, such as Alzheimer's disease, neuronal degeneration and loss results in striking changes in the cytoarchitecture of some brain regions ( Fig. 1.2-2).

FIGURE 1.2-2 Nissl-stained sections of the superficial layers of the intermediate region of human entorhinal cortex. In the control brain (A), layer II contains clusters or islands of large, intensely stained neurons. In Alzheimer's disease (B), these layer II neurons are particularly vulnerable to degeneration, and their loss produces a

marked change in the cytoarchitecture of the region. Roman numerals indicate the location of the cortical layers. Calibration bar (200 µm) applies to A and B.

Other types of histological techniques, such as silver stains, selectively label the myelin coating of axons and, consequently, reveal the myeloarchitecture of the brain. For example, certain regions of the cerebral cortex—such as area MT, a portion of the temporal cortex involved in processing visual information—can be identified by a characteristic pattern of heavy myelination in the deep cortical layers. The progression of myelination is highly region-specific, may not be complete for years after birth, and may be a useful anatomical indicator of the functional maturation of brain regions. Immunohistochemical and other related techniques—which identify the location of neurotransmitters, their synthetic enzymes, or other molecules within neurons—can be used to determine the chemoarchitecture of the brain (Fig. 1.2-3B). In some cases, these techniques reveal striking regional differences in the chemoarchitecture of the brain that are difficult to detect in cytoarchitecture.

FIGURE 1.2-3 Adjacent sagittal sections through the medial temporal lobe of the human brain labeled to reveal the cytoarchitecture ( A—Nissl stain) and chemoarchitecture (B—nonphosphorylated neurofilament protein immunoreactivity) of the entorhinal cortex. Arrows indicate the rostral (left) and caudal (right) borders of the entorhinal cortex, and letters indicate some of its subdivisions. Calibration bar (2 mm) applies to both panels. (Reprinted with permission from Beall MJ, Lewis DA: Heterogeneity of layer II neurons in human entorhinal cortex. J Comp Neurol 321:241, 1992.)

Connections Every function of the human brain is a consequence of the activity of specific neural circuits. The circuits form as a result of several developmental processes. First, each neuron extends an axon, either after it has migrated to its final location or, in some cases, before. The growth of an axon along distinct pathways is guided by molecular cues from its environment and eventually leads to the formation of synapses with specific target neurons. Although the projection of axons is quite precise, some axons initially produce an excessive number of axon branches or collaterals and thus contact a broader set of targets than are present in the adult brain. During later development the connections of particular neurons are focused by the pruning or elimination of axonal projections to inappropriate targets. Within the adult brain the connections among neurons or neural circuits follow several important principles of organization. First, many but not all connections between brain regions are reciprocal; that is, each region tends to receive input from those regions to which it sends axonal projections. In some cases the axons arising from one region may directly innervate the reciprocating projection neurons in another region; in other cases local circuit interneurons are interposed between the incoming axons and the projection neurons that furnish the reciprocal connections. For some projections the reciprocating connection is indirect, passing through one or more additional brain regions and synapses before innervating the initial brain region. Second, many neuronal connections are either divergent or convergent in nature. A divergent system involves the conduction of information from one neuron or a discrete group of neurons to a much larger number of neurons that may be located in diverse portions of the brain. The locus ceruleus, a small group of norepinephrine-containing neurons in the brainstem that sends axonal projections to the entire cerebral cortex and other brain regions, is an example of a divergent system. In contrast, the output of multiple brain regions may be directed toward a single area, forming a convergent system. Third, the connections among regions may be organized in a hierarchical or parallel fashion or both. For example, visual input is conveyed in a serial or hierarchical fashion through several populations of neurons in the retina to the lateral geniculate nucleus, to the primary visual cortex, and then progressively to the multiple visual association areas of the cerebral cortex. Within the hierarchical scheme, different types of visual information (e.g., motion, form) may be processed in a parallel fashion through different portions of the visual system. Finally, regions of the brain are specialized for different functions. For example, lesions of the left inferior frontal gyrus (Broca's area, Fig. 1.2-4A) produce a characteristic impairment in speech production. However, speech is a complex faculty that depends not only on the integrity of Broca's area but also on the distributed processing of information across a number of brain regions through divergent and convergent, serial and parallel interconnections. Thus, the role of any particular brain region or group of neurons in the production of specific behaviors or in the pathophysiology of a given neuropsychiatric disorder cannot be viewed in isolation but must be considered within the context of the neural circuits connecting those neurons with other brain regions.

FIGURE 1.2-4 Photographs of the lateral (top) and medial (bottom) of the left hemisphere of a human brain indicating the location of major surface landmarks. F indicates frontal lobe, O indicates occipital lobe, P indicates parietal lobe, T indicates temporal lobe, Th indicates thalamus, cc G indicates the genu of the corpus callosum, ccS indicates the splenium of the corpus callosum.

Distinctiveness of the Human Brain The human brain is substantially larger than the brains of other primate species and certain areas of the human brain have expanded disproportionately. For example, the prefrontal cortex has been estimated to occupy only 3.5 percent of the total cortical volume in cats and 11.5 percent in monkeys but close to 30 percent of the much larger cortical volume of the human brain. Conversely, the relative representation of other regions is decreased in the human brain; for example, the primary visual cortex accounts for only 1.5 percent of the total area of the cerebral cortex in humans, but in monkeys a much greater proportion (17 percent) of the cerebral cortex is devoted to that region. Thus, the distinctiveness of the human brain is attributable both to its size and to the differential expansion of certain regions, particularly those areas of the cerebral cortex devoted to higher cognitive functions. The expansion and the differentiation of the human brain is associated with substantial differences in the organization of certain elements of neural circuitry. For example, when compared with rodents, the dopaminergic innervation of the human cerebral cortex is much more widespread and regionally specific. The primary

motor cortex and certain posterior parietal regions receive a dense dopamine innervation in both monkeys and humans, but those areas receive little dopamine input in rats. These types of species differences indicate that there are limits to the accuracy of the generalizations made about human brain function when studies on rodents or even nonhuman primates are used as the basis for the inference. However, direct investigation of the organization of the human brain is obviously restricted and complicated by a number of factors. As indicated above, the expansion of the human brain is associated with the appearance of additional regions of the cerebral cortex. For example, the entorhinal cortex of the medial temporal lobe is sometimes considered to be a single cortical region, yet in the human brain the cytoarchitecture and the chemoarchitecture of that cortex differs substantially along its rostral-caudal extent ( Fig. 1.2-3). It is tempting to identify those regions by their location relative to other structures, but sufficient interindividual variability exists in the human brain to make such a topological definition unreliable. In the case of the entorhinal cortex, the location of its different subdivisions relative to adjacent structures, such as the amygdala and the hippocampus, varies somewhat across human brains. Therefore in all studies, particularly those using the human brain, areas of interest must be defined such that investigators can accurately identify the same region in all cases. An additional limitation to the study of the human brain concerns the changes in morphology and biochemistry that can occur during the interval between the time of death and the freezing or fixation of brain specimens. In addition to the influence of the known postmortem interval, such changes may begin to occur during the agonal state preceding death. When comparing aspects of the organization of the human brain with that of other species, the researcher must try to account for changes that may have occurred in the human brain as a result of postmortem delay or agonal state. Furthermore, in the study of disease states appropriate controls must be used because differences in neurotransmitter content or other characteristics among cases could be a result of factors other than the disease state. Studies of the human brain in vivo—using such imaging techniques as positron emission tomography, magnetic resonance imaging, and magnetic resonance spectroscopy—circumvent many of those problems but are limited by a level of resolution that is insufficient for the study of many aspects of human brain organization.

STRUCTURAL COMPONENTS Major Brain Structures In the early stages of the development of the human brain, three primary vesicles can be identified in the neural tube: the prosencephalon, the mesencephalon, and the rhombencephalon (Table 1.2-1). Subsequently, the prosencephalon divides to become the telencephalon and the diencephalon. The telencephalon gives rise to the cerebral cortex, the hippocampal formation, the amygdala, and some components of the basal ganglia. The diencephalon becomes the thalamus, the hypothalamus, and several other related structures. The mesencephalon gives rise to the midbrain structures of the adult brain. The rhombencephalon divides into the metencephalon and the myelencephalon. The metencephalon gives rise to the pons and the cerebellum; the medulla is the derivative of the myelencephalon.

Table 1.2-1 Derivatives of the Neural Tube

The cerebral cortex of each hemisphere is divided into four major regions; the frontal, parietal, temporal, and occipital lobes (Fig. 1.2-4). The frontal lobe is located anterior to the central sulcus and consists of the primary motor, premotor, and prefrontal regions. The primary somatosensory cortex is located in the anterior parietal lobe; in addition, other cortical regions that are related to complex visual and somatosensory functions are located in the posterior parietal lobe. The superior portion of the temporal lobe contains the primary auditory cortex and other auditory regions; the inferior portion contains regions devoted to complex visual functions. In addition, some regions of the superior temporal sulcus receive a convergence of input from the visual, somatosensory, and auditory sensory areas. The occipital lobe consists of the primary visual cortex and other visual association areas. Beneath the outer mantle of the cerebral cortex are a number of other major brain structures, such as the caudate nucleus, the putamen, and the globus pallidus ( Fig. 1.2-5 and Fig. 1.2-6). Those structures are components of the basal ganglia, a system involved in the control of movement. The hippocampus and the amygdala, which are components of the limbic system, are located deep in the medial temporal lobe ( Fig. 1.2-6 and Fig. 1.2-7). In addition, the derivatives of the diencephalon, such as the thalamus and the hypothalamus, are prominent internal structures; the thalamus is a relatively large structure composed of a number of nuclei that have distinct patterns of connectivity with the cerebral cortex ( Fig. 1.2-6 and Fig. 1.2-7). In contrast, the hypothalamus is a much smaller structure that is involved in autonomic and endocrine functions.

FIGURE 1.2-5 Drawing of a coronal section through the optic chasm of a human brain. The inset below indicates the level of the section. (Adapted from Nieuwenhuys R, Voogd J, van Huijzen C: The Human Central Nervous System: A Synopsis and Atlas, ed 3. Springer, New York, 1988.)

FIGURE 1.2-6 Drawing of a coronal section at the level of the mamillary bodies. The inset below indicates the level of the section. (Adapted from Nieuwenhuys R,

Voogd J, van Huijzen C: The Human Central Nervous System: A Synopsis and Atlas, ed 3. Springer, New York, 1988.)

FIGURE 1.2-7 Drawing of a coronal section through the posterior thalamus. The inset below indicates the level of the section. (Adapted from Nieuwenhuys R, Voogd J, van Huijzen C: The Human Central Nervous System: A Synopsis and Atlas, ed 3. Springer, New York, 1988.)

Ventricular System As the neural tube fuses during development, the cavity of the neural tube becomes the ventricular system of the brain. It is composed of two C-shaped lateral ventricles in the cerebral hemispheres that can be further divided into five parts: the anterior horn (which is located in the frontal lobe), the body of the ventricle, the inferior or temporal horn in the temporal lobe, the posterior or occipital horn in the occipital lobe, and the atrium ( Fig. 1.2-8). The foramina of Monro (interventricular foramina) are the two apertures that connect the two lateral ventricles with the third ventricle, which is found on the midline of the diencephalon. The cerebral aqueduct connects the third ventricle with the fourth ventricle in the pons and the medulla.

FIGURE 1.2-8 Drawing of a cast of the ventricular system of the human brain. The C shape of the lateral ventricles within the cerebral hemispheres is shown. (Adapted from Nieuwenhuys R, Voogd J, van Huijzen C: The Human Central Nervous System: A Synopsis and Atlas, ed 3. Springer, New York, 1988.)

The ventricular system is filled with cerebrospinal fluid (CSF), a colorless liquid containing low concentrations of protein, glucose, and potassium and relatively high concentrations of sodium and chloride. The majority (70 percent) of the CSF is produced at the choroid plexus located in the walls of the lateral ventricles and in the roof of both the third and fourth ventricles. The choroid plexus is a complex of ependyma, pia, and capillaries that invaginate the ventricle. In contrast to other parts of the brain, the capillaries in the choroid plexus are fenestrated, which allows substances to pass out of the capillaries and through the pia mater. The ependymal or choroid epithelial cells, however, have tight junctions between cells to prevent the leakage of substances into the CSF; that provides what is sometimes referred to as the blood-CSF barrier. In other parts of the brain, the endothelial cells of the capillaries exhibit tight junctions that prevent the movement of substances from the blood to the brain; that is referred to as the blood-brain barrier. The CSF is produced constantly and circulates through the lateral ventricles to the third ventricle and then to the fourth ventricle. The CSF then flows through the medial and lateral apertures to the cisterna magna and pontine cistern and finally travels over the cerebral hemispheres to be absorbed by the arachnoid villi and released into the superior sagittal sinus. Disruptions in the flow of the CSF usually cause some form of hydrocephalus; for example, if an intraventricular foramen is occluded, the associated lateral ventricle becomes enlarged, but the remaining components of the ventricular system remain normal. Several functions are attributed to the CSF: it serves to cushion the brain against trauma, to maintain and control the extracellular environment, and to spread endocrine hormones. Since the CSF bathes the brain and is in direct communication with extracellular fluid, it is possible to measure the amount of certain compounds in the CSF as a correlate of the amount of that substance in the brain. For example, concentrations of homovanillic acid (HVA), a metabolite of the neurotransmitter dopamine, are thought to reflect functional activity of that neurotransmitter. Thus, the concentration of HVA in samples of the CSF taken in a lumbar puncture may provide a picture of brain dopaminergic function. However, because the CSF bathes the entire brain, the concentrations of HVA in CSF may not be a valid indicator of the activity of dopamine neurons in any particular brain area. Consequently, caution must be exercised in interpreting the findings of investigations that rely on CSF measurements as indicators of neurotransmitter activity.

FUNCTIONAL BRAIN SYSTEMS The relation between the organizational principles and the structural components of the human brain are illustrated in three functional systems—the thalamocortical, basal ganglia, and limbic systems. Thalamocortical Systems Thalamus The largest portion of the diencephalon consists of the thalamus, a group of nuclei that serve as the major synaptic relay station for the information reaching the cerebral cortex. On an anatomical basis the thalamic nuclei can be divided into six groups: anterior, medial, lateral, reticular, intralaminar, and midline nuclei. A thin Y-shaped sheet of myelinated fibers, the internal medullary lamina, delimits the anterior, medial, and lateral groups of nuclei ( Fig. 1.2-9). In the human thalamus the anterior and medial groups each contain a single large nucleus, the anterior and medial dorsal nuclei. The lateral group of nuclei can be further subdivided into dorsal and ventral tiers. The dorsal tier is composed of the lateral dorsal, the lateral posterior, and the pulvinar nuclei; the ventral tier consists of the ventral anterior, the ventral lateral, the ventral posterior lateral, and the ventral posterior medial nuclei. The lateral group of nuclei are covered by the external medullary lamina, another sheet of myelinated fibers. Interposed between those fibers and the internal capsule is a thin group of neurons forming the reticular nucleus of the thalamus. The intralaminar nuclei, the largest of which is the central median nucleus, are located within the internal medullary lamina. The final group of thalamic nuclei, the midline nuclei, cover portions of the medial surface of the thalamus. The midline nuclei of each hemisphere may fuse to form the interthalamic adhesion, which is variably present.

FIGURE 1.2-9 Drawing of the nuclei of the thalamus as seen on the left side of the brain. (Adapted with permission from Kelly JP: The neural basis of perception and movement. In Principles of Neural Science, ed 3, ER Kandel, JH Schwartz, TM Jessell, editors. Elsevier, New York, 1991.)

Thalamic nuclei can also be classified into several groups based on the pattern and information content of their connections ( Table 1.2-2). For example, relay nuclei project to and receive input from specific regions of the cerebral cortex. Those reciprocal connections apparently allow the cerebral cortex to modulate the thalamic input it receives. Specific relay nuclei process input either from a single sensory modality or from a distinct part of the motor system. For example, the lateral geniculate nucleus receives visual input from the optic tract and projects to the primary visual area of the occipital cortex. As summarized in Figure 1.2-10, neurons of the thalamic relay nuclei furnish topographically organized projections to specific regions of the cerebral cortex, although some cortical regions receive input from more than one nucleus.

Table 1.2-2 Connections of Thalamic Nuclei*

FIGURE 1.2-10 Schematic drawings of the lateral (A) and medial (B) surfaces of the right cerebral hemisphere and the right thalamus (C). Shading patterns depict the cortical projection zones of some thalamic relay nuclei. (Adapted from Burt AM: Textbook of Neuroanatomy. Saunders, Philadelphia, 1993.)

In contrast, association relay nuclei receive highly processed input from more than one source and project to larger areas of the association cortex. or example, the medial dorsal thalamic nucleus receives input from the hypothalamus and the amygdala and is reciprocally interconnected with the prefrontal cortex and certain premotor and temporal cortical regions. In contrast to relay nuclei, diffuse-projection nuclei receive input from diverse sources and project to widespread areas of the cerebral cortex and to the thalamus. The divergent nature of the cortical connections of those nuclei indicates that they may be involved in regulating the level of cortical excitability and arousal. Finally, the reticular nucleus is somewhat unique in that it receives input from collaterals of the axons that reciprocally connect other thalamic nuclei and the cerebral cortex. Each portion of the reticular nucleus then projects to that thalamic nucleus from which it receives input. The pattern of connectivity may indicate that the reticular nucleus samples both cortical afferent and efferent activity and then uses that information to regulate thalamic function. Cerebral Cortex The cerebral cortex is a laminated sheet of neurons, several millimeters thick, that covers the cerebral hemispheres. More that 90 percent of the total cortical area consists of the neocortex, which has a six-layered structure (at least at some point during development). The remainder of the cerebral cortex is referred to as the allocortex and consists of the paleocortex and the archicortex, regions that are restricted to the base of the telencephalon and the hippocampal formation, respectively. Within the neocortex, the two major neuronal cell types are the pyramidal and stellate or nonpyramidal neurons. Pyramidal neurons, which account for approximately 60 percent of all neocortical neurons, usually have a characteristically shaped cell body that gives rise to a single apical dendrite that ascends vertically toward the cortical surface. In addition, the neurons have an array of short dendrites that spread laterally from the base of the cell. The dendrites of pyramidal neurons are coated with short protrusions, called spines, that are the sites of most of the excitatory inputs to these neurons. Most pyramidal cells are projection neurons that are thought to use excitatory amino acids as neurotransmitters. In contrast, nonpyramidal cells are generally small, local-circuit neurons, many of which use the inhibitory neurotransmitter g-aminobutyric acid (GABA). These neurons can be divided into distinct functional subclasses based on their biochemical and morphological features (Fig. 1.2-11). For example, the chandelier class of GABA neurons contains the calcium-binding protein parvalbumin, and exerts powerful inhibitory control over pyramidal neurons through synaptic inputs to the axon initial segment of pyramidal cells. In contrast, double bouquet cells contain the calcium-binding protein calbindin and provide inhibitory synapses to the dendritic shafts of pyramidal neurons, as well as to other local circuit neurons.

FIGURE 1.2-11 Schematic drawings of different morphological subclasses of GABA-containing local circuit neurons in the primate prefrontal cortex. As illustrated, the axons of some subclasses of GABA neurons selectively target different portions of pyramidal neurons (P). C indicates chandelier neuron, CRC indicates Cajal-Retzius cell, DB indicates double-bouquet cell, M indicates Martinotti cell, N indicates neurogliaform neuron. (Adapted with permission from Condé F, Lund JS, Jacobowitz DM, Baimbridge KG, Lewis DA: Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: Distribution and morphology. J Comp Neurol 341:95, 1994.)

Neocortical neurons are distributed across six layers of the neocortex; those layers are distinguished by the relative size and packing density of their neurons ( Fig. 1.2-12 and Fig. 1.2-13). Each cortical layer tends to receive particular types of inputs and to furnish characteristic projections. For example, afferents from thalamic relay nuclei terminate primarily in deep layer III and layer IV, whereas corticothalamic projections originate mainly from layer VI pyramidal neurons. These laminar distinctions provide important clues for dissecting possible pathophysiological mechanisms in psychiatric disorders. For example, reports of decreased somal size and diminished spine density on deep-layer pyramidal neurons in the prefrontal cortex of schizophrenic subjects suggests that these changes may be related to abnormalities in afferent projections from the medial dorsal thalamic nucleus. Consistent with this interpretation, the number of neurons in the medial dorsal nucleus has been reported to be decreased in schizophrenia.

FIGURE 1.2-12 Nissl-stained sections of (A) Brodmann's area 4 (primary motor cortex) and (B) area 41 (primary auditory cortex) from a control human brain. Roman numerals indicate the cortical layers. Marked differences in neuronal size and packing density across the layers of the two regions are evident. Calibration bar (200 µm) applies to A and B.

FIGURE 1.2-13 Nissl-stained sections of (A) Brodmann's area 46 (dorsolateral prefrontal cortex), (B) area 9 (dorsomedial prefrontal cortex) and (C) area 17 (primary visual cortex) from a control human brain. Roman numerals indicate the cortical layers. Note the marked differences in laminar organization between the prefrontal and visual areas, but the more subtle differences between the two prefrontal regions. Calibration bar (200 µm) applies to A-C.

In addition to the horizontal laminar structure, many aspects of cortical organization have a vertical or columnar characteristic. For example, the apical dendrites of pyramidal neurons and the axons of some local-circuit neurons have a prominent vertical orientation, indicating that those neural elements may sample the input to or regulate the function of neurons in multiple layers, respectively. Afferent inputs to the neocortex from other cortical regions also tend to be distributed across cortical layers in a columnar fashion. Finally, physiological studies in the somatosensory and visual cortices have shown that neurons in a given column respond to stimuli with particular characteristics, whereas those in adjacent columns respond to stimuli with different features. The neocortex can be divided into two general types of regions. Regions with a readily identifiable six-layer appearance are known as the homotypical cortex and are found in association regions of the frontal, temporal, and parietal lobes. In contrast, some regions of the neocortex do not retain a six-layer appearance. Those regions, called the heterotypical cortex, include the primary motor cortex, which lacks a defined layer IV, and primary sensory regions, which exhibit an expanded layer IV. The neocortex can be further divided into discrete areas, each area having a distinctive architecture, a certain set of connections, and a role in particular brain functions. Most subdivisions of the human neocortex have been based on cytoarchitectural features; that is, subdivisions differ in the size, packing density, and arrangement of neurons across layers (Fig. 1.2-12 and Fig. 1.2-13). The most widely used system is that of Korbinian Brodmann ( Fig. 1.2-14), who divided the cortex of each hemisphere into 44 numbered areas. Some of these numbered regions correspond closely to functionally distinct areas, such as area 4 (primary motor cortex in the precentral gyrus) and area 17 (primary visual cortex in the occipital lobe). In contrast, other Brodmann's areas appear to encompass several cortical zones that differ in their functional attributes. Although Brodmann's brain map has been extensively used in postmortem studies of psychiatric disorders, many of the distinctions among regions are quite subtle (Fig. 1.2-13A and Fig. 1.2-13B), and the locations of the boundaries between regions may vary among persons.

FIGURE 1.2-14 Drawing of the cytoarchitectonic subdivisions of the human brain as determined by Brodmann. Top, lateral view; bottom, medial view.

Although a given cortical area may receive other inputs, it is heavily innervated by projections from particular thalamic nuclei and from certain other cortical regions either in the same hemisphere (association fibers) or the opposite hemisphere (commissural fibers). The patterns of connectivity make it possible to classify cortical regions into different types. Primary sensory areas are dominated by inputs from specific thalamic relay nuclei and are characterized by a topographic representation of visual space, the body surface, or the range of audible frequencies on the cortical surface of the primary visual, primary somatosensory, and primary auditory cortices, respectively. Those regions project in turn to nearby unimodal association regions, which are also devoted to processing information from a particular sensory modality. Output from those regions converges in multimodal association areas, such as the prefrontal cortex or the temporoparietal cortical regions. Neurons in those regions respond to complex stimuli and are thought to be mediators of higher cognitive functions. Finally, those regions influence the activity of the motor areas of the cerebral cortex that control behavioral responses. Although this classification scheme of cortical regions is accurate in many respects, it fails to account for some of the known complexities of cortical information processing. For example, somatosensory input from the thalamus projects to several distinct, topographically organized maps in the cerebral cortex. In addition, information flow within the cortex is not confined to the serial processing route implied in the classification scheme but also involves parallel processing streams, such as sensory input from the thalamus to both the primary and association areas. Although this discussion has not distinguished between the cerebral hemispheres, certain brain functions, such as language, are localized to one hemisphere ( Fig. 1.2-15). The structural bases for the lateralization of function have not been determined, but some anatomical differences between the cerebral hemispheres have been observed. For example, a portion of the superior temporal cortex, called the planum temporale, is generally larger in the left hemisphere than in the right hemisphere. That cortical area, which is located close to the primary auditory cortex and includes the region called Wernicke's area (Fig. 1.2-4A), appears to be involved in receptive language functions that are localized to the left hemisphere. In addition, Brodmann's area 44, in the left inferior frontal cortex contains larger pyramidal neurons than the homotopic region of the right hemisphere, a difference that may contribute to the specialization of Broca's area for motor speech function.

FIGURE 1.2-15 Drawing of the dorsal surface of the human brain showing the tendency for certain functions to be preferentially localized to one hemisphere. However, it is important to note that the intact brain may not be as lateralized as some studies (e.g., of patients with commissurotomies) suggest, that the degree of lateralization differs across individuals, and that in the intact brain it is rare that one hemisphere can mediate a function that the other hemisphere is completely unable to perform. (Reprinted with permission from Fuchs AF, Phillips JO: Association cortex. In Textbook of Physiology, HD Patton, AF Fuchs, B Hillie, AM Scher, R Steiner, editors, vol 1, ed 21. Saunders, Philadelphia, 1989.)

Functional Circuitry The connections between the thalamus, the cortex, and certain related brain structures comprise three thalamocortical systems, each with different patterns of functional circuitry. Those three systems—sensory, motor, and association systems—are described separately here but are heavily interconnected. THALAMOCORTICAL SENSORY SYSTEMS Several general principles govern the organization of the thalamocortical sensory systems. First, sensory receptors transduce certain stimuli in the external environment to neural impulses. The impulses ascend, often through intermediate nuclei in the spinal cord and the medulla, and ultimately synapse in specific relay nuclei of the thalamus. Second, projections from peripheral sensory receptors to the thalamus and the cortex exhibit topography; that is, a particular portion of the external world is mapped onto a particular region of the brain. For example, in the somatosensory system, axons carrying information regarding a distinct part of the body synapse in a discrete part of the ventral posterior nucleus of the thalamus. Specifically, the ventral posterior medial nucleus receives inputs regarding the head, and the ventral posterior lateral nucleus receives inputs regarding the remainder of the body. The nuclei then project topographically to the primary somatosensory cortex, where several representations of the contralateral half of the body can be found. Those representations are distorted; regions heavily innervated by sensory receptors, such as the fingers, are disproportionately represented in the primary somatosensory cortex. Third, in some cases, sensory inputs travel to the thalamus in a segregated manner according to the submodality of the information conveyed. The inputs are then processed in a parallel fashion; particular pathways may be exclusively devoted to processing a submodality. An example of such segregation is evident in the somatosensory system, where most fibers carrying tactile and proprioceptive information travel in the medial lemniscus, but pain and temperature information is conveyed to the ventral posterior thalamic nuclei through the spinothalamic tract. Although some tactile information is carried in the spinothalamic tract, the submodalities of pain and temperature are largely segregated from tactile and proprioceptive inputs as they ascend to the thalamus. Finally, sensory pathways exhibit convergence; that is, primary sensory areas process sensory information and then project to unimodal association areas. Subsequently, the unimodal areas project to and converge in multimodal association areas. An illustration of convergence in sensory pathways is found in the somatosensory system. The primary somatosensory cortex, located in the anterior parietal lobe ( Fig. 1.2-16), has been divided into four regions on the basis of cytoarchitecture. Each of the cytoarchitectonic regions—numbered 1, 2, 3a, and 3b by Brodmann—contains a topographical representation of the body. The regions are heavily interconnected, and all project to the next level of somatosensory processing in area S-II. That type of projection, from one level of processing to a more advanced level, is termed a feedforward projection. The reciprocal connection, from the more advanced processing level back to the simpler level, is called a feedback projection. Both projections have distinct patterns of laminar termination: feedforward projections originate in the superficial layers of cortex (layer III) and terminate in layer IV; feedback projections originate in layers III, V, and VI and terminate outside layer IV. Further processing of somatosensory information occurs in higher-order somatosensory areas, such as area 7b of the posterior parietal cortex, which receive feedforward projections from S-II. Lesions of the posterior parietal cortex reflect the complexity of the information processed there; after a person has sustained a posterior parietal lesion, the ability to understand the significance of sensory stimuli is impaired, and extreme cases result in contralateral sensory neglect and inattention. However, the processing of somatosensory information within

the cortex is clearly much more complex than what has been described here (Fig. 1.2-17).

FIGURE 1.2-16 Drawing of the location of the somatosensory cortices in the human brain. A: Somatosensory cortices are located in the anterior and posterior parietal cortex. B: Primary somatosensory cortex (S-I) is divided into four cytoarchitectonic regions, as shown on the drawing of the section taken at the level depicted in (A). (Reprinted with permission from Martin JH, Jessell TM: Anatomy of the somatic sensory system. In Principles of Neural Science, ed 3, ER Kandel, JH Schwartz, TM Jessell, editors. Elsevier, New York, 1991.)

FIGURE 1.2-17 A proposed organizational scheme of the connectivity among cortical areas involved in somatosensory information processing. Hierarchical assignments were made on the basis of feedforward and feedback patterns of connections, as described in the text. (Reprinted with permission from Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1:36, 1991.)

THALAMOCORTICAL MOTOR SYSTEMS The thalamocortical motor systems exhibit some unique organizational principles but also share many of the features present in the sensory systems. First, in contrast to sensory systems, which primarily ascend from sensory receptor to cortical association areas, motor systems descend from association and motor regions of the cortex to the brainstem and the spinal cord. For example, the corticospinal tract originates in layer V neurons of the premotor and primary motor cortices of the frontal lobe and terminates in the spinal cord to influence motor behavior. Second, motor systems exhibit strong topography at both the thalamic and the cortical levels. For example, the corticospinal tract is organized so that a topographical representation of the contralateral half of the body is evident in the primary motor and premotor cortices. The representation of the body is disproportionate, with large regions of the motor cortex devoted to areas of the body involved in fine movement, such as the face and the hands. Finally, there is a convergence of projections from several sensory association regions to the motor regions of the frontal cortex. For example, the premotor cortex receives a convergence of afferents from higher-order somatosensory and visual areas of the posterior parietal cortex, whereas afferents from the primary somatosensory cortex converge on the primary motor cortex. In addition to cortical input, the primary motor cortex receives afferents from the ventral lateral nucleus of the thalamus; that nucleus receives afferents predominantly from the cerebellum. The premotor cortex receives input from the ventral anterior thalamic nucleus, which receives much of its input from the globus pallidus. THALAMOCORTICAL ASSOCIATION SYSTEMS The multimodal association areas of the cortex are organized according to several general principles. First, association regions receive a convergence of input from a variety of sources, including unimodal and multimodal association regions of the cortex, the association nuclei of the thalamus, and other structures. For example, the prefrontal cortex receives afferents from higher-order sensory cortices of the parietal and temporal lobes, the contralateral prefrontal cortex, the cingulate cortex of the limbic system, the medial dorsal nucleus of the thalamus, an association relay nucleus, and portions of the amygdala. The medial dorsal nucleus receives highly processed inputs from many sources, including some regions, such as the amygdala, that project directly to the prefrontal cortex. The redundant (direct and indirect) projections may serve to attach additional significance to certain inputs received by the prefrontal cortex. The significance of these inputs may also be influenced by their temporal and spatial coincidence with modulatory inputs from brainstem nuclei that utilize the monoamine neurotransmitters dopamine, norepinephrine, or serotonin. Interestingly, the density of the monoamine afferent systems differs substantially across cortical regions of the human brain ( Fig. 1.2-18), suggesting that the relative influence of these systems differs with the functional characteristics of the cortical region.

FIGURE 1.2-18 Photomicrographs illustrating the differential distribution of dopamine-containing axons in different regions of the human prefrontal (A, B, D) and anterior cingulate (C) cortices. The center panel represents a coronal section through the human prefrontal cortex at the level of the genu of the corpus callosum (cc), and the surrounding panels show the density of dopamine axons (white lines) at the indicated locations. Roman numerals indicate the cortical layers, and WM indicates white matter. Calibration bars equal 200 µm. (Reprinted with permission from Lewis DA: The catecholaminergic innervation of primate prefrontal cortex. J Neural Transm 36:179, 1992.)

Second, the projections that terminate in multimodal association regions exhibit a topographical organization. Since the information conveyed in those projections is highly processed, it does not appear that the topographical organization of the afferents is a representation of the external world. Nonetheless, a distinct pattern is present in the afferents received by association areas. For example, different cytoarchitectonic regions of the medial dorsal nucleus project to discrete regions of the prefrontal cortex. In addition, some of the cortical afferents received by the prefrontal cortex are topographically organized; certain regions of the prefrontal cortex

predominantly receive highly processed information from one modality. The patterns of connectivity are clearly related to some of the functional characteristics attributed to the prefrontal cortex. For example, in monkeys, lesions of the dorsolateral prefrontal cortex consistently produce an impairment in the monkey's ability to perform spatial delayed-response tasks. Those tasks require the monkey to maintain a spatial representation of the location of an object during a delay period in which the object is out of sight; it has been suggested that the prefrontal cortex plays a role in maintaining the spatial representation of the object. Such a function would require that the prefrontal cortex receive information regarding the location of objects in space; indeed, the dorsolateral prefrontal cortex is innervated by afferents from association regions of the parietal cortex that convey such information. Although the dorsolateral prefrontal cortex is necessary for the performance of delayed-response tasks in the monkey, it is not sufficient for the performance of the task. For example, lesions of the medial dorsal nucleus in the monkey result in similar impairments on the performance of spatial delayed-response tasks. Thus, the functions attributed to the prefrontal cortex are a result of the neural circuitry involving the region. Knowledge of the integration of afferent inputs into the neural circuitry of certain prefrontal regions may also be important for understanding the nature of prefrontal cortical dysfunction in schizophrenia. Schizophrenic patients perform poorly on tasks that are known to be mediated by the prefrontal cortex. Those findings have been correlated with other measures to suggest, albeit indirectly, that the dopamine projections to the prefrontal cortex are impaired in schizophrenia. For example, studies in nonhuman primates have shown that performance of delayed-response tasks, the same type of behaviors that are impaired in schizophrenic subjects, requires an appropriate level of dopamine input to the dorsolateral prefrontal cortex. CEREBELLO-THALAMOCORTICAL SYSTEMS The cerebellum has traditionally been considered to be involved solely with motor control, regulating posture, gait, and voluntary movements. However, recent studies indicate that the cerebellum may also play an important role in the mediation of certain cognitive abilities through inputs to portions of the thalamus that project to association regions of the cerebral cortex. The cerebellum is located in the posterior cranial fossa, inferior to the occipital lobes ( Fig. 1.2-4). The external surface of the cerebellum, the cerebellar cortex, is composed of small folds, termed folia, separated by sulci. Viewed from the dorsal surface, the cerebellum contains a raised central portion, called the vermis, and lateral portions called the cerebellar hemispheres (Fig. 1.2-19). Located within the cerebellum are the deep cerebellar nuclei that are arranged as follows: the fastigial nucleus is located next to the midline; located slightly more lateral are the globose and emboliform nuclei; and the largest nucleus, the dentate, occupies the most lateral position. In general, the cerebellar cortex can be considered to process the inputs to the cerebellum, and the deep nuclei to process the outputs.

FIGURE 1.2-19 Schematic drawing of the dorsal view of the cerebellum showing the relative location and size of the cerebellar nuclei situated deep within the cerebellum. (Adapted from Hendelman WJ: Student's Atlas of Neuroanatomy. Saunders, Philadelphia, 1994.)

Although many portions of the cerebellum are interconnected with brain regions that regulate motor actions, from the standpoint of psychiatric illness the circuitry of the cerebellum involved in cognitive functions is of greatest interest. For example, the lateral cerebellar cortex and the dentate nucleus are markedly expanded in the primate brain. It has been suggested that these changes are associated with an increase in the size of cortical areas (especially the prefrontal regions) influenced by cerebellar output and an expanded role of the cerebellum in cognitive functions. Recent studies in nonhuman primates have shown that the dorsolateral prefrontal cortex receives inputs from two ipsilateral thalamic nuclei (medial dorsal and ventral lateral), which in turn receive inputs from the contralateral cerebellar dentate nucleus. The cells of the dentate nucleus involved in these connections are distinct from those that influence the motor and premotor regions of the cerebral cortex. Interestingly, functional imaging studies in schizophrenic subjects have revealed abnormal patterns of activation in the cerebellum, thalamus, and prefrontal cortex, suggesting that dysfunction of this circuitry might be associated with the disturbances in cognitive processes exhibited by these patients. Basal Ganglia System The basal ganglia are a collection of nuclei that have been grouped together on the basis of their interconnections. These nuclei play an important role in regulating movement and in certain disorders of movement (dyskinesias), which include jerky movements (chorea), writhing movements (athetosis), and rhythmic movements (tremors). In addition, recent studies have shown that certain components of the basal ganglia play an important role in many cognitive functions. Major Structures The basal ganglia are generally considered to include the caudate nucleus, the putamen, the globus pallidus (referred to as the paleostriatum or pallidum), the subthalamic nucleus, and the substantia nigra (Fig. 1.2-20). The term striatum refers to the caudate nucleus and the putamen together; the term corpus striatum refers to the caudate nucleus, the putamen, and the globus pallidus; and the term lentiform nucleus refers to the putamen and the globus pallidus together.

FIGURE 1.2-20 Schematic drawing of the isolated basal ganglia as seen from the dorsolateral perspective, so that the caudate nucleus is apparent bilaterally. In the bottom panel, the basal ganglia from the left hemisphere has been removed, exposing the medial surface of the right putamen and globus pallidus, as well as the subthalamic nucleus and substantia nigra. (Adapted from Hendelman WJ: Student's Atlas of Neuroanatomy. Saunders, Philadelphia, 1994.)

Although these nuclei are generally agreed to belong to the basal ganglia, some controversy exists concerning whether other nuclei should be included in the definition of the basal ganglia. Some investigators believe that additional regions of the brain have anatomical connections that are similar to other components of the basal ganglia and should, therefore, be included in the definition. Those additional regions are usually termed the ventral striatum and the ventral pallidum. The ventral striatum includes the nucleus accumbens ( Fig. 1.2-20), which is the region where the putamen and the head of the caudate nucleus fuse, and the olfactory tubercle. The ventral pallidum is a region that receives afferents from the ventral striatum and includes but is not limited to a group of neurons termed the substantia innominata (Fig. 1.2-5). This section focuses on the structures generally accepted as belonging to the basal ganglia but also discusses additional structures when relevant to the functional anatomy of the system. CAUDATE NUCLEUS The caudate nucleus is a C-shaped structure that is divided into three general regions. The anterior portion of the structure is referred to as the

head, the posterior region is the tail, and the intervening region is the body (Fig. 1.2-20). The caudate nucleus is associated with the contour of the lateral ventricles: the head lies against the frontal horn of the lateral ventricle, and the tail lies against the temporal horn ( Fig. 1.2-5, Fig. 1.2-6, and Fig. 1.2-7). The head of the caudate nucleus is continuous with the putamen; the tail terminates in the amygdala of the temporal lobe. PUTAMEN The putamen lies in the brain medial to the insula and is bounded laterally by the fibers of the external capsule and medially by the globus pallidus ( Fig. 1.2-5 and Fig. 1.2-6); the putamen is continuous with the head of the caudate nucleus ( Fig. 1.2-20). Although bridges of neurons between the caudate nucleus and the putamen show the continuity of the nuclei, the two structures are separated by fibers of the anterior limb of the internal capsule. GLOBUS PALLIDUS In contrast to the caudate nucleus and the putamen, which are telencephalic in origin, the globus pallidus is derived from the diencephalon. The globus pallidus constitutes the inner component of the lentiform nucleus ( Fig. 1.2-20, bottom panel); with the putamen it forms a conelike structure, with its tip directed medially (Fig. 1.2-5 and Fig. 1.2-6). The posterior limb of the internal capsule bounds the globus pallidus medially and separates it from the thalamus; the putamen borders the globus pallidus laterally. In the human the medial medullary lamina divides the globus pallidus into external (lateral) and internal (medial) segments ( Fig. 1.2-5 and Fig. 1.2-6). SUBTHALAMIC NUCLEUS The subthalamic nucleus (of Luys) is also derived from the diencephalon. The large-celled nucleus lies dorsomedial to the posterior limb of the internal capsule and dorsal to the substantia nigra ( Fig. 1.2-6 and Fig. 1.2-20). Discrete lesions of the subthalamic nucleus in humans lead to hemiballism, a syndrome characterized by violent, forceful choreiform movements that occur on the side contralateral to the lesion. SUBSTANTIA NIGRA The substantia nigra is present in the midbrain between the tegmentum and the basis pedunculi and is mesencephalic in origin ( Fig. 1.2-6). The substantia nigra consists of two components: a dorsal cell-rich portion referred to as the pars compacta and a ventral cell-sparse portion called the pars reticulata. Most of the neurons in the pars compacta of the substantia nigra in humans are pigmented because of the presence of neuromelanin; those cells contain the neurotransmitter dopamine. The dendrites of the pars compacta neurons frequently extend into the pars reticulata, where they receive synapses from the neurons of the pars reticulata that use the inhibitory neurotransmitter GABA. In rodents, the dopamine-containing neurons of the substantia nigra (A9 region) have been distinguished from those located in the ventral tegmental area (A10 region) and the retrorubral field (A8 region), but recent studies in monkey and human brains suggest that dopamine neurons can be more meaningfully parcellated at a functional level into dorsal and ventral tiers ( Fig. 1.2-21). The dorsal tier is formed by a medially and laterally oriented band of neurons that includes the dopamine-containing cells that are (1) located in the medial ventral mesencephalon, (2) scattered dorsal to the dense cell clusters in the substantia nigra, and (3) distributed lateral and caudal to the red nucleus. The ventral tier is composed of the dopamine neurons that are densely packed in the substantia nigra and the cell columns that penetrate into the substantia nigra pars reticulata. Dorsal-tier dopamine neurons express relatively low concentrations of the messenger ribonucleic acids (mRNAs) for the dopamine transporter and the dopamine type 2 (D 2) receptor, contain the calcium-binding protein calbindin, and send axonal projections to the regions of the striatum that are dominated by input from limbic-related structures and association regions of the cerebral cortex. In contrast, ventral-tier neurons contain high concentrations of the mRNAs for the dopamine transporter and the D 2 receptor, typically lack calbindin, and send axonal projections to the sensorimotor regions of the striatum. Each of these features may contribute to the greater vulnerability of ventral-tier neurons to the pathology of Parkinson's disease, whereas dorsal tier neurons may be more likely to be involved in the pathophysiology of schizophrenia.

FIGURE 1.2-21 Schematic drawing of the topographic organization of dopamine-containing neurons in the mesencephalon and their projections to the ventral striatum and the sensorimotor-related dorsal striatum. All areas of the ventral striatum receive inputs from the dorsal tier neurons, with the shell region of the nucleus accumbens innervated almost exclusively by dorsal tier neurons (filled circles). In contrast, the ventral columns of cells (open circles) in the ventral tier send projections selectively to the sensorimotor-related striatum. The neurons of the densocellular zone (stars) of the ventral tier are unique in that they project to both the ventral and sensorimotor-related striatum. AC, anterior commissure; C, caudate nucleus; NA, nucleus accumbens; P, putamen. (Adapted from Lynda-Balta E, Haber SN: The organization of midbrain projections to the ventral striatum in the primate. Neuroscience 59:625, 1994.)

Internal Organization The caudate nucleus and the putamen are frequently referred to together because of their common characteristics. For example, in the rodent these nuclei are a continuous structure, and in all mammals, they are composed of histologically identical cells. The majority of neurons in the striatum are medium-sized cells (10–20 µm in diameter) that possess spines on their dendrites; these so-called medium spiny neurons are known to send their axons out of the striatum. In addition to medium spiny neurons, medium-sized cells without spines ( medium aspiny neurons) are present, as are large cells with and without spines (large spiny neurons and large aspiny neurons). With the exception of the medium and large spiny cells, most other striatal neurons are local circuit neurons. Immunohistochemical and receptor-binding studies have shown a discontinuity in the distribution of certain neurotransmitter-related substances that form the functional circuitry of the basal ganglia. For example, in the striatum, zones that contain a low density of acetylcholinesterase enzymatic activity are surrounded by regions rich in acetylcholinesterase activity. The acetylcholinesterase-rich regions are referred to as the matrix, and the acetylcholinesterase-poor zones are termed either striosomes in the primate or patches in the rodent. The organization of several neuropeptide systems follows this system. For example, the distributions of enkephalin, substance P, and somatostatin immunoreactivity show the compartmentalization of the striatum. In addition, in the rodent certain subtypes of dopamine receptors are present predominantly in one compartment as compared with the other. In addition, the distribution of some afferent systems terminating in the striatum follows the striosome-matrix organization. For example, afferents from the thalamus terminate preferentially in the matrix rather than in the striosome. Functional Circuitry Projections into, within, and out of the basal ganglia are topographically organized and maintain that topography throughout he processing circuits of the basal ganglia. The existence of such patterns of connectivity has resulted in the hypothesis that parallel, independent circuits in the basal ganglia process information from different regions of the brain and subserve separate complex functions. INPUTS TO THE BASAL GANGLIA The striatum is the major recipient of the inputs to the basal ganglia. Three major afferent systems are known to terminate in the striatum: the corticostriatal, the nigrostriatal, and the thalamostriatal afferents ( Fig. 1.2-22). The corticostriatal projection originates from all regions of the neocortex, arising primarily from the pyramidal cells of layers V and VI, which utilize the excitatory neurotransmitter glutamate. A topography governing corticostriatal projections has been found in the monkey. Afferents from the sensorimotor cortex terminate predominantly in the putamen; association regions of the cortex terminate preferentially in the caudate nucleus. The prefrontal regions, in particular, provide a heavy input to the head of the caudate nucleus. In addition, afferents from the limbic cortical areas and from the hippocampus and the amygdala terminate in the ventral striatum. The second major class of afferents utilize the neurotransmitter dopamine. In Figure 1.2-22, these projections are shown arising from the substantia nigra pars compacta, but as noted previously ( Fig. 1.2-21), different portions of the striatum receive input from either the dorsal- or ventral-tier dopamine-containing neurons of the ventral mesencephalon. Electron microscopy studies have shown that many of the synapses formed by dopamine axon terminals on medium spiny neuron dendrites are immediately adjacent to the synapses provided by corticostriatal axons, suggesting that dopamine may play an important role in modulating the excitatory influence of cortical projections on striatal neurons. The third afferent system originates in the thalamus. The thalamic nuclei providing the projections are the intralaminar nuclei, particularly the central median nucleus.

FIGURE 1.2-22 Diagram of the inputs to the basal ganglia system. Three major afferent systems have been identified: the corticostriatal, thalamostriatal, and nigrostriatal pathways.

Disruption of the input pathways of the basal ganglia has been associated with some movement disorders, such as Parkinson's disease, which is characterized by muscular rigidity, fine tremor, shuffling gait, and bradykinesia. The most consistent neuropathological feature of Parkinson's disease is a degeneration of the dopamine neurons in the substantia nigra pars compacta, accompanied by a loss of dopamine terminals in the striatum. Levodopa (Larodopa, Dopar), a precursor in the biosynthesis of dopamine, is used as a treatment for Parkinson's disease because of its ability to augment the release of dopamine from the remaining terminals. Conversely, the administration of dopamine receptor antagonists (so-called typical antipsychotics) agents in the treatment of schizophrenia is frequently associated with Parkinsonian features and other motor-system abnormalities; the fact that these agents are D 2-receptor antagonists is thought to explain their movement-related adverse effects. INTERNAL PROCESSING The major processing pathways within the basal ganglia are summarized in Figure 1.2-23. Within the striatum, the subclass of medium spiny neurons that contain the neuropeptide substance P send inhibitory projections to the internal segment of the globus pallidus in what is termed the direct pathway. In contrast, the subpopulation of medium spiny neurons that contain the neuropeptide enkephalin provides inhibitory projections to the external segment of the globus pallidus, which in turn sends inhibitory afferents to the internal segment of the globus pallidus in what is termed the indirect pathway. The globus pallidus external also projects to the pars reticulata of the substantia nigra. The topography found in the afferent projections to the striatum appears to be maintained in that processing pathway. For example, the sensorimotor territories of the striatum project most heavily to the ventral portion of the globus pallidus, whereas association territories project to the dorsal regions of the globus pallidus.

FIGURE 1.2-23 Diagram of the intrinsic circuitry of the basal ganglia. Substance P (SP)-containing striatal neurons send an inhibitory projection directly to the internal segment of the globus pallidus, whereas those containing enkephalin provide an inhibitory projection to GABA neurons in the external segment of the globus pallidus, which in turn project to the internal segment of the globus pallidus. The subthalamic nucleus receives a projection from the external segment of the globus pallidus and projects back to both segments. Finally, the subthalamic nucleus and globus pallidus external project to the substantia nigra pars reticulata.

The external segment of the globus pallidus also gives rise to an inhibitory projection that terminates in the subthalamic nucleus. In contrast, neurons in the subthalamic nucleus provide excitatory projections that terminate in both segments of the globus pallidus and in the pars reticulata. Although most connections within the basal ganglia are unidirectional, a reciprocal projection is found between the external segment of the globus pallidus and the subthalamic nucleus. The intrinsic circuitry of the basal ganglia is disrupted by a severe loss of neurons in the striatum in Huntington's disease. This autosomal-dominant disorder is characterized by progressive chorea and dementia. Although the gene for Huntington's disease has been identified, how the excessive number of trinucleotide repeats in this gene leads to the selective degeneration of striatal cells is currently a matter of intense investigation. Interestingly, recent studies indicate that cortical neurons are also subject to degeneration in Huntington's disease. OUTPUT OF BASAL GANGLIA The internal segment of the globus pallidus is the source of much of the output of the basal ganglia ( Fig. 1.2-24). That segment of the globus pallidus provides a projection to the ventral lateral and ventral anterior nuclei of the thalamus and to the intralaminar thalamic nuclei—in particular, the central median nucleus. The pars reticulata of the substantia nigra also provides a projection to the ventral anterior and ventral lateral thalamic nuclei. Those portions of the ventral lateral and ventral anterior thalamic nuclei then project to the premotor and prefrontal cortices. As a result of the projections of the premotor and prefrontal cortices to the primary motor cortex, the basal ganglia are able to indirectly influence the output of the primary motor cortex. In addition, the cortical output of the basal ganglia exhibits marked convergence, that is, although the striatum receives afferents from all regions of the neocortex, the eventual output of the globus pallidus and the pars reticulata is largely conveyed through the thalamus to a much smaller portion of the neocortex, the premotor and prefrontal regions.

FIGURE 1.2-24 Diagram of the output of the basal ganglia system. The internal segment of the globus pallidus projects to the central median (CM), ventral lateral (VL), and ventral anterior (VA) nuclei of the thalamus. Those nuclei then project to sensorimotor, prefrontal, and premotor cortices. The substantia nigra pars reticulata also projects to the VL and VA nuclei.

The functional consequences of the neural circuitry of the basal ganglia can also be considered in the context of some of the neurotransmitters used ( Fig. 1.2-23 and Fig. 1.2-24). Since the afferents from the cortex are thought to use glutamate, which is an excitatory neurotransmitter, cortical afferents presumably excite the

structures of the basal ganglia in which they terminate. Many of the processing pathways within the basal ganglia use the inhibitory neurotransmitter GABA. Finally, the output pathways of the basal ganglia—namely, the globus pallidus and the substantia nigra pars reticulata—use GABA as well. Thus, excitation from cortical afferents eventually disinhibits the target structures of the basal ganglia because of the back-to-back inhibitory pathways of the basal ganglia. Historically, motor systems have been divided into pyramidal (corticospinal) and extrapyramidal (basal ganglia) components; that division is based on clinical findings suggesting that lesions of each system result in distinct motor syndromes. For example, lesions of the extrapyramidal system result in involuntary movements, changes in muscle tone, and slowness of movement; lesions of the pyramidal system lead to spasticity and paralysis. Because of these findings the pyramidal and extrapyramidal systems were thought to independently control voluntary and involuntary movement, respectively. However, for several reasons that division is no longer accurate. First, other structures of the brain outside the traditional pyramidal and extrapyramidal systems, such as the cerebellum, are involved in the control of movement. Second, the pyramidal and extrapyramidal systems are not independent—their neural circuits are interconnected. For example, the basal ganglia influence motor behavior through certain regions of the cerebral cortex, which then directly (through the corticospinal tract) or indirectly (through specific brainstem nuclei) produce motor activity. Finally, although the basal ganglia are important in the control of movement, they also appear to be involved in other functions of the brain. For example, recent studies of the connections of the basal ganglia in nonhuman primates also support a role for these structures in cognitive functions. The dorsolateral prefrontal cortex has been shown to receive inputs from portions of the thalamus that are the targets of projections from specific locations within the internal segment of the globus pallidus, providing evidence for a distinct pallido-thalamo-cortical pathway. Thus, in addition to linking association regions of the cerebral cortex, such as the prefrontal and posterior parietal areas, with the control of motor activity in the primary motor cortex, some of the output of the basal ganglia appears to be directed back to regions of the prefrontal cortex. These findings suggest that “closed” loops exist between the prefrontal cortex and basal ganglia, which presumably have a cognitive rather than a motor function. Limbic System The concept of the limbic system as a neural substrate for emotional experience and expression has a rich but controversial history. More than 100 years ago Pierre Broca applied the term “limbic” (from the Latin limbus for border) to the curved rim of the cortex, including the cingulate and the parahippocampal gyri, located at the junction of the diencephalon and the cerebral hemispheres ( Fig. 1.2-25). In 1937, primarily on the basis of anatomical data James Papez postulated that these cortical regions were linked to the hippocampus, the mammillary body, and the anterior thalamus in a circuit that mediated emotional behavior (Fig. 1.2-26). That concept was supported by the work of Heinrich Klüver and Paul Bucy, who demonstrated that temporal lobe lesions, which disrupt components of the circuit, alter affective responses in nonhuman primates. In 1952, Paul MacLean coined the term limbic system to describe Broca's limbic lobe and related subcortical nuclei as the neural substrate for emotion.

FIGURE 1.2-25 Schematic drawing of the major anatomical structures of the limbic system. Note that the cingulate and parahippocampal gyri form the “limbic lobe,” a rim of tissue located along the junction of the diencephalon and the cerebral hemispheres. (Adapted from Hendelman WJ: Student's Atlas of Neuroanatomy. Saunders, Philadelphia, 1994.)

FIGURE 1.2-26 Diagram of the neural circuit for emotion as originally proposed by James Papez.

However, over the last 45 years it has become clear that some limbic structures (e.g., the hippocampus) are also involved in other complex brain processes such as memory. In addition, expanding knowledge of the connectivity of traditional limbic structures has made it increasingly difficult to define the boundaries of the limbic system. Despite those limitations, the concept of a limbic system may still be a useful way to describe the circuitry that relates certain telencephalic structures and their cognitive processes with the hypothalamus and its output pathways that control autonomic, somatic, and endocrine functions. Major Structures There is no unanimity on which brain structures constitute the limbic system. This section includes the brain regions that are most commonly listed as components of the limbic system: the cingulate and parahippocampal gyri (limbic cortex), the hippocampal formation, the amygdala, the septal area, the hypothalamus, and related thalamic and cortical areas. LIMBIC CORTEX The limbic cortex is composed of two general regions, the cingulate gyrus and the parahippocampal gyrus ( Fig. 1.2-25). The cingulate gyrus, located dorsal to the corpus callosum, includes several cortical regions that are heavily interconnected with the association areas of the cerebral cortex. As the cingulate gyrus travels posteriorly, it becomes continuous (via the cingulum bundle of fibers in the white matter) with the parahippocampal gyrus, located in the medial temporal lobe, which contains several distinct cytoarchitectonic regions. One of the most important of those regions is the entorhinal cortex, which not only funnels highly processed cortical information to the hippocampal formation but is also a major output pathway from the hippocampal formation. HIPPOCAMPAL FORMATION Three distinct zones—the dentate gyrus, the hippocampus, and the subicular complex—constitute the hippocampal formation, which is located in the floor of the temporal horn of the lateral ventricle (see Fig. 1.2-7). Those zones are composed of adjacent strips of cortical tissue that run in a rostral-caudal direction but fold over each other mediolaterally in a spiral fashion, resulting in a C-shaped appearance. The dentate gyrus is composed of three layers: an outer, acellular molecular layer, which faces the subarachnoid space of the hippocampal fissure; a middle layer composed of granule cells; and an inner polymorphic layer (Fig. 1.2-27). The granule cells extend their dendritic trees into the molecular layer and give rise to axons that form the mossy fiber projection to the hippocampus.

FIGURE 1.2-27 Nissl-stained coronal section through the dentate gyrus of the human hippocampal formation. Medial is to the left. M, molecular layer; G, granular layer; P, polymorphic layer. Calibration bar equals 1.0 mm.

The hippocampus is also a trilaminate structure composed of molecular and polymorphic layers and a middle layer that contains pyramidal neurons. On the basis of differences in cytoarchitecture and connectivity, the hippocampus can be divided into three distinct fields, which have been labeled CA3, CA2, and CA1. ( CA is derived from the term cornu ammonis after the Egyptian deity Ammon, who was depicted with ram's horns, which some early investigators thought described the shape of the hippocampus.) The white matter adjacent to the polymorphic layer of the hippocampus is known as the alveus. The axons in that structure contribute to the fimbria, which at the caudal end of the hippocampus becomes the crus of the fornix. Those bilateral structures converge to form the body of the fornix, which travels anteriorly and then turns inferiorly to form the columns of the fornix, which pass through the hypothalamus into the mammillary bodies ( Fig. 1.2-28). The subicular complex is generally considered to have three components—the presubiculum, the parasubiculum, and the subiculum—which together serve as transition regions between the hippocampus and the parahippocampal gyrus.

FIGURE 1.2-28 Schematic drawing of a cross-sectional view of the hippocampal formation and the path of the fornix running between that structure and the mammillary bodies. (Adapted from Hendelman WJ: Student's Atlas of Neuroanatomy. Saunders, Philadelphia, 1994.)

The components of the hippocampal formation have a distinct pattern of intrinsic connectivity that is largely unidirectional and provides for a specific flow of information (Fig. 1.2-29). The major input to the hippocampal formation arises from neurons in layers II and III of the entorhinal cortex that project through the perforant path (i.e., through the subiculum and the hippocampus) to the outer two thirds of the molecular layer of the dentate gyrus, where they synapse on the dendrites of granule cells. The mossy fiber axons of the granule cells then provide a projection to the pyramidal neurons of the CA3 field of the hippocampus. Axon collaterals from CA3 pyramidal neurons project within CA3 and, through the so-called Schäffer collaterals, to the CA1 field of the hippocampus. That region in turn projects to the subicular complex, which provides output to the entorhinal cortex, completing the circuit.

FIGURE 1.2-29 Diagram of the intrinsic neural circuitry of the hippocampal formation.

AMYGDALA Located in the medial temporal lobe just anterior to the hippocampal formation are a group of nuclei referred to as the amygdala (see Fig. 1.2-6). Those nuclei form several distinct clusters: the basolateral complex, the centromedial amygdaloid group, and the olfactory group, including the cortical amygdaloid nuclei. The basolateral complex, the largest of the three groups, differs from the remaining amygdaloid nuclei in a number of respects. Although the basolateral complex is not a laminated structure, its connectivity and some other anatomical characteristics are more similar to cortical regions than to the remaining amygdaloid nuclei. For example, the basolateral nuclei are directly and reciprocally connected with the temporal, insular, and prefrontal cortices. In addition, like some cortical regions, the basolateral complex shares bidirectional connections with the medial dorsal thalamic nucleus, and it receives projections from the midline and intralaminar thalamic nuclei. Finally, neurons of the basolateral complex with a pyramidal-like morphology appear to furnish projections to the striatum that use excitatory amino acids as neurotransmitters. Thus, on the basis of those anatomical characteristics, the basolateral complex can be said to function like a multimodal cortical region. In contrast, the centromedial amygdala appears to be part of a larger structure that is continuous through the sublenticular substantia innominata with the bed nucleus of the stria terminalis. That larger structure, which has been termed the extended amygdala, consists of two major subdivisions. The central subdivision of the extended amygdala includes the central amygdaloid nucleus and the lateral portion of the bed nucleus of the stria terminalis. That subdivision is reciprocally connected with brainstem viscerosensory and visceromotor regions and with the lateral hypothalamus. In addition, it receives afferents from cortical limbic regions and the basolateral amygdaloid complex. In contrast, the medial subdivision of the extended amygdala, composed of the medial amygdaloid nucleus and its extension into the medial part of the bed nucleus of the stria terminalis, is distinguished by reciprocal connections with the medial or endocrine portions of the hypothalamus. SEPTAL AREA The septal area is a gray matter structure located immediately above the anterior commissure ( Fig. 1.2-30). The septal nuclei are reciprocally connected with the hippocampus, the amygdala, and the hypothalamus and project to a number of structures in the brainstem.

FIGURE 1.2-30 Schematic drawing of some components of the limbic system showing the major output pathways of the amygdala, the stria terminalis and the ventral amygdalofugal pathway. (Adapted from Hendelman WJ: Student's Atlas of Neuroanatomy. Saunders, Philadelphia, 1994.)

HYPOTHALAMUS The hypothalamus, a relatively small structure within the diencephalon, is a crucial component of the neural circuitry regulating not only emotions but also autonomic, endocrine, and some somatic functions. In addition to its relations with other components of the limbic system, it is interconnected with various visceral and somatic nuclei of the brainstem and the spinal cord, and it provides an output that regulates the function of the pituitary gland. On its inferior surface the hypothalamus is bounded rostrally by the optic chiasm and caudally by the posterior edge of the mammillary bodies. The area of the hypothalamus between those two structures, called the tuber cinereum, gives rise to the median eminence, which is continuous with the infundibular stalk and then the posterior lobe of the pituitary gland (Fig. 1.2-31). On the basis of these features the hypothalamus is subdivided from anterior to posterior into three zones: the supraoptic region, the tuberal region, and the mammillary region. (In addition, the preoptic area, a telencephalic structure located immediately anterior to the supraoptic region is usually considered part of the hypothalamus.) These three zones are also divided on each side into medial and lateral areas by the fornix as it travels through the body of the hypothalamus to the mammillary bodies. As shown in Table 1.2-3, the six parts of the hypothalamus contain different nuclei.

FIGURE 1.2-31 Schematic drawing of the nuclei in the medial hypothalamus. (Adapted from Burt AM: Textbook of Neuroanatomy. Saunders, Philadelphia, 1993.)

Table 1.2-3 Hypothalamic Nuclei

Those different nuclei subserve the diverse functions of the hypothalamus. For example, the suprachiasmatic nucleus receives both direct and indirect projections from the retina and appears to be important in the regulation of diurnal rhythms. The supraoptic and paraventricular nuclei contain large cells (magnocellular neurons) that send oxytocin and vasopressin-containing fibers to the posterior neural lobe of the pituitary. In addition, some neurons of the paraventricular nucleus project to the median eminence, where they release neuropeptides, such as corticotropin-releasing factor, into the portal blood system. These neuropeptides then control the synthesis and the release of anterior pituitary hormones. The paraventricular nucleus also gives rise to descending projections that regulate the sympathetic and parasympathetic autonomic areas of the medulla and the spinal cord. Within the medial tuberal region of the hypothalamus, the ventromedial and arcuate nuclei also participate in the regulation of the anterior pituitary function. In addition, the ventromedial nucleus may play an important role in reproductive and ingestive behavior. The medial posterior section of the hypothalamus contains the posterior nucleus and the mammillary bodies. Within the mammillary bodies, the lateral and medial mammillary nuclei receive hippocampal input through the fornix (Fig. 1.2-28) and project to the anterior nuclei of the thalamus. The posterior nucleus shares reciprocal connections with the extended amygdala. That nucleus appears to be more developed in primates than in rodents, suggesting that it plays an important role in the human brain, one that has still to be clarified. The lateral portions of the hypothalamus contain a relatively low density of neurons scattered among longitudinally running fibers of the medial forebrain bundle, which is interconnected with multiple regions of the forebrain, the brainstem, and the spinal cord. Functional Circuitry The major structures of the limbic system are interconnected with each other and with other components of the nervous system in a variety of ways. However, several major output pathways of the limbic system are clearly defined. In one pathway ( Fig. 1.2-32) highly processed sensory information from the cingulate, the orbital and temporal cortices, and the amygdala is transmitted to the entorhinal cortex of the parahippocampal gyrus and from there to the hippocampal formation. After traversing the intrinsic circuitry of the hippocampal formation, information is projected through the fornix either to the anterior thalamus, which in turn projects to the limbic cortex or to the septal area and the hypothalamus. Those latter two regions provide feedback to the hippocampal formation through the fornix. In addition, the mammillary bodies of the hypothalamus project to the anterior thalamus. Finally, the hypothalamus and the septal area project to the brainstem and the spinal cord.

FIGURE 1.2-32 Functional neural circuitry of the limbic system. This diagram illustrates the manner in which the hippocampal formation and the anterior thalamus provide a mechanism for the integration of information between the cerebral cortex and the hypothalamus. F, fornix; MTT, mammillothalamic tract. (Adapted from Nolte J: The Human Brain: An Introduction to Its Functional Anatomy, ed 3. Mosby, St. Louis, 1993.)

Another major pathway within the limbic system centers on output from the amygdala (Fig. 1.2-33). Highly processed sensory information, primarily from the association regions of the prefrontal and temporal cortices, projects to the amygdala. Output from the amygdala is conducted through two main pathways ( Fig. 1.2-30). A dorsal route, the stria terminalis, accompanies the caudate nucleus in an arch around the temporal lobe and contains axons that project primarily to the septal area and the hypothalamus. The second major output route, the ventral amygdalofugal pathway passes below the lenticular nucleus and contains fibers that terminate in a number of regions, including the septal area, the hypothalamus, and the medial dorsal thalamic nucleus. The medial dorsal nucleus in turn projects heavily to prefrontal and some temporal cortical regions.

FIGURE 1.2-33 Functional neural circuitry of the limbic system. This diagram illustrates how the amygdala and the medial dorsal thalamus serve to integrate information processing between prefrontal and temporal association cortices and the hypothalamus. V, ventral amygdalofugal pathway; ST, stria terminalis. (Adapted from Nolte J: The Human Brain: An Introduction to Its Functional Anatomy, ed 3. Mosby, St. Louis, 1993.)

Both these pathways reveal how the limbic system is able to integrate the highly processed sensory and cognitive information content of the cerebral cortical circuitry with the hypothalamic pathways that control autonomic and endocrine systems. In addition, the limbic system interacts with components of the basal ganglia system (Fig. 1.2-34). For example, the ventral amygdalofugal pathway also projects to the nucleus accumbens (ventral striatum), the area where the head of the caudate nucleus fuses with the putamen (Fig. 1.2-20). That region sends efferents to the ventral palladium, an extension of the globus pallidus, which in turn projects to the medial dorsal thalamic nucleus. The pathway indicates that the functions of the basal ganglia extend beyond the regulation of motor activities and shows the necessity of considering the function or dysfunction of particular brain regions in the context of all aspects of their circuitry.

FIGURE 1.2-34 Functional neural circuitry of the limbic system. This drawing illustrates the interaction between the limbic system and certain components of the basal ganglia. (Adapted from Nolte J: The Human Brain: An Introduction to Its Functional Anatomy, ed 3. Mosby, St. Louis, 1993.)

SUGGESTED CROSS-REFERENCES Section 1.4 discusses monoamine neurotransmitters, Section 1.5 discusses amino acid neurotransmitters, Section 1.8 discusses intraneural signaling pathways, Section 2.5 discusses movement disorders, Section 3.5 discusses the brain circuitry that subserves memory, Section 12.3 discusses brain structure and function in schizophrenia, Chapter 37 discusses communication disorders, Section 51.2b discusses central nervous system changes in normal aging, Section 51.2e and Section 51.2f discuss neuroimaging, and Section 51.3e discusses Alzheimer's disease and other dementing disorders. SECTION REFERENCES Alexander GE, Crutcher MD: Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends Neurosci 13:266, 1990. Beall MJ, Lewis DA: Heterogeneity of layer II neurons in human entorhinal cortex. J Comp Neurol 321:241, 1992. Bloom FE, Björklund A, Hökfelt T, editors: Handbook of Chemical Neuroanatomy, vol 13. New York, Elsevier, 1997. Burt AM: Textbook of Neuroanatomy. Saunders, Philadelphia, 1993. Calabresi P, De Murtas M, Bernard G: The neostriatum beyond the motor function: Experimental and clinical evidence. Neuroscience 78:39, 1997. Castro-Alamancos MA, Connors BW: Thalamocortical synapses. Prog Neurobiol 51:581, 1997. Chesselet M-F, Delfs JM: Basal ganglia and movement disorders: An update. Trends Neurosci 19:417, 1996. Condé F, Lund JS, Jocobowitz DM, Baimbridge KG, Lewis DA: Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: Distribution and

morphology. J Comp Neurol 341:95, 1994. Felleman DJ, Van Essen DC: Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1:36, 1991. Gloor P: The Temporal Lobe and Limbic System. Oxford, New York, 1997. Guillery RW, Feig SL, Lozsádi DA: Paying attention to the thalamic reticular nucleus. Trends Neurosci 21:28, 1998. *Heimer L, Harlan RE, Alheid GF, Garcia MM, De Olmos J: Substantia innominata: A notion which impedes clinical-anatomical correlations in neuropsychiatric disorders. Neuroscience 76:957, 1997. Hendelman WJ: Student's Atlas of Neuroanatomy. Saunders, Philadelphia, 1994. Kandel ER, Schwartz JH, Jessel TM, editors: Principles of Neural Science, ed 3. Elsevier, New York, 1991. Lewis DA: Development of the prefrontal cortex during adolescence: Insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology 16:385, 1997. Lewis DA: The catecholaminergic innervation of primate prefrontal cortex. J Neural Transm 36:179, 1992. *Lewis DA, Sesack SR: Dopamine systems in the primate brain. In Handbook of Chemical Neuroanatomy, FE Bloom, A Björklund, T Hökfelt, editors, vol 13. Elsevier, New York, 1997. Lynda-Balta E, Haber SN: The organization of midbrain projections to the ventral striatum in the primate. Neuroscience 59:625, 1994. Nieuwenhuys R, Voogd J, Van Huijzen C: The Human Central Nervous System: A Synopsis and Atlas, ed 3. Springer, New York, 1988. *Nolte J: The Human Brain: An Introduction to its Functional Anatomy. Mosby, St. Louis, 1993. O'Donnell P, Grace AA: Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull, in press. Parent A, Hazrati L-N: Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev 20:91, 1995. Parent A, Hazrati L-N: Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Rev 20:128, 1995. Raymond JL, Lisberger SG, Mauk MD: The cerebellum: A neuronal learning machine? Science 272:1126, 1996. *Ricci PT, Zelkowitz BJ, Nebes RD, Meltzer CC, Mintun MA, Becker JT: Functional neuroanatomy of semantic memory: Recognition of semantic associations. Neuroimage 9:88, 1999. Risold PY, Thompson RH, Swanson LW: The structural organization of connections between hypothalamus and cerebral cortex. Brain Res Rev 24:197, 1997. *Salloway S, Cummings J: Subcortical structures and neuropsychiatric illness. Neuroscientist 2:66, 1996. Shink E, Bevan MD, Bolam JP, Smith Y: The subthalamic nucleus and the external pallidum: Two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience 73:335, 1996. *Stahl SM: Substance P and the neurokinins: Novel peptide neurotransmitters in psychopharmacology. J Clin Psychiatry 60:77, 1999. *Young PA, Young PH: Basic Clinical Neuroanatomy. William & Wilkins, Baltimore, 1997.

Textbook of Psychiatry

1.3 DEVELOPMENTAL NEUROBIOLOGY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.3 DEVELOPMENTAL NEUROBIOLOGY KATHRYN J. KOTRLA, M.D. AND DANIEL R. WEINBERGER, M.D. Prenatal Development Early Postnatal Development Neuronal Plasticity Suggested Cross-References

Human behaviors, thoughts, and emotions reside in the interface between the mind and the brain. The mind is experienced; the brain is the substrate on which mind depends. Basic neuroscience research provides an impressive array of information about the brain. The genes and molecules required for normal brain formation and functioning are being discovered, as are the many neural networks that subserve different aspects of cognition, memory, and mood. The practicing psychiatrist does not need to know the details of neuronal connectivity and functioning. However, moving from a knowledge of the concepts of basic neuroscience to an understanding of the mind is within the domain of psychiatry and will impact psychiatric care substantially. Three threads of basic neuroscience research are particularly important. Developmental neurobiology explores the mechanisms underlying prenatal and postnatal brain development. Psychiatric conditions like schizophrenia and autistic disorder are likely to have their origins in utero. Understanding development will illuminate the etiology of such disorders, and may suggest novel treatment and prevention strategies. During postnatal development there are critical periods in which the fine-tuning of cortical connections occurs. Understanding critical periods during early childhood may help to explain the lifelong difficulties of individuals who suffer trauma, abuse, or neglect in early life. Lastly, neuroscience is investigating the continued plasticity of the adult brain. Understanding how the adult brain changes with time and experience has implications for how psychiatric disorders change in their expression and treatment responsiveness over a lifetime.

PRENATAL DEVELOPMENT The wonder of development is that a structure as complex as the human brain originates from a flat sheet of embryologic ectoderm. The final, formed brain shows remarkable order in its predictable cortical layering, its diversity of cortical areas, and the numerous networks linking specific cortical areas and subcortical structures. To have cells choosing to become a certain neuronal type, attaining the correct laminar position, finding the correct target, and expressing the correct neurotransmitters at first seems overwhelmingly difficult. However, the final, breathtakingly complex set of connections in the human brain depends on a series of much simpler decisions as neurons become progressively more restricted in the choices they make. These decisions require the subtle interplay of genetic and environmental factors; much has been learned at a molecular level about these processes. At first glance this information seems most relevant to mental retardation or autistic disorder, in which abnormal brain development results in lifelong disability. However, even schizophrenia is believed to originate in subtle aberrant brain development, and understanding it requires an understanding of its etiology. Neurogenesis and Neural Identity The cerebral cortex possesses an orderly six-layered array of neuronal and glial cell types; layer I is the most superficial layer closest to the meninges, layer VI lies deeper, closest to white matter. Each layer has characteristic interconnections, with the superficial layers connecting with other cortical areas, and the deeper layers connecting to subcortical structures. Across the cortex there are microscopic variations in the appearance of the array, corresponding to areas of cortex with distinct functions, connections, receptors, and neurotransmitters ( Fig. 1.3-1). Such complexity arises via a series of progressive restrictions in cell fate.

FIGURE 1.3-1 The cerebral cortex contains discrete areas with differing cytoarchitecture. This drawing shows the six layers of the cortex (I-VI). The five different panels illustrate marked differences in cortical structure in different brain areas. Note the variations in neuronal size and morphology. (Reprinted with permission from Carpenter MB, Sutin J: Human Neuroanatomy, ed 8. Williams & Wilkins, Baltimore, 1983.)

The initial decision to form a brain depends on the embryonic mesoderm inducing the overlying ectoderm to become nervous system. This sheet of ectoderm, the neural plate, invaginates to form the neural tube as cells are progressively determined to form forebrain, midbrain, and hindbrain even before any neurons have been generated. On the inner surface of the neural tube there is a rapidly dividing pseudostratified epithelium that forms a ventricular zone. From the neural ectoderm arise neuroblasts, which are precursor cells located in the ventricular zone. Neuroblasts divide and produce a lineage of daughter cells that migrate into the developing cortex to form cortical neurons. In humans, cortical neurons are born from around gestational day 40 until day 125. The first postmitotic neurons leave the neuroepithelium and accumulate beneath the pial surface to form the preplate. This is split by later-generated neurons, the cortical plate, into a superficial, marginal zone (future layer I) and a deep subplate zone. As cortical plate neurons are born, they populate layers VI through II of the adult cortex, between the marginal and subplate zones. Normally, the six cortical layers are generated in an orderly sequence, with first-born neurons residing in the deeper cortical layers, and later-born neurons residing in more superficial layers. One early decision a neuron faces is to which cortical layer to belong. This decision is reached before the final cell division producing the daughter neuron, and is based on cues in the neuron's microenvironment, including previously generated cells. This was shown experimentally by transplanting younger cortex making deep-layer neurons into older cortex making superficial-layer neurons. If neuroblasts are transplanted before daughter neurons are born, the daughter neurons become superficial-layer neurons, consistent with the local environment. However, if the progenitor neuroblasts are transplanted closer to the daughter neurons' birth, the daughter neurons migrate to deep cortical layers, true to their original laminar fate. Laminar identity is probably marked molecularly, and this marker may be used during later neuronal migration and target finding. The microenvironment may also provide other information about a neuron's fate, such as what kind of cortex to become. For example, limbic cortex is marked by a protein that distinguishes it from other cortical areas. Very soon after neurogenesis, the cells destined to form the prefrontal, cingulate, perirhinal, and hippocampal cortices are marked on their surfaces by a specific molecule, called limbic system-associated membrane protein (LAMP). The neocortex as a whole is also distinct from other forebrain regions in its expression of specific regulatory genes. Later differences in neocortical areas, like whether to become visual cortex or sensory cortex, are likely to be determined by epigenetic factors and afferent inputs. Other localizing information, which may guide afferent ingrowth, seems to be provided around neurogenesis. Positional information in the neuroepithelium is probably imparted to preplate cells around the time they are generated; this information is used in the subplate to control the targeting of ingrowing thalamocortical axons, at

least in the neocortex. Abnormalities in the assignment of laminar identity or cortical area markers could result in disordered cortical layers or in the formation of incorrect afferent and efferent connections. Neuronal Migration Once neurons are born in the ventricular zone, they migrate past earlier born neurons to assume their final laminar position. The formation of the six cortical layers is complete between gestational age 26 and 29 weeks. To reach their laminar location, neurons migrate along radial glial fibers that stretch from the ventricular to superficial surface, a journey that may take place over tens of millimeters. Neurons must travel through a complex, rapidly expanding zone containing afferents from the thalamus and other cortical areas ( Fig. 1.3-2).

FIGURE 1.3-2 To form the cortex, neurons are born in the ventricular zone and migrate along radial glial cells to assume their position in the correct cortical layer. The upper figure clarifies the relationship between the ventricular surface, where neurons are born, and their final destination in the cortical plate. More detail is provided in the lower left drawing. This figure labels the ventricular zone, the large expanse of the intermediate zone through which the neuron migrates, and the final developing cortical layers in the cortical plate. The drawing on the lower right demonstrates the morphology of a migration neuron as it climbs along a radial glial cell through the intermediate zone. (Reprinted with permission from Maxwell Cowan W: The development of the brain. Sci Am 241:124, 1979.)

During migration, there appear to be transient synapses and expression of neurotransmitters and neuromodulators, suggesting a chemical interaction between the migrating neurons and the embryonic environment, which influences the rate of neuronal migration. Also, contact interaction between migrating neurons and the surfaces of neighboring cells plays a crucial role in selecting migratory pathways, and in choosing to detach from the radial glial fiber and stop migrating. Stopping migration is probably an active process, and may depend on cell surface markers conferring laminar identity. The vast majority of neurons find the correct position; the small percentage of neurons that migrate to the wrong location mostly degenerate during the later phase of naturally occurring cell death. Establishing Connections After finding the correct layer comes the intricate decision to establish connections between different brain regions. This process occurs between subcortical and cortical areas, within cortical areas, and between cortical areas. The final fate and functioning of neocortex are very dependent on the connections it establishes. How does a neuron extend its axon through the complex embryonic environment to find its correct target? The leading edge of the axon, the growth cone, has an array of molecules on its surface. It interacts with molecules on other cells, axons, and the extracellular matrix in the embryonic environment. The molecules in the growth cone's environment are differentially adhesive or repellent. They cause the growth cone to grow where there are adhesive molecules and to avoid repulsive molecules that cause the growth cone to collapse. To choose among the number of possible pathways in the embryonic environment, the growth cone samples among the choices by means of its filopodia, and grows along specific pathways to which it is adherent or does not encounter repulsive molecules. There also appear to be diffusible gradients towards which some growth cones grow. To illustrate the complexity of pathfinding, axons from the lateral geniculate nucleus, the visual thalamus, must navigate long distances to find the visual cortex, and then grow specifically into layer IV to synapse. Thalamic afferents presumably select their cortical targets based on molecular information on target cells or in the extracellular matrix. The subplate plays a crucial role during development, allowing afferents from thalamic neurons to wait under the developing cortex until layer IV neurons are born and migrate to their final location. In the absence of the subplate, ingrowing thalamic afferents grow past the visual cortex and fail to find their appropriate target. Finding the appropriate cortical layer is likely to depend on laminar addresses conferred when neurons are born. For example, just as thalamic afferents to the visual cortex find layer IV, axons of layer III cortical neurons bypass layer IV to make specific connections with layer V. Even if layer V neurons are transplanted to foreign locations, they still send their axons to appropriate targets. The molecules guiding pathway selection are being identified and characterized rapidly. One of the first discovered was the neural cell adhesion molecule (NCAM). NCAM is one of a family of molecules that mediates cell-cell or cell-substrate adhesion, and is found in many parts of the developing nervous system. Deficits in NCAM expression result in subtle cytoarchitectural abnormalities in specific brain areas. Similarly, growth-associated protein (GAP-43) is a molecule that plays a key role in guiding axon growth and modulating new connections. If GAP-43 is overexpressed, aberrant extra connections are formed in the hippocampus and other areas of the central nervous system and the peripheral nervous system. Conversely, in the absence of GAP-43, grossly abnormal connections are established. However, there are molecules that provide more specific pathway selection information. The LAMP molecule, which marks the identity of limbic and prefrontal cortices, is needed for the formation of axon pathways between neurons in the prefrontal, cingulate, and limbic areas. It is also required for the thalamus to send correct inputs into these cortical areas, completing a network linking cortical and subcortical structures. Cell Death Once cortical neurons are created and assume their connections, there is a period of naturally occurring cell death ( apoptosis) in widespread areas. Apoptosis is a complex cellular process, including the expression of specific gene sequences, that ultimately leads to deoxyribonucleic acid (DNA) fragmentation and nuclear dissolution. It is distinctly different from necrosis in that cells are not damaged by external agents but die after the activation of an internal program. Also, apoptosis does not produce an inflammatory response like necrosis does. Neurons that make an adequate number of appropriate connections do not express the genes leading to apoptosis, presumably because of the trophic factors they receive from their connections, which prevent expression of the apoptotic program. Apoptosis occurs mostly during the second half of gestation, and may result in the loss of 25 to 40 percent of the neurons in different cortical layers. The extent of cell death is controlled by influences from the neuron's synaptic targets, afferent input to the neurons, and local glial-derived and extracellular matrix molecules. If the amount of target or afferent input is diminished, more cell death results; similarly, if target or afferents are increased, the number of surviving neurons increases. Notably, even in adults neurons continue to depend on their efferent and afferent connections both for their survival and the maintenance of normal morphology and biosynthetic events. Neuronal Differentiation and Neurotransmitter Selection The cues governing final neuronal phenotype and neurotransmitter selection also arise from multiple sources. These include previously generated neurons, glia, the extracellular matrix, various trophic factors, growth factors, and local neurotransmitters. One critical factor in neuronal differentiation appears to be cortical afferents. The differentiation of neurons in layers VI, V, and IV coincides with the ingrowth of thalamocortical fibers, that of layer III with the arrival of interhemispheric fibers, and that of layer II with the arrival of cortico-cortical fibers. Postsynaptic targets also produce differentiation factors, which alter gene expression in the presynaptic neuron and influence the choice of neurotransmitter and neuropeptides synthesized. A neuron's target can even influence which other cells connect with the neuron's dendrites. Because differentiation factors can be communicated through efferent and afferent connections, these factors regulate neuronal phenotype very precisely. They can influence the functioning of a limited number of neurons linked together in a network, without causing changes in the large numbers of nearby cells. Even in postembryonic, functional neurons, normal fluctuations in neuronal activity or hormone levels or an insult to the system can alter transmitter and neuropeptide expression. Implications for Psychiatry What happens when the developmental plan goes awry? Aberrations in the formation of neural ectoderm or in the formation of neuroblasts are likely to result in gross abnormalities like anencephaly. A generalized failure of the migration of daughter neurons into cortical layers is seen in a lissencephalic brain, characterized by an agyric (smooth) cerebral surface. Mutations in certain cell adhesion molecules affect neural migration or axonal outgrowth, and are associated with inherited hydrocephalus. Such gross pathology is unlikely to result in an illness appreciated as psychiatric because children with these

disorders have severe mental retardation and neurological syndromes. Abnormalities of neural migration have been implicated in radiation exposure, fetal alcohol syndrome, epilepsy, reading disorder, autistic disorder, and schizophrenia. A relatively well-researched example is the radiation exposure during Hiroshima and Nagasaki, which caused a disruption of neural migration in fetuses exposed during midgestation (weeks 10 to 17). Postmortem examination showed massive heterotopia, attenuation of superficial cortical layers, and a reduction in cortico-cortical connections; epilepsy and mental retardation were frequent medical sequelae. However, given the intricate interplay of molecules and cells during development, the potential for even more subtle aberrations in cortical development and connections abounds. Localized Abnormalities If abnormalities develop within certain neural networks, specific behavioral, cognitive, or mood symptoms recognized as a psychiatric disorder could conceivably result. Examples of localized abnormalities abound in developmental neurobiology. If monkeys are enucleated in utero, developing visual cortex diminishes in size, and surrounding cortical areas show abnormal cytoarchitecture; even localized neuronal morphologies and neurotransmitter receptor patterns show changes. Efferent connections can also be altered by abnormal afferent connections. If somatosensory input from the thalamus is routed to and synapses with visual cortex, primary visual cortical neurons retain a projection to the spinal cord, acting like somatosensory cortex. Such subtle developmental anomalies are being discovered in many animal species. In the fruitfly, when a cell surface adhesion molecule is deleted genetically, the fly develops a characteristic set of behavioral dysfunction. The fly can walk and jump, but not fly; it has abnormal visual orientation and drinking behavior. This suggests that the molecule is crucial for the development of neural circuits controlling a subset of behavior. There are mutant mice strains characterized by abnormal neural migration localized to the hippocampus. The hippocampus is divided into areas such as CA1, CA2, and CA3. The neurons of the hippocampus are generated during characteristic prenatal intervals in the ventricular zone lining the lateral ventricle. As in other cortical areas, the neurons migrate along primarily radial glial fibers to reach their final location. The migratory path followed by neurons destined for areas CA1 and CA2 is fairly direct. The path followed by neurons destined for area CA3, in contrast, is tortuous and lengthens during the migratory process because of hippocampal growth. One autosomal-dominant mutation, the hippocampal lamination defect mutation, affects only late-generated pyramidal cells destined for area CA3. In this mutation, this very discrete population of pyramidal cells stops in its migration and resides in an ectopic position below earlier-generated cells. This mutant demonstrates that heterotypic neuronal lamination can be limited to certain cell types in specific cortical areas. Kallman's syndrome, an inherited human disorder characterized by hypogonadism and anosmia, is thought to result from the lack of a substrate adhesion molecule. During normal development, olfactory and gonadotropin-releasing hormone neurons migrate along a common pathway. In Kallman's syndrome this migration appears to be arrested, possibly because of a failure in neuronal interaction or synaptogenesis of olfactory neurons and their target in the olfactory bulb. Neuroanatomical findings include aplasia of the olfactory gyri and absent olfactory tracts and bulbs, which implies that an abnormality of a specific molecule causes dysfunction in discrete neuronal areas. Neurodevelopmental Hypothesis of Schizophrenia Although future investigations may suggest that the seeds of other psychiatric illnesses are sown during development, the implications that abnormal brain development has for psychiatry are best illustrated in schizophrenia. The etiology of schizophrenia has been explored using in vivo neuroimaging, and postmortem neuropathological examinations. The neurodevelopmental hypothesis states that schizophrenia results from abnormal brain development, which manifests characteristic symptoms during early adulthood. One dysfunctional neural network in schizophrenia links the association cortices of the frontal, parietal, and temporal lobes and the limbic cortex and subcortical structures. This network contains cortices that are the most evolutionarily advanced, and are critical to executive functioning, memory, and attention ( Fig. 1.3-3) functions that are particularly impaired in persons with schizophrenia. Because these cerebral areas are well defined, it is possible to investigate their integrity, both with in vivo neuroimaging techniques and via postmortem neuropathological examinations.

FIGURE 1.3-3 Cortical and subcortical areas are physically connected into discrete neural networks that subserve distinct aspects of cognition, affect, and behavior. A crucial goal of development is the establishment of the correct neural connections to form these networks. This drawing is a simplification of the multiple pathways connecting the frontal, parietal, and temporal cortices, areas involved in attention and memory, and implicated in schizophrenia. The hatched areas reveal inputs from one thalamic nucleus. (Reprinted with permission from Goldman-Rakic PS: Parallel distributed networks in primate association cortex. Annu Rev Neurosci 11:143, 1988.)

NEUROIMAGING Imaging the brain with magnetic resonance imaging (MRI) allows for volumetric measurements of brain structures. In schizophrenia, reductions on the order of 10 to 15 percent are reported in overall temporal lobe size, in temporal lobe gray matter, and in specific mesial and lateral temporal lobe structures. Recent MRI studies suggest subtle volumetric reductions in widespread cortical areas, including the frontal and parietal secondary association areas, and in the thalamus. Neuroimaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET) can investigate the functioning of these brain regions in vivo. By imaging subjects during tasks, cerebral activity patterns reflect the functioning of neural networks necessary to perform the tasks. In numerous studies individuals with schizophrenia show dysfunction within frontal-parietal-temporal networks, even during different tasks that utilize these cerebral areas. An example is the Wisconsin Card Sorting Test, an abstract problem-solving test requiring attention and working memory. Monozygotic twins discordant for schizophrenia underwent PET blood flow scans while performing this test. In all but one pair the ill twin had relatively decreased prefrontal cerebral blood flow; the mesial temporal lobe limbic region in the ill twin was invariably hyperactive. In vivo studies do not speak to when or how the functional abnormality arose. However, finding functional consequences in cerebral areas defined as abnormal in neuropathological investigations is essential to correlate neurodevelopmental abnormalities with the clinical symptoms of schizophrenia. NEUROPATHOLOGY Postmortem morphometric studies of brains from patients with schizophrenia are consistent with in vivo imaging studies. Schizophrenia is associated with enlarged ventricles and apparently focal decreases in the size of mesial temporal lobe structures, including the amygdala, hippocampus, parahippocampal gyrus, and entorhinal cortex. Similarly, reduced neuronal counts and decreased neuropil have been reported in selected cortical and periventricular regions. One crucial observation is the lack of gliosis in schizophrenia. A proliferation of glial cells is seen in most degenerative brain conditions and encephalopathies that arise after birth. This suggests that whatever causes the brain abnormalities in schizophrenia does so before the third trimester of gestation, when glial cells become responsive to injury. Of considerable interest in understanding the developmental neurobiology of schizophrenia are studies exploring cortical cytoarchitecture, particularly in the networks showing in vivo dysfunction. In the entorhinal cortex of individuals with schizophrenia, heterotopic groups of neurons belonging to layer II are found displaced into layer III. This may indicate abnormal neuronal migration that results in heterotopic neuronal islands, and abnormal cytoarchitecture; unfortunately, not all studies replicate this finding. However, other investigators report reduced numbers of small neurons and abnormal neuronal aggregates in the anterior cingulate. Layer II of the prefrontal cortex of persons with schizophrenia shows reduced numbers of small neurons and higher densities of pyramidal neurons in layer V. A neuron-specific stain for nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) has been used to study brains from patients with schizophrenia. NADPH-d-staining cells are seen in cortex and in subcortical white matter and are likely to be the remnants of subplate neurons. In the prefrontal and lateral temporal

lobe cortex of some patients with schizophrenia these neurons are decreased in the cortex and its subjacent white matter, but are present in abnormally high numbers in deeper white matter. This is consistent with the hypothesis of aberrant neuronal migration in schizophrenia. CONSEQUENCES OF ABNORMAL CYTOARCHITECTURE The number of studies exploring the extent, type, and location of cytoarchitectural abnormalities in schizophrenia is limited. Nevertheless, each positive finding implicates a failure of neurons assuming the correct laminar location, a process that occurs during the second trimester of intrauterine brain development. This could reflect a defect not only in migration, but in the ability to attract the correct afferents or make normal efferent connections. If one area of cortex is abnormal, there will be ramifications in the organization and function of cortical and subcortical areas from which it receives afferents and to which it sends efferents. Because cortical areas depend on their afferent and efferent connections to survive cell death, the reports of reduced cell numbers in schizophrenia could be due to the effects of disordered cortex elsewhere. This is consistent with the subtle cortical volume reductions found in MRI studies of schizophrenia. Not surprisingly, multiple postmortem biochemical and molecular abnormalities are also associated with schizophrenia. These include mesial temporal lobe abnormalities of choline acetyltransferase, glutamate decarboxylase, glutamate, aspartate, serotonin, neurotensin, and substance P. Abnormalities in receptor subtypes include k-opioid, b-adrenergic, serotonin (5-hydroxytryptamine [5-HT]) type 1A [HT 1A], 5-HT 2, g-aminobutyric acid (GABA), as well as alterations in glutamate reuptake sites and adenylate cyclase. In the prefrontal cortex, reported abnormalities include serotonin reuptake sites and met-enkephalin, 5-HT 1A and 5-HT2 muscarinic cholinergic, glutamate and GABA A receptors. Molecules crucial to normal brain development and postnatal plasticity are being investigated in schizophrenia. In brains of persons with schizophrenia abnormalities of NCAM have been reported. GAP-43 is essential for the initial establishment and reorganization of synaptic connections, and remains high throughout life in the limbic system and neocortex, areas involved in the processing and storage of information. In frontal cortex and visual association areas of persons with schizophrenia, levels of GAP-43 protein are increased, which is perhaps a reflection of the plasticity of inputs to prefrontal cortex. GAP-43 messenger ribonucleic acid (mRNA), a measure of intrinsic prefrontal efferent plasticity, is reduced. Levels of synaptophysin also are reduced; synaptophysin is a synaptic–vesicle-associated protein involved in neurotransmitter release that is used as a marker of presynaptic terminal density. Reduced synaptophysin mRNA concentrations are also found in specific regions of the mesial temporal lobe. Although the precise mechanisms controlling these molecular changes remain unknown, the results suggest abnormal synaptic connectivity. If abnormal brain development causes schizophrenia, why does onset of symptoms occur in late adolescence or early adulthood? Frontal–lobe-linked networks, which appear to be dysfunctional in schizophrenia, undergo substantial postnatal maturation. Schizophrenic symptoms may not appear until a critical network is tested at a particular time in postnatal maturation. However, it should be noted that individuals destined to develop schizophrenia showed subtle but significant delays in early-childhood milestones like walking and speech development. This suggests that abnormalities are present virtually from birth, but that their clinical manifestations may vary over time.

EARLY POSTNATAL DEVELOPMENT The early postnatal years are marked by a rapid maturation of cognitive, social, and behavioral abilities as infants progress from helplessness to autonomy, and children and adolescents develop more sophisticated ways of thinking. The information and abilities acquired by infants, children, and adolescents are staggering. The impact that these early years have on personality development and behavior is profound, longlasting, and at times, refractory to treatment interventions. The consequences of physical or emotional childhood trauma are seen in every psychiatric practice. For such dramatic cognitive, behavioral, and emotional changes, there must be an underlying neurobiological substrate. Neuroscience is exploring the structural and functional foundations of normal postnatal maturation and how it is impacted by the environment. Postnatal Cortical Maturation The number of cortical synapses changes dramatically in early postnatal life. Newborn monkeys have approximately the same number of synapses as adult monkeys do. Synaptic density increases in the first few months of life until it is about 40 percent higher than adult values. Synaptic density remains high until adolescence when it decreases to adult levels, and then remains fairly constant throughout life. The pruning of cortical synapses appears to involve primarily excitatory connections. Local circuit interneurons, which are GABAergic, appear to maintain stable synapses from childhood into adulthood. This suggests that exuberant excitatory synaptic connections are selectively remodeled into adultlike connectivity by experience. The maturation of neuronal structure was investigated by a postmortem examination of prefrontal cortex from 10 weeks' gestational age through adulthood. Neurons were stained, and their location and morphology was studied. Distinct cortical areas and layers assume adult morphology at different rates. The subplate has disappeared by birth in the visual and somatosensory cortices, but is present in the prefrontal cortex of the newborn and gradually declines during the first 6 months of life. It may continue to serve a role in the development of postnatal prefrontal cortico-cortical projections. Many neuronal types alter their shape postnatally, corresponding to altered synaptic connections. In several cortical layers in the prefrontal cortex and other association cortices, pyramidal neurons continue dendritic outgrowth and spine formation throughout the first 2 postnatal years. Pyramidal neurons in layers III and V of the prefrontal cortex may not develop adultlike dendritic fields until adolescence. The pyramidal neurons of layer III are a major source of cortico-cortical connections, and they show intensive spine growth during early childhood, possibly as targets of thalamocortical and cortico-cortical fibers. Similarly, the interneurons that modulate pyramidal neurons show postnatal changes. Implications for Psychiatry The continued maturation of prefrontal cortex in early life offers ample opportunities for childhood experience to permanently shape the cortex that controls thought, behavior, and mood. At a gross level, if the processes governing synaptic remodeling and maturation go awry, severe conditions can occur. Fragile X syndrome, the second most common inherited form of mental retardation, is associated with abnormal synapses. Individuals with fragile X show thin, elongated dendritic spines with smaller synaptic contacts, much like the appearance of immature synapses during normal neocortical development. However, environmental input to otherwise normal cortex can also produce dramatic changes in cortical structure and function. Environmental Effects on Cortical Connections During early life the cortex is fine-tuning its connections dependent on patterns of neural activity caused by environmental input. An example is human infants with congenital cataracts. The cataracts must be removed before 4 to 6 months of age, or permanent visual impairment results. Also, if strabismus is not corrected by about 7 years of age, the squinting eye is permanently visually handicapped. The timing of these critical periods corresponds with the normal timing of exuberant synapse elimination. In the human visual cortex, synapse elimination begins at about 6 months and is complete by age 6 or 7 years. The impact of left-hemisphere damage on language development reveals an analogous process. If the brain damage occurs before 8 years of age, language development may recover and seem normal; after 8 years of age, aphasia results. These clinical examples illustrate that the availability of exuberant synapses facilitates functional plasticity. Similarly, normal cortical language representation can be visualized using functional MRI. Individuals who learned two languages during infancy show similar cortical activity when exposed to either language. In contrast, individuals who learned a second language in early adulthood show distinct Broca's area representations of the native and second languages. This illustrates how cortical organization and plasticity is dependent on the time of the environmental influence. However, to more fully understand the mechanisms underlying this plasticity requires experimental animal models. David Hubel and Torsten Wiesel described the impact of environmental manipulations on the visual system in cats and monkeys. Analogous to humans, there is a critical period during visual cortical development during which the cortex is exquisitely sensitive to changes in environmental input. Once the critical period passes, cortical abnormalities are irreversible. In contrast, adult visual cortex is much less sensitive to environmental input; a year of monocular lid closure in an adult cat leads to no detectable cortical effects. If one eyelid is sutured during the critical period, there is little visual input from that eye; if the eye is opened later, vision remains permanently impaired. This is reflected cortically by reduced representation from the sutured eye and expanded representation from the open eye ( Fig. 1.3-4). In the lateral geniculate nucleus, the synaptic waystation between the retina and visual cortex, there is profound atrophy in the geniculate layers receiving input from the covered eye. In the visual cortex, the terminals from visually deprived afferents are smaller, have fewer mitochondria, and make immature-appearing synapses. GAP-43, a molecule implicated in axonal connectivity, has its highest expression in primary visual cortex during the critical period as synapses are remodeled.

FIGURE 1.3-4 Early postnatal environmental inputs dramatically alter cortical structure. The top picture (A) shows an autoradiograph from layer IV of the primary visual cortex of a normal monkey. The light areas reveal inputs from one eye; the dark bands are inputs from the other eye. Equal cortical representation from both eyes is evident. Picture B, an autoradiograph from a monkey whose right eye was closed during infancy, illustrates what happens after monocular deprivation. Note the marked expansion of the light areas, and the shrinkage of the dark bands. The light areas are the inputs from the eye that was open during the experiment. (Reprinted with permission from LeVay S, Wiesel TN, Hubel DH: The development of ocular dominance columns in normal and visually deprived monkeys. J Comp Neurol 191:11, 1980.)

If kittens are deprived of visual input altogether, compensatory changes are seen in the visual areas; there are now neurons that respond to auditory and somatosensory stimulation. Within altered cortex there are alterations in the concentration of serotonin, dopamine, norepinephrine, glutamate, and acetylcholinesterase. This demonstrates that the morphological synaptic, and molecular plasticity of the critical period is crucial for normal cortical connectivity and functioning. Strabismus has also been experimentally induced in cats and monkeys by unilateral ablation of one extraocular muscle. Although these animals are born with a normal CNS, the abnormal visual input and neural activity induced by strabismus causes structural CNS changes. The morphology of retinogeniculate axons is altered, with smaller arbors and fewer boutons compared to normal. The lateral geniculate nucleus contains smaller neuronal cell bodies. The anatomical organization of the visual cortex is also altered with a reduction in the proportion of cells that respond to binocular input and a loss of the normal orientation selectivity. Early environmental manipulations may also impact higher cognitive functioning. This has been elegantly explored in a series of experiments investigating monkey visual recognition memory. Visual recognition memory is the ability to see an object and to consciously remember having seen it before. This capacity requires the interaction of visual pathways and the limbic system. In adult monkeys, area TE is critical for this interaction. Area TE is a cortical region on the lateral temporal lobe that receives projections from multiple visual areas in prestriate cortex, and sends direct and indirect projections to the amygdala, perirhinal cortex, and hippocampus. Adult lesions in area TE significantly impair visual recognition memory. In contrast, infant lesions in area TE leave visual recognition memory intact. This sparing of function is explained by the enhanced plasticity of the immature brain that results from the redundancy of connections. In infants, normally transient projections distribute memory functions throughout several visual association areas. During normal maturation, visual memory becomes more localized to area TE as projections to other areas retract. In animals with TE lesions during infancy, these immature projections are maintained. Moreover, visual areas not normally involved in recognition memory take over that function after early TE lesions. These findings offer evidence for substantial remodeling of cognitive neural networks in response to early environmental manipulations. Additionally, the observation that a specific set of neural connections involved in memory processing normally regresses after infancy has potentially fascinating implications for understanding phenomena such as infantile amnesia. Critical Periods for Cognition and Emotion The importance of critical periods does not apply solely to visual and language cortices. It has stunning implications for how early childhood experiences can leave brain traces that affect brain function and behavior throughout adult life. Just as visual cortex is shaped by experience, neural systems subserving cognition and affect may be equally impacted. For example, animals reared in complex environments have a greater width of the cortical mantle with increased dendritic arborizations, increased numbers of synapses per neuron, and longer postsynaptic densities compared to animals reared in standard cages. Early postnatal environmental manipulations result in long-lasting changes in hippocampal and prefrontal cortical glucocorticoid receptors, which may permanently alter an animal's stress response. Early brain manipulations can also have delayed effects on the regulation of neurochemical systems implicated in adult-onset psychiatric illness. For example, scientists have recently shown that neonatal rat pups who undergo a hippocampal lesion during the first week of life appear relatively normal during their equivalent of childhood. However, during early adulthood they manifest dramatically abnormal behavioral responses to environmental and pharmacological stresses. Antipsychotic medications ameliorate some of these abnormal responses. The abnormalities appear to be modiated by rewiring of the connections involved in the regulation of mesolimbic dopaminergic function. Rats with this developmental lesion have been studied as a potential animal model of a number of phenomena associated with schizophrenia. Behavioral studies in monkeys have shown that early childhood experience can have a profound impact on adult adaptation, especially in the context of social stress. When infant monkeys are removed from their mothers, even for relatively brief periods, their tolerance for stress during adulthood may be reduced. Moreover, the genetic tendency of an animal to be stress sensitive interacts with maternal separations. If a monkey is innately hyperresponsive to environmental stress, childhood maternal separation leads to exaggerated stress responses as an adult. Recently, the molecular consequences of early stress are being identified. In rats, variations in maternal behavior predict alterations in the expression of synaptic markers in the brain of adult animals. Thus, animal studies suggest that early environmental influences have a permanent impact on underlying cerebral structure and function. In humans, there is evidence that early environmental stimulation, even before preschool, improves learning with an effect that lasts for years. Preliminary work suggests that children who have survived global environmental neglect may have underdevelopment of cerebral structures. Similarly, children exposed to chronic trauma have behavioral impulsivity, cognitive distortions, and difficulties with cognitive organization. These children also evidence an array of physiological abnormalities, including hyperarousal, an increased startle response, sleep difficulties, and affect-regulation problems. The plasticity of postnatal cerebral systems provides a neurobiological explanation for the major impact that childhood experiences have on adult functioning. It also offers a substantial opportunity for early childhood therapeutic interventions in vulnerable populations.

NEURONAL PLASTICITY Synaptic plasticity is a property of adult as well as developing or young cortex, and reflects how synaptic strength changes with experience. Its relevance to psychiatry is seen in the course of the illnesses psychiatrists treat. Clinical research supports the notion that psychiatric illnesses progress and become more refractory to treatment over time. This has been demonstrated most clearly in bipolar disorders and schizophrenia. The expression or severity of an illness changing over time implies an underlying change in the neurobiology of the illness. Neuroscience studies of learning and memory have helped to illuminate the plasticity of adult cortex, which can be used as a blueprint for brain changes associated with psychiatric illnesses. What evidence is there for structural brain changes with learning? Cortical Remodeling Human functional neuroimaging studies demonstrate changes in neural activity patterns as a behavior or a response is learned. In nonhuman primates, this can be investigated by recording the firing pattern of cortical neurons. When an adult monkey learns a task, its behavior reflects alterations of neuronal firing patterns distributed in the cortical regions involved in the task. An altered neuronal firing pattern can lead to cortical remodeling; for example, if an adult monkey attends to a tactile stimulus to its finger, the cortical representations from that digit increase. How can neuronal firing patterns lead to a remodeled cortex? Short-term changes, or memory, result from the strengthening of existing synapses. This occurs via the covalent modification of existing proteins after the activation of second-messenger systems. Long-term memory requires neuronal gene expression and protein synthesis, resulting in the growth of new synaptic connections ( Fig. 1.3-5).

FIGURE 1.3-5 Neurons show plasticity associated with learning and experience. This drawing is of identified neurons from the sea slug Aplysia. The sensory neuron and motor neuron are responsible for a behavior that can be observed. The control panel (A) represents the synaptic connections in an untrained animal. After learning trials the number of synaptic connections increases, as demonstrated in B. (Reprinted with permission from Kandel ER: Genes, nerve cells, and the remembrance of things past. J Neuropsychiatry Clin Neurosci 1:118, 1989.)

Long-Term Potentiation (LTP) Learning is being actively explored in mammals, using a model called long-term potentiation in which a prolonged excitatory stimulus delivered to presynaptic hippocampal neurons leads to a long-lasting increased response in postsynaptic neurons. Somehow, the postsynaptic neuron senses the coincidence between its own and presynaptic activity and sends a signal back to concurrently active presynaptic inputs to selectively increase their strength. Neurotransmitters modulate the changes associated with learning and synaptic strengthening. Dopamine is a good candidate as a neuromodulator in the hippocampus, because late LTP can be blocked by dopamine type 1 receptor (D 1) antagonists. Acetylcholine and norepinephrine probably play major roles in facilitating cortical plasticity, and serotonin plays a role in invertebrate systems. LTP involves several phases. Initially, presynaptic stimulation leads to a transient increase in postsynaptic calcium. The increase in intracellular calcium leads to a brief presynaptic increase in neurotransmitter release. However, calcium returns to resting levels within minutes; therefore long-lasting changes in synaptic strength involve additional processes in the presynaptic and postsynaptic neurons. The signal that goes from the postsynaptic to the presynaptic neuron is still being explored, although it may involve nitric oxide. The signal activates second messengers presynaptically, which induce autonomous protein kinase activation. Protein kinases are enzymes that phosphorylate multiple substrates, altering their functioning, altering neuronal physiology, and increasing synaptic strength. When protein kinases become autonomously activated, they are independent of the second messenger. This explains how a short-lived increase in second messengers results in longer-lasting changes in synaptic strength. Protein kinases involved in LTP include protein kinase C (PKC), calcium/calmodulin-dependent kinase II (CaMKII), the cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA), and protein tyrosine kinase (PTK). Substrates for phosphorylation implicated in long-term potentiation include GAP-43 for PKC, the glutamate receptor by CaMKII, and synaptophysin, the nicotinic acetylcholine receptor, and the glutamate receptor by PTKs. Phosphorylating GAP-43 may increase presynaptic neurotransmitter release; it also is associated with inducing a neuronal state of growth and synaptic sprouting. Following activation of protein kinases, LTP depends on RNA transcription and protein synthesis and cAMP plays a central role in this process. cAMP concentrations increase in LTP due to calcium and calmodulin stimulation of adenylyl cyclase, the enzyme that produces cAMP. Additionally, D 1 and D5 receptors are coupled to a G protein that increases cAMP concentration when activated. cAMP concentration is crucial to LTP because of its effect on gene transcription. There is a cAMP response element (CRE), which when phosphorylated activates gene transcription. The mRNAs of several CRE-linked genes, including the immediate early gene c- fos, increase during long-term potentiation. The synaptic remodeling underlying learning depends on gene expression. Learning and Gene Expression Immediate early genes (IEG) encode nuclear regulatory proteins that cause stable alterations in the transcription of late genes. Triggering IEG expression can lead to a cascade of gene transcription and synaptic remodeling. In addition to LTP IEGs are implicated in more behaviorally relevant learning paradigms. One-day-old chicks learn to avoid a bitter-tasting bead after a single training exposure. Training induces the IEGs c- fos and c-jun in certain brain regions. After c-fos and c-jun induction, there is enhanced synthesis of a variety of proteins, and increased fucosylation of membrane glycoproteins, including NCAM. Structurally, training results in a 60 percent increase in the density of dendritic spines, increases in synaptic number, and a 60 percent increase in the numbers of synaptic vesicles per synapse. The net result is synaptic remodeling, with active synapses showing increased numbers of boutons. GAP-43 is another molecule important in adult cortical plasticity. In the neocortex of adult humans and nonhuman primates, GAP-43 remains present in limbic and associative areas, suggesting that these areas continue to undergo structural changes associated with learning and memory. Even when networks are formed, the precise connections within them remain responsive to environmental input. The guiding principle, both in final synaptic selections in development and in adult cortical plasticity is summed up in the adage “neurons that fire together wire together.” Implications for Psychiatry Because psychiatric illnesses are thought to be associated with a pattern of neuronal activity, this activity may result in a type of learning that strengthens activity patterns representing the ill state. If the principle “neurons that fire together wire together” operates in psychiatric illnesses, this predicts that, if untreated, psychiatric illnesses would somehow become more entrenched neurobiologically and perhaps become more refractory to treatment. Alternatively, episodes of illness could become more frequent or more severe. Progression of Illness In schizophrenia, the longer a person goes without seeking treatment, the more refractory the illness becomes, requiring more time on and higher doses of medication before symptoms remit. Similar observations are true of mood disorders. Most patients who have one episode of a mood disorder will have repeat episodes, and, especially in bipolar disorder, the intervals between episodes may become shorter. Although the initial episodes of mood disorders are often associated with stressors, later episodes can arise spontaneously. These observations support the hypothesis that the neurobiological underpinnings of these disorders are dynamic, changing with time and as a result of cortical remodeling. Two experimental models have been used to explain the progression of bipolar disorder. One is kindling, in which electrical current in the amygdala induces seizures in rats. After a number of current-induced seizures, spontaneous epilepsy develops in the absence of stimulation. The second is stimulant-induced sensitization, where an animal shows greater behavioral changes to a consistent amount of stimulant after repeated exposures. In both these models, the environmental manipulations rapidly activate neurotransmitter pathways, and over the long term, also activate gene expression, including of c-fos. The abnormal neural activity induced by seizures results in axonal growth and synaptic reorganization in limbic structures, analogous to the changes seen in memory. Treatment Implications The clinical implications of these models are critical. Neuroscience predicts that preventing subsequent episodes of a major psychiatric illness will positively alter the course of the disorder. This argues that pharmacological prophylaxis is essential. There is supporting evidence in this regard for schizophrenia, major depression, and bipolar disorder. However, there is ample room to speculate about parallel neurobiological processes in posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, and substance-related disorders. Additionally, if abnormal cellular processes contribute to the etiology of major psychiatric disorders, how do pharmacological interventions normalize these processes? Are medications effective only because of their neurotransmitter receptor profiles? Or do they influence second-messenger systems, gene transcription, and protein translation, as in learning? The time course of pharmacological efficacy suggests that medications do not merely affect neurotransmitters, but also alter underlying cellular functioning. Dopamine, norepinephrine, acetylcholine, glutamate, and opiates have all been associated with changing gene expression. Not surprisingly, antipsychotic medications induce the expression of c- fos and c-jun. In rats, the short-term administration of clinical doses of antipsychotic agents, such as haloperidol (Haldol), clozapine (Clozaril), and olanzapine (Zyprexa) induce c- fos in the nucleus accumbens. Antipsychotic agents that clinically cause extrapyramidal symptoms (e.g., haloperidol) also induce c- fos in the dorsal striatum. Clozapine, which clinically does not cause extrapyramidal adverse effects, does

not induce c-fos in this region. This suggests that extrapyramidal and antipsychotic effects can be dissociated in terms of their respective molecular neuroanatomies. Antidepressant treatments increase intracellular phosphorylation of cAMP-responsive proteins (e.g., CRE) that lead to transcription of specific genes. One of these genes, brain-derived neurotrophic factor, has also been implicated in neuronal plasticity and may play a role in the potential restitutive effects of treatment with antidepressant medications. These recent observations on the intracellular effects of psychiatric medications have potentially far-reaching implications for the understanding of mental illness and approaches to their treatments. The traditional view that psychiatric medications can be characterized by their actions at synapses where they bind to cell surface proteins (e.g., receptors) is yielding to a more enlightened vision that the synapse is only the tip of the iceberg of cellular function and plasticity that is of relevance to psychiatry.

SUGGESTED CROSS-REFERENCES Functional neuroanatomy is discussed in Section 1.2, perception and cognition in Section 3.1, and psychopharmacology in Chapter 31. SECTION REFERENCES Bachus SE, Kleinman JE: The neuropathology of schizophrenia. J Clin Psychiatry 57:72, 1996. Barbe MF, Levitt P: Attraction of specific thalamic input by cerebral grafts depends on the molecular identity of the implant. Proc Natl Acad Sci USA

89:3706, 1992.

Barbeau D, Liang JJ, Robitaille Y, Quiron R, Srivastava LK: Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc Natl Acad Sci USA 92:2785, 1995. Benowitz LI, Routtenberg A: GAP-43: An intrinsic determinant of neuronal development and plasticity. Trends Neurosci 20:84, 1997. Bymaster FP, Rasmussen K, Calligaro DO, Nelson DL, DeLapp NW, Wong DT, Moore NA: In vitro and in vivo biochemistry of olanzapine: A novel, atypical antipsychotic drug. J Clin Psychiatry 58(Suppl):28, 1997. Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT: Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits. Proc Natl Acad Sci USA 94:5401, 1997. Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597, 1997. Glantz LA, Lewis DA: Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry 54:660, 1997. *Goodman CS, Shatz CJ: Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72:77(Suppl), 1993. Jessell TM, Kandel ER: Synaptic transmission: A bidirectional and self-modifiable form of cell-cell communication. Cell 72(Suppl):1, 1993. Kim KHS, Relkin NR, Lee K-M, Hirsch J: Distinct cortical areas associated with native and second languages. Nature 388:171, 1997. Kotrla KJ: Functional neuroimaging in psychiatry. In Textbook of Neuropsychiatry, ed 3, RE Hales, S Cyudofsky, editors. American Psychiatric Press, Washington, DC, 1997. Kotrla KJ, Weinberger DR: Brain imaging in schizophrenia. In Annual Review of Medicine, vol 46, WP Creger, CH Coggins, EW Hancock, editors. Annual Reviews, Palo Alto, CA, 1995. Lander AD: Understanding the molecules of neural cell contacts: Emerging patterns of structure and function. Trends Neurosci 12:189, 1989. Lieberman J, Jody D, Geisler S, Alvir J, Loebel A, Szymanski S, Woerner M, Borenstein M: Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psychiatry 50:369, 1993. Liu D, Kiorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky P, Meaney M: Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277:1659, 1977. Maletic-Savatic M, Malinow R, Svoboda K: Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283:1923, 1999. Marin-Padilla M: Early ontogenesis of the human cerebral cortex. In Cerebral Cortex, vol 7, A Peters, EG Jones, editors. Plenum, New York, 1988. McConnell SK: The generation of neuronal diversity in the central nervous system. Annu Rev Neurosci 14:269, 1991. Merzenich MM, Sameshima K: Cortical plasticity and memory. Curr Opin Neurobiol 3:187, 1993. Milleret C: Visual callosal connections and strabismus. Behav Brain Res 64:85, 1994. Mrzljak L, Uylings HBM, Van Eden CG, Judas M: Neuronal development in human prefrontal cortex in prenatal and postnatal stages. In Progress in Brain Research, vol 85, HBM Uylings, CG Van Eden, JPC De Bruin, MA Corner, MGP Feenstra, editors. Elsevier Science, New York, 1990. Nowakowski RS: Some basic concepts of the development of the central nervous system. In Fetal Neural Development and Adult Schizophrenia, SA Mednick, TD Cannon, CE Barr, M Lyon, editors. Cambridge University Press, Cambridge, England, 1991. *O'Leary DDM, Schlaggar BL, Tuttle R: Specification of neocortical areas and thalamocortical connections. Annu Rev Neurosci 17:419, 1994. Oppenheim RW: Cell death during development of the nervous system. Annu Rev Neurosci 14:453, 1991. Patterson PH, Nawa H: Neuronal differentiation factors/cytokines and synaptic plasticity. Cell 10:123, 1993. Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL: Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc Natl Acad Sci USA 93:14182, 1996. Perry WS, Neal R, McDowell JE, Braff DL: Schizophrenia and frontal lobe functioning: Evidence from neuropsychology, cognitive neuroscience, and psychophysiology. In The Human Frontal Lobes: Functions and Disorders, BL Miller, JL Cummings, editors. Guilford, New York, 1999. *Post RM: Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999, 1992. *Rakic P: Development of the cerebral cortex in human and nonhuman primates. In Child and Adolescent Psychiatry. A Comprehensive Textbook, ed 2, M Lewis, editor. Williams & Wilkins, Baltimore, 1996. Roberson ED, English JD, Sweatt JD: A biochemist's view of long-term potentiation. Learning Memory 3:1, 1996. Rose SPR: Cell-adhesion molecules, glucocorticoids and long-term memory formation. Trends Neurosci 18:502, 1995. Rugarli EI, Ballabio A: Kallman syndrome: From genetics to neurobiology. JAMA 270:2713, 1993. Toldi J, Feher O, Wolff J-R: Neuronal plasticity induced by neonatal monocular and binocular enucleation. Prog Neurobiol 48:191, 1996. Webster MJ, Bachevalier J, Ungerleider LG: Development and plasticity of visual memory circuits. 1-14. In Maturational Windows and Adult Cortical Plasticity, SFI Studies in the Sciences of Complexity, vol 24. Addison-Wesley, 1995. Weiler IJ, Hawrylak N, Greenough WT: Morphogenesis in memory formation: Synaptic and cellular mechanisms. Behav Brain Res 66:1, 1995. *Weinberger DR: Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660, 1987. Weinberger DR, Lipska BK: Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: A search for common ground. Schizophr Res 16:87, 1995.

Wong EV, Kenwrick S, Willems P, Lemmon V: Mutations in the cell adhesion molecule L1 cause mental retardation. Trends Neurosci 18:168, 1995.

Textbook of Psychiatry

1.4 MONOAMINE NEUROTRANSMITTERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.4 MONOAMINE NEUROTRANSMITTERS LAURENCE H. TECOTT M.D., PH.D. Anatomy of Monoamine Systems Monoamine Synthesis, Storage, and Degradation Receptors Suggested Cross-References

Historically the monoamine neurotransmitters and acetylcholine have been strongly implicated in the etiology and treatment of a wide variety of neuropsychiatric disorders. The monoamines serotonin, norepinephrine, dopamine, and histamine are widely distributed throughout the central nervous system (CNS). The activity of each monoamine neurotransmitter system modulates multiple neuronal pathways that mediate diverse behavioral and physiological processes. Conversely, each CNS function is regulated by multiple interactive neurotransmitter systems. In light of this complexity, determining the mechanisms through which monoamine systems impact the etiology and treatment of psychiatric disorders poses a major challenge. Advances in molecular neurobiology provide powerful new tools to aid in this endeavor. Molecular cloning studies have led to the identification and functional characterization of gene products that contribute to monoaminergic transmission, such as monoamine receptors, transporters, and synthetic and degradative enzymes. More recently, these genes have provided targets for powerful techniques that enable the precise introduction of mutations into the mouse genome. Thus, the functional consequences of perturbing gene function may be examined in the context of the intact, behaving organism. The molecular cloning of genes involved in monoaminergic transmission has also led to the identification of allelic variants of human genes, which raises the intriguing prospect that the inheritance of particular variants may contribute to disease susceptibility and to the efficacy of therapeutic agents.

ANATOMY OF MONOAMINE SYSTEMS The anatomical organization of monoaminergic systems shares a number of common features. Monoaminergic systems are strikingly divergent: monoaminergic cell bodies are generally found in aggregates located in a few restricted subcortical brain regions. Individual monoaminergic neurons typically possess long and extensively branched axonal processes, innervating a large number of postsynaptic cells. This organization may permit monoaminergic systems to exert control in a coordinated manner over diverse brain regions. The actions of monoamines in particular brain areas are determined not only by the extent of monoamine innervation, but also by the receptor subtypes expressed in these regions. Monoaminergic receptors are diverse with regard to their regional and synaptic localization within the brain, and to the intracellular signaling systems to which they couple. This receptor diversity provides a means through which a single signaling molecule may produce effects that vary in different postsynaptic neurons. Serotonin Although approximately one in a million brain neurons are serotonergic, serotonin systems influence CNS activity at all levels of the neuraxis. Serotonergic neurons are clustered in midline raphe nuclei of the midbrain, pons, and medulla. These neurons project extensively throughout the brain and descend to the spinal cord (Fig. 1.4-1). The majority of the serotonergic innervation of the forebrain arises from the dorsal and median raphe nuclei of the midbrain. Ascending projections from these nuclei course through the medial forebrain bundle before diverging to many target regions. Whereas the median raphe nucleus provides the majority of the serotonergic innervation of the limbic system, the dorsal raphe nucleus provides the primary innervation of the striatum and thalamus. In addition to the differences in target areas innervated by the median raphe and dorsal raphe, structural differences in the axonal projections from these nuclei have been observed. Whereas fibers from the dorsal raphe are fine, with small vesicle-containing swellings called varicosities, median raphe axons are beaded, with large spherical varicosities. These axons show differential sensitivity to the neurotoxic effects of the amphetamine analog 3,4-methylene-dioxymethamphetamine (MDMA, “ecstasy”). This agent produces a selective loss of fine axons while sparing the larger beaded projections derived from the median raphe. The significance of the morphological differences in these projection fibers remains to be determined. Both types of fibers are found in the neocortex, which receives a rich serotonergic innervation derived from both nuclei. The divergent nature of serotonergic projections is illustrated by this innervation; it has been estimated that each serotonergic neuron may influence 500,000 target neurons. Furthermore, each cortical neuron may be associated with over 200 serotonergic varicosities, which provides a means through which serotonin could affect widespread and coordinated modulation of cortical function. The caudal raphe serotonergic neurons project to the medulla, cerebellum, and spinal cord.

FIGURE 1.4-1 Brain serotonergic pathways (in rats). Serotonergic neurons are located in brainstem midline raphe nuclei and project throughout the neuraxis. (There is an approximate similarity between monoamine pathways in rats and in humans.) Abbreviations: AMG, amygdala; BFC, basal forebrain complex; CBM, cerebellum; cc, corpus callosum; CP, caudate putamen; CRN, caudal raphe nuclei; CTX, neocortex; DR, dorsal raphe nucleus; HI, hippocampus; HY, hypothalamus; LC, locus ceruleus; LTN, lateral tegmental noradrenergic nuclei; MPC, mesopontine complex; MR, median raphe nucleus; NAc, nucleus accumbens; OB, olfactory bulb; PFC, prefrontal cortex; PI, pituitary; SNC, substantial nigra pars compacta; TE, tectum; TH, thalamus; TM, tuberomammillary nucleus of hypothalamus; VTA, ventral tegmental area.

Dopamine Dopamine neurons are more widely distributed than those of other monoamines, residing in the midbrain substantia nigra and ventral tegmental area, and in the periaqueductal gray, hypothalamus, olfactory bulb, and retina. Of particular relevance are three dopamine containing systems: (1) the nigrostriatal, (2) mesocorticolimbic, and (3) tuberohypophyseal system ( Fig. 1.4-2). The nigrostriatal dopamine system has been the most extensively studied of the dopaminergic pathways. Dopamine cell bodies located in the pars compacta division of the substantia nigra send ascending projections to the dorsal striatum, particularly the caudate and putamen. This projection modulates motor function, as highlighted by the motor disturbances of Parkinson's disease, a disorder characterized by degeneration of the nigrostriatal system. In addition, the extrapyramidal adverse effects of antipsychotic drugs are believed to result from the blockade of striatal dopamine receptors.

FIGURE 1.4-2 Brain dopaminergic pathways (in rats). The three principal dopaminergic pathways: (1) nigrostriatal pathway, (2) mesocorticolimbic pathway, and (3) tuberohypophyseal pathway.

The midbrain ventral tegmental area lies medial to the substantia nigra and contains dopaminergic neurons that give rise to the mesocorticolimbic dopamine system. These neurons send ascending projections that innervate limbic structures, such as the nucleus accumbens and amygdala, as well as associated cortical structures, particularly the prefrontal cortex. The mesoaccumbens projection is believed to regulate the rewarding properties of a wide variety of stimuli, including drugs of abuse. The mesocortical projection is believed to be a major target for the antipsychotic properties of dopamine receptor antagonist drugs. In this regard, the decreased predisposition of clozapine (Clozaril) to produce extrapyramidal adverse effects has been attributed to relatively selective actions on the mesocortical system. The tuberohypophyseal system consists of dopaminergic neurons in the hypothalamic arcuate and periventricular nuclei, and their projections to the pituitary gland. These projections provide inhibitory regulation of prolactin release. The administration of dopamine receptor antagonist antipsychotic drugs may lead to a disinhibition of release, resulting in galactorrhea. Norepinephrine and Epinephrine Norepinephrine-producing neurons are found in the pons and medulla, in two major clusterings: the locus ceruleus and the lateral tegmental noradrenergic nuclei ( Fig. 1.4-3). Noradrenergic projections from both these regions ramify extensively as they project throughout the neuraxis. In humans the locus ceruleus is found in the dorsal portion of the caudal pons, and contains approximately 12,000 tightly packed neurons on each side of the brain. These cells provide the major noradrenergic projections to the neocortex, hippocampus, thalamus, and midbrain tectum. The activity of locus ceruleus neurons varies with the sleep/wake cycle and is responsive to sensory stimuli, indicating a role for this structure in arousal state and vigilance. The projections from lateral tegmental noradrenergic nuclei neurons, which are loosely scattered throughout the ventral pons and medulla, partially overlap with those of the locus ceruleus. Fibers from both cell groups innervate the amygdala, septum, and spinal cord. Other regions, such as the hypothalamus and lower brainstem, receive adrenergic inputs predominantly from the lateral tegmental noradrenergic nuclei. The relatively few neurons that utilize epinephrine as a neurotransmitter are located in the caudal pons and medulla, intermingled with noradrenergic neurons. Projections from these groups ascend to innervate the hypothalamus, locus ceruleus, and visceral efferent and afferent nuclei of the midbrain.

FIGURE 1.4-3 Brain noradrenergic pathways (in rats). Projections of noradrenergic neurons located in the locus ceruleus and lateral tegmental noradrenergic nuclei.

Histamine Central histaminergic neural pathways have only recently been characterized by immunocytochemistry using antibodies to the synthetic enzyme histidine decarboxylase and to histamine. Histaminergic cell bodies are located within the tuberomammillary nucleus of the posterior hypothalamus. As with other monoaminergic systems, histaminergic fibers project diffusely throughout the brain and spinal cord ( Fig. 1.4-4). Ascending projections course with other monoaminergic fibers in the medial forebrain bundle, and descending projections travel through the midbrain central gray to the dorsal hindbrain and spinal cord. The fibers have varicosities that are seldom associated with classical synapses. The hypothalamus receives the densest histaminergic innervation, consistent with a role for this transmitter in the regulation of autonomic and neuroendocrine processes.

FIGURE 1.4-4 Brain histaminergic pathways (in rats). Histaminergic neurons are located in the tuberomammillary nucleus of the caudal hypothalamus and project to the hypothalamus and more distant brain regions.

Acetylcholine The axonal processes of cholinergic neurons may either project to distant brain regions (projection neurons) or contact local cells within the same structure (interneurons). Two large clusters of cholinergic projection neurons are found within the brain: the basal forebrain complex and the mesopontine complex (Fig. 1.4-5). The basal forebrain complex provides the vast majority of the cholinergic innervation to the nonstriatal telencephalon. It consists of cholinergic neurons within the medial septal nucleus, the nucleus of the diagonal band, the substantia innominata, the preoptic field, and the nucleus basalis of Meynert. In Alzheimer's disease the majority of nucleus basalis neurons are lost, leading to substantial impairments in the cortical cholinergic innervation. These impairments are believed to contribute to the symptoms of the disease and to correlate with the severity of dementia. The mesopontine complex consists of cholinergic neurons within the pedunculopontine and laterodorsal tegmental nuclei of the midbrain and pons. Regions innervated by these projections include the lateral hypothalamus, thalamus, tectum, substantia nigra, raphe nuclei, locus ceruleus, and cranial nerve nuclei. Acetylcholine is also found within interneurons of several brain regions, including the striatum. The modulation of striatal cholinergic transmission has been implicated in the antiparkinsonian actions of anticholinergic agents. Within the periphery, acetylcholine is a prominent neurotransmitter, located in preganglionic autonomic neurons, postganglionic parasympathetic neurons, and motoneurons innervating skeletal muscle.

FIGURE 1.4-5 Brain cholinergic projection pathways (in rats). The majority of cholinergic projection neurons are located in the basal forebrain complex and the mesopontine complex.

MONOAMINE SYNTHESIS, STORAGE, AND DEGRADATION In addition to similarities in neuronal organization, monoaminergic systems are similar with regard to their synthesis, storage, and degradation ( Fig. 1.4-6). Monoamines are synthesized within neurons from common amino acid precursors (Fig. 1.4-6, Step 1) and taken up into synaptic vesicles via a vesicular monoamine transporter (Fig. 1.4-6, Step 2). Upon stimulation, vesicles within nerve terminals release neurotransmitter into the synaptic cleft ( Fig. 1.4-6, Step 3). Once released, the monoamines interact with postsynaptic receptors to alter the excitability of postsynaptic cells ( Fig. 1.4-6, Step 4). Monoamines may also interact with presynaptic autoreceptors located on the nerve terminal to suppress further release ( Fig. 1.4-6, Step 5). In addition, released monoamines may be taken back up from the synaptic cleft into the nerve terminal by plasma membrane transporter proteins ( Fig. 1.4-6, Step 6). Reuptake plays an important role in limiting the magnitude and duration of action of synaptically released monoamines. Once monoamines are taken up, they may be subject to enzymatic degradation ( Fig. 1.4-6, Step 7) or they may be protected from degradation by uptake into vesicles. The processing of acetylcholine differs from this scheme, and is described below.

FIGURE 1.4-6 Schematic diagram of monoaminergic synapse. Steps involved in synaptic transmission are described in the text.

Serotonin The CNS contains less than 2 percent of the serotonin in the body; peripheral serotonin is located in platelets, mast cells, and enterochromaffin cells of the gastrointestinal system. Despite the abundance of peripheral serotonin, its inability to cross the blood-brain barrier necessitates the synthesis of serotonin within the brain. Serotonin is synthesized from the amino acid tryptophan, which is derived from the diet. The rate-limiting step in serotonin synthesis is the hydroxylation of tryptophan by the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan (Fig. 1.4-7). Under normal circumstances this enzyme is not saturated by substrate, so tryptophan concentration can impact the rate of serotonin synthesis; therefore much attention has focused on the factors that determine tryptophan availability. Unlike serotonin, tryptophan is taken up into the brain via a saturable active carrier mechanism. Because tryptophan competes with other large neutral amino acids for transport, brain uptake of this amino acid is determined both by the amount of circulating tryptophan and by the ratio of tryptophan to other large neutral amino acids. This ratio may be elevated by carbohydrate intake, which induces insulin release and the uptake of many large neutral amino acids into peripheral tissues. Conversely, high-protein foods tend to be relatively low in tryptophan, thus lowering this ratio. The administration of specialized low-tryptophan diets has been found to produce significant declines in brain serotonin levels. Following tryptophan hydroxylation, 5-hydroxytryptophan is rapidly decarboxylated by aromatic amino acid decarboxylase to form serotonin.

FIGURE 1.4-7 Synthesis and catabolism of serotonin.

The first step in the degradation of serotonin is mediated by monoamine oxidase (MAO) type A. A (MAO A), which oxidizes the amino group to form an aldehyde. MAO A is located in mitochondrial membranes and is nonspecific in its substrate specificity; in addition to serotonin, it oxidizes norepinephrine. The elevation of serotonin levels by MAO inhibitors (MAOIs) is believed to underlie the antidepressant efficacy of these drugs. Following oxidation by MAO A, the resulting aldehyde is further oxidized to 5-hydroxyindoleacetic acid (5-HIAA). Catecholamines The catecholamines are synthesized from the amino acid tyrosine, which is taken up into the brain via an active transport mechanism ( Fig. 1.4-8). Within catecholaminergic neurons, tyrosine hydroxylase catalyzes the addition of a hydroxyl group to the meta position of tyrosine, yielding dopa. This rate-limiting step in catecholamine synthesis is subject to inhibition by high levels of catecholamines (end-product inhibition). Because tyrosine hydroxylase is normally saturated with substrate, manipulation of tyrosine levels does not readily impact the rate of catecholamine synthesis. Once formed, dopa is rapidly converted to dopamine by dopa decarboxylase, which is located in the cytoplasm. It is now recognized that this enzyme acts not only on dopa, but on all naturally occurring aromatic l-amino acids, including tryptophan. Thus, this enzyme is more accurately termed aromatic amino acid decarboxylase. In noradrenergic and adrenergic neurons, dopamine is oxidized in catecholaminergic vesicles by dopamine b-hydroxylase to form norepinephrine. This promiscuous enzyme will oxidize most phenylethylamines, producing metabolites that may replace norepinephrine at nerve terminals. These metabolites may act as false neurotransmitter, producing minimal postsynaptic effects. In adrenergic neurons, norepinephrine is converted to epinephrine by phenylethanolamine N-methyltransferase (PNMT), which is located within the cytoplasmic compartment.

FIGURE 1.4-8 Synthesis of catecholamines.

Two enzymes that play major roles in the degradation of catecholamines are monoamine oxidase and catechol O-methyltransferase (COMT). Monoamine oxidase is located on the outer membrane of mitochondria and oxidatively deaminates catecholamines to their corresponding aldehydes. Two MAO isozymes with differing substrate specificities have been identified: MAO A, which preferentially deaminates serotonin and norepinephrine, and MAO type B (MAO B), which deaminates dopamine, histamine, and a broad spectrum of phenylethylamines. The blockade of monoamine catabolism by MAOIs produces elevations in brain monoamine levels. MAO is also found in peripheral tissues such as the gastrointestinal tract and liver, where it prevents the accumulation of toxic amines. MAO inhibitors may produce adverse effects by elevating the levels of these peripheral amines. For example, peripheral MAO degrades dietary tyramine, an amine that can displace norepinephrine from sympathetic postganglionic nerve endings, producing hypertension. Thus, patients treated with MAOIs are cautioned to avoid pickled and fermented foods that typically have high levels of this amine. COMT is widely distributed throughout the brain and peripheral tissues. It has a wide substrate specificity, catalyzing the transfer of methyl groups from S-adenosyl methionine to the m-hydroxyl group of most catechol compounds. The catecholamine metabolites produced by these and other degradative enzymes are frequently measured as indicators of the activity of catecholaminergic systems. In humans the predominant metabolites of dopamine and norepinephrine are homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively. Histamine As is the case for serotonin, the brain contains only a small portion of the histamine found in the body. Histamine is distributed throughout most tissues of the body, predominantly in mast cells. Because it does not readily cross the blood-brain barrier, histamine is believed to be synthesized within the brain where it is formed by the decarboxylation of the amino acid histidine by a specific histidine decarboxylase. As this enzyme is not normally saturated with substrate, histamine synthesis is sensitive to histidine levels, which is consistent with the observation that the peripheral administration of histidine elevates brain histamine levels. Histamine is metabolized in the brain by histamine methyltransferase, producing methylhistamine; in turn, methylhistamine undergoes oxidative deamination by MAO B. Acetylcholine Acetylcholine is synthesized by the transfer of a methyl group from acetyl coenzyme A to choline in a reaction mediated by choline acetyltransferase (CAT). Choline availability is the rate-limiting factor in acetylcholine synthesis. The majority of choline within the brain is transported from the blood, and a high-affinity transport mechanism exists within cholinergic nerve terminals, where CAT is also found. The rate of choline transport is regulated such that increased cholinergic neural activity is associated with enhanced choline uptake. Following synthesis, acetylcholine is stored in synaptic vesicles through the action of a vesicular acetylcholine transporter. Following vesicular release into the synaptic cleft, acetylcholine is rapidly hydrolyzed to choline by acetylcholinesterase located in the synaptic cleft. Choline is then taken back into the presynaptic terminal via the choline transporter. One strategy in the treatment of dementia due to Alzheimer's disease is the augmentation of cholinergic transmission using cholinesterase inhibitors, such as tacrine (Cognex). Plasma Membrane Transporters A great deal of progress has been made in the molecular characterization of the monoamine plasma membrane transporter proteins. These membrane proteins mediate the reuptake of synaptically released monoamines into the presynaptic terminal. The reuptake of monoamines across the presynaptic membrane into the nerve terminal is an energy-requiring process dependent upon the activity of a Na +, K+-activated adenosine triphosophatase (ATPase). Monoamine reuptake is an important mechanism for limiting the extent and duration of activation of monoaminergic receptors; also, transporters serve as molecular targets for a number of antidepressant drugs, psychostimulants, and monoaminergic neurotoxins. Whereas transporter molecules for serotonin, dopamine, and norepinephrine have been well characterized, transporters selective for histamine and epinephrine have not been demonstrated. The molecular cloning of serotonin, dopamine, and norepinephrine transporter molecules has confirmed that all belong to a common gene family of transporter molecules that also includes those for g-aminobutyric acid (GABA), glycine, and choline. These proteins share strong sequence homologies and are believed to be integral membrane proteins that span the plasma membrane twelve times. In contrast to monoaminergic receptors, there is evidence for only a single type of transporter molecule for serotonin, dopamine, and norepinephrine. The expression of these proteins appears to be restricted to the corresponding class of monoaminergic neurons. For example, the messenger ribonucleic acid (mRNA) encoding the serotonin transporter molecule is restricted to serotonergic neurons, the one coding the dopamine transporter molecule is restricted to dopaminergic neurons, and the one coding the norepinephrine transporter molecule is restricted to noradrenergic neurons. Monoaminergic transporters are molecular targets for psychotherapeutic drugs as well as substances of abuse. The therapeutic effects of tricyclic drugs, such as amitriptyline and imipramine, have been associated with their blockade of the serotonin transporter molecule and the norepinephrine transporter molecule although these drugs also interact directly with several monoaminergic receptor subtypes. More blockers of serotonin transporter molecules, such as the selective serotonin receptor inhibitors (SSRIs) (e.g., citalopram [Celexa], fluoxetine [Prozac], fluvoxamine [Luvox], paroxetine [Paxil], and sertraline [Zoloft]), are used in the treatment of depressive, anxiety, and a variety of other disorders. Conversely, compounds with relative selectivity for the norepinephrine transporter molecules, such as nortriptyline (Pamelor) and desipramine (Norpramin), also have antidepressant efficacy. Among drugs of abuse, cocaine binds with high affinity to all three known monoamine transporters, although the rewarding and stimulant properties of the drug have been attributed primarily to its blockade of the dopamine transporter molecule. This view has been recently supported by the absence of cocaine-induced locomotor stimulation in a strain of mutant mice engineered to lack this molecule. In fact, psychostimulants produce a paradoxical locomotor suppression in these animals that has been attributed to the serotonin molecule transporter-blocking properties of these compounds. Transporters may also provide routes that allow neurotoxins to enter and damage monoaminergic neurons; examples include the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the serotonergic neurotoxin MDMA. Vesicular Monoamine Transporter In addition to the reuptake of monoamines into the presynaptic nerve terminal, a second transport process serves to concentrate and store monoamines within synaptic vesicles. The transport and storage of monoamines in vesicles may serve several purposes: (1) to enable the regulated release of transmitter under appropriate physiological stimulation, (2) to protect monoamines from degradation by MAO, and (3) to protect neurons from the toxic effects of free radicals produced by the oxidation of cytoplasmic monoamines. In contrast with the plasma membrane transporters, a single type of vesicular monoamine transporter is believed to mediate the uptake of monoamines into synaptic vesicles within the brain. Consistent with this, blockade of this vesicular monoamine transporter by the antihypertensive drug reserpine (Serpasil) has been found to deplete brain levels of serotonin, norepinephrine, and dopamine. The molecular cloning of this transporter has revealed it to have 12 putative membrane-spanning domains; however, it does not display sequence homology to the plasma membrane transporters. Moreover, it utilizes a H + gradient rather than Na +/Cl – gradients. Vesicular transport requires a H + pumping ATPase, which establishes a concentration gradient of H + across the vesicle membrane. In the presence of this gradient, the vesicular monoamine transmitter takes up neurotransmitter in a manner that is coupled to the release of luminal protons; the activity of the transporter is altered by amphetamine-like agents. These compounds are taken up via plasma membrane transporters into monoaminergic terminals, where they act as weak bases to disrupt pH gradients. This produces a reversal of vesicular monoamine transmitter activity, leading to monoamine release from vesicles and reversal of plasma membrane transporter activity. The resulting release of monoamines from presynaptic terminals contributes to the stimulant properties of these compounds. The anorectic agent fenfluramine is believed to stimulate serotonin release in an analogous manner. Recently a separate vesicular transporter for acetylcholine has been molecularly cloned; its structure is homologous to that of the vesicular monoamine transmitter, and both are believed to have a common bioenergetic mechanism.

RECEPTORS Ultimately the effects of monoamines on CNS function and behavior depend upon their interactions with receptor molecules. The binding of monoamines to these plasma membrane proteins initiates a series of intracellular events that modulate neuronal excitability. Unlike the transporters, multiple receptor subtypes exist for each monoamine transmitter (Table 1.4-1). The initial classification of many receptor subtypes was based on radioligand binding studies. Receptor binding sites were identified on the basis of the rank order of binding affinities for a number of agonist and antagonist compounds. More recently, the molecular cloning of monoamine

receptors has confirmed that many of the sites initially defined by these binding studies did indeed correspond to distinct receptor proteins encoded by unique genes. Molecular cloning has also led to the identification of previously unknown receptors, and to the introduction of powerful tools to characterize receptor structure and function.

Table 1.4-1 Monoamine Receptors: Overview

Neurotransmitter receptors produce intracellular effects by one of two basic mechanisms: (1) via interactions with G proteins that couple receptors to intracellular effector systems, and (2) by providing channels through which ions flow when transmitters bind (ligand-gated ion channels). With the exception of the serotonin type 3 (5-HT3) receptor subtype (a ligand-gated ion channel), all known monoaminergic receptors belong to the superfamily of G-protein–coupled receptors. However, within each monoaminergic receptor family, the subtypes are heterogeneous with regard to the G proteins with which they interact, and to the second-messenger effects that they produce. Monoaminergic receptors are also diverse in their regional patterns of expression within the brain, their neurotransmitter binding affinities, and in their synaptic localization. Whereas many receptor subtypes are located exclusively in postsynaptic membranes, others are located presynaptically in axon terminal membranes. Some receptors on the presynaptic terminal respond to monoamines that are released by that neuron and these presynaptic autoreceptors often act to inhibit neurotransmitter release. Several monoaminergic receptor subtypes are located presynaptically in some brain regions and postsynaptically in others. In the wake of the recent proliferation of known receptors subtypes, much work needs to be done to determine the functional roles of individual receptors. In many instances this effort is hampered by the paucity of selective agonist and antagonist drugs. Recently, a molecular genetic approach to examining receptor function has been applied to complement pharmacological studies. Gene targeting procedures have enabled the generation of mouse strains with disruptions in genes that encode individual receptor subtypes; the resulting mutant mice have a complete and specific absence of the targeted receptor. Studies in these animals are providing clues to receptor function and to the contributions of the targeted receptors to the actions of nonspecific drugs. Molecular and pharmacological approaches will guide the generation of subtype-selective compounds and facilitate the development of therapeutic agents that will alter monoaminergic transmission in a more refined manner. Serotonin Receptors Brain serotonin receptors were initially characterized on the basis of radioligand binding studies into two classes: serotonin type 1 (5-HT 1) receptors, to which [ 3H]5-HT bound with high affinity, and 5-HT 2 which were labeled with high affinity by [ 3H]spiperone. Subsequent binding studies revealed that each of these classes consisted of multiple subtypes. The application of molecular cloning techniques has produced a proliferation in the number of known subtypes. The great diversity of serotonin receptors provides a means whereby a single neurotransmitter may produce a wide variety of cellular effects in multiple neuronal systems. At present, at least 14 distinct serotonin receptor subtypes have been identified and molecularly cloned, which has led to rapid advances in determining the structure, pharmacology, brain distribution, and effector mechanisms of these receptors and to a more precise classification of serotonin receptor subfamilies on the basis of their structural homologies and primary effector mechanisms. The 5-HT 1 receptors comprise the largest serotonin receptor subfamily, with human subtypes designated: 5-HT 1A, 5-HT1Da, 5HT1Db, 5-HT1E, and 5-HT 1F. All five 5-HT 1 receptor subtypes display intronless gene structures and high affinities for serotonin and adenylate cyclase inhibition. The most intensively studied of these has been the 5-HT1A receptor, a subtype that is found on postsynaptic membranes and serotonergic neurons, where it functions as a somatodendritic autoreceptor. The stimulation of these autoreceptors suppresses the activity of serotonergic neurons. The desensitization of 5-HT 1A autoreceptors by the chronic administration of SSRIs has been implicated in their antidepressant effects. An additional role for this receptor subtype in the regulation of anxiety is suggested by the anxiolytic properties of partial 5-HT 1A receptor agonists such as buspirone (Buspar) and by the enhancement of anxiety-related behaviors in a strain of mutant mice lacking 5-HT 1A receptors. The 5-HT 1Da and 5-HT 1Db receptors resemble each other in structure and brain localization. 5-HT 1D receptors are found on axon terminals of serotonergic and nonserotonergic neurons, where they act to reduce neurotransmitter release. The study of these receptors has been hindered by a lack of selective pharmacological tools. This is also true for the 5-HT 1E and 5-HT 1F receptor subtypes. The highest levels of 5-HT 1E receptor expression are found in the striatum and entorhinal cortex whereas 5-HT1F receptor expression is highest in the dorsal raphe nucleus, hippocampus, cortex, and striatum. In addition, 5-HT 1D and 5-HT 1F receptors are expressed in cerebral vessels, and are stimulated by the antimigraine drug sumatriptan (Imitrex). The relative importance of these receptors in the therapeutic efficacy of this drug remains to be determined. At least three receptor subtypes mediate the effects previously attributed to a single 5HT 2 receptor subtype. The classic 5-HT 2 receptor has thus been renamed 5-HT 2A to indicate that it is a member of a serotonin receptor subfamily. A second receptor initially termed 5-HT 1C has been renamed 5-HT 2C to indicate that it belongs within this subfamily. The third known 5HT 2 receptor, termed 5-HT 2B, contributes to the contractile effects of serotonin in the stomach fundus. All three subtypes exhibit high sequence homology, similar pharmacological binding profiles, and stimulation of phosphoinositide turnover. High levels of 5-HT 2A receptors are found in the neocortex and in peripheral locations such as platelets and smooth muscle. Much recent attention has focused on the contributions of 5-HT 2A and 5-HT 2C receptors to the actions of serotonin-dopamine antagonists, such as clozapine (Clozaril), risperidone (Risperdal), and olanzapine (Zyprexa). Analysis of the receptor-binding properties of these drugs has led to the hypothesis that 5-HT 2A receptor blockade correlates with the therapeutic effectiveness of these antipsychotic agents. The relative importance of related serotonin receptors to the efficacy of these agents remains to be determined. The 5-HT 2C receptor is expressed at high levels in many CNS regions including the hippocampal formation, prefrontal cortex, amygdala, striatum, hypothalamus, and choroid plexus. Stimulation of 5-HT 2C receptors has been proposed to produce anxiogenic and anorectic effects. Accordingly, a transgenic mouse strain lacking this receptor subtype exhibits an obesity syndrome associated with overeating; these animals also display an enhanced susceptibility to seizures, implicating this receptor in the regulation of neuronal network excitability. A variety of antidepressant and antipsychotic drugs antagonize 5-HT 2C receptors with high affinity. Conversely, hallucinogens such as lysergic acid diethylamide (LSD) display agonist activity at 5-HT 2 serotonin receptor subtypes, among others. The 5-HT 3 receptor is unique among monoaminergic receptors in its membership within the ligand-gated ion channel superfamily. Rather than activating G proteins, the binding of serotonin to this receptor permits passage of Na + and K+ ions through an ion channel located within the 5-HT 3 receptor complex. This produces rapid excitatory effects in postsynaptic neurons. The receptor is expressed within the hippocampus, neocortex, amygdala, hypothalamus, and brainstem motor nuclei. Outside the brain, it is found in the pituitary gland, enteric nervous system sympathetic ganglia, and in sensory ganglia. 5-HT 3 receptor antagonists such as ondansetron (Zofran) have been used as antiemetic agents and are under evaluation as potential antianxiety and cognitive-enhancing agents. Investigations into the functions of recently identified 5-HT 4; 5-HT5, including subtypes 5-HT 5A and 5-HT5B; 5-HT6 and 5-HT 7 receptors are hindered by a lack of selective agonist and antagonists. Studies of the cloned receptors reveal that all but the 5-HT 5 receptor are linked to the stimulation of adenylate cyclase. The primary effector mechanisms of the 5-HT5 receptors remain to be determined. The 5-HT 4 receptors are expressed in the hippocampus, striatum, substantia nigra, and superior colliculus, and have been implicated in the serotonergic regulation of cognition and anxiety. The two 5-HT 5 receptor subtypes are highly homologous, and are expressed in the neocortex, hippocampus, raphe nuclei, and cerebellum. 5-HT 6 receptors may contribute to the actions of the several antidepressant, antipsychotic, and hallucinogenic drugs that bind with high affinity. These receptors are expressed in the neocortex, hippocampus, striatum, and amygdala; highest concentrations of 5-HT7 receptor expression are found in the hypothalamus and thalamus. These receptors have been proposed to contribute to the serotonergic modulation of circadian rhythms. Although it is premature to assign functional roles to these new receptor subtypes with confidence, it is likely that these receptors will ultimately provide targets for the development of useful therapeutic compounds.

Dopamine Receptors In 1979 it was clearly recognized that the actions of dopamine are mediated by more than one receptor subtype. Two dopamine receptors, termed type 1 (D1) and type 2 (D 2) were distinguished on the basis of differential binding affinities of a series of agonists and antagonists, distinct effector mechanisms, and distinct distribution patterns within the CNS. It was subsequently found that the therapeutic efficacy of antipsychotic drugs correlated strongly with their affinities for the D 2 receptor, implicating this subtype as an important site for the action of antipsychotic drugs. Until recently, these were the only two identified dopamine receptors; however, molecular cloning studies have revealed additional receptor heterogeneity. Three additional dopamine receptor genes have been identified, encoding the D 3, D4, and D 5 dopamine receptors. Based on their regional brain distributions and primary effector mechanisms, the D 3 and D4 receptors are considered to be D2-like, and the D 5 receptor is considered to be D 1-like. The functional roles of these subtypes remain to be determined, although several intriguing possibilities are under investigation. The D 1 receptor was initially distinguished from the D 2 subtype by its high affinity for the antagonist SCH 23390 and its relatively low affinity for butyrophenones such as haloperidol (Haldol). Whereas D 1 receptor activation stimulates cAMP formation, D 2 receptor stimulation produces the opposite effect on cAMP formation. In addition to the stimulation of adenylate cyclase, D 1 receptors may also stimulate phosphoinositide turnover. D 1 receptor mRNA is expressed in the terminal fields of the nigrostriatal and mesocorticolimbic pathways, with high levels in the dorsal striatum, nucleus accumbens, and amygdala. In contrast, little D 1 mRNA expression is found in dopamine cell body regions such as the substantia nigra pars compacta and the ventral tegmental area. This finding, and the persistence of D 1 receptor binding following lesions of dopaminergic neurons, suggests that this receptor subtype is not found on dopaminergic neurons and is therefore not an autoreceptor. Electrophysiological studies have indicated that D 1 receptor activation is required for striatal D 2 receptor activation to produce its maximal effect. The proposed synergistic effects of striatal D 1 and D2 receptor activation have recently received support from studies in a mouse strain with a targeted elimination of D 1 receptors. The effects of both D 1 and D2 receptor activation were attenuated in these animals; moreover, these mice were resistant to the hyperlocomotor effects of cocaine, indicating that D 1 receptors contribute significantly to the effects of cocaine on the CNS. The D 5 receptor was molecularly cloned on the basis of its sequence homology with the D 1 receptor. The two receptors have a higher degree of homology with each other than with the D2 and D4 subtypes. This structural similarity is reflected in the similar affinities of a wide variety of dopaminergic drugs for these two receptors. The main distinguishing feature of their binding profiles is that the binding affinity of dopamine is higher for D 5 than for D1 receptors. Not surprisingly, these two receptors are also similar in that they both stimulate adenylate cyclase activity. However, these receptors differ in their regional distributions within the CNS: the expression of D 5 receptors appears to be highly restricted to limbic system structures such as the hippocampus and hypothalamus. The lack of selective drugs hinders attempts to distinguish the functional roles of D 1 and D5 receptors. The dopamine D2 receptor was initially distinguished from the D 1 receptor on the basis of its high affinity for butyrophenones. Moreover, D 2 receptor stimulation was observed to inhibit rather than to stimulate adenylate cyclase activity. Subsequently, the D 2 receptor subtype was found to display interactions with a variety of G proteins, leading to diverse second-messenger effects such as modulation of Ca ++ and K+ channel function and the alteration of phosphoinositide production. The intracellular consequences of D 2 receptor activation appear to depend upon the cell type in which the receptor is expressed. In addition to D 2 receptor mRNA expression in brain regions that receive dopaminergic innervation, D 2 transcripts are found in dopaminergic neurons of the ventral tegmental area and substantia nigra. The D 2 receptor may have either a postsynaptic function or an autoreceptor function. D 2 autoreceptors may be found on dopaminergic terminals or on the cell bodies and dendrites of dopaminergic neurons. D 2 receptors are also expressed in the anterior pituitary and mediate the dopaminergic inhibition of prolactin and melanocyte-stimulating hormone release. Molecular cloning has revealed a long and short form of the D 2 receptor that differ in length by 29 amino acids, products of alternative splicing of a single gene; differences in the functional roles of the long and short forms remain to be determined. A great deal of attention has focused on the clinical correlates of D 2 receptor function. It has been proposed that the brains of untreated schizophrenia patients have elevations in D 2 receptor density. Furthermore, radioligand binding studies have revealed a correlation between the clinical efficacy of antipsychotic drugs and their antagonist affinities for this receptor subtype. This finding has contributed significantly to the “dopamine hypothesis” of schizophrenia. The extrapyramidal adverse effects of antipsychotic drugs, such as dystonia and parkinson-like symptoms, have been attributed to the blockade of striatal D 2 receptors. A significant contribution of D2 receptors to the dopaminergic regulation of motor function is further highlighted by a parkinson-like movement disorder observed in a mutant mouse strain that lacks this receptor subtype. The D 3 and D4 receptors are considered to be D 2-like on the basis of similarities in their gene structures, sequence homologies, and pharmacology. These receptors are expressed in lower abundance than the D 2 receptor and their regional distributions are distinct. Whereas D 3 receptor expression is high in the nucleus accumbens, highest levels of D 4 receptors are expressed in the frontal cortex, midbrain, amygdala, and medulla. Whereas little D 3 receptor expression has been detected outside the nervous system, D4 receptors are more abundant in the heart than in the brain. The primary effector mechanisms associated with the stimulation of brain D3 and D4 receptors remain to be determined. Particular attention has been paid to a potential role of D 4 receptors in schizophrenia. On postmortem, elevated D 4 receptor levels have been found in the brains of patients with schizophrenia. Moreover, the atypical antipsychotic drug clozapine (Clozaril) has a high affinity for the D4 receptor; this receptor is highly polymorphic in humans and at least 25 distinct alleles have been identified. Studies are therefore under way to determine whether particular D 4 alleles are associated with psychotic disorders or with responsiveness to antipsychotic drugs. Adrenergic Receptors Adrenergic receptor heterogeneity was first discovered in the 1940s, when a and b subtypes were identified in pharmacological studies of isolated peripheral tissues. Subsequently, radioligand binding and molecular cloning studies have identified three main adrenergic receptor subfamilies; a 1, a2, and b. Each subfamily consists of at least three distinct receptor subtypes. Receptors within each subfamily share similar sequence homologies, pharmacological binding profiles, and effector mechanisms. The activation of a 1 receptors (subtypes designated a 1A, a1B, and a1C) stimulates phosphoinositide turnover. These receptors are believed to play a significant role in regulating smooth muscle contraction and have been implicated in the control of blood pressure, nasal congestion, and prostate function. Although all three subtypes are expressed in the brain, their contributions to the central actions of norepinephrine remain to be determined. The a2 receptors (designated including subtypes a 2A, a2B, and a2C) have been implicated in the regulation of cardiovascular function, autonomic nervous system activity, and arousal. The functions of a 2 receptor subtypes have been difficult to determine because of a lack of selective agonists and antagonists; a 2 receptors display both presynaptic autoreceptor and postsynaptic actions, and all appear to inhibit cAMP formation. The stimulation of a 2 autoreceptors inhibits firing of the noradrenergic neurons of the locus ceruleus, which have been implicated in arousal states. This mechanism has been proposed to underlie the sedative effects of the a2 receptor agonist clonidine (Catapres). In addition, the stimulation of brainstem a 2 receptors has been proposed to reduce sympathetic nervous system activity and to augment parasympathetic nervous system activity, which may relate to the utility of clonidine in lowering blood pressure and in suppressing the sympathetic hyperactivity associated with opiate withdrawal. The a 2 receptor antagonist yohimbine (Yocon) is used in the treatment of erectile disorder (impotence); the neural mechanisms that underlie this effect remain to be determined. Like the a-adrenergic receptors described, b-adrenergic receptors (designated including subtypes b 1, b2, and b3) are found both in the brain and in many peripheral tissues. The functional roles of the peripheral b-adrenergic receptors are better understood than are its central functions. Cardiac b 1 receptors play a major role in the regulation of heart function, and b 2 receptors regulate bronchial muscle contraction. b 3 receptors are found in adipose tissue, where they stimulate fat catabolism. Although b 1 and b2 receptors are widely distributed in the CNS, their contributions to catecholamine function are not well understood. Propranolol (Inderal) is a widely used nonspecific antagonist of both b 1 and b2 receptors. In addition to its utility for the treatment of hypertension and arrhythmias, its effectiveness in blunting autonomic symptoms underlies its utility in the management of social phobia; also, through mechanisms that are currently unknown, it is also effective in the treatment of akathisia. Histamine Receptors Histaminergic systems have been proposed to modulate arousal, wakefulness, feeding behavior, and neuroendocrine responsiveness. Three histaminergic receptor subtypes have been identified. Histamine type 1 (H 1) receptors are expressed throughout the body, particularly in smooth muscle of the gastrointestinal tract and blood vessel walls. H 1 receptors are widely distributed throughout the CNS, with particularly high levels in the forebrain and cerebellum. H 1 receptor activation stimulates phosphoinositide turnover, and tends to increase excitatory neuronal responses. These receptors are the targets of antihistaminergic agents used in the treatment of allergic rhinitis and conjunctivitis. The well-known sedative effects of these compounds have been attributed to their actions in the CNS. In addition, the sedation and weight gain produced by a number of antipsychotic and antidepressant drugs have been attributed to H 1 receptor antagonism;

conversely, H1 receptor agonists stimulate arousal and suppress food intake in animal models. H 2 receptors are also widely distributed throughout the body, and are found in gastric mucosa, smooth muscle, cardiac muscle, and cells of the immune system. Within the CNS, H 2 receptors are abundantly expressed in the neocortex, hippocampus, amygdala, and striatum. Activation of these receptors stimulates adenylate cyclase and produces excitatory effects in neurons of the hippocampal formation and thalamus. H 2 receptor antagonists are widely used in the treatment of peptic ulcer disease. The functional significance of central H 2 receptors is unclear, although several studies indicate that stimulation of these receptors produces antinociceptive effects. Unlike H 1 and H2 histamine receptors, H 3 receptors are located presynaptically on axon terminals. Those located on histaminergic terminals act as autoreceptors to inhibit histamine release. H 3 receptors are also located on nonhistaminergic nerve terminals, where they inhibit the release of a variety of neurotransmitters. Particularly high levels of H 3 receptor binding are found in the frontal cortex, striatum, amygdaloid complex, and substantia nigra. Lower levels are found in peripheral tissues such as the gastrointestinal tract, pancreas, and lung. Antagonists of H 3 receptors have been proposed to have appetite suppressant, arousing, and cognitive-enhancing properties. Cholinergic Receptors Two major classes of cholinergic receptors exist: G protein–coupled muscarinic receptors and nicotinic ligand-gated ion channels. Muscarinic receptors have been implicated in learning and memory, sleep regulation, pain perception, and the regulation of seizure susceptibility. The five known subtypes of muscarinic receptors are heterogeneous with regard to regional brain distribution and primary effector mechanisms. The muscarinic type 1 (M 1), M 3, and M5 receptors stimulate phosphatidylinositol (PI) turnover, and the M 2 and M4 receptors inhibit adenylate cyclase. The functional roles of the individual subtypes within the CNS are not well understood because highly subtype-selective agonists and antagonists have been unavailable. Based on brain distribution and the actions of nonspecific drugs, M1 receptors have been implicated in learning and memory processes. Striatal M 4 receptors have been implicated as putative targets for anticholinergics used as antiparkinson agents. Recently, a line of mice lacking functional M 1 receptors has been generated and found to be resistant to the convulsant effects of muscarinic agonists. In the periphery, M 2 receptors regulate heart rate and contractility and M 3 receptors mediate smooth muscle contraction and glandular secretion. Nicotinic acetylcholine receptors, like 5-HT 3 receptors, are members of the ligand-gated ion channel superfamily. They are composed of a pentameric complex of membrane protein subunits radially arranged around a central ion pore. The binding of acetylcholine to this receptor permits passage of Na + and K+ ions through the ion channel, depolarizing the postsynaptic cell. Nicotinic acetylcholine subunits are heterogeneous and associate in varied combinations. Thus, the properties of an individual complex will depend upon its particular subunit composition. The relative frequencies of various subunit combinations in discrete brain regions and their functional significance remain to be fully clarified. Within the human brain, nicotinic acetylcholine receptors are found at highest densities within the hippocampal formation, neocortex, substantia nigra, ventral tegmental area, dorsal raphe nucleus, periaqueductal gray, and the basal forebrain cholinergic complex. Consistent with this distribution, these receptors have been implicated in cognitive function. Cortical acetylcholine receptors are diminished in Alzheimer's disease, and nicotine administration improves attention defects in some patients. In some schizophrenia patients nicotine administration improves measures of sensory gating. This and other data have led to the proposal that the high incidence of cigarette smoking in this population represents a form of self-medication. Recently, some rare familial epilepsy syndromes have been associated with mutations of nicotinic acetylcholine receptors. Finally, the reinforcing properties of tobacco use are proposed to involve the stimulation of nicotinic acetylcholine receptors located in mesolimbic reward pathways.

SUGGESTED CROSS-REFERENCES The intracellular consequences of receptor activation are discussed in Section 1.8. The electrophysiological effects of brain monoamines are described in Section 1.9. The basic concepts of molecular biology that are relevant to current monoamine research are presented in Section 1.18. Alzheimer's disease and seizure disorders are covered in Chapter 10. Section 31.5 presents b-adrenergic receptor antagonists, Section 31.6 presents anticholinergics, Section 31.7 presents antihistamines, Section 31.15 presents cholinesterase inhibitors, Section 31.17 presents dopamine receptor antagonists, 31.26 presents serotonin-dopamine antagonists, and Section 31.25 presents selective serotonin reuptake inhibitors. SECTION REFERENCES Baik JH, Picetti R, Saiardi G, Thiriet A, Dierich A, Depaulis A, Le Meur M, Borrelli E: Parkinsonian-like locomotor impairment in mice lacking dopamine D

2

receptors. Nature 377:424, 1995.

*Barker EL, Blakely RD: Norepinephrine and serotonin transporters: Molecular targets of antidepressant drugs. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven, New York, 1995. *Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, ed 7. Oxford University Press, New York, 1996. *Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG: Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science

283:397, 1999.

Giros B, Jaber M, Jones SR, Wightman BM, Caron MG: Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606, 1996. Gotti C, Fornasari D, Clementi F: Human neuronal nicotinic receptors. Prog Neurobiol 53:199, 1997. Hamilton SE, Loose MD, Qi M, Levey AI, Hille B, McKnight GS, Idzerda RL, Nathanson NM: Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proc Natl Acad Sci USA 94:13311, 1997. *Hartman DS, Civelli O: Dopamine receptor diversity: Molecular and pharmacological perspectives. Prog Drug Res 48:173, 1997. Heisler L, Chu HM, Brennan T, Danao J, Bajwa P, Parsons L, Tecott LH: Elevated anxiety and antidepressant-like responses in serotonin 5-HT 1A receptor mutant mice. Proc Natl Acad Sci USA 95:15049, 1998. Hu XT, Moratalla R, Graybiel AM, White FJ, Tonegawa S: Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D 79:945, 1994.

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receptor mutant mice. Cell

Knable MB, Weinberger DR: Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol 11:123, 1997. Leurs R, Smit MJ, Timmerman H: Molecular pharmacological aspects of histamine receptors. Pharmacol Ther 66:413, 1995. Lindvall O, Bjorklund A: Dopamine- and norepinephrine-containing neuron systems: Their anatomy in rat brain. In Chemical Neuroanatomy, PC Emson, editor. Raven, New York, 1983. *Liu Y, Edwards RH: The role of vesicular transport proteins in synaptic transmission and neural degeneration. Ann Rev Neurosci 20:125, 1997. MacKinnon AC, Spedding M, Brown CM: Alpha 2-adrenoceptors: More subtypes but fewer functional differences. Trends Pharmacol Sci 15:119, 1994. Minneman KP, Esbenshade TA: Alpha 1-adrenergic receptor subtypes. Ann Rev Pharmacol Toxicol 34:117, 1994. Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R: Serotonin receptor 1A knockout: An animal model of anxiety-related disorder. Proc Natl Sci USA 95:14476, 1998. *Schwartz JC, Arrang JM, Garbard M, Traiffort E: Histamine. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven, New York, 1995. Tecott LH: Serotonin receptor diversity: Implications for psychopharmacology. In American Psychiatric Press Review of Psychiatry, vol 15, LJ Dickstein, MB Riba, JM Oldham, editors. American Psychiatric Press, Washington, DC, 1996. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D: Eating disorder and epilepsy in mice lacking 5HT2 Tork I: Anatomy of the serotonergic system. Ann NY Acad Sci 600:9, 1990.

C

serotonin receptors. Nature 374:542, 1995.

Weiner N, Molinoff PB: Catecholamines. In Basic Neurochemistry, ed 5, GH Siegel, BW Agranoff, RW Albers, PB Molinoff, editors. Raven, New York, 1994.

Textbook of Psychiatry

1.5 AMINO ACID NEUROTRANSMITTERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.5 AMINO ACID NEUROTRANSMITTERS RICHARD P. SHANK, PH.D., VIRGINIA L. SMITH-SWINTOSKY, PH.D. AND ROY E. TWYMAN, M.D. Neurophysiological Significance of Excitatory Amino Acids Neurophysiological Significance of Inhibitory Amino Acids Amino Acids as Cotransmitters Biochemical Processes that Mediate Transmitter Function Amino Acid Neurotransmitter Receptors Gaba Receptors GABA Clinical Considerations Suggested Cross-References

Throughout the first half of the twentieth century there was a prevailing view that neurons within the vertebrate central nervous system (CNS) are electrically coupled at their synapses and that synaptic transmission therefore could only be mediated electrically. About 1950 John Eccles and his colleagues realized that this could not be not true, and they were forced to conclude that synaptic transmission must be primarily a chemically mediated process. This realization stimulated research to identify the chemical messengers (neurotransmitters or transmitters). Electrophysiological experiments revealed that several amino acids either increased or decreased the excitability of neurons when applied to the extracellular surface. The amino acids that increased neuronal excitability include glutamate, aspartate, cysteate, and homocysteate, which are all similar structurally. Those that decreased neuronal excitability include g-aminobutyric acid (GABA), glycine, b-alanine and taurine, which also exhibit structural similarity. After the neuronal effects of these amino acids were reported, a debate arose as to whether these amino acids were really neurotransmitters or served some other undefined function in regulating or modulating the excitability of neurons. This debate is still not fully resolved, in part because there is not yet a precise understanding of all the chemical events that regulate neuronal excitability and their physiological significance. Nevertheless, rigorous criteria have been developed that can be used to determine whether an amino acid is actually a neurotransmitter. Currently, three amino acids (glutamate, GABA, and glycine) meet the criteria sufficiently to allow a consensus conclusion that they are true neurotransmitters. Furthermore, there is now little doubt that glutamate is the major excitatory neurotransmitter and that GABA and glycine are the major inhibitory neurotransmitters in the brain and spinal cord, respectively. Two more, aspartate and taurine, are likely to serve a significant, but as yet undefined, role in modulating the excitability of neurons. A role for cysteate, homocysteate, and b-alanine is less certain.

NEUROPHYSIOLOGICAL SIGNIFICANCE OF EXCITATORY AMINO ACIDS Nontransmitter Functions of Glutamate and Aspartate Glutamate and aspartate serve several functions in neural tissues unrelated to their role as neurotransmitters. Both are major constituents in proteins and several peptides, including N-acetylaspartylglutamate, a putative transmitter or cotransmitter. Aspartate is a precursor of N-acetylaspartate, a primary organic anion in the CNS. Glutamate and aspartate also have a role in energy metabolism; they are intermediates in the malate-aspartate shuttle, a metabolic pathway that reoxidizes cytosolic nicotine adenine dinucleotide (NADH) formed by aerobic glycolysis and captures the energy within mitochondria for adenosine triphosphate (ATP) formation ( Fig. 1.5-1). Because glucose is rapidly consumed via aerobic metabolism in neural tissues, this pathway is quite active.

FIGURE 1.5-1 The metabolic components of the malate-aspartate shuttle. Although it is not evident from the diagram, the flux of aspartate (ASP) across the mitochondrial membrane is coupled to the flux of glutamate (GLUT) in the reverse direction. The fluxes of malate (MAL) and a-ketoglutarate (a-KG) may be similarly coupled. OAA, oxaloacetate.

Glutamate is also the immediate metabolic precursor of nearly all GABA synthesized in neural tissues, which presumably occurs only in neurons that use GABA as a neurotransmitter (i.e., GABAergic neurons). Glutamate also can serve as an intermediate in the detoxification of ammonia. Glutamate as a Neurotransmitter Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS). Most neurons that use glutamate as a neurotransmitter (termed either glutamatergic or glutaminergic) are projection neurons—exemplified by the pyramidal neurons that arise in the cerebral cortex and project to various subcortical regions or other cortical areas—somatic primary afferent sensory neurons, and ganglion neurons that arise in the retina and project to the lateral geniculate ( Table 1.5-1). Glutamatergic interneurons include cerebellar granule cells, bipolar cells in the retina, and granule cells in the hippocampus. Glutamatergic neurons are particularly prevalent in the hippocampus, where they appear to have a significant role in memory formation.

Table 1.5-1 Principal Glutamatergic Pathways, Neuron Types and Behavioral Roles*

Aspartate as a Neurotransmitter Although aspartate has been shown to be a potent stimulatory factor in the CNS, its role in the brain is unclear. No specific receptors for aspartate have been identified, but it may be a physiologically relevant agonist (ligand) at some types of glutamate receptors. Compelling evidence indicates that some interneurons within the hippocampus and spinal cord concentrate aspartate within their synaptic terminals and release this amino acid during

membrane depolarization. However, it has not been established that aspartate is concentrated in specific types of synaptic vesicles released via exocytosis.

NEUROPHYSIOLOGICAL SIGNIFICANCE OF INHIBITORY AMINO ACIDS GABA as a Neurotransmitter GABA is prevalent throughout the CNS but at comparatively low concentrations brainstem and spinal cord, where glycine concentration is high. GABA is generally not found in peripheral neurons, but it is detected in some endocrine tissues, including b islets in the pancreas and in ovaries. GABA is not an essential amino acid and is not used as a building block for protein, but it is a constituent of some peptides, such as homocarnosine, a dipeptide of GABA and histidine. GABA is now recognized as the major inhibitory neurotransmitter within the CNS, but actual proof of this awaited identification of specific receptors for GABA in the postsynaptic membranes adjacent to presynaptic terminals and a demonstration that vesicles within the synaptic terminals of neurons that synthesize GABA (GABAergic neurons) selectively accumulate and concentrate GABA. The latter criterion was essential because the release of neurotransmitter molecules from synaptic terminals is quantal, which implies that transmitter molecules are released from synaptic vesicles into the synaptic cleft by an exocytotic process. Within the CNS GABA is synthesized only in select types of neurons, which are likely to GABAergic neurons. These are usually small interneurons with short axons, but some projection neurons, such as the Purkinje cells in the cerebellum and the striatonigral and pallidonigral neurons in the basal ganglia are GABAergic ( Table 1.5-2). Physiologically, the most common function of inhibitory GABAergic neurons appears to be to focus and refine the firing pattern (nerve-impulse generation) of the projection neurons that transfer neural information from one functional unit to another. An example of this is surround inhibition, which occurs when excitatory projection neurons activate inhibitory interneurons via collateral axons; which in turn inhibit surrounding projection neurons via synaptic contacts on the cell soma near the axon hillock. GABAergic neurons can also facilitate the output of excitatory projection neurons by a process of disinhibition, which occurs when two GABAergic neurons are linked synaptically in series. The first inhibits the ability of the second to depress the activity of an excitatory neuron, thereby increasing the excitatory output. GABA also mediates presynaptic inhibition, which occurs when a small presynaptic terminal impinges on a larger one and inhibits the release of transmitter molecules from it.

Table 1.5-2 Principal GABAergic Neuron Anatomical Locations, Neuron Types, and Neural Pathway Influenced

Glycine as a Neurotransmitter Glycine is present throughout the CNS but is more prevalent in the brainstem and spinal cord, which are the primary areas where it appears to serve a transmitter function. In all tissues, glycine is a major constituent of protein and several peptides such as glutathione. Virtually all criteria required to establish glycine as a neurotransmitter have been met. These include the identification of specific receptors in the postsynaptic membrane adjacent to presynaptic terminals and a demonstration that vesicles within the synaptic terminals of presumptive glycinergic neurons selectively accumulate and concentrate glycine. Anatomically, glycinergic neurons are usually small interneurons, predominantly located in the brainstem and spinal cord, and often functionally associated with a-motoneurons. Taurine Taurine, a sulfonated amino acid, is prevalent throughout the CNS and many other tissues. Taurine is highly concentrated (10 to 20 mmol/L) in the immature brain and declines during synaptogenesis. It is also abundant in white matter and therefore does not have a tissue distribution expected of a neurotransmitter. There is no compelling evidence that taurine activates specific receptors localized to synaptic terminals or that it accumulates into synaptic vesicles. Therefore, although the inhibitory effects of taurine on neuronal excitability suggest that this amino acid does function to depress neuronal excitability, it is not likely to be involved in synaptic signaling.

AMINO ACIDS AS COTRANSMITTERS Some glutamatergic and GABAergic neurons also use another agent, usually a peptide, as a neurotransmitter. For example, glutamatergic primary afferent neurons also release substance P. In addition, enkephalin and cholecystokinin have been colocalized with glutamate in the perforant path fibers of the hippocampus. Some glutamatergic neurons may also use aspartate or N-acetylaspartylglutamate as a cotransmitter. Cholecystokinin-8 (CCK-8), neuropeptide Y, and galanin are each colocalized with GABA in some cortical, limbic, and spinal neurons, respectively. Enkephalin and thyrotropin-releasing hormone (TRH) are also localized in some spinal GABAergic neurons. Some studies suggest that the peptide neurotransmitters are released from synaptic terminals primarily during periods of high-frequency neuronal firing.

BIOCHEMICAL PROCESSES THAT MEDIATE TRANSMITTER FUNCTION Synthesis and Regulation of the Neurotransmitter Pool of Glutamate Glutamate is rapidly synthesized from glucose in neural tissues, including synaptic terminals, but this reflects the role of glutamate in energy metabolism. The biochemical process used to replenish the neurotransmitter pool appears to involve a net synthesis of glutamate precursors in astrocytes, which are released and subsequently taken up into glutamatergic synaptic terminals and converted to glutamate. Glutamine is the most firmly established precursor serving this function, but a-ketoglutarate and malate may also be used in this capacity ( Fig. 1.5-2).

FIGURE 1.5-2 Some biochemical events associated with the neurotransmitter functions of glutamate and GABA. Many of the molecules of glutamate and GABA released from presynaptic terminals are transported into astrocytes and therein converted to glutamine and possible an intermediate of the tricarboxylic acid cycle, which are released and transported into the nerve terminals for subsequent conversion back into glutamate or GABA. MAL, malate, aKG, a-ketoglutarate.

The transmitter pool of glutamate may be defined as the molecules stored within synaptic vesicles. Glutamate is concentrated within vesicles by an ATP-dependent transporter specific for glutamate and present only in the membrane of vesicles in glutamatergic terminals. The vesicle transporter can concentrate glutamate approximately tenfold above the cytosolic level (~10 mmol/L). By comparison, the concentration of glutamate in the synaptic cleft when the synaptic terminal is inactive (resting state) is approximately 1 µmol/L. Sodium ion (Na+)-Dependent transporters with high affinity for both glutamate and aspartate present in the

cytoplasmic membrane also contribute to the regulation of the transmitter function of glutamate and aspartate. Specific types of transporters are expressed in neurons and astrocytes. Transporters in astrocytes and in neuronal synaptic membranes contribute to neurotransmitter inactivation by maintaining low extracellular concentrations around synapses, whereas neuronal transporters in nonsynaptic regions may contribute to regulating the excitability of neurons by controlling the ratio of the intracellular to extracellular concentration within neurons. In this regard, although the transporters generally function as uptake systems (sometimes termed reuptake), they can also serve an export function during membrane depolarization. Regulation of the neurotransmitter pool of aspartate is presumed to be similar to that for glutamate. A major difference is that relatively few neurons appear to contain synaptic vesicles with ATP-dependent transporters specific for aspartate. Therefore aspartate may function as a neurotransmitter in comparatively few neurons. Synthesis and Regulation of the Neurotransmitter Pool of GABA Glutamate is the major metabolic precursor of GABA, although a small amount of GABA is derived from polyamines. Glutamate decarboxylase (GAD) catalyses the reaction, and two distinct forms of this enzyme exist—GAD I and GAD II. The enzyme requires pyridoxal phosphate (vitamin B 6) as a coenzyme, which also serves a regulatory function. GABA is synthesized from a pool of glutamate that is rapidly formed from a-ketoglutarate, a tricarboxylic acid cycle intermediate. Much of the GABA synthesized via this pathway is probably not in synaptic terminals and therefore is not within the transmitter pool. Although some of the GABA molecules formed via this pathway may be released into extracellular fluid via a transport process, most is likely converted immediately to succinate by the enzyme GABA transaminase. The primary metabolic pathway by which the transmitter pool of GABA is replenished appears to be one in which glutamine and possibly a-ketoglutarate are supplied by astrocytes to GABAergic synaptic terminals. These are transported into the synaptic terminals and metabolized to glutamate, which is then converted to GABA, and transported into the synaptic vesicles ( Fig. 1.5-2). Release of Transmitter Molecules From Synaptic Terminals Amino acid neurotransmitters are released from synaptic terminals by a process similar to that for acetylcholine and the monoamine neurotransmitters. Glutamate, GABA, glycine, and aspartate are each accumulated in their own specific type of synaptic vesicle via a Na+-independent vesicular ATP-dependent transporter (pump). Neurotransmitters are concentrated within synaptic vesicles at concentrations about tenfold that the cytoplasmic concentration, resulting in an intravesicular concentration of nearly 100 mmol/L. Because the diameter of synaptic vesicles is about 10 –7 meter, one vesicle can contain approximately 5000 molecules. Transmitter release is triggered by depolarization of the presynaptic membrane by an action potential. This results in the opening of voltage-dependent calcium ion (Ca2+) channels, allowing calcium to flow into the presynaptic terminal. The rise in intracellular Ca 2+ concentration initiates a cascade of events involving at least eight proteins (mostly protein kinases) that enable the vesicles to dock at specific sites within the presynaptic membrane, whereupon the vesicles fuse with the membrane and release their contents into the synaptic cleft. Although the presynaptic terminal of neurons within the CNS may contain numerous vesicles, a single action potential typically induces transmitter release from only a few (1 to 3). This suffices to raise the concentration of neurotransmitter molecules within the synaptic cleft to nearly 1 millimeter for a few milliseconds, which will effectively saturates adjacent postsynaptic receptors. Removal of Transmitter Molecules From the Synaptic Cleft (Transmitter Inactivation) Transmitter molecules within the cleft can readily diffuse into extracellular fluid adjacent to the synapse, where the concentration of transmitter molecules is at least 1000-fold lower. As long as the 1000-fold gradient is maintained, diffusion can restore the resting concentration within the cleft to micromolar concentrations within a few milliseconds. Uptake of transmitter molecules back into the presynaptic terminal or into the postsynaptic neuron also contributes to the inactivation process. A key element in the inactivation of the transmitter function of glutamate, GABA, and aspartate is the vigorous uptake of the amino acids by transporters in the cytoplasmic membrane of astrocytes. This is primarily how a low (£ µmol/L) extracellular concentration (£µmol/L) of these amino acids is maintained, thereby allowing diffusion to remove molecules from the synaptic cleft rapidly. The molecules of glutamate, GABA, and aspartate taken up by astrocytes are metabolized to glutamine and intermediates of the tricarboxylic acid cycle ( Fig. 1.5-2).

AMINO ACID NEUROTRANSMITTER RECEPTORS Glutamate Receptors Glutamate receptors are found throughout the brain and are expressed on both neurons and glia, although not all glutamate receptor subtypes are found on both cell types. Glutamate receptors, sometimes referred to as excitatory amino acid receptors, were initially classified into N-methyl-D-aspartate (NMDA), quisqualate, and kainate receptors on the basis of their preferential activation by these exogenous agonists. More recently, five categories of glutamate receptors (NMDA, kainate, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA], L-2-amino-4-phosphonobutyrate (L-AP4), and trans-1-aminocyclopentane-1,3-dicarboxylic acid [ACPD] receptors) have been established on the basis of pharmacological, electrophysiological, and molecular biological criteria. The L-AP4 receptor type is defined by its agonist and acts as an inhibitory autoreceptor, while the quisqualate receptors of the previous classification have been subdivided by means of more-specific agonists into AMPA and ACPD receptors. AMPA and Kainate receptors are sometimes collectively referred to as non-NMDA receptors. NMDA, kainate and AMPA receptors are ionotropic glutamate receptors; the L-AP4 and ACPD receptors are grouped as metabotropic receptors. Ionotropic receptors are ligand-gated cation-specific channels that are activated rapidly (milliseconds), whereas metabotropic receptors coupled to G proteins and second-messenger systems function more slowly on a scale of several hundred milliseconds to seconds. Representative agonists and antagonists for each of these glutamate receptor classes are shown in Table 1.5-3.

Table 1.5-3 Common Glutamate Receptor Agonists and Antagonists

AMPA Receptors Recent cloning efforts have clearly demonstrated that AMPA and kainate receptors are distinct receptor complexes, although they can be activated by the same agonists. Four genes encode the AMPA receptor ( GluR1 through GluR4 [GluR-A through GluR-D]) and five genes encode the kainate receptor ( GluR5 through GluR7 and KA1 and KA2). The four AMPA receptor subunits are similar in size and amino acid sequence. Each subunit exists in two different forms, “flip” and “flop,” created by alternative splicing. AMPA receptor subunits are expressed predominantly in the flip form in embryonic brains and gradually change over to the flop form, which dominates in the adult brain. The AMPA receptor channels are permeable to Na + and potassium (K +) predominantly but will allow permeability to Ca +2 in the absence of the GluR2 (GluR-B) subunit. This however is only known to occur in a small population of hippocampal and neocortical nonpyramidal neurons in the brain. The AMPA receptor has at least three binding sites at which agonists or antagonists can interact: glutamate binding, desensitization and intra-ion-channel binding sites. Recently, a family of drugs called ampakines have been shown to selectively increase AMPA receptor-gated currents and improve cognitive performance in a series of behavioral tasks. Kainate Receptors Although kainate is an effective agonist of AMPA receptors, it also activates its own distinct class of ionotropic receptors, the kainate-preferring receptors. The five subunits are divided into two groups; GluR5 through GluR7 represent the low-affinity kainate-binding site ( Kd = 50 nmol/L), whereas KA1 and KA2 correspond to the high-affinity kainate-binding site ( Kd = 5 nmol/L). Each group is of similar size and amino acid sequence identity, with the KA1 and KA2 subunits being slightly larger than the GluR5 through GluR7 subunits. Despite their wide distribution throughout the CNS, the physiological significance of kainate receptors remains largely unknown, although they have been implicated in fast glutamatergic transmission in hippocampal neurons. In addition to postsynaptic functions, kainate receptors act presynaptically on mossy fiber terminals within the hippocampus to generate epileptiform activity. NMDA Receptors NMDA receptors mediate excitatory neurotransmission in the CNS in different ways from AMPA and kainate receptors. They are characterized by voltage-dependent block by magnesium ions (Mg 2+), a high permeability to Ca 2+, and slow gating kinetics. The NMDA receptor is a ligand-gated ion channel composed of two different subunits: NMDAR1 and NMDAR2. NMDAR1 can exist in seven splice variants, and there are four different genes encoding variants of NMDAR2 (2A, B, C, D). At present it is not clear how many R1 and R2 subunits are present in each functional NMDA receptor or if additional subunits exist, although

the receptor is thought to be pentameric. However, it is known that NMDAR1 serves as the core subunit of a functional NMDA receptor, with the NMDAR2 subunits acting as modulatory components of the receptor. Both NMDAR1 and NMDAR2 are required for receptor function. NMDA receptors have a number of distinct recognition sites for endogenous and exogenous ligands, each with discrete binding domains. At present there are at least seven pharmacologically distinct sites through which compounds can alter the activity of this receptor ( Fig. 1.5-3). Drugs that affect NMDA receptor function are divided into four groups, those acting at (1) the glutamate and NMDA recognition site, which is highly conserved on the NMDA NR2 subunits; (2) the strychnine-insensitive glycine binding site, where glycine is required as a coagonist for channel opening; (3) the intraion-channel binding site, where Mg 2+ sits blocking ionic currents through the receptor at resting potentials; and (4) modulatory sites such as the redox modulatory site, the proton sensitive site, the zinc (Zn 2+) site, and the polyamine site.

FIGURE 1.5-3 Diagrammatic illustration of the NMDA receptor–ion-channel complex and its modulatory sites. PCP, phencyclidine.

The NMDA receptor has three characteristic features: (1) at resting potentials it remains blocked by Mg 2+, and ionic currents flow through the receptor only if the neuronal membrane is partially depolarized; (2) significant amounts of extracellular Ca 2+ enter the cell interior during activation of the receptor; and (3) NMDA receptor–mediated neurotransmission occurs slowly and lasts for a prolonged period. Because of these properties, it has been shown that the NMDA receptor serves a critical role in synapse development and plasticity, including the phenomena of long-term potentiation and long-term depression. Abnormal functioning of the NMDA receptor can lead to a variety of neurological disorders. Overactivation of the NMDA receptor has been indicated in ischemic insults, head trauma, and epileptic seizures, triggering a cascade of cellular events that culminate in neuronal cell death. On the other hand, hypofunction of the NMDA receptor elicits a psychomimetic state that closely resembles schizophrenia. Metabotropic Receptors Not as much is known about the last group of glutamate receptors, the metabotropic receptors. The metabotropic receptor proteins belong to the superfamily of G-protein–coupled receptors, all of which contains seven-transmembrane domains. So far, the metabotropic receptor gene ( mGluR) family has been shown to contain eight members, which are closely related in primary structure and can be divided into three groups on the basis of amino acid sequence homology, agonist sensitivity, and associated signal-transduction mechanisms. Group I receptors (mGlu1 and mGlu5) are coupled to the inositol (1,4,5) triphosphate-Ca 2+ cascade, while group II (mGlu2 and mGlu3) and group III (mGlu4 and mGlu6 through mGlu8) lead to the inhibition of adenylate cyclase. Some members of the mGluR families exist in alternatively spliced variants. Several lines of evidence suggest that the N-terminal large extracellular domain of the receptors contains glutamate binding sites, while the C-terminal domain plays a role in determining the potency of agonists regulating the transduction mechanisms of the metabotropic receptors. Glutamate, quisqualate, and ibotenate activate both mGluRs and ionotropic receptors. Some glutamate analogues, such as ACPD and L-AP4, are specific for metabotropic receptors, while their potencies differ for each mGluR subtype ( Table 1.5-3). Generally, metabotropic receptor agonists induce a slow membrane depolarization (a rise time of around 5 seconds and lasting up to 60 seconds, which is about 1000-fold slower than ionotropic receptors) accompanied by an increase in firing rate in many neurons. These effects are attributed to direct inhibitory effects on K + channels. In addition to direct excitatory postsynaptic effects, metabotropic receptor activation suppresses both excitatory and inhibitor transmission at synapses by presynaptic mechanisms via an autoreceptor-type mechanism, thereby modulating presynaptic activity. Several metabotropic receptors have been implicated in synaptic plasticity that occurs in learning and memory.

GABA RECEPTORS GABAA Receptor The GABA A receptor is a member of the superfamily of ligand-activated ion channels in the cell membrane. GABA type A (GABA A) receptors are most closely related to strychnine-sensitive glycine receptors, more distantly related to acetylcholine nicotonic receptors and serotonin 5-hydroxytryptamine (5-HT) [5-HT] type receptors, and even more distantly related to glutamate ionotropic receptors (AMPA and kainate receptors and NMDA receptors). GABA A receptors are heteropentameric protein complexes, which when activated undergo a series of conformational changes that form an open channel (pore) selectively permeable to anions, specifically chlorine anion (Cl –) and to a lesser degree (HCO –3). Receptor activation normally results in an influx of Cl – which rapidly and transiently hyperpolarizes the membrane, a process generally referred to as the generation of an inhibitory postsynaptic potential. The increase in Cl – flux also decreases the resistance of the membrane, which acts as a shunt to impede the ability of depolarizing excitatory postsynaptic potentials to elicit action potentials (nerve impulses). For this reason, inhibitory synapses are most effective when located near the point at which action potentials are initiated, usually the axon hillock. Therefore, it is not surprising that GABAergic inhibitory synapses are often concentrated on neuronal cell bodies near the axon hillock. GABAA receptors are heteromeric in that the receptor can comprise at least four types of subunit proteins, termed a, b, g, and d. It is pentameric in that each receptor has a total of five proteins; therefore all GABA A receptors have more than one copy of at least one type of subunit protein. There are multiple subtypes of three of the subunit proteins, at least six subtypes of a, three of b, and two of g. Although theoretically there could be many thousands of GABA A receptor subtypes, it is likely that fewer than 20 exist naturally. Most often the receptors contain two a, two b, and one g, or one a, two b, and two g subunits. The different subunits and the different subtypes of each subunit from which a particular type of receptor is formed can influence the physiological properties of the receptor (e.g., channel open time and rate of desensitization) as well as susceptibility to pharmacological agents as discussed below. GABAA receptors are regulated by phosphorylation of some serine hydroxyl residues in the inner loop of the b subunits. Phosphorylation can be mediated by protein kinase A or protein kinase C. Depending on the type of b subunit, phosphorylation can affect the channel gating properties (e.g., channel open time and rate of receptor desensitization) either positively or negatively. A variety of pharmacological agents can influence the activity of GABA A receptors. At least five separate drug binding sites have been identified ( Fig. 1.5-4 and Fig. 1.5-5). Many clinically useful drugs are known to bind to benzodiazepine or barbiturate sites. These sites are allosteric to the GABA binding site. Drugs that bind to them influence the ability of GABA to activate the receptor by either altering the affinity between GABA and its binding sites (GABA A receptors probably possess two GABA binding sites) or by altering the channel open time and rate of receptor desensitization. It now seems unlikely that either of these sites serves a physiological purpose. An unusual characteristic of the benzodiazepine site is that drugs binding to it can exert either a positive modulatory (an agonist) or negative modulatory (an inverse agonist) effect, or no effect at all (an antagonist). The steroid site may have some yet-undetermined physiological relevance. Several of the pharmacological effects of ethanol are mediated through effects on GABA A receptors, but it may not act at a specific and unique site.

FIGURE 1.5-4 Diagrammatic illustration of the GABAA, receptor–ion-channel complex and its modulatory sites.

FIGURE 1.5-5 Structure of the prototypical GABAA and benzodiazepine receptor agonists and antagonists. (Courtesy of Daniel C. Javitt, M.D., Ph.D., and Stephen R. Zukin, M.D.)

GABAB Receptors The metabotropic GABAB receptors are a member of the superfamily of G-protein-coupled receptors expressed in the cell membrane. These receptors generally exert an inhibitory effect on neuronal excitability by generating hyperpolarizing potentials that are much slower in onset and longer in duration than those mediated by GABA A receptors. Because GABAB receptors are G-protein coupled, receptor activation initiates guanosine triphosphate (GTP) hydrolysis and thereby causes dissociation of the G-protein subunits (a, b, g) from the receptor. GABA B receptors are coupled to a G i subtype of G protein, and the dissociated a subunit activates a type of K + channel, thereby hyperpolarizing the membrane. GABA B receptors are often located on presynaptic terminals where they serve to inhibit transmitter release by reducing the efficacy of action potentials to activate Ca 2+ influx.

CLINICAL CONSIDERATIONS Glutamate and Aspartate Glutamate and aspartate function effectively as excitatory neurotransmitters because their extracellular and intracellular concentrations are tightly regulated by several biochemical processes, most of which require a constant source of energy (e.g., ATP). These include the vigorous transport systems in the membrane of astrocytes and neurons that rapidly remove glutamate from extracellular fluid (e.g., synaptic cleft) and transport systems within the synaptic vesicles from which the transmitter molecules are released into the synaptic cleft. Glutamate and aspartate can be rapidly metabolized, but only intracellularly. Therefore any condition that impairs the ability of the membrane transport systems to maintain these amino acids at very low extracellular levels can have a severe impact on the physiological activity of neurons. Ischemia-Induced Neurodegeneration The events that cause neuronal cell death as a result of stroke, head trauma, or any condition involving a dramatic loss of oxygen or glucose supply to the brain are complex and not clearly elucidated. However, it is likely that a breakdown in the regulation of glutamate is a major factor. Early metabolic consequences of ischemia or hypoxia include accumulation of lactic acid, a concomitant decrease in pH, and a decrease in energy storage molecules (phosphocreatine and ATP). This has an immediate deleterious effect on the activity of the sodium-potassium ion pump, which accounts for more than 50 percent of ATP-supplied energy use in the CNS. This in turn results in a dissipation of transmembrane gradients for K + and Na+ and a concomitant depolarization of the cell membrane. Dissipation of the Na + gradient inhibits the removal of glutamate from extracellular fluid, and membrane depolarization activates voltage-sensitive Ca 2+ channels in synaptic terminals, thereby promoting excessive glutamate release. Consequently, high levels of glutamate accumulate in the synapse, causing excessive activation of NMDA and AMPA receptors. Because of the prevalence of these receptors, the intracellular accumulation of Ca 2+ is greatly exacerbated. This pathological accumulation of Ca 2+ promotes a cascade of events that can result in neuronal cell death. Neurological disorders in which this pathological cascade may be involved include global and focal ischemia (stroke) but also hypoglycemia, head trauma, spinal injury, status epilepticus, drug abuse, and certain food toxicities (e.g., monosodium glutamate, and mussel poisoning). Chronic Neurodegenerative Disorders Dysregulation of glutamate and aspartate and overactivation of their receptors may contribute neuronal cell loss in chronic disorders such as acquired immune deficiency syndrome (AIDS) dementia, Parkinson's disease, motor neuron disease (including amyotrophic lateral sclerosis), Huntington's disease, and Alzheimer's disease. Tissue-specific defects in glial transporter genes resulting in impaired glutamate uptake have been identified in several cases of the sporadic form of amyotrophic lateral sclerosis. Lathyrism, which is clinically similar to amyotrophic lateral sclerosis, has been linked to the ingestion of cycad beans, which contain an excitotoxin b- N-methylamino-L-alanine. Abnormal activation of excitatory pathways within the basal ganglia appears to play a part in the symptom expression of parkinsonism in animal models. In primates, NMDA and non-NMDA antagonists increase the therapeutic efficacy of the dopaminergic drug, levodope (Larodopa). Epilepsy Epilepsy is a group of neurological disorders characterized by spontaneous recurrent seizures. A seizure is an abnormal paroxysmal firing of cerebral neurons in synchronous fashion and is often associated with motor signs and sensory, autonomic, or psychic symptoms. Loss or impairment of consciousness often occurs. Epileptic syndromes are defined on the basis of clusters of signs and symptoms that generally occur together in a patient with recurrent seizures. They are classified on the basis of the seizures: localization related, generalized, undetermined, or a special syndrome (1989 International League Against Epilepsy classification). The epileptic syndromes are further divided by etiology: idiopathic, cryptogenic, or symptomatic. Epilepsy occurs in 1 to 2 percent of the population worldwide, and epileptic patients account for a major proportion of the return visits in neurological clinics. Although compounds that antagonize the action of glutamate at NMDA receptors or AMPA and kainate receptors are generally effective in blocking seizures, the only marketed antiepileptic drug in which glutamate antagonism is thought to be a prominent component of its antiseizure activity is topiramate (Topamax). Topiramate selectively antagonizes AMPA and kainate receptors. Although many neurobiological factors may contribute to seizure formation, a prominent feature of most seizures is an abnormal and excessive firing of glutamatergic neural pathways. Therefore, abnormalities in the regulation of glutamate may be a factor in the initiation, spread and maintenance of seizure activity in some types of epilepsy. The involvement of glutamatergic receptors in seizures and epilepsy is widely accepted on the basis of evidence that injections or focal applications of glutamatergic agonists at NMDA receptor or AMPA and kainate receptors seem to produce seizures or epileptic-like activity in numerous in vitro and animal models of epilepsy. Furthermore, selective antagonists to these receptors reduce epileptic activity or are potent anticonvulsants in several models. Elevated plasma concentrations of glutamate have been observed in a epileptic-like mouse strain and in probands with generalized epilepsy. Some studies using in vitro or ex vivo techniques and studies in animal models indicate that glutamate or aspartate release increases during seizure activity. A study using chronically implanted microdialysis probes in bilateral hippocampi of epileptic humans showed marked increases in extracellular glutamate concentrations immediately prior to the onset of seizures on the side of seizure origin. Many patients with temporal lobe or complex partial epilepsy have neuronal loss and sclerosis, particularly in mesial hippocampus. Mesial temporal sclerosis is a common finding in surgical specimens removed from patients suffering from chronic refractory complex partial seizures. Neuronal loss is prominent in CA1, CA3 and

dentate hilus. Interestingly, the pathology closely resembles the findings seen in model systems of prolonged seizure activity or in those induced by application of excitotoxins. Kindling, which is a gradual induction of a hyperexcitable neuronal state, can occur by focal repetitive subconvulsive stimulation of the hippocampus, amygdala, or some other brain areas. Kindling results in increased susceptibility toward seizures and has been studied extensively in animals, particularly rodents. The basis for the persistent hyperexcitable state remains controversial, and the actual involvement of excitatory amino acid receptors in this hyperexcitable state remains unclear. However, there is good evidence that glutamatergic receptors, particularly NMDA types, play a role in the development and enhancement of the kindled or seizure-prone state. NMDA receptor antagonists can prevent the kindling phenomenon despite the expression of seizurelike discharges in in vitro models such as hippocampal slices. A variety of NMDA antagonists, including those that act as channel inhibitors or compete with the glutamate recognition or glycine recognition sites, appear to be highly effective in blocking the development of kindling. They do not appear to be as effective as anticonvulsants in fully expressed seizures unless they are used at dosages that produce significant toxic effects, such as neurological or behavioral impairment. In contrast, AMPA receptor antagonists are highly effective in blocking the expression of seizures, but they seem to have little effect on the induction of the kindled state. Further research is needed to define the role of excitatory amino acids in kindling and hippocampal injury. Much of the research has focused on ionotropic glutamate receptors. With the recent discovery of more-selective metabotropic glutamate receptor agonists and antagonists, along with the cloning of metabotropic receptor genes, the role of metabotropic receptors is now being explored. Schizophrenia The cause of schizophrenia remains elusive, although several observations suggest that it may involve abnormalities in glutamatergic transmission. This hypothesis has been spurred on by the knowledge that phencyclidine (PCP, “angel dust”), a noncompetitive NMDA receptor antagonist, generates psychomimetic behaviors similar to those seen in schizophrenia. Clinical data supporting a role for glutamate in the etiology of schizophrenia are sparse but interesting. In the 1980s it was observed that glutamate concentration was lower in the cerebrospinal fluid (CSF) of schizophrenic patients than in that of control patients. These results have not been replicated successfully. Postmortem studies of schizophrenics have shown a consistent increased density of glutamate receptors (NMDA and non-NMDA) within the frontal and temporal cortex, together with some evidence for decreased production or release of glutamate, or both. Such results suggest that schizophrenia involves decreased glutamatergic transmission. Neuropathic Pain Activation of afferent C fibers with nociceptive stimuli produces pain sensations that are enhanced during pathological conditions. Activity-dependent increases in excitability are induced in the spinal dorsal horn neurons by repetitive stimulation of C fibers. This is thought to contribute to the development and maintenance of chronic pain symptoms. NMDA antagonists, ketamine (Ketalar) and D-amino-propyl-valeric acid, have consistently reduced this activity in the rat dorsal horn nociceptive neurons, suggesting that the NMDA receptor contributes to this phenomenon. AMPA and kainate receptors may also play a role in modulating pain. In situ hybridization studies have revealed that expression of kainate receptor gene GluR5 is particularly prominent in dorsal root ganglion neurons. Animal studies have indicated that kainate receptor antagonists significantly reduce nociception, and early human trials with some of these agents show them to be promising for analgesia. Substance Abuse Several lines of evidence indicate that one of the acute effects of ethanol is to inhibit glutamate receptor function, particularly NMDA and kainate receptors. Such inhibition leads to depressed synaptic transmission and may result in ethanol-induced cognitive deficits. Indeed, low concentrations of ethanol are known to inhibit long-term potentiation in the hippocampus.

GABA Epilepsy Like the glutamatergic system, GABA and GABA receptor subtypes play a central role in the expression of seizures. GABA, as the major inhibitory neurotransmitter in the CNS, can be found in up to 30 percent of CNS synapses. In general, for the mature brain, loss or blockade of GABA inhibition can result in increased hyperexcitability and expression of seizures. Unlike with the glutamatergic system, several GABAergic drugs are widely used in the treatment of epilepsy. Clinically effective benzodiazepines and barbiturates likely act at GABA A receptors to enhance inhibition. Both have been shown to be effective in the control of partial, complex partial, and generalized tonic-clonic seizures. Benzodiazepines are also effective in the short-term treatment of generalized absence, but a functional tolerance tends to develop, thereby reducing their efficacy. Barbiturates may exacerbate generalized absence seizures. Benzodiazepines are also effective in the treatment of atypical absence and myoclonic seizures. Anticonvulsant benzodiazepines and barbiturates are highly sedating, which limits their use. Phenobarbital (Solfoton) an anticonvulsant barbiturate, has been used for the treatment of epilepsy since the early 1900s, and it is still the most widely used anticonvulsant in the world, primarily because of its low cost. Other evidence that the GABAergic system is important in the expression of seizures is that manipulation of GABA A receptor function can cause, exacerbate, or reduce seizure activity. The mushroom poisons picrotoxin and bicucculine antagonize GABA A receptors noncompetitively and competitively, respectively, and can elicit seizures. Penicillin given at high doses (especially in renal failure patients or intrathecally) can result in partial or generalized seizures. Penicillin reduces GABA-induced chloride current flow by blocking the ion channel pore. The GABA A receptor has numerous modulatory sites that can allosterically increase or decrease the chloride ion channel current flow. For example, negative modulators that act at the benzodiazepine site (e.g., b-carbolines) or the steroid site (e.g., pregnenolone sulfate) can lower seizure thresholds. In the mature or adult brain, enhancement of GABA A receptor function generally raises the seizure threshold. Certain naturally occurring and synthetic pregnane-derived steroids are potent positive modulators, now called neuroactive steroids, or neurosteroids. Some data support the role of the endogenous neurosteroids in cyclical changes in behavior and in catamenial or menstrually related epilepsy. A pregnane-derived synthetic neurosteroid is in clinical trials for treatment of epilepsy. Not only does positive modulation of these allosteric sites result in anticonvulsant activity, increases in GABA availability also seem to be of clinical benefit. Reduction of GABA clearance by inhibition of GABA uptake or reduction of GABA degradation by poisoning GABA transaminase are both effective. A GABA uptake inhibitor has been recently approved for treatment of partial seizures, but it may exacerbate generalized absence seizures. An irreversible inhibitor of GABA transaminase also effective in the treatment of partial seizures is in the late stages of development. Finally, some evidence in animal models suggests that modulation of GABA B receptors may play a role in the treatment of generalized absence seizures. Anesthesia Pentobarbital (Nembutal) has been a popular drug for induction of anesthesia. Like phenobarbital, pentobarbital allosterically enhances GABA A receptor function, but over a narrow concentration range it also can directly activate GABA A receptors. Pentobarbital also has activity in blocking glutamate receptors and voltage-gated calcium channels. The potent benzodiazepines midazolam (Versed) and lorazepam (Ativan) have replaced diazepam (Valium) as a drug of choice for induction of anesthesia. In the 1990s pentobarbital was replaced by propofol (Diprivan), which is more easily titrated and is especially useful in the neurosurgical setting. Propofol, which has a short duration of action, allosterically enhances GABA A function and directly activates these receptors. Several neurosteroids also can directly activate GABA A receptors, and it has been proposed that this direct effect is in part responsible for the anesthetic qualities of these agents. In the 1940s, parenteral administration of cholesterol was shown to induce sedation in animals, and this subsequently led to the development of synthetically derived steroids for sedation. Although its mechanism of action was unknown at the time, one derivative, alfaxalone (Alfathesin) was a popular agent during the early 1970s for the induction of anesthesia. It has been subsequently discovered that alfaxalone's pregnane-based structure is similar to that for the neurosteroids and that it is a potent enhancer of GABAA receptor function. Anxiety- and Sleep-Related Disorders Benzodiazepines and barbiturates have a long history in the treatment of anxiety and insomnia. Diazepam was once the most prescribed medication in the United States. With the cloning of GABA receptor genes, it is now recognized that the hints of subtypes of GABA A receptors from previous pharmacological experiments are true. This is especially true for subclasses of benzodiazepine-sensitive receptors. Benzodiazepines with greater anxiolytic than sedative-hypnotic properties are in use clinically, and their efficacy may be related to preferential binding to particular subtypes of GABA A receptors. Spasticity Loss of spinal and supraspinal inhibition may result in spasticity or hyperreflexic states. One particular disorder, stiff person syndrome, is associated with increased reflexivity and muscle spasms and occasionally with seizures, diabetes or both in some patients. The disorder is frequently associated with circulating antibodies to GAD, the GABA synthesis enzyme. Interestingly, antibodies to GAD are associated with type I diabetes (autoimmune-associated juvenile form). Benzodiazepines, especially diazepam, and baclofen are mainstays in the treatment of spasticity. However, these agents are often only moderately effective,

especially in supraspinal forms of spasticity. Substance Abuse Ethanol enhances GABA receptor function in some in vitro preparations potentially via a protein-binding site. Although studies have been controversial, many accept that ethanol may selectively alter function of some subtypes of GABA receptors. GABA A-active benzodiazepines and barbiturates are known for their development of tolerance and potential addictive activity during long-term administration. Glycine Glycinergic neurotransmission is important in the circuits for local inhibitory control in the spinal cord. Genetic defects in glycine subunit genes have been identified as causes of hypersensitive reflexes and spasticity in both humans and animals. Opportunities for pharmacotherapeutic modulation of glycine receptors have been rather limited by the lack of readily identifiable allosteric regulatory sites. Strychnine, a potent antagonist, has long been used as a poison for rodents and in humans, where it has been used as an instrument of malicious intent. Clinically relevant positive modulators of the glycine receptor include ethanol and the anesthetic propofol.

SUGGESTED CROSS-REFERENCES Further information about the neuroanatomy of specific excitatory and inhibitory projections can be found in Section 1.2 on neuroanatomy. Further information on the receptor transduction mechanisms can be found in Section 1.9 on electrophysiology. Information regarding the contributions of specific cortical regions and pathways in schizophrenia can be found in Section 12.3 on brain structure and function and Section 12.4 on neurochemical, vital, and immunological studies in schizophrenia. The role of GABA benzodiazepine receptors in mood disorders is discussed in Chapter 14, and their role in anxiety disorders is discussed in Chapter 15. The clinical use of benzodiazepines is discussed in Section 31.10. Epilepsy is covered in Section 2.4. SECTION REFERENCES *Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SN: International Union of Pharmacology. XV. Subtypes of g-aminobutyric acid A receptors: Classification on the basis of subunit structure and receptor function. Pharmacol Rev 50:291, 1998. *Betz H, Kuhse J, Fischer M, Schmieden V, Laube B, Kuryatov A, Langosch D, Meyer G, Bormann J, Rundstrom N, Matzenbach B, Kirsch J, Ramming M: Structure, diversity and synaptic localization of inhibitory glycine receptors. J Physiol (Paris) 88:243, 1998. Bigge CF, Boxer PA, Ortwine DF: AMPA/kainate receptors. Curr Pharm Design 2:397, 1996. Cacabelos R, Takeda M, Winblad B: The glutamatergic system and neurodegeneration in dementia: Preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatr 14:3, 1999. Cooper JR, Bloom FE, Roth RH: Amino acid neurotransmitters. In The Biochemical Basis of Neuropharmacology, ed 7. Oxford University Press, New York, 1996. Dingledine R, Borges K, Bowie D, Traynelis SF: The glutamate receptor ion channels. Pharmacol Rev 51:7, 1999. Javitt DC, Zukin SR: Amino acid neurotransmitters. In Comprehensive Textbook of Psychiatry/VI, vol 1, HI Kaplan, BJ Sadock, editors. Williams & Wilkins, Baltimore, 1995. Kvamme E, editor: Glutamine and Glutamate in Mammals. CRC Press, Boca Raton, FL, 1988. *McGeer PL, McGeer EG: Amino acid neurotransmitters. In Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, GJ Siegel, BW Agranoff, RW Albers, PB Molinoff, editors. Raven, New York, 1989. *Michaelis EK: Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 54:415, 1998. Millhorn DE, Hokfelt T: Chemical messengers and their coexistence in individual neurons. News Physiol Sci 3:1, 1988. *Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney J-W: Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106, 1999. Ozawa S, Kamiya H, Tsuzuki K: Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 54:581, 1998. Seeburg PH: The TINS/TIPS Lecture: The molecular biology of mammalian glutamate receptor channels. Trends Neurosci 16:359, 1993. Shepherd GM: Neurobiology, ed 3. Oxford University Press, New York, 1994. *Tamminga CA: Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21, 1998.

Textbook of Psychiatry

1.6 NEUROPEPTIDES: BIOLOGY AND REGULATION Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.6 NEUROPEPTIDES: BIOLOGY AND REGULATION MICHAEL J. OWENS, PH.D., CHARLES B. NEMEROFF, M.D., PH.D. AND GARTH BISSETTE, PH.D. Distribution Biosynthesis Peptide Processing Receptors and Second Messengers Peptidases Neuroendocrine Secretion Neuropeptides in Psychiatric Disorders Suggested Cross-References

The past several decades have witnessed a veritable explosion of knowledge about the central nervous system (CNS), and in no area has this been as impressive as in peptide neurobiology. Numerous peptide neurotransmitter candidates have been identified and characterized, their CNS distributions mapped, and their genes cloned. The tenet “one neuron-one transmitter” erroneously attributed to Dale has been convincingly refuted with numerous demonstrations of neurons containing multiple peptides or combinations of peptide and nonpeptide neurotransmitters. Additionally, since the early 1980s there has been an embarrassment of riches in the form of knowledge about neurotransmitter receptor diversity, diversity of receptor-effector coupling, and neurotransmitter transporters. These discoveries have not yet been fully integrated into what is known about normal or aberrant CNS function, although dysfunction at virtually any level could conceivably lead to neuropsychiatric deficits. This chapter summarizes, with several examples, the general principles governing neuropeptide biology and includes a review of several neuropeptides that have been unequivocably demonstrated to be involved in the pathophysiology of one or another neuropsychiatric disorders. By definition, a neuropeptide is a chain of two or more amino acids linked by peptide bonds, and differs from other proteins only in the length of the amino acid chain. Over 100 unique biologically active peptide sequences have been purified from biological sources; their sizes range from two (carnosine and anserine) to over 40 amino acids (corticotropin-releasing factor [CRF] and growth hormone-releasing factor [GRF]) ( Table 1.6-1). Most of the other known active peptides fall within these size limits. By convention, peptides greater than 90 amino acids in length (about 10,000 molecular weight) are considered proteins. The five examples discussed here are somatostatin (somatotropin release-inhibiting factor [SRIF]), thyrotropin-releasing hormone (TRH), neurotensin neuromedin N, and CRF. Their structures are illustrated Table 1.6-2, and are written by convention from the amino terminus (NH 2–) beginning on the left to the carboxyl terminus (–COOH) on the right. Somatostatin, CRF, and TRH are hypothalamic hypophysiotropic hormones and, like neurotensin and neuromedin N, function in the CNS as neurotransmitters in ways that are often quite distinct from their effects on the endocrine axes. Neuropeptides have been implicated as chemical mediators in pathways subserving a variety of behavioral and physiological effects, including such diverse behaviors as thermoregulation, food and water consumption, sex, sleep, locomotion, memory, learning, responses to stress and pain, and emotion. Those actions have stimulated interest in the contribution of the peptidergic neuronal systems to the symptoms and behaviors exhibited in such major psychiatric illnesses as psychotic disorders, mood disorders, and dementia. In addition to their endocrine and neurotransmitter roles, many peptides and their receptors apparently play active roles in development and often appear transiently in various anatomical regions or in such abundance that a trophic effect is postulated, an effect that does not necessarily persist beyond early development. An example of this ontogenetic shift is found in the distribution of messenger ribonucleic acid (mRNA) for SRIF in developing rats. The mRNA exhibits more regional heterogeneity in developing rats than it does in adult animals, with the hypothalamic mRNA concentrations being much higher than the cerebrocortical expression.

Table 1.6-1 Selected Neuropeptide Transmitters

Table 1.6-2 Selected Neuropeptide Structures

Many of the known behavioral effects of neuropeptides are observed only after their direct injection into the CNS because most peptides do not penetrate the blood-brain barrier in amounts sufficient to produce effects before being inactivated by serum and tissue enzymes that degrade them. The degradation is usually the result of the cleavage of specific amino acid sequences targeted by a specific peptidase designed for that purpose. Peptide fragments often possess full or partial biological activity at peptide receptors, and the relatively lengthy period of peptide-induced effects may be attributable to this delayed cessation of activity. How much neuropeptide must be injected to elicit a physiological or behavioral effect is debatable because endogenous neuropeptides exist in picomolar to femtomolar concentrations whereas nanomolar concentrations are often required to produce such effects. Such differences should be expected, however, when it is realized that the anatomical substrate mediating the behavior or effect may be quite far from the site of injection, that the preexisting endogenous peptide signal and its regulatory and feedback systems must be overwhelmed, that a gauntlet of peptidases must be negotiated, and that synaptic concentrations may indeed reach high nanomolar concentrations. Another disconcerting fact about neuropeptides is the propensity for a property or effect to be elicited by one or more apparently unrelated peptides. Although often frustrating and potentially confounding to researchers, that property can be explained by the ability of more than one sequence of amino acids to assume similar three-dimensional shapes and charge distributions, all of which may be recognized by the receptor, by the presence of multiple receptor types contained on neurons initiating the behavior, and by possible similarities between second-messenger transduction mechanisms activated by discrete and distinct peptide receptor types. The tertiary structure for recognition is also used by the immune system for the production of specific antibodies, as well as by biological receptors. Because both descriptive (immunohistochemical) and quantitative (radioimmunoassay) methods for detecting the small concentrations of endogenous peptides rely on immunological techniques, it is always possible that a similarly shaped structure could confound the interpretation of immunoassay results. Thus, descriptions of antisera specificity and amount of cross-reactivity with other potential ligands are crucial to the proper evaluation of results. The dichotomy in methodology for detecting neuronal localization of peptide versus regional peptide concentration is also seen in the tools for peptide receptor identification by

autoradiography (localization) and regional membrane preparations for receptor quantification (“grind and bind”). The analogous procedures for detecting peptide mRNA are in situ hybridization (localization), Northern blot analysis, ribonuclease protection assay, and the polymerase chain reaction for regional mRNA quantification. Measurements of neuropeptide concentration changes do not indicate which of several mechanisms may be mediating the observed changes. Increases in concentration may represent increased synthesis and release, decreased release with continued synthesis, or decreased degradation. Attempts to verify peptide turnover may be made if the mRNA concentration, peptide concentration, receptor up-regulation or down-regulation, and degradative activity are known. Although methods to achieve each of these goals are now available, they have not generally been applied in combination to the same tissue sample. Whereas the differences between neuropeptides and the classic monoamine and amino-acid neurotransmitters are often striking, their CNS effects are similar in that they primarily excite or inhibit discrete neurons upon direct application. Because both these effects may be observed among neurons from the same region, effects observed in one location cannot be generalized to either immediate or distal neurons. However, the onset of activity is often delayed for neuropeptides (seconds) as compared with the classic transmitters (milliseconds), whereas the duration of activity can be relatively delayed for neuropeptides (minutes) as compared with most of the classic transmitters (seconds).

DISTRIBUTION Neuropeptides are found throughout the CNS, as well as in various peripheral organs, such as the gastrointestinal tract, pancreas, and adrenal glands. Many CNS peptides, such as neurotensin and SRIF, play dual roles in the brain and gut. The full extent of any communication between the CNS and gut systems employing the same peptide is not known with certainty, but may be considerable. Although CNS neuropeptides are found predominantly in neurons, peptide receptors have been reported in glia. Neuropeptides were originally purified from hypothalamic extracts and thus it is not surprising that some of the highest concentrations of certain neuropeptides are found in the hypothalamus. This is true for all four of the example peptides: TRH, CRF, SRIF, and neurotensin. These many other neuropeptides are also widely distributed in extrahypothalamic brain areas and may occur in either intrinsic interneurons or in longer projection neurons. Immunohistochemical and retrograde tracing studies have focused on the locations and morphological types of neurons containing SRIF. In the hypothalamus most of the SRIF-containing neurons that project to the median eminence have been shown to emanate from cell bodies mainly in the rostral periventricular nucleus, with some in the paraventricular nucleus and none in the arcuate nucleus. Thus, the other hypothalamic regions (arcuate, suprachiasmatic, ventromedial) containing SRIF neurons probably do not project to the median eminence and may perform a regulatory or feedback function on neurons containing other hypothalamic releasing factors, such as GRF, CRF, TRH, or their afferents. In the cortex of rats SRIF is found in some of the large stellate-shaped neurons and in abundance among the fusiform-shaped, nonpyramidal neurons of layers II to V, and particularly in layer V of the sensory cortex. In monkeys, however, layer III is where SRIF is predominantly located in visual, auditory, or association cortex, and cortical neurons containing SRIF are usually oriented vertically in layers II to V and horizontally in layer VI. In human entorhinal cortex, SRIF neurons are abundant in the white matter underlying the cortex and are relatively uniformly distributed throughout the cortical layers, being absent only in the outer molecular layer. A recent comparison of human and monkey distribution of the prosomatostatin-derived peptides SRIF-28, SRIF-14, and SRIF-28 1-12 in the prefrontal cortex found reduced staining of SRIF-28 in unperfused monkeys and human brain obtained 5 hours after death, indicating that the processing of peptides may continue after death. In the rat striatum SRIF is extensively colocalized in neuropeptide-Y–containing neurons, and although not influenced by lesions of the dopamine neurons innervating the striatum, SRIF concentrations are increased by the destruction of cortical inputs. In the human hippocampus, SRIF neurons are arranged in a manner similar to that in rats and nonhuman primates, with cell bodies in the deep layers of the dentate gyrus projecting fibers to the outer two thirds of the molecular layer. In the basal forebrain region of nonhuman primates, SRIF is contained within small neurons of the nucleus basalis of Maynert, which apparently communicate with the cholinergic neurons there. Those data indicate that the neuronal cell types and afferent and efferent connections of SRIF-containing neurons vary widely among different brain regions and that species differences occur with enough frequency to render direct extrapolations between species difficult. Many neuropeptides have now been shown to be colocalized in neurons that also contain classic transmitters, other neuropeptides, or both. Neurotensin is found in neurons containing the dopamine synthetic enzyme tyrosine hydroxylase in the ventral tegmental area and arcuate nucleus of the hypothalamus of rats. Neurotensin is found in dense-core vesicles only in tyrosine hydroxylase-positive staining cell bodies in ventral tegmental area. Other nerve terminals that were stained for neurotensin did not contain tyrosine hydroxylase. These findings are discordant with other evidence showing decreases in both dopamine and neurotensin concentrations after reserpine and the dual release of frontal cortex dopamine and neurotensin after electrical stimulation of the median forebrain bundle. Another subset of ventral tegmental area neurons projecting to the frontal cortex has been shown to contain neurotensin, cholecystokinin (CCK), and tyrosine hydroxylase. Many other examples of colocalization have been cited, including reports of three to six peptides in a single neuron. TRH colocalization with another peptide, substance P, and a classic transmitter, serotonin, has been described in a population of neurons on the median raphe nucleus and spinal cord. Corticotropin-releasing factor has been reported to be colocalized with three other neuropeptides (vasopressin, oxytocin, and neurotensin) in some neurons of the hypothalamic paraventricular nucleus in both rats and humans. Somatostatin has been found in g-aminobutyric acid (GABA) neurons of the thalamus of cats and the cortex of rats, and with neuropeptide Y in the striatum, hippocampus, and cortex. Colocalization reports may be more species specific than is generally realized, as the neurotensin-dopamine colocalization in the ventral tegmental area and frontal cortex was clearly demonstrated to be absent in humans and nonhuman primates. The two main methods for mapping peptides, immunohistochemistry and radioimmunoassay, are complementary in their determination of neuropeptide locations and concentrations, respectively, but they do not indicate which immunoreactive neuronal cell bodies are connected to the various immunoreactive terminal fields. Through the use of retrograde tracing methods and dual staining techniques, several pathways for certain peptides have now been delineated. They include projections of amygdala neurons containing neurotensin, SRIF, or CRF to the parabrachial nucleus of the mesencephalon, and a neurotensin-containing projection from the lateral parabrachial nucleus back to the central amygdala has also been described. Two other neurotensin projections that have been observed in rats are those from the ventral tegmental area to the nucleus accumbens and from the endopiriform nucleus and prepiriform cortex to the diagonal band area. This methodology has also led to the identification of TRH neurons in the paraventricular nucleus and bed nucleus of the stria terminalis as the origin of projections to the median eminence and septum, respectively. Lesion studies with excitotoxic amino acids or electrocoagulation have also demonstrated putative connections between discrete anatomical loci, such as the increased TRH immunoreactive concentrations in the nucleus of the solitary tract after bilateral electrolytic lesions of the TRH-containing paraventricular nucleus in rats. Although such work is beginning to elucidate neuropeptide wiring diagrams in mammalian brain, the association between discrete anatomical pathways containing a neuropeptide and the behaviors or effects observed after neuropeptide administration remains nascent. One of the best examples of this kind of association is seen in the response of CRF neuronal systems to stressful stimuli. The distribution of CRF neurons in the rat CNS is illustrated in Figure 1.6-1. Radioimmunoassay studies have documented increased CRF content in the locus ceruleus and decreased CRF concentrations in the median eminence after a regimen of acute or chronic stress in rats. Other studies have shown that CRF-containing nerve terminals impinge upon noradrenergic neurons of the locus ceruleus and that exogenous CRF applied to those neurons alters their firing rate. Some of the noradrenergic locus ceruleus neurons, in turn, project to the hypothalamic paraventricular nucleus where their input increases CRF synthesis and release. Because CRF injection into the locus ceruleus elicits fearful or anxious behavior, one could postulate that stress activates the CRF neurons terminating in the locus ceruleus noradrenergic neurons and that the increased CRF content in the locus represents an increased release of the CRF in this region onto the noradrenergic cell bodies. One can further postulate that the resulting increased noradrenergic signal, and perhaps other inputs to the paraventricular nucleus of the hypothalamus, mediates the stress-induced increased release of CRF from the median eminence, which is detected as decreased CRF concentrations. Thus, both an observed increase and decrease in regional CRF content can be hypothesized as resulting from an increased release of CRF with or without concomitant new synthesis of CRF to replace the released peptide. An alternative explanation for the apparent decrease in median eminence CRF concentrations after stress versus increased concentrations in the locus ceruleus is that they are both released, but the CRF released from the median eminence is removed by the pituitary portal system whereas that in the locus ceruleus remains in the tissue that is dissected. Similar studies utilizing mRNA measures are ongoing under the hypothesis that changes in mRNA production might more accurately reflect biosynthetic rates of neuropeptide production.

FIGURE 1.6-1 Major CRF-stained cell groups (dots) and fiber systems in the rat brain. CC, corpus callosum; HIP, hippocampus; SEPT, septal region; AC, anterior

commissure; BST, bed nucleus of the stria terminals; SI, substantia innominata; CcA, central nucleus of the amygdala; MPO, medial preoptic area; PVH, PVN of hypothalamus; ME, median eminence; PP, posterior pituitary; LHA, lateral hypothalamic area; mfb, median forebrain bundle; MID THAL, midline thalamic nuclei; ST, stria terminalis; POR, perioculomotor nucleus; CG, central gray; DR, dorsal raphe; MR, median raphe; LDT, laterodorsal tegmental nucleus; LC, locus ceruleus; PB, parabrachial nucleus; MVN, medial vestibular nucleus; DVC, dorsal vagal complex; A 5, A1 noradrenergic cell groups. (Reprinted with permission from Swanson LW, Sawchenko PE, Rivier J, Vale WW: Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: An immunohistochemical study. Neuroendocrinology 36:165, 1983.)

BIOSYNTHESIS The biosynthesis of neuropeptides involves the transcription of mRNA sequences from deoxyribonucleic acid (DNA) templates contained on the appropriate genes. Since the 1980s the application of molecular biological techniques has allowed the genes of many of the various peptides to be cloned and the complementary DNA probes constructed that allow mapping of the regions where the mRNA's coding for the peptide prohormone is located. A good example of the exploitation of such techniques is provided by TRH. Although TRH was the first of the hypothalamic releasing factors to be chemically identified in 1969, the TRH precursor was the last of the releasing-factor prohormones to be described. The gene for TRH in humans resides on chromosome 3; in the rat it consists of three exons (coding regions) separated by two introns (noncoded sequences). The first exon contains the 5' untranslated end of the mRNA encoding the TRH preprohormone, the second exon contains the signal sequence and much of the remaining amino terminal end of the precursor peptide, and the third contains the remainder of the sequence, including five copies of the TRH precursor sequence, the carboxy terminal region, and the 3' untranslated region. Regions in the 5' flanking sequence correspond to promoter regions and have sequence homologies with a glucocorticoid receptor binding site and the thyrotropin b subunit gene that may regulate the expression of the TRH gene. Although some disagreement about the precise sizes of the TRH precursors exists, the TRH prohormone has been mapped immunohistochemically to regions previously shown to exhibit TRH-containing cell bodies, including the paraventricular nucleus of the hypothalamus and the raphe nuclei, whereas the axons and terminals that have been identified as containing TRH do not stain as intensely for the precursor. The neurotensin-neuromedin N gene was originally cloned from canine ileal mucosa, and complementary deoxyribonucleic acid (cDNA) probes constructed against this form were used to clone the rat gene. The rat gene contains four exon sequences separated by three introns and spans approximately 10.2 kilobases. In the rat the neurotensin-neuromedin N sequence is contained in the fourth exon and the single copies of each peptide sequence are separated by a pair of dibasic residues. The human neurotensin gene has been localized to chromosome 12 (12q21). In pheochromocytoma (PC-12) neurons in culture, the neurotensin-neuromedin N gene is regulated by lithium, nerve growth factor, cyclic adenosine monophosphate (AMP) activators, and dexamethasone through their effects on a 5' cis-regulating region. The distribution of the neurotensin-neuromedin N mRNA is generally the same as described for neurotensin-containing neuronal cell bodies, except in the hippocampus and subiculum, where few neurons stain immunohistochemically for neurotensin and yet an abundance of the neurotensin-neuromedin N mRNA is found. The role of 5' regulatory sequences on peptide genes has been well described for the SRIF gene. The human SRIF gene is located on chromosome 3. The regulatory region in the SRIF gene is upstream from the sequence coding the SRIF mRNA and contains the palindrome sequence of eight base pairs that is found in other genes regulated by cyclic AMP. The promoter region acts on the downstream sequence as an enhancer for transcription and exhibits both distance and orientation sensitivity for the sequence being enhanced. This cyclic AMP response element demonstrates recognition sites for protein kinases A and C and casein kinase II, which may in turn regulate that activity.

PEPTIDE PROCESSING Because neuropeptides are first synthesized as larger precursor molecules, a wide variety of processes can come into play in the cleavage of the active peptide forms from the precursor (Fig. 1.6-2). For example, SRIF is first produced as a 116 amino acid prohormone called preprosomatostatin, and it contains a 24 amino acid signal sequence that is removed in the formation of the 92 amino acid prosomatostatin. It is further processed to either SRIF-28 or SRIF-14, and a major site of the processing step has been identified as the Golgi apparatus. The last processing step shows significant species differences, which should be considered when extrapolating between human and animal studies. For example, the 12 amino acid sequence of SRIF-28 that is cleaved in the formation of SRIF-14 is much more abundant in rodent than in human brain. The joint actions of a basophilic aminoprotease and an endoprotease contained in secretory granules cleaves SRIF-14 from SRIF-28. Most active peptide sequences are flanked by dibasic amino acids (Arg and Lys), which act as cleavage sites for the carboxypeptidase-B types of enzymes. However, SRIF-28 is cleaved at a single arginine from its prosomatostatin precursor. Related peptides are often contained in the same prohormone sequence, as is the case for neurotensin and neuromedin N. Those peptides are separated by a single pair of dibasic residues on their common mRNA and yet have distinctly different distribution patterns in the brain. Other tissues may also exhibit processing that is different from that of the brain, as is seen for neuromedin N in the mouse ileum. Multiple active peptide copies can also be contained in the prohormone structure as is noted with TRH, which has five complete copies in the mammalian 285 amino acid prohormone. Studies using antisera that recognize the intervening sequences between the five copies of TRH within the prohormone indicate that all five copies are liberated during processing. Regional differences of prohormone processing have been demonstrated within the brain, as is clearly seen for TRH. In the hypothalamus, the main storage forms of TRH are TRH, pre-pro TRH (160-169), pre-pro TRH (178-199), and two additional forms that are found in the olfactory bulb region. The differences in the ratio of TRH to its prohormone precursor in various extraneuronal tissues also indicates widely varying regional differences in processing of the TRH precursors. Processing also differs across the life cycle, as has been reported for TRH. Hypothalamic TRH prohormone processing in mice was observed to accelerate during development based on the ratio of TRH to its precursors, and immunohistochemical staining or in situ hybridization autoradiography indicated that a significant amount of processing occurred during post-Golgi transport and storage.

FIGURE 1.6-2 The peptide neuron. The figure shows the main steps in the chain of events from the information stored in the DNA molecule to the peripherally detected peptide fragments. The DNA sequence in the nucleus is transcribed to the mRNA molecule for further transport to the endoplasmic reticulum, where a translation takes place to form a large precursor protein (preproprotein). That protein is prepared for axonal transport by packaging into neurosecretory vesicles within the Golgi complex. During transport, the precursor protein is processed by specific cleavage enzymes into active and inactive peptide fragments. After release, the peptides are further degraded into smaller peptide fragments or constituent amino acids. (Courtesy of Thomas Davis, Ph.D.)

Although many known peptides are complete and biologically active when cleaved from the prohormone, many others are subjected to posttranslational processing. Certain peptides have a metabolically blocked carboxy terminus that is often amidated. A glycine residue in the prohormone sequence often acts as the amide donor, and in the case of TRH is attacked by a monoxygenase that is contained in secretory granules. TRH is further processed on the N-terminus where glutamine is cyclized by a glutamylcyclase. These alterations are usually effective in reducing susceptibility to degradation, and are often required for biological activity, as is the case for TRH, which is rendered inactive when the C-terminal amide is removed by proline endopeptidase to generate the free-acid structure. Other posttranslational processing events for active peptides include glycosylation and cyclization, which are often required for either biological activity or transport.

RECEPTORS AND SECOND MESSENGERS

Neuropeptide receptors have undergone the same process of discovery and characterization that receptors for other neurotransmitters have enjoyed. The process begins with the pharmacological characterization of the receptor's physicochemical binding properties by assessing the affinity of various metabolically derived and synthetic peptide fragments, and the native molecule, for the receptor binding site found in membrane preparations. Peptide receptor locations are mapped with radioactive or fluorescent tags that are inserted into peptide molecules, which often contain substituted amino acids at the most vulnerable peptidase cleavage sites. Previously, once the peptide receptor was characterized pharmacologically, it was usually purified from some relatively enriched biological tissue source or brain region by affinity column chromatography. After it had been purified, binding parameters and activity were recharacterized for the reconstituted purified receptor protein and structural information obtained by X-ray crystallography. This process was closely followed in the purification of the neurotensin-neuromedin N receptor. Because neurotensin and neuromedin N share significant sequence homology, the latter is active in displacing ligands from the neurotensin receptor, but with approximately 20 times less potency. The neurotensin receptor was first characterized by photoaffinity labeling and cross-linking of radioiodinated ligands, which resulted in two labeled subunits of about 49 Kd and 51 Kd from rat brain synaptosomes. The receptor was next solubilized and characterized for ligand affinity and binding capacity in mouse brain, which was followed by affinity column chromatographic purification and confirmation of an aggregate molecular weight of approximately 100,000. However, similar work with bovine cerebral cortex yielded a purified neurotensin receptor of approximately 72,000, indicating that significant species differences may exist. The neurotensin receptor mRNA has been cloned, and regional in situ hybridization mapping studies indicate that its distribution is generally the same as was shown for the receptor using radioactive ligands and autoradiography. The location is particularly rich in dopamine cell body regions and some dopamine terminal regions, and thus it is not surprising that dopamine neuronal activity seems to regulate neurotensin receptor expression. Neurotensin receptors have been shown to be colocalized with enzymes that degrade both neurotensin and neuromedin N in primary cultures of neurons from the forebrains of 14-day-old mouse embryos. The much more powerful tools of molecular biology have been utilized more recently. Utilizing expression cloning techniques or a variety of low-stringency hybridization screening methods, numerous receptors and peptides have been cloned. Transfection studies allow for the production of highly enriched cell preparations expressing a variety of peptides or peptide receptors. Moreover, now that it is possible to purify mRNAs for peptide receptors, the induction of mutations allows for the identification of the regions controlling ligand binding. The distribution of receptors mapped with autoradiographic techniques has been largely verified by in situ hybridization using receptor mRNA probes. That information will make it possible to design drugs specifically to fit those binding sites on the receptor, leading to the ability to manipulate peptide systems in ways that are currently enjoyed by the more classic neurotransmitters. Finally, transgenic techniques such as targeted gene overexpression and gene knockouts or knockdowns will contribute to our understanding of the physiological roles of these peptides and their receptors. Receptor populations for peptides exhibit changes in the numbers of binding sites on the basis of the magnitude of transmitter signal received and the input from second messenger feedback regulation. The up-regulation and down-regulation of peptide receptors has been most often demonstrated in the anterior pituitary, but has also been described in the cerebral cortex and other brain regions. Peptide receptor affinity for ligands usually remains stable in the face of this regulation of receptor number. Receptor expression fluctuates in various brain regions during development as well. Autoradiography has demonstrated high concentrations of SRIF receptors in rat somatosensory cortex at day 16 of the embryo in the intermediate zone and a transient decrease in cortical plate SRIF receptors at birth. Decreases to adult levels of SRIF receptors in somatosensory cortex are achieved by postnatal day 21. Somatostatin receptors in the cerebellum of 13-day-old rats have been shown to be pharmacologically similar to those of adults in binding parameters. Several research groups have described different classes of SRIF receptors on the basis of selective binding by various pharmacological ligands. Regional differences in the binding of SRIF-28 and SRIF-14 and their inability to desensitize each other's binding site has indicated that separate receptor populations may exist for these two forms. Further evidence for distinct populations of SRIF-28 and SRIF-14 receptors is provided by their production of different second messenger effects, and their opposite effects on potassium conductance in rat cortex. Five different SRIF receptor subtypes have been identified with molecular techniques. Neuropeptide receptors have been associated with just about every type of second messenger signal transduction system that has been identified. Mechanisms using cyclic AMP; cyclic guanosine monophosphate (cGMP); protein kinases A and C; sodium, potassium, and calcium channels; and inositol phosphate and diacylglycerol have all been identified as neuropeptide receptor signal transduction mechanisms. Such mechanisms offer a myriad of possible modulatory effects, from the amplification to the attenuation of postsynaptic signals, and contribute greatly to the integrative power of neural networks. Both the neurotensin and the TRH receptors are internalized within the postsynaptic cell upon binding of their endogenous ligand or the appropriate agonist, where portions of the complex may eventually be transported to the receptive cell's nucleus with subsequent regulatory effects. Specific peptide receptor antagonists have been difficult to develop, with opioid antagonists being the most successful. Altered molecular forms of native peptides, such as a-helical CRF 9-41, have been used but are not ideal owing to size constraints on diffusion and lack of ability to penetrate the blood-brain barrier. The inability to block specific neuropeptide signals pharmacologically has severely hindered research into the roles of the endogenous peptides in various behaviors and physiological effects. The disadvantages of trying to decipher a substance's role in neurotransmission by examining only the effects of excess concentrations should be obvious to even casual observers. As noted previously, this is an area in which the use of transgenic laboratory animals can be of great service, although the results are potentially confounded by differing roles for neuropeptides and receptors in early development and adulthood. More recently, several pharmaceutical companies have synthesized nonpeptidergic, lipophilic compounds that act as neuropeptide agonists or antagonists.

PEPTIDASES Peptides are degraded to smaller fragments, and eventually to single amino acids, by specific enzymes termed peptidases. As yet, peptides or their fragments have not been shown to be actively taken up by presynaptic nerve terminals, as is the case for the monoamines. The enzymes may be found bound to post- or presynaptic neural membranes or in solution in the cytoplasm and extracellular fluid, and they are distributed widely in peripheral organs and serum as well as in the CNS. They often have a metal ion among their subunit components; those components form the active site for cleavage of the target peptide sequence, and that active site often forms a three-dimensional cleft where the specific peptide bond cleavage occurs. There are several general classes of peptidases, with several distinct enzymes in each class. Those classes include the serine endopeptidases containing such enzymes as trypsin and chymotrypsin; the thiol peptidases, such as pyroglutamate amino peptidase and cathepsin B and C; the acid proteases, such as pepsin and renin; the metalloendopeptidases, such as neural endopeptidase and angiotensin-converting enzymes; and the metalloexopeptidases, such as the aminopeptidases and the carboxypeptidases such as enkephalin-convertase and carboxypeptidase A and B. These degradative enzymes are often the same as those used in processing but have different subcellular locations. An example is carboxypeptidase B, which cleaves the dibasic amino acid residues flanking the active peptide sequence in the prohormone during processing, or reduces activity at the receptor if the peptide contains dibasic amino acids in the active sequence, such as neurotensin. Peptidases have pH and temperature optimums for activity and can be inhibited by various chemicals or chelators or by amino acid substitution at vulnerable points in the peptide chain. Alterations in peptidase activity or concentration can contribute to alterations in the synaptic availability of a peptide, and the regulation of peptidase levels may be as exquisitely controlled as receptor number and peptide synthesis and release. Table 1.6-2 shows the potential cleavage points for neuromedin N, neurotensin, SRIF, and TRH. Cleavage of the actively released form of the peptide usually ends or significantly reduces biological activity, but examples abound of partial or complete receptor activation by partially metabolized peptides or their fragments. The metabolism of TRH has been investigated fairly completely, principally because of the limited number of fragments that can be generated from a tripeptide. The principal cleavage enzymes are pyroglutamyl amino peptidase, which cleaves the cyclized glutamyl residue from the C-terminus and generates a histidine-proline (His-Pro) fragment. That fragment spontaneously cyclizes into a diketopiperazine, the so-called cyclo His-Pro, after the N-terminal amide has been removed by the action of the proline endopeptidase. The active site of the pyroglutamyl amino peptidase enzyme has been shown to contain tyrosine; histidine, arginine, and possibly lysine residues, but does not contain serine, cysteine, aspartate, or glutamate. Regional differences in TRH degradation have been described, with spinal cord metabolism of TRH generating more deamidated TRH than cerebral cortex degradation. The half-life of TRH in serum is estimated at only 2 to 3 minutes, and CSF is now known to contain pyroglutamyl amino peptidase activity. Neonatal CSF has less of activity of this enzyme when compared to the CSF of adults, and differences in subcellular localization of the enzyme in the adult hypothalamus (soluble fraction) and cerebral cortex (membrane bound) has been reported as well, with the brain activity of both forms decreasing during development. Both of those TRH peptidases have been detected in the cytosol of brain homogenates, but are found only in trace amounts in the soluble fraction of synaptosomes; most of their activity is associated with synaptosomal membranes. Thyroid hormones have been shown to regulate pyroglutamyl amino peptidase in the membrane-bound fraction but not in the soluble form, although in serum the peptidase does not appear to be influenced by thyroid hormones. Thus peptidases offer yet another opportunity for the integration and regulation of neuropeptide transmitter actions and synaptic availability. Because the present peptidase inhibitors are relatively nonspecific in their ability to inhibit various peptidases, there have been few attempts to influence peptide concentrations by pharmacological blockade of their associated peptidases; however, the angiotensin-converting enzyme (ACE) inhibitors such as captopril are one exception. It is expected that second- and third-generation peptidase inhibitors, with discrete peptidase and possibly regional specificity, will be developed that eventually may allow the truly elegant manipulation of endogenous neuropeptide concentrations. In addition, the genes coding for the peptidases are being cloned, and knockout experiments will provide novel and valuable information.

NEUROENDOCRINE SECRETION With the exception of neuromedin N, each of the example peptides are known to play major roles in pituitary-target endocrine organ regulation, including CRF-induced release of proopiomelanocortin products, such as adrenocorticotropic hormone (ACTH) and b-endorphin; TRH release of thyrotropin (thyroid-stimulating hormone [TSH]) and prolactin; and SRIF-induced inhibition of the release of growth hormone, thyrotropin, gonadotropins, and ACTH. Neurotensin, which is abundant in the hypothalamus and median eminence, may mediate the preovulatory release of luteinizing hormone and receive feedback for the induction of mRNA synthesis by estrogen, but it is not a hypothalamic hypophysiotropic hormone in the classic sense. A sexually dimorphic distribution of the neurotensin-neuromedin N mRNA in the preoptic hypothalamus also supports such a role for neurotensin in rodents. The peptides involved in neuroendocrine regulation have cell bodies residing in the hypothalamus that receive feedback from all levels of the endocrine axes. The complexity of those interactions has been well demonstrated for the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-adrenal axis and have now been extended to the molecular level. The regulatory feedback of thyroid hormones onto the TRH-synthesizing neurons of the paraventricular nucleus was first demonstrated with evidence of TRH concentration changes, reported to be reduced in the median eminence after thyroidectomy, but not in the rest of the hypothalamus, and which could be prevented by thyroid hormone replacement. The treatment of normal rats with exogenous thyroid hormone decreases TRH concentration in the paraventricular nucleus and the posterior nucleus of the hypothalamus. That effect was corroborated for the TRH prohormone as well, with median eminence levels of TRH prohormone being reduced by thyroidectomy and the precursor levels increasing toward normal concentrations after thyroxine treatment. The TRH mRNA also exhibits such regulation by thyroid hormone as expected, with increased mRNA concentration in the paraventricular nucleus 14 days after thyroidectomy. Unilateral tri-iodothyronine implants prevent the increase in TRH mRNA that is seen on the contralateral untreated side in propylthioruracil-induced hypothyroidism. The effects of thyroid hormones on TRH expression in the paraventricular nucleus of developing rats are not observed until between embryo day 20 and 7 days after birth, although TRH mRNA is evident as early as embryo day 16. The ability of thyroid hormones to regulate TRH mRNA can be superseded by other stimuli that activate the hypothalamic-pituitary-thyroid axis. In that regard repeated exposure to cold (which releases TRH from the median eminence) induces increases in the levels of TRH mRNA in the paraventricular nucleus despite concomitantly elevated concentrations of thyroid hormones. Further evidence of the different levels of communication of the hypothalamic pituitary-thyroid axis are seen in the ability of TRH to regulate the production of mRNA for the pituitary TRH receptor and for TRH concentrations to regulate the mRNA coding for both the a and b subunits of the TSH molecule. The latter effect has been shown to be dependent on intracellular calcium and protein kinase C. The regulatory interplay also extends to the accessible pools of second messenger phosphoinositides, whose pool size is regulated by TRH receptor number. TRH-containing synaptic boutons have been observed in contact with TRH-containing cell bodies in the medial and periventricular subdivisions of the paraventricular nucleus, thus providing anatomical evidence for ultrashort feedback regulation of TRH concentrations there. Regional differences in CRF receptor regulation by corticosterone have also been reported, which have been shown to partly result from differential glycosylation of the CRF receptor. The regulation of neuropeptide mRNA concentrations may be influenced by other neuropeptides, as well as by components of the particular endocrine axis normally associated with the particular peptide, as demonstrated by the ability of neuropeptide Y to increase hypothalamic CRF mRNA. Because many endocrine systems are cyclic in their regulatory functions, it is not surprising that neuropeptides often exhibit rhythms in concentrations that are based on diurnal, lunar, and circannual periodicities. Hypothalamic and certain extrahypothalamic regional concentrations of CRF exhibit increased concentrations in the afternoon as compared to morning concentrations, and this increase can be attenuated by corticosterone only in certain brain regions such as the hypothalamus. Somatostatin, CRF, and TRH concentrations in the CSF of nonhuman primates exhibit daily fluctuations, and the monthly cycles in gonadotropins of mammals exhibiting estrus are well recognized. Circannual rhythms of neurotensin and SRIF concentrations that are 180 degrees out of phase in rodent hypothalamus have been noted. Changes in mRNA expression during development have been seen in CRF mRNA, which is present at gestational day 17, but decreases from day 19 to day 21, when concentrations again rise to attain adult levels by 4 days after birth. Other peptide mRNAs, such as SRIF, do not exhibit such fluctuations during development, but do show differential distribution during ontogeny. Daily fluctuations in rat paraventricular nucleus CRF mRNA expression are lowest during the period of highest plasma corticosterone levels during the 24-hour cycle.

NEUROPEPTIDES IN PSYCHIATRIC DISORDERS Humans are less than ideal subjects for neuropeptide research for several reasons. The peripheral sources of many peptides, the relatively high concentration of serum peptidases, and the blood-brain barrier all conspire to render serum concentrations of CNS neuropeptides difficult to interpret at best. The use of biopsy to assess tissue concentrations directly is not routinely repeatable, is limited to superficial structures, suffers from potential morbidity, and would provide only limited information. However, CSF has been shown to reflect extracellular fluid concentrations of transmitter substances, is in direct contact with the CNS, is screened from peripheral serum sources by the blood-brain barrier, and may be sampled across time. The limitations of CSF studies include a lack of information about the regional CNS source of any concentration changes detected, the use of lumbar CSF, which is somewhat removed from higher CNS sources of peptides and subject to spinal cord peptide contributions, and the potentially confounding effects of previous drug treatments or disease episodes. Postmortem tissue studies of neuropeptide concentration changes in psychiatric disease are affected by agonal state, postmortem delay, previous drug treatment, and coexisting illnesses. Most of the data on CSF concentration changes or tissue concentration changes of neurotransmitters have been derived from comparisons between diagnostically defined psychiatric groups and control groups. However, the controls may be so-called neurologically or psychiatric controls, not healthy volunteers, and the accuracy and consistency of the diagnoses may be less than optimal. In addition, the etiology of a diagnostic class of disease may differ among subjects in the same diagnostic group. Even after matching for age, gender, or other demographic variables, heterogeneity among human research populations results in individual variations of absolute peptide values that are often quite wide. Such variations severely reduce the power of group comparisons to detect alterations in peptide concentrations. The use of pretreatment and posttreatment CSF samples, or of samples taken during the active disease state versus when the patient is in remission, has begun to address the serious limitations in study design. For such progressive diseases as schizophrenia or Alzheimer's disease, serial CSF samples may be a valuable indicator of disease progression or response to treatment. Even with these constraints, significant progress has been made in describing the effects of various psychiatric disease states on neuropeptide systems in the CNS. Alzheimer's Disease Dementia of the Alzheimer's Type represents up to two thirds of the demented population encountered in clinical practice, and over half of the nursing home beds in the United States are currently occupied by such patients. The disease is characterized by a progressive, gradually worsening dementia that cannot be ascribed to metabolic disorders, pharmacological treatment, or infectious agents and is neuropathologically associated with the pathological presence of senile plaques and neurofibrillary tangles within the CNS. The first described specific neurochemical deficit to be associated with Alzheimer's disease was reduced amounts of choline acetyltransferase-containing nerve terminals in cortical regions as a result of degeneration of cholinergic neuronal perikarya in the nucleus basalis of Meynert in the substantia innominata region of the basal forebrain. Within a few years of that finding, SRIF was found to be markedly reduced in concentration in the cerebral cortex of Alzheimer's disease patients. Subcortical regions containing SRIF, such as the substantia innominata, hypothalamus, and bed nucleus of the stria terminalis, were spared whereas SRIF receptors in the cortex were decreased in number. In regions such as the hippocampus, findings of SRIF depletions were less consistent than in the cortex, but when depleted in the hippocampus, the SRIF neurons colocalized with neuropeptide Y were spared. Somatostatin concentration in the CSF of Alzheimer's disease patients has also been consistently found to be decreased, and this decrease has been correlated with the magnitude of cognitive impairment. Therapies that slow or partially reverse the dementia associated with Alzheimer's disease have been reported to also partially reverse the decrease in CSF SRIF. However, CSF SRIF concentrations are also decreased in delirium, major depressive disorder, schizophrenia, multiple sclerosis, and dementia associated with Parkinson's disease. Increased activity of an SRIF cleaving peptidase have been described in certain cortical regions of the brain tissue of persons with Alzheimer's disease, raising the possibility that increased SRIF degradation may contribute to the decreases in SRIF concentration observed. Treatment of Alzheimer's disease patients with SRIF infusion systemically, however, has not been successful in reversing the dementia, probably because of poor penetration across the blood-brain barrier. In experimental animals cysteamine depletion of hippocampal SRIF leads to deficits in performance on tasks requiring retention of information. It is unclear whether the neuropeptide deficits precede, succeed, or occur in tandem with the cholinergic deficits seen in Alzheimer's disease, and whether the neurochemical systems and regions first exhibiting deficits are the site of the onset of pathology. The CRF-containing interneurons of the cortex are also consistently depleted in Alzheimer's disease ( Fig. 1.6-3). As with SRIF, subcortical areas containing CRF neurons may be spared, but unlike SRIF, CRF receptors are increased in number (up-regulated) with no change in affinity. Various research groups have reported the CRF concentrations in the CSF of patients with Alzheimer's disease to be increased, decreased, or unchanged; these inconsistencies are likely due to when the CSF sample was obtained. Other peptides have been shown to be altered less consistently in Alzheimer's disease, such as substance P or neurotensin, whereas most peptides are reported to be unchanged, including TRH, vasoactive intestinal peptide, CCK, and the enkephalins. Only one peptide, galanin, is reported to be reliably increased in concentration in Alzheimer's disease. Novel agonists at peptide receptors such as CRF or SRIF may allow for the development of new treatments; currently, compounds that increase the availability of CRF by competing for the binding site on the CRF-binding protein are being planned for clinical trial in Alzheimer's disease patients.

FIGURE 1.6-3 Regional brain concentrations of CRF in patients with dementia of the Alzheimer's type and in controls. N = 7-13 per group. Data presented as mean ± SE 7 * P < 0.01 by Student's t-test. (Data derived from Bissette G, Reynolds GP, Kilts CD, Widerlov E, Nemeroff CB: Corticotropin-releasing factor like immunoreactivity in senile dementia of the Alzheimer type. JAMA 254:3067, 1985.)

Mood Disorders Corticotropin-Releasing Factor After a search spanning nearly three decades, CRF was isolated and characterized in 1981 as a 41-amino acid peptide. CRF is the primary hypothalamic ACTH-secretagogue in most species; it also functions as an extrahypothalamic neurotransmitter in a CNS network that apparently coordinates global responses to stressors. CRF and its homologs represent an ancient family of peptides subserving numerous functions. In higher organisms, including mammals, convincing evidence supports the hypothesis that CRF plays a complex role in integrating the endocrine, autonomic, immunological, and behavioral responses of an organism to stress. Hyperactivity of the hypothalamic-pituitary-adrenal axis in major depressive disorder remains one of the most consistent findings in biological psychiatry. The reported hypothalamic-pituitary-adrenal axis alterations in major depression include hypercortisolemia, resistance to dexamethasone suppression of cortisol secretion, blunted ACTH responses to intravenous CRF challenge, and elevated concentrations of CRF in CSF. The exact pathological mechanisms underlying hypothalamic-pituitary-adrenal axis dysregulation in major depressive disorder and other mood disorders remains to be elucidated. Defects have been postulated to exist at corticolimbic loci, hypothalamic loci, or both. Once the phenomenon of hypothalamic-pituitary-adrenal axis hyperactivity in patients with major depression was established, many clinical research groups utilized various provocative neuroendocrine challenge tests as a “window into the brain” in attempts to elucidate pathophysiological mechanisms. In normal subjects the CRF stimulation test, using either rat or human CRF or ovine CRF, yields robust ACTH, b-endorphin, b-lipotropin, and cortisol responses following intravenous or subcutaneous administration. However, in patients with major depressive disorder, blunting of ACTH or b-endorphin secretion with a normal cortisol response has been repeatedly reported. Patients with posttraumatic stress disorder, 50 percent of whom also fulfill the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder also show blunted ACTH secretion in response to a CRF challenge. Importantly, researchers have reported normalization of the ACTH response to CRF following clinical recovery from depression, suggesting that the blunted ACTH response, like dexamethasone nonsuppression, may be a state marker for depressive disorders. Mechanistically, two hypotheses have been advanced to account for the ACTH blunting following exogenous CRF administration. The first hypothesis suggests that pituitary CRF receptor down-regulation occurs as a result of hypothalamic CRF hypersecretion. The second hypothesis postulates altered sensitivity of the pituitary to glucocorticoid negative feedback. Substantial support has accumulated favoring the first hypothesis. It should be kept in mind that neuroendocrine studies represent a secondary measure of CNS activity; the pituitary ACTH responses principally reflect the activity of hypothalamic CRF rather than that of the corticolimbic CRF circuits, which are most likely to be involved in the pathophysiology of depression. A potentially more direct method for evaluation of extrahypothalamic CRF tone may be obtained from measurements of CRF concentrations in CSF. A marked dissociation between CSF and plasma neuropeptide concentrations has been described, thus indicating that neuropeptides are secreted directly into CSF from brain tissue as opposed to being derived from plasma-to-CSF transfer. Evidence that CRF concentrations in CSF originate from nonhypophysiotropic CRF has been obtained from studies in which CRF concentrations in CSF were repeatedly measured over the course of the day. Two independent research groups reported that CRF concentrations in the CSF of in rhesus monkeys are not entrained with pituitary-adrenal activity. The proximity of corticolimbic, brainstem, and spinal CRF neurons to the ventricular system suggests that these areas make substantial contributions to the CRF pool in CSF. A series of studies have demonstrated significant elevations of CRF concentrations in the CSF of drug-free patients with major depression or following suicide ( Fig. 1.6-4). Additionally, severity of depression appears to correlate significantly with CRF concentrations in the CSF of patients with anorexia nervosa, multiple sclerosis, and Huntington's disease. The elevation of CRF concentrations in the CSF of patients with anorexia nervosa reverts to the normal range as these patients approach normal body weight. No alterations of the concentrations of CRF in CSF have been reported in other psychiatric disorders including mania, panic disorder, and somatization disorders as compared to controls.

FIGURE 1.6-4 Scatterplot showing the mean cerebrospinal fluid neuropeptide values in patients with major depression. Each individual point represents an individual study. Mean % Control ± SEM for all studies shown by hollow symbols. (Adapted from Owens MJ, Plotsky PM, Nemeroff CB: Peptides and affective disorders. In Biology of Schizophrenia and Affective Disorders, SJ Watson, editor. American Psychiatric Press, Washington, DC, 1996.)

Of particular interest is our demonstration that the elevated concentrations of CRF in CSF in drug-free depressed patients are significantly decreased 24 hours after their final ECT treatment, indicating that CSF CRF concentrations, like hypercortisolemia, represent a state rather than a trait marker; other recent studies have confirmed the normalization of CRF concentrations in CSF following successful treatment with fluoxetine. One group demonstrated significant reduction of elevated CRF concentrations in the CSF of 15 female patients with major depression who remained depression free for at least 6 months following antidepressant treatment as compared to little significant treatment effect on the CRF concentrations in the CSF of 9 patients who relapsed in this 6-month period. This suggests that elevated or increasing CRF concentrations in CSF during antidepressant drug treatment may be the harbinger of a poor response in major depressive disorder despite early symptomatic improvement. Interestingly, treatment of normal subjects with desipramine fluoxetine-containing antidepressants is associated with a reduction in the concentration of CRF in CSF. In preclinical studies, CRF hypersecretion is associated with CRE-receptor down-regulation. Depression is a major determinant of suicide more than 50 percent of completed suicides are accomplished by patients with major depressive disorder. If CRF hypersecretion is a characteristic of depression, evidence of related CRF-receptor down-regulation should be evident in the CNS of depressed suicide victims. Indeed, it has been reported that there is a marked (23 percent) decrease

in the density of CRF receptors in the frontal cortex of suicide victims as compared to matched control samples; these findings have been confirmed in a second study. Somatostatin Like a number of other neuropeptides, somatostatin was serendipitously discovered during attempts to purify growth hormone-releasing factor (GRF). As the name implies, SRIF inhibits the release of growth hormone from the anterior pituitary. Since its structural identification 20 years ago, SRIF has been unequivocally shown to be the major inhibitory influence on growth hormone secretion. Also, SRIF fulfills a number of criteria for neurotransmitter status within the CNS. The acceptance of a role for SRIF as a neurotransmitter has led to its investigation in a number of psychiatric and neurological diseases. Nonhyphysiotropic SRIF-containing neurons may play a role in a number of disorders including but not limited to depressive disorders, dementia, and epilepsy. Like many other neuropeptide transmitters, central administration of SRIF produces a variety of behavioral and physiological effects. Briefly, the peptide produces a non–opioid-mediated analgesia in animals and man. Sleep patterns, food consumption, locomotor activity, and memory processes are also altered by central SRIF administration. Of particular interest is the fact that the sleep, eating, psychomotor activity, and anterior pituitary hormone secretion are all altered in depressed patients. Investigation of a role for this peptide in mood disorders was therefore of interest. The clearest evidence for involvement of SRIF in psychiatric illness has come from studies of major depression. A consistent decrease has been reported in SRIF concentrations in the CSF of drug-free depressed patients ( Fig. 1.6-4). Research has revealed that a number of neuropeptides in CSF are almost exclusively of central origin, though the actual sites of production remain obscure. Decreases in SRIF concentrations in CSF are proposed to be the result of decreased neuronal synthesis and release. Whether this is a primary or secondary effect of the illness is unknown. Moreover, although SRIF levels in CSF did not correlate with severity of depression, clinically improved patients exhibited a rise in SRIF towards normal concentrations. In nine patients with bipolar I disorder followed longitudinally, SRIF concentrations in CSF were significantly decreased during the major depressive episode state versus mood-improved manic episodes. Although the data is still relatively limited, overview of the extant literature suggests that decreases in concentrations of SRIF in CSF are a consistent state-dependent finding in depression. Indeed, secondary to the hypercortisolemia associated with depression, this is one of the more consistent findings in biological psychiatry. However, the finding has little apparent diagnostic usefulness because similar changes are observed in a number of neurological disorders without psychiatric comorbidity. However, reductions in SRIF concentrations in CSF do appear to be associated with impairment in cognitive function. Some investigators have suggested that the decrease in SRIF concentrations in CSF may be related to the hypothalamic-pituitary-thyroid axis overactivity commonly found in patients with depression. Whether one is responsible for the other, or whether both are responses to dysregulation of other neurotransmitter systems associated with depression is unknown. Rational design of peptide or nonpeptide-based drugs selectively active at different SRIF receptor subtypes will certainly aid in understanding its role in behavior, and may ultimately lead to novel therapeutic agents. Thyrotropin-Releasing Hormone The early availability of adequate tools such as assays and synthetic peptides to assess hypothalamic-pituitary-thyroid axis function, coupled with observations that primary hypothyroidism is associated with depressive symptomatology, ensured extensive investigation of the involvement of this axis in mood disorders. Indeed, TRH, a pyroglutamylhistidylprolinamide tripeptide, was the first of the hypothalamic-releasing hormones to be isolated and characterized. Early studies established the hypothalamic and extrahypothalamic distribution of TRH. The extrahypothalamic presence of TRH quickly led to speculation that TRH might function as a neurotransmitter or neuromodulator; indeed, a large body of evidence supports such a role for TRH. Interest in putative CNS actions of TRH were stimulated by studies of the hypothalamic-pituitary-thyroid axis and depression by Prange and colleagues. In the 1970s it was hypothesized that thyroid function was integral to the pathogenesis of, and recovery from, mood disorders because of the copious interactions among thyroid hormones, catecholamines, and adrenergic receptors in the CNS. Overall, these studies suggest a role for thyroid dysfunction in refractory depression and are consonant with clinical studies that suggest the existence of an increased rate of hypothyroidism among patients with refractory depression. The use of TRH as a provocative agent for assessment of hypothalamic-pituitary-thyroid axis function evolved rapidly after its isolation and synthesis. Clinical use of a standardized TRH stimulation test revealed blunting of the TSH response in approximately 25 percent of euthyroid patients with major depression; these data have been widely confirmed. The observed TSH blunting in depressed patients does not appear to be the result of either excessive negative feedback resulting from hyperthyroidism or to SRIF hypersecretion. In fact, depressed patients exhibit reduced CSF concentrations of SRIF. It is possible that TSH blunting is a reflection of pituitary TRH receptor down-regulation as a result of median eminence hypersecretion of endogenous TRH. Indeed, the observation that concentrations of TRH in CSF are elevated in depressed patients as compared to controls supports the hypothesis of TRH hypersecretion but does not elucidate the regional CNS origin of this tripeptide. These elevations may be relatively specific to depression because no such alteration has been reported in patients with Alzheimer's disease, anxiety disorders, or alcoholism. Some investigators have suggested that the development of autoimmune thyroiditis gives rise to hypersecretion of hypothalamic TRH as a compensatory mechanism to maintain normal plasma triiodothyronine (T 3) and thyroxine (T4) concentrations. Clearly, further studies in which CSF TRH concentrations in CSF are measured are needed. Schizophrenia Both clinical and postmortem investigations of schizophrenia patients, as well as animal studies, have sought to elucidate the role of neuropeptides in the pathological manifestations of schizophrenia. Although constrained by diagnostic uncertainties and drug treatment effects, the research to date on the postmortem brain tissue of schizophrenia patients has not revealed major alterations of neuropeptide systems. A number of peptides (endogenous opioids, substance P, cholecystokinin [CCK], SRIF) have been reported to be altered in the CSF of schizophrenia patients, but many of these findings either have not been independently reproduced or describe a marginally statistically significant difference in CSF peptide concentrations among groups of patients and controls with variance of over 100 percent around the mean. Further confounds are the effects of treatment with antipsychotic drugs on peptide systems; such drugs have been described for regional neurotensin, CCK, substance P, and SRIF concentrations in laboratory animals. How much time is necessary to abolish those drug-induced alterations of neuropeptide system concentration changes is not known for humans, but may significantly exceed the 2 to 3 weeks of drug holiday used in most clinical studies. The most likely candidate neuropeptide with evidence of selective alteration in schizophrenia is neurotensin. It was first shown to have pharmacological interactions with dopamine while undergoing characterization of its potent hypothermic and sedative potentiating activity. Subsequent work indicated that neurotensin possessed many properties that were also shared by antipsychotic drugs, including the ability to inhibit avoidance responding, but not escape, in a conditioned active avoidance task; the ability to block the effects of indirect dopamine agonists or endogenous dopamine in the production of locomotor behavior; and the ability to elicit increases in dopamine release and turnover. Unlike antipsychotic drugs, neurotensin is not able to displace dopamine from its receptor; neurotensin is colocalized in certain subsets of dopamine neurons and is coreleased with dopamine in the mesolimbic and medial prefrontal cortex dopamine terminal regions that are implicated as the site of dopamine dysregulation in schizophrenia. Antipsychotic drugs that act at dopamine type 2 (D 2) and D4 receptors increase the synthesis and concentration of neurotensin in those dopamine terminal regions but not in others. That effect of antipsychotic drugs in increasing neurotensin concentrations persists after months of treatment and is accompanied by the expected increase in neurotensin mRNA concentrations, as well as expression of the “immediate early gene” c- fos and the transcription factor Fos within hours of initial drug treatment. The altered regulation of neurotensin expression by antipsychotic drugs apparently extends to the peptidases that degrade the peptide; recent reports have revealed decrease neurotensin metabolism in rat brain slices 24 hours after the administration of haloperidol. Decreased neurotensin concentrations in CSF have been reported in several populations of patients with schizophrenia when compared to controls or patients with other psychiatric disorders. Although treatment with antipsychotic drugs has been observed to increase neurotensin concentrations in the CSF, it is not known whether this increase is causal or merely accompanies the decrease in psychotic symptoms seen with successful treatment. Postmortem studies have shown an increase in neurotensin concentrations in the dopamine-rich Brodmann's area 32 of the frontal cortex, but that result may have been confounded by premortem antipsychotic treatment. Other researchers have found no postmortem alterations in neurotensin concentrations of a wide sampling of subcortical regions. A comparison of the genomic sequence of the neurotensin neuromedin N gene in schizophrenia patients compared with age- and sex-matched controls found no differences in the gene sequence in the coding region. A critical test of the hypothesis that neurotensin may act as an endogenous antipsychotic-like substance awaits the development of a neurotensin receptor agonist that can penetrate the blood-brain barrier.

SUGGESTED CROSS-REFERENCES Section 1.10 discusses basic molecular neurobiology, Section 1.11 discusses psychoneurocadocrinology, and the psychiatric aspects of endocrine disorders are discussed in Section 25.6.

SECTION REFERENCES Betancur C, Azzi M, Rostène W: Nonpeptide antagonists of neuropeptide receptors: Tools for research and therapy. Trends Pharmacol Sci 18:372, 1992. Bissette G, Reynolds GP, Kilts CD, Widerlov E, Nemeroff CB: Corticotropin-releasing factor-like immunoreactivity in senile dementia of the Alzheimer's type. J Am Med Assoc

254:3067, 1985.

*Bissette G, Nemeroff CB: The neurobiology of neurotensin. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. Bissette G: Neuropeptides and Alzheimer's disease pathology. Ann NY Acad Sci 814:17, 1997. *De Souza EB, Grigoriadis DE: Corticotropin-releasing factor: Physiology, pharmacology, and role in central nervous system and immune disorders. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. *Engstroem G, Westrin A, Ekman R, Traeskman-Bendz L: Relationships between CSF neuropeptides and temperament traits in suicide attempters. Pers Individ Dif 26:13, 1999. Heit S, Owens MJ, Nemeroff CB: Corticotropin-releasing factor, stress, and depression. Neuroscientist 3:186, 1997. *Hökfelt TGM, Castel M-N, Morino P, Zhang X, Dagerlind A: General overview of neuropeptides. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. Le F, Cusack B, Richelson E: The neurotensin receptor: Is there more than one subtype? Trends Pharmacol Sci 17:1, 1996. *Mason GA, Garbutt JC, Prange AJ Jr: Thyrotropin-releasing hormone: Focus on basic neurobiology. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. Nemeroff CB, editor: Neuropeptides in Psychiatric Disorders. American Psychiatric Press, Washington, DC, 1991. Nemeroff CB, editor: Neuroendocrinology. CRC Press, Boca Raton, 1992. Owens MJ, Nemeroff CB: The physiology and pharmacology of corticotropin-releasing factor. Pharmacol Rev 43:425, 1992. Owens MJ, Plotsky PM, Nemeroff CB: Peptides and affective disorders. In Biology of Schizophrenia and Affective Disorders, SJ Watson, editor. American Psychiatric Press, Washington, DC, 1996. Patel YC: Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest 20:348, 1997. Perone MJ, Windeatt S, Castro MG: Intracellular trafficking of prohormones and proneuropeptides: Cell type-specific sorting and targeting. Exper Physiol 82:609, 1997. Reichlin S: Neuroendocrinology. In Williams Textbook of Endocrinology, ed 8, JD Wilson, DW Foster, editors. WB Saunders, Philadelphia, 1992. *Rubinow DR, Davis CD, Post RM: Somatostatin in the central nervous system. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995.

Textbook of Psychiatry

1.7 NEUROTROPHIC FACTORS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.7 NEUROTROPHIC FACTORS ERIC STEPHEN LEVINE, PH.D. AND IRA B. BLACK, M.D. Neurotrophins and Their Receptors Regulation of Gene Expression Roles of Neurotrophins During Development Neurotrophins in the Central Nervous System Other Neurotrophic Factor Families Suggested Cross-References

Trophic factors are survival molecules that are essential for the development of the nervous system. These factors regulate a wide range of developmental events that transcend their survival-promoting effects, including modulation of neurite outgrowth, phenotypic differentiation, and synaptogenesis. In addition to their roles during development, trophic factors regulate neuronal function and response to injury throughout life. The neurotrophin gene family is a widely distributed group of factors that subserves multiple functions in the nervous system. Neurotrophic factors have been implicated in pathophysiological mechanisms underlying neuropsychiatric disease, including schizophrenia and depression. These factors may also be important in neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and Parkinson's disease; each involves the selective loss of a neurotrophin-sensitive neuronal population.

NEUROTROPHINS AND THEIR RECEPTORS The prototypical trophic factor is nerve growth factor (NGF), discovered by Rita Levi-Montalcini and Viktor Hamburger in the 1950s. NGF was originally isolated based on its ability to dramatically promote neurite outgrowth from sympathetic and sensory ganglia. It was later discovered to be essential for the survival and development of peripheral sympathetic and certain sensory neuronal populations. In the absence of NGF or when its action is blocked, there is a virtually complete loss of these responsive neuronal populations. Importantly, specific neuronal systems in the brain also respond to NGF and related trophic factors, greatly expanding their functional roles. NGF is one member of a gene family of closely related trophic factors known as neurotrophins. This family includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4/5, each of which shares high-sequence homology with NGF. These factors are expressed in neurons and glial cells throughout the nervous system. BDNF, NT-3, and NT-4/5 are found in virtually all areas of the brain, with highest levels of expression in the cerebral cortex and hippocampus. The distribution of NGF is much more restricted, with expression in cortex and hippocampus, but low levels in most other areas. Neurotrophin expression reaches its peak during development, but persists throughout life. Neurotrophin expression is also increased following specific neuronal insults, suggesting roles in responses to injury. The biological effects of neurotrophins are mediated via binding to specific transmembrane receptors that trigger changes in intracellular second messengers. Neurotrophins bind to two distinct classes of receptor. Members of the trk tyrosine kinase receptor family appear to mediate most of the biological actions of these factors. The trk family consists of three related receptors, trkA, trkB, and trkC. TrkA is the primary receptor for NGF, trkB for BDNF and NT-4/5 and trkC for NT-3, although NT-3 also interacts at lower affinity with trkA and trkB as well ( Fig. 1.7-1). These receptors have intrinsic tyrosine kinase activity and become autophosphorylated upon binding of the appropriate ligand. Phosphorylated tyrosine residues, in turn, provide binding sites for several downstream second messenger signals that attach to recognition sites (e.g., src homology 2 [SH-2] domains) on the intracellular domain of the trk receptor. The diverse second messengers include various protein kinases and transcription factors. These multiple, parallel signaling pathways evoke distinct biological effects on neurons, such as neurite outgrowth or survival itself.

FIGURE 1.7-1 Schematic representation of the ligand-receptor relationship between neurotrophins and the trk family of tyrosine kinase receptors. Primary ligand-receptor interactions are indicated by thick arrows; secondary interactions are indicated by thin, dashed arrows. Only full-length receptor isoforms are depicted in this diagram. (Adapted from Barbacid M: J Neurobiol 25:1386, 1994.)

The distribution of trk receptors is widespread in the nervous system; trkB and trkC, in particular, are expressed in virtually all regions of the brain, with highest levels in cortex and hippocampus. They are also found in thalamus, hypothalamus, cerebellum, basal ganglia, and brainstem, implying functional roles within neuronal populations subserving diverse functions, such as sensory perception, motor activity, endocrine regulation, cognition, motivation, and emotion. Distribution of the trkA receptor is more restricted, with high levels of expression only in the striatum and basal forebrain, suggesting that NGF acts on a limited population of central neurons. Several different isoforms of the trk receptors are expressed in the nervous system. These splice variants are encoded by alternate messenger ribonucleic acid (mRNA) derived from the trk genes. In addition to the full-length, signaling receptors, trkB and trkC receptors are expressed in truncated forms. These truncated receptors contain the extracellular, ligand-binding domain, but lack the intracellular tyrosine kinase signaling domain. Functional roles of these receptors are unclear, but they may act as dominant-negative inhibitors of trk signaling or they may play a role in ligand clearance or presentation. The truncated receptors are the major variant expressed by glial cells. Expression of truncated forms is also higher during maturity than during development. These alternate receptor forms may provide added flexibility in neurotrophin signaling. In addition to high-affinity binding to respective trk receptors, all the neurotrophins bind with relatively equal (and lower) affinity to the common neurotrophin receptor, known as p75. The functional role of this receptor is unclear. It is a member of the tumor necrosis factor family and may play roles in cell death. Signaling mechanisms mediated by p75 have not been readily identified but are thought to include activation of the sphingomyelin pathway. In some cellular populations, (e.g., oligodendrocytes), activation of p75 can trigger death, in contrast to the survival-promoting effects associated with neurotrophin signaling via trk receptors. Thus, differential expression of these two receptor systems may provide a mechanism for balancing opposing neurotrophin effects.

REGULATION OF GENE EXPRESSION To appreciate the physiological significance of neurotrophin action in the brain, it is essential to understand the regulation of availability. In peripheral target organs, neurotrophins are synthesized and released constitutively by nonneuronal cells, independent of the influence of innervating neurons. In the brain, however, neuronal expression of neurotrophin genes is modulated by impulse activity itself. For example, trophin expression in vivo in the hippocampus and neocortex is increased by limbic seizures. Dramatic increases in NGF and BDNF mRNA concentrations are produced by different methods of seizure induction, including dentate gyrus lesions, kainic acid injections, and electrical stimulation. Increased neurotrophin expression may facilitate further seizure activity, suggesting potential roles in mechanisms

underlying epilepsy and kindling. Specific mechanisms governing activity-dependent regulation of trophin gene expression have been characterized in vitro. Direct pharmacological depolarization markedly increases hippocampal neuron NGF and BDNF mRNAs, potentially leading to increased protein concentrations. BDNF expression increases almost fourfold within 3 hours and attains a maximal increase within 6 hours whereas NGF mRNA exhibits a smaller and more sluggish response. Activation of specific neurotransmitter receptors mimics these effects. In particular, excitatory glutamatergic and cholinergic inputs increase neurotrophin mRNAs and inhibitory g-aminobutyric acid (GABA)-ergic inputs decrease message levels. The persistent activation of neurotrophin genes by transient electrical activity may be critical in triggering changes in downstream gene expression. In turn, these sequelae may result in long-term changes in neuronal function. Neurotrophins and Long-Term Potentiation Direct stimulation of intrinsic anatomical pathways also regulates neurotrophin gene expression, providing a critical physiological context. In vivo, pharmacological activation of hippocampal afferent pathways increases BDNF and NT-3 mRNAs. Electrical stimulation evokes similar effects in vitro. Of particular interest is the relationship between neurotrophin gene expression and long-term potentiation, which is a form of activity-dependent synaptic plasticity most commonly studied in the hippocampus; it has been invoked as a cellular substrate for learning and memory. Stimulation patterns that induce long-term potentiation increase both BDNF and neurotrophin-3 messages in the hippocampus. Moreover, gene knockout animals with null mutations (i.e., inactivation) of the BDNF gene exhibit impaired long-term potentiation, which supports the contention that neurotrophins play critical roles in synaptic plasticity and perhaps in memory. Neurotrophins and Stress Neurotrophin gene expression in the brain is modulated by stressful stimuli, with potential relevance to neuropsychiatric disease. Physiological responses to stress resemble symptoms of depression, and chronic stress exacerbates clinical depression. Chronic stress also increases neuronal vulnerability to a wide variety of insults (e.g., metabolic toxins, seizure activity), mediated at least in part by increased circulating glucocorticoids. BDNF expression is decreased in response to short-term or long-term stressors (e.g., forced immobilization), which may contribute to resulting hippocampal damage. NT-3 mRNA levels increase in response to stress whereas treatment with antidepressant agents produces a decrease. It is not yet clear whether these changes in neurotrophin availability play a role in adaptive changes. These complex interactions between environmental stimuli and neurotrophins may mediate cognitive changes that occur in response to stress and in the course of psychiatric or degenerative disease, an area that is being actively studied. Although the regulation of neurotrophin gene expression has been intensely studied, much less is known about the mechanisms underlying neurotrophin release. This is crucial, however, because it is only after release and subsequent receptor binding that neurotrophins exert biological effects. Recent studies have begun to identify the mechanisms that control neuronal neurotrophin release. In the hippocampus, both NGF and BDNF are released from neuronal axon terminals and dendritic processes in an activity-dependent manner. Atypically, release is dependent on sodium, but independent of extracellular calcium, although intracellular calcium stores are involved. Much remains to be elucidated concerning the spatial localization and kinetics of trophin release. Nevertheless, activity-dependent regulation of neurotrophin gene expression and release provides a set of mechanisms through which the external or internal environment may regulate availability.

ROLES OF NEUROTROPHINS DURING DEVELOPMENT Neurotrophins play an essential role in coordinating diverse developmental processes. The most dramatic effects of NGF are on the survival of peripheral sensory and sympathetic neurons. During development, there is widespread, naturally occurring cell death, and the survival of many neuronal populations appears to be dependent on access to target-derived trophic factors. In many targets, neuronal innervation density is proportional to NGF synthesis. Thus, the neurotrophic hypothesis states that competition for limiting amounts of neurotrophins provides a mechanism to match the number of afferent neurons to target size. Lack of NGF results in the loss of most sympathetic and some sensory neurons. Exogenous NGF, on the other hand, rescues a larger number of neurons than normally survive during the period of developmental cell death. The effects of neurotrophins on survival are complex and appear to be critically dependent on the specific cellular context. Neuronal cell death arises from two distinct processes: apoptosis or necrosis. Apoptotic or programmed cell death is an active process requiring new protein synthesis, and can be induced in vitro by serum deprivation or calcium channel blockers. This type of cell death is commonly associated with development as well as with neurodegenerative disease. Apoptosis can be markedly reduced or prevented by treatment with neurotrophic factors, consistent with their role as survival-promoting agents. Neurotrophins also prevent cell death after axotomy, an apoptotic type of cell death caused by trophic factor deprivation. However, necrotic cell death often occurs after an acute insult or injury, such as oxygen-glucose deprivation; this type of cell death can be enhanced by neurotrophins under some conditions. The situation is complicated by the fact that both necrotic and apoptotic cell death occur under most complex conditions, such as stroke and brain trauma. Thus, the therapeutic potential of trophic factors after neuronal injury may be critically related to the specific nature of the insult, the temporal profile of the derangement, and its physiological context. Trophic factors exert widespread actions throughout the nervous system and are not limited to the foregoing examples. Other neurotrophin family members act on specific neuronal populations during development. For example, BDNF, NT-3, and NT-4/5 promote the survival of developing motor neurons. BDNF and NT-4/5 acting through the trkB receptor, promote the survival of nodose ganglion neurons. BDNF also increases expression of substance P in neural–crest-derived sensory neurons. Many other neurotransmitter and neuropeptide systems are also targets for neurotrophin modulation.

NEUROTROPHINS IN THE CENTRAL NERVOUS SYSTEM Neurotrophins and their receptors are widely distributed in the central nervous system, with distinct differences in modes of action from the peripheral model. Trophic support in the central nervous system can be derived from target neurons as well as afferent neurons and local support cells, including astrocytes, oligodendrocytes, and microglia. In addition, brain neurons are not critically dependent on a single factor for survival, but instead have overlapping trophic dependence. This has been most clearly shown in animals with targeted inactivation of specific neurotrophin genes or their receptors. Although specific peripheral neuronal populations are severely depleted in these animals, there is little dramatic neuronal loss in the brain. One of the best-characterized NGF-responsive cell populations in the brain are the cholinergic neurons of the basal forebrain. These neurons provide a dense modulatory input to the hippocampus. Taken together, the basal forebrain-hippocampal system plays a central role in attention, learning, and memory, with a particular emphasis on spatial learning and declarative memory. The prominent degeneration of basal forebrain cholinergic neurons in dementia of the Alzheimer's type is thought to be responsible for many of the ensuing cognitive deficits of the disorder. NGF enhances the survival of these neurons after axotomy or injury in animal models, and modulates neuronal function by increasing activity of choline acetyltransferase, an essential enzyme in acetylcholine biosynthesis. Thus, NGF may be clinically efficacious in rescuing this degenerating neuronal population and enhancing function of surviving neurons in disease states, with potential therapeutic implications. NGF also has actions in the spinal cord that play a role in nociception. NGF promotes the survival of pain fibers and induces expression of voltage-gated ionic conductances in spinal nociceptive neurons, including induction of the peripheral nerve-type PN-1 sodium channel, which may play a role in the regulation of nociception. Animals with a targeted deletion of the NGF gene or chronic exposure to NGF blocking antisera exhibit decreased responsiveness to pain and temperature and a selective loss of small-diameter dorsal root ganglion neurons. Trophic factor interventions may therefore be useful in alleviating chronic pain syndromes. BDNF and NT-4/5 acting via the trkB receptor, have a range of effects on multiple neuronal populations implicated in neuropsychiatric and neurodegenerative disease. These include the basal forebrain cholinergic neurons as well as dopaminergic neurons of the substantia nigra. Degeneration of nigral dopamine neurons results in the motor deficits observed in Parkinson's disease. BDNF enhances expression of dopamine synthetic enzymes, and protects these cells from exogenous neurotoxins. Trophic factors also increase axonal sprouting, resulting in increased connectivity with target neurons that may compensate for neuronal loss. This range of actions provides potential therapeutic opportunities for treating degenerative disease. BDNF has also been implicated in the pathophysiology of mood disorders, including depression. Current treatment for clinical depression centers on enhancement of serotonergic neurotransmission, through the use of serotonin-specific reuptake inhibitors. Administration of BDNF also evokes antidepressant-like effects in some animal models, which may result from changes in the activity of serotonergic systems. BDNF promotes sprouting of serotonergic axons, increases serotonin synthesis, and dramatically enhances the survival of these neurons after exposure to neurotoxins. Because the typical therapeutic effects of antidepressant medications take several weeks to achieve clinical efficacy, it is possible that growth–factor-induced changes in neuronal morphology or connectivity might play a role in these processes. Thus, BDNF may ameliorate neuropsychiatric conditions that involve dysfunction of monoaminergic (e.g., serotonergic, noradrenergic) systems. Neurotrophins and Synaptic Transmission Synapses are the main communicative junctions between neurons, and modulation of synaptic transmission is thought

to be central to learning and memory, cognition, and plasticity of circuits underlying motivation and emotion. In addition to well-established effects on neuronal survival, growth, and differentiation, recent work indicates that neurotrophins also acutely regulate synaptic efficacy, greatly expanding their functional relevance. Neurotrophins affect synaptic transmission through multiple mechanisms of action, including induction of ion channel expression, enhancement of presynaptic neurotransmitter release, and modulation of postsynaptic receptor responsiveness. These newly discovered effects have been identified both in the developing and mature nervous systems, indicating that mechanisms responsible for the formation of neural circuits during development also play roles in the dynamic regulation of activity within established circuits. Direct presynaptic effects on neurotransmitter release have been best characterized at the neuromuscular junction, one of the more accessible and easily studied synapses in the nervous system. At developing neuromuscular synapses in culture, BDNF and NT-3 potentiate evoked synaptic currents within minutes of exposure by enhancing acetylcholine release from presynaptic nerve terminals. Increased transmitter release results from local effects at the terminal and does not require cell body signaling. In addition to this short-term effect, long-term exposure to BDNF or NT-3 for several days enhances synaptic maturation through effects on presynaptic processes. Similar effects are observed in mammalian systems in vitro, where NGF and BDNF directly potentiate the release of acetylcholine and glutamate in the hippocampus and cortex. Moreover, this enhanced transmitter release augments synaptic transmission in a subpopulation of neurons. Neurotrophins also modulate synaptic activity via postsynaptic mechanisms. In the hippocampus, BDNF elicits sustained enhancement of action–potential-driven synaptic activity within minutes of exposure. This increase results from modulation of postsynaptic responsiveness to excitatory input via phosphorylation-dependent mechanisms (Fig. 1.7-2). TrkB receptor activation is critical for this response because neurotrophin-4, another trkB ligand, elicits similar effects. In contrast, the related neurotrophins NGF and neurotrophin-3, as well as the unrelated growth factors epidermal growth factor and basic fibroblast growth factor, do not share this effect. A postsynaptic locus of action is substantiated by the finding that the full-length trkB receptor is an intrinsic component of the postsynaptic density, a specialization of the postsynaptic membrane that anchors neurotransmitter receptors and second messenger signaling molecules. Furthermore, BDNF acutely enhances phosphorylation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the isolated postsynaptic density, leading to altered receptor function. BDNF-induced modulation of NMDA receptor activity appears to play a critical role in the modulatory effects of BDNF on synaptic transmission.

FIGURE 1.7-2 A. BDNF-induced potentiation of synaptic transmission. Whole-cell voltage clamp recordings from a hippocampal neuron before and 3 minutes after exposure to BDNF. Downward deflections represent excitatory postsynaptic currents. B. The postsynaptic component of BDNF modulation. Time course of a recording from an individual neuron shows the effect of bath-applied BDNF (50 ng/ml; diamonds). The effect of BDNF is decreased by postsynaptic injection of the trk tyrosine kinase inhibitor K-252a (200 nM; triangles), and enhanced by injection of the phosphatase inhibitor okadaic acid (OA; 0.5 µM; circles). Each point represents the average synaptic activity for a 1-minute period. (Reprinted with permission from Levine ES, Dreyfus LF, Black IB, Plummer MR: Proc Natl Acad Sci USA 92:8074, 1995.)

Thus, neurotrophins potentiate synaptic transmission via both presynaptic and postsynaptic effects, increasing the efficacy of synaptic transmission and the probability of triggering postsynaptic action potentials. The effects of neurotrophins on synaptic activity may have specific consequences for activity-dependent plasticity in the hippocampus, including long-term potentiation, a potential cellular substrate of learning and memory. Animals with a targeted deletion of the BDNF gene have deficits in long-term potentiation that can be restored by reintroduction of BDNF. Endogenous BDNF enhances long-term potentiation, although specific mechanisms are controversial. Modulation of postsynaptic glutamate receptors by neurotrophins may contribute to changes in long-term potentiation. Similar mechanisms are thought to occur in widespread areas of the brain, subserving multiple adaptive processes. Taken together, these data point to an important role for neurotrophins in the regulation of synaptic plasticity and potentially for the learning and memory processes that are dependent on this type of plasticity. Increasing neurotrophin availability may represent a novel approach towards reversing cognitive deficits resulting from injury, disease, or aging. In addition to direct effects on synaptic efficacy, neurotrophins also regulate expression of voltage-gated ion channels that regulate neuronal excitability. This has been most closely examined in a pheochromocytoma cell line (PC-12) that differentiates into a sympathetic neuron-like phenotype in response to NGF. In these cells NGF induces the expression of multiple types of sodium, potassium, and calcium channels. The increase in sodium channel expression is mediated at least in part by cyclic adenosine-monophosphate–dependent protein kinase (PKA). NGF also increases expression of voltage-gated sodium, calcium, and potassium currents in a neuroblastoma cell line. Whereas continuous exposure to NGF causes the induction of a family of sodium channels, brief exposure selectively induces expression of the peripheral nerve-type sodium channel gene PN-1. Although these effects have been typically characterized in clonal cell lines, similar mechanisms occur in primary neurons. For example, functional expression of N-type calcium (Ca 2+) channels is greatly enhanced by NGF in sympathetic neurons; in dorsal root ganglia, NGF accelerates the acquisition and diversity of sodium currents. Thus, modulation of ionic currents represents another important facet of neurotrophin modulation. These mechanisms also occur in the brain, with functional implications for psychiatric and neurodegenerative disease resulting from basal forebrain-hippocampal dysfunction. In basal forebrain cholinergic neurons, NGF increases both L-type and N-type components of voltage-gated calcium currents. This effect is specific to NGF because BDNF does not have a similar effect. Calcium entry via these voltage-dependent channels regulates neurotransmitter release and neuronal firing patterns and also modulates neuronal gene expression. Thus, calcium influx via these channels may mediate some of the well-known trophic actions of NGF. Since these neurons provide a dense cholinergic input to the hippocampus, this effect of NGF may also play a role in modulation of hippocampal synaptic transmission. Regulation of these ionic currents could therefore have long-lasting consequences for neuronal responsiveness to synaptic inputs. Importantly, the memory loss and cognitive impairment that accompanies dementia of the Alzheimer's type is thought to result from deficits in the basal forebrain-hippocampal system. Neurotrophins therefore are potential candidates for underlying pathophysiology and as a potential treatment opportunity. Regulation of Neuronal Connectivity In addition to dynamic changes in electrical activity, modulation of neuronal function can result from changes in neural architecture and circuit formation. Along these lines, neurotrophins may influence synaptic transmission in the brain via direct effects on axonal outgrowth, dendritic morphology, and synaptic connectivity. In addition to promoting survival (neurotrophism), these factors also have neurotrophic effects, guiding the direction of neurite growth. For example, growth cones of sensory neurons in vitro grow towards a source of NGF. It is not known whether NGF acts in vivo to guide axons to their proper targets, but once they reach their targets, NGF can regulate the shape and arborization of terminal contacts. NGF promotes neurite elaboration in developing cerebellar Purkinje neurons, and these effects are dependent on neuronal activity, requiring simultaneous exposure to NGF and depolarizing agents. NT-3 also enhances neurite outgrowth and branching in cultures of embryonic rat hippocampus. In developing cortex, endogenous neurotrophins regulate the development of characteristic dendritic branching patterns and laminar organization. Specific neurotrophins increase the length and complexity of dendrites of cortical neurons. Basal dendrites of neurons in each cortical layer respond most strongly to a single neurotrophin, whereas apical dendrites respond to several neurotrophins. These effects are also dependent on interactions with ongoing neuronal activity. The physiological relevance of these effects may relate to activity-dependent formation of neuronal circuitry during development and its reorganization after injury. For example, during the development of the visual system, axons from the thalamus carrying visual information become segregated into eye-specific patches (ocular dominance columns) within their target in the primary visual cortex. This reorganization results from activity-dependent synaptic competition between axons representing the two eyes. Infusion of BDNF or NT-4/5 into cat primary visual cortex blocks column formation. Neurotrophin-receptor antagonists, which block the actions of endogenous neurotrophins, also inhibit the formation of these columns. These data suggest that neurotrophins, normally present in limiting amounts within visual cortex, are necessary for the selective growth and segregation of thalamic axons into ocular dominance columns.

OTHER NEUROTROPHIC FACTOR FAMILIES

Many other growth and trophic factor families are expressed in the CNS, with specific neuronal targets that overlap and are distinct from neurotrophin targets. Examples include glial-derived neurotrophic factor (GDNF), a recently discovered trophic molecule isolated from an astrocyte cell line, that is a distant member of the transforming growth factor-b (TGF-b) family. GDNF is the most potent survival factor yet identified for dopamine neurons, which degenerate in Parkinson's disease, and motor neurons, which degenerate in amyotrophic lateral sclerosis. Thus, trophic factors may represent a promising therapeutic approach to rescuing these vulnerable neuronal populations. Dopamine neurons are also implicated in the pathophysiology of schizophrenia, and most antipsychotic medications target specific dopamine receptor subtypes. Dopaminergic neurotransmission may also be acutely modulated by trophic factors, providing therapeutic alternatives for clinical intervention. Other important growth factors include ciliary neurotrophic factor, which in addition to promoting survival of cultured ciliary neurons also acts on a wide range of neurons, including motor neurons and basal forebrain cholinergic neurons. The fibroblast growth factor family promotes cellular proliferation (mitogenesis) in a variety of cell types. In addition, basic fibroblast growth factor and acidic fibroblast growth factor, members of a gene family that now numbers seven related factors, also promote the survival and differentiation of numerous cellular types. Thus, disorders involving various transmitter systems may be potential targets for intervention using different trophic factors. Many questions regarding the functional roles of trophic factors remain unanswered. Are there discrete families of factors that preferentially act on specific neuronal systems? What is the function of the overlapping responsiveness to different neurotrophins? Are there distinct signaling pathways mediating different downstream trophic effects? The recently discovered neuromodulatory effects of trophic factors suggest that targeting these molecules may represent a novel strategy for subtly fine-tuning nervous system function. The growing knowledge of neurotrophin roles in the adult nervous system will have important consequences for understanding brain function and dysfunction as it relates to neuropsychiatric and neurodegenerative disease.

SUGGESTED CROSS-REFERENCES Neuroanatomy is discussed in Section 1.2 and Section 1.3. Excitatory amino acid neurotransmitters are presented in Section 1.5. Section 1.8 discusses intraneuronal signaling pathways, and Section 1.9 covers basic electrophysiology. SECTION REFERENCES Barbacid M: The trk family of neurotrophin receptors. J Neurobiol 25:1386, 1994. Bothwell M: Functional interactions of neurotrophins and neurotrophin receptors. Annu Rev Neurosci 18:223, 1995. Cabelli RJ, Hohn A, Shatz CJ: Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF. Science 267:1662, 1995. *Chao MV, Hempstead BL: p75 and trk: A two-receptor system. Trends Neurosci 18:321, 1995. Cohen-Cory S, Dreyfus CF, Black IB: NGF and excitatory neurotransmitters regulate survival and morphogenesis of cultured cerebellar Purkinje cells. J Neurosci 11:462, 1991. DiCicco-Bloom E, Friedman WJ, Black IB: NT-3 stimulates sympathetic neuroblast proliferation by promoting precursor survival. Neuron 11:1101, 1993. Elliott RC, Inturrisi CE, Black IB, Dreyfus CF: An improved method detects differential NGF and BDNF gene expression in response to depolarization in cultured hippocampal neurons. Brain Res Mol Brain Res 26:81, 1994. Gall CM, Isackson PJ: Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245:758, 1989. Kang H, Schuman EM: Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267:1658, 1995. Kang HJ, Welcher AA, Shelton D, Schuman EM: Neurotrophins and time: Different roles for trkB signaling in hippocampal long-term potentiation. Neuron 19:653, 1997. *Kaplan DR, Stephens RM: Neurotrophin signal transduction by the trk receptor. J Neurobiol 25:1404, 1994. Korsching S: The neurotrophic factor concept: A reexamination. J Neurosci 13:2739, 1993. *Levi-Montalcini R: The nerve growth factor 35 years later. Science 237:1154, 1987. Levine ES, Crozier RA, Black IB, Plummer MR: Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc Natl Acad Sci USA 95:10235, 1998. Levine ES, Dreyfus CF, Black IB, Plummer MR: Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci USA 92:8074, 1995. Levine ES, Dreyfus CF, Black IB, Plummer MR: Differential effects of NGF and BDNF on voltage-gated calcium currents in embryonic basal forebrain neurons. J Neurosci

15:3084, 1995.

Lindholm D, Castren E, Berzaghi M, Blochl A, Thoenen H: Activity-dependent and hormonal regulation of neurotrophin mRNA levels in the brain—implications for neuronal plasticity. J Neurobiol 25:1362, 1994. Lo DC: Neurotrophic factors and synaptic plasticity. Neuron 15:979, 1995. Lu B, Yokoyama M, Dreyfus CF, Black IB: Depolarizing stimuli regulate nerve growth factor gene expression in cultured hippocampal neurons. Proc Natl Acad Sci USA 88:6289, 1991. Meakin SO, Shooter EM: The nerve growth factor family of receptors. Trends Neurosci 15:323, 1992. *Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T: Distribution and retrograde transport of trophic factors in the central nervous system: Functional implications for the treatment of neurodegenerative diseases. Prog Neurobiol 57:451, 1999. Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M: Neurotrophin expression in rat hippocampal slices: A stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9:1081, 1992. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM: Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56:131, 1997. *Snider WD: Functions of the neurotrophins during nervous system development: What the knockouts are teaching us. Cell 77:627, 1994. Snider WD, Lichtman JW: Are neurotrophins synaptotrophins? Molec Cell Neurosci 7:433, 1996. Snider WD, Wright DE: Neurotrophins cause a new sensation. Neuron 16:229, 1996. Suen PC, Wu K, Levine ES, Mount HTJ, Xu JL, Lin SY, Black IB: Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1. Proc Natl Acad Sci USA 94:8191, 1997. *Thoenen H: Neurotrophins and neuronal plasticity. Science 270:593, 1995. Thoenen H, Bandtlow C, Heumann R: The physiological function of nerve growth factor in the central nervous system: Comparison with the periphery. Rev Physiol Biochem Pharmacol 109:145, 1987. Wetmore C, Olson L: Expression and regulation of neurotrophins and their receptors in hippocampal systems. Hippocampus 3:171, 1993. Wu K, Xu JL, Suen PC, Levine ES, Huang YY, Mount HTJ, Lin SY, Black IB: Functional trkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density. Mol Brain Res 43:286, 1996. Zafra F, Castren E, Thoenen H, Lindholm D: Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci USA 88:10037, 1991.

Textbook of Psychiatry

1.8 INTRANEURONAL SIGNALING PATHWAYS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.8 INTRANEURONAL SIGNALING PATHWAYS JAY M. BARABAN, M.D., PH.D. Major Signaling Pathways Synaptic Plasticity Suggested Cross-References

Prior to delineating the organization of specific intraneuronal signaling pathways, it is important to consider, in general terms, their role in helping neurons interpret and respond to the barrage of afferent stimulation impinging on them continuously. From an evolutionary perspective, second messenger systems predate neurotransmitters and neurotrophins, examples of first messengers detected by cell surface receptors. Before the advent of neurotransmitters, prokaryotic organisms relied on cyclic adenosine monophosphate (cAMP) and other intracellular signaling pathways to coordinate diverse responses located in disparate parts of these unicellular organisms to changes in ambient nutrients or conditions. Neurotransmitters and neurotrophins have evolved subsequently to take advantage of these internal signaling pathways that have undergone a parallel growth process. Intraneuronal signaling pathways do more than merely enlarge the sphere of influence of afferent stimuli beyond the local environment of the cell surface receptor. With the aid of these internal signaling pathways, the postsynaptic neuron partakes actively in amplifying or muting the initial signal conveyed by a particular receptor and is not relegated to the subservient status of a totally passive partner in responding to these external cues. Although each neurotransmitter receptor is dedicated to recognizing a specific molecular structure, the flexibility inherent in the organization of intraneuronal signaling pathways allows that recognition event to have entirely different meanings depending on the current context of the signal as well as the neuron's past experience. In other words, these internal signaling pathways empower neurons to shape their responses to incoming stimuli; collectively, these changes in ensembles of neurons are of paramount importance in enabling the nervous system to adapt to its environment and learn from experience. The concept that neurons or networks of neurons have the ability to modify their responses to a given stimulus is also directly relevant to understanding the actions of psychotropic drugs. In the absence of second messenger systems, drugs would be expected to exert consistent effects with repeated administration. Thus, all of the complex time-dependent changes in psychotropic drug action, such as tolerance to opiates or benzodiazepines, or the delayed therapeutic response to antidepressant or antipsychotic drugs, ultimately result from the ability of neurons, through their internal signaling pathways, to mount a compensatory response to this form of stimulation. In some instances, this adaptation may run counter to the desired clinical effect, such as tolerance to the analgesic effects of opioids or substance dependence. Alternatively, this active adaptation can be highly desirable because it presumably underlies the therapeutic action of antidepressant or antipsychotic agents, which develop after a lag of days to weeks following the onset of treatment. These examples underscore the direct relevance of intraneuronal signaling pathways to the most challenging problems facing psychiatry. Although the overwhelming majority of psychiatric drugs target extracellular receptors or uptake sites, the explosion of information on intraneuronal signaling pathways suggests that these may represent suitable drug targets. In particular, the availability of transgenic approaches to examine the phenotype caused by deleting a specific component of a signaling pathway will be invaluable in developing a new generation of psychiatric drugs aimed at signaling pathways that function beneath the neuronal surface. Furthermore, insights gleaned from the ongoing search for genes involved in inherited psychiatric syndromes may help to focus attention on specific pathways as therapeutic avenues that are capable of compensating for these pathological defects. Psychiatrists have long been taught that a true understanding of normal and abnormal behavior requires an appreciation of the interplay of forces lurking beneath the surface. Advances in defining the signaling pathways mediating neurotransmitter and neurotrophin action indicate that this notion rings true at the cellular level. Accordingly, deciphering the logic of intraneuronal signaling pathways is of paramount importance in understanding how neurons behave and represents a new frontier in dissecting the molecular and cellular basis of behavior and of the action of psychiatric drugs.

MAJOR SIGNALING PATHWAYS Cyclic AMP System The classic cross-perfusion experiments conducted by Otto Loewi at the turn of the century led to the identification of acetylcholine as a neurotransmitter and revolutionized the conception of synaptic transmission. In a similar manner, the discovery of cAMP by Sutherland and Rall nearly half a century later using an analogous approach established the principle that intracellular transmitters or second messengers are instrumental in conveying information from cell surface receptors to their targets within the cell. The accumulation of decades of research on this system has revealed its operating principles in great detail and has served as a blueprint for deciphering other signaling pathways as well. For this signaling pathway, generation of cAMP is controlled by the balance between the activity of its synthetic enzyme, adenylyl cyclase, which converts adenosine triphosphate (ATP) to cAMP, and phosphodiesterase, which cleaves cAMP to an inactive breakdown product, AMP. Adenylyl cyclase is regulated by cell surface receptors, via a family of adapter proteins referred to as G proteins because they bind guanosine 5'-triphosphate (GTP) when the receptor is activated. In this activated configuration, the a subunit of the G protein complex dissociates from the bg subunits, enabling it to regulate cyclic AMP formation. The a subunit possesses an intrinsic GTPase activity that converts GTP to guanosine diphosphate (GDP), which allows the subunits to reassemble into an inactive configuration. Neurotransmitter receptors may couple to adenylate cyclase via different classes of G proteins, referred to as G s or G i, depending on whether they stimulate or inhibit cyclic AMP formation (Fig. 1.8-1). In this way, the net effect of the transmitter on a given neuron is determined by the specific receptor subtypes expressed on its surface. For example, norepinephrine stimulates adenylate cyclase via its interaction with b-adrenergic receptors, the type that speed heart rate, and it inhibits adenylate cyclase via the muscarinic cholinergic receptor subtype.

FIGURE 1.8-1 Organization of the cyclic AMP system. Generation of cyclic AMP from ATP by adenylyl cyclase can be stimulated or inhibited by receptor-G protein linkages. In the example shown, the b-adrenergic receptor coupled to G s stimulates cyclic AMP synthesis whereas an M 2 muscarinic receptor inhibits this process via its linkage to G i. Cyclic AMP exerts many of its cellular actions via its ability to activate protein kinase A.

Cyclic AMP exerts a wide variety of actions on neuronal function via its stimulatory effect on cyclic AMP-dependent kinase, which has a broad range of substrate proteins involved in regulating virtually every aspect of neuronal function from ion channel gating to axonal transport, much as the autonomic nervous system influences the activity of diverse organ systems to achieve a cohesive response. One target of the cAMP system that has been the focus of attention in recent years is a transcription regulatory factor that enables elevations in cyclic AMP to regulate gene expression. This factor, referred to as cAMP response element binding (CREB)

protein, binds to a short sequence of deoxyribonucleic acid (DNA) in the regulatory regions of its target genes. Phosphorylation of CREB on a specific serine residue is required for it to promote transcription of target genes. Thus, alterations in cyclic AMP levels can affect neuronal function over a broad range of time scales. Rapid effects can be induced by targeting ion channel gating or transmitter release machinery. On a more sluggish time scale, cyclic AMP can influence neurotransmitter synthesis or energy metabolism. Furthermore, longer-lasting changes in neuronal function can be achieved by this messenger as a result of its ability to control the expression of specific target genes. Cyclic GMP Besides cyclic AMP, another cyclic nucleotide, cyclic guanosine monophosphate (GMP) has been identified as a second messenger regulated by neurotransmitter receptor stimulation. The discovery of cyclic GMP-dependent protein kinases suggested that both cyclic nucleotide systems followed similar blueprints. However, subsequent studies have revealed startling contrasts between these systems. The link between neurotransmitter receptor activation and stimulation of guanylate cyclase does not appear to rely primarily on G protein coupling. Instead, the available evidence indicates that elevations in intracellular calcium trigger increases in nitric oxide production, which in turn activate guanylyl cyclase ( Fig. 1.8-2). This complex cascade introduces a novel element, (i.e., a gaseous second messenger that is capable of diffusing both within cells as well as across membranes to neighboring cells, blurring the semantic distinction between first and second messengers). Nitric oxide has the ability to coordinate responses in clusters of cells within its sphere of diffusion, ensuring that neighboring neurons can be made aware of the status of postsynaptic neurons in their vicinity, as well as the activity of afferents emanating from distant parts of the nervous system. Furthermore, nitric oxide has the ability to influence afferent terminals, a retrograde feedback function that may be important in regulating the activity of incoming stimuli. Thus, the discovery of nitric oxide as a neuronal messenger breaches the classical notion that synapses convey information in only one direction. Recent studies have also suggested that another diffusible gas, carbon monoxide, which is also capable of activating guanylate cyclase, may also function in an analogous fashion to nitric oxide.

FIGURE 1.8-2 Organization of the cyclic GMP system. In contrast to cyclic AMP, cyclic GMP synthesis is regulated by stimulation of guanylyl cyclase by nitric oxide. Beyond this point in the pathway, cyclic GMP mimics cyclic AMP as it acts by stimulating its cognate kinase, protein kinase G.

Phosphoinositide (PI) Characterization of the neurotransmitter receptors coupled to the cAMP system revealed that there were many receptors that did not act via this second messenger pathway. This discrepancy generated interest in the possible existence of other second messenger systems operating in parallel with the cAMP system. This line of research came to fruition in the early 1980s with the emergence of a coherent view of the phosphoinositide second messenger system. This second messenger system parallels many aspects of the cAMP system (Fig. 1.8-3). Neurotransmitter receptor stimulation is coupled, via G proteins, to activation of a second messenger generating enzyme, phospholipase C. This enzyme cleaves inositol-containing phospholipids located in the plasma membrane into two second messengers, diacylglycerol and inositol trisphosphate (IP 3). Thus, activation of neurotransmitter receptors linked to the phosphoinositide system generates a pair of second messenger signals that can affect cellular responses via distinct pathways.

FIGURE 1.8-3 Organization of the PI system. In this system neurotransmitter receptor stimulation leads via G protein coupling to activation of phospholipase C. This enzyme cleaves the membrane phospholipid, PIP 2, into the second messengers, IP3 and diacylglycerol (DAG). IP 3 releases calcium from intracellular stores; DAG stimulates protein kinase C.

Because the effects of cAMP are mediated to a large extent via activation of a kinase, it was generally assumed that each of these second messengers acted in a similar fashion. This turned out to be true of diacylglycerol, which activates protein kinase C, a kinase that is highly enriched in the brain. In contrast, IP 3 acts much like an intracellular transmitter that has its own receptor present on the cytoplasmic face of intracellular organelles that store calcium. Binding of IP 3 to its receptor triggers release of calcium from these intracellular stores. Calcium, in turn, is a second messenger in its own right that is capable of regulating many intracellular processes, ranging from regulation of ion channel activity to gene expression. Previous studies had led to an appreciation of the vital role calcium plays as a mediator of transmitter release following action potential invasion of nerve terminals. In that situation, calcium enters the nerve terminal via opening of voltage-dependent calcium channels. Thus, it had been assumed that neurotransmitter regulation of intracellular calcium levels was mediated by their ability to elicit depolarization and subsequent activation of voltage-dependent calcium channels. In contrast, the IP 3 system provides an alternative route by which neurotransmitters can regulate intracellular levels of calcium, an important determinant of cellular function. It is noteworthy that lithium (Eskalith) played an important role in the studies that led to the current understanding of the phosphoinositide second messenger system. It had been noted in studies aimed at defining the effects of lithium on the central nervous system that lithium caused a modest decrease in concentrations of inositol, a sugar closely related to glucose. In pursuing the basis for this effect, investigators noted that lithium was an effective inhibitor of a phosphatase that converted inositol phosphate into inositol. Lithium could then be used to force accumulation of inositol phosphates, providing a convenient means of measuring activation of the phosphoinositide system. As a result of lithium treatment, researchers were able to detect the presence of inositol trisphosphate and realized that it was generated by phospholipase C acting on PI biphosphate (PIP 2), producing both diacylglycerol and IP 3 in one reaction. The discovery that lithium acts as an inhibitor of a key enzyme that generates free inositol needed to replenish inositol phospholipids has prompted the hypothesis that depletion of inositol and subsequent rundown of the PI cycle may underlie lithium's therapeutic action. However, this view has been challenged recently in light of animal studies demonstrating that inositol levels in brain are unaffected by lithium concentrations within its therapeutic range. Direct Coupling Between G Proteins and Ion Channels The elucidation of the cAMP, cyclic GMP, and PI second messenger systems focused attention on the importance of diffusible small molecules, which acted much like intracellular neurotransmitters. Instead of being released from a presynaptic site and diffusing across the synaptic cleft to act at receptor sites on the postsynaptic side, they diffused from their site of formation on the cytoplasmic side of the plasma membrane to act on their receptors within the cell whether they be kinases, as in the case of cAMP, calcium, or diacylglycerol, or receptors, as found for IP 3. However, diffusible second messengers are not universal components of the signaling pathways that mediate the actions of G–protein–coupled neurotransmitter receptors. In many important situations, the G proteins themselves link neurotransmitter receptor activation to ion channels shortcircuiting the rest of the cascade. Prominent examples of this type

of arrangement are provided by opioid receptors and muscarinic receptors involved in vagal slowing of the heart. As these receptors had been shown to be linked to Gi and cause inhibition of adenylate cyclase, it had been taken for granted their important effects on ion channel regulation, in particular opening of potassium channels causing hyperpolarization, was a result of lowering cAMP concentrations. However, this theory was shattered by experiments in which restoration of cAMP concentrations was ineffective in reversing this effect. Analysis of this paradox revealed that even though G i was involved in mediating this response, it was due to a direct effect of G i on the potassium channels (Fig. 1.8-4). Subsequently, this direct coupling has been found to be a common type of linkage between neurotransmitter receptors and ion channels.

FIGURE 1.8-4 Regulation of ion channels by G-protein–coupled receptors. Not all the effects of cyclic nucleotides are mediated by protein kinases. As shown in upper panel, G proteins can directly link neurotransmitter receptors to ion channels. This configuration underlies regulation of potassium channels that slow the heart in response to vagal stimulation of muscarinic cholinergic receptors. Alternatively, cyclic nucleotides can directly affect ion channels in a kinase-independent fashion, as illustrated in the middle panel. Cyclicnucleotide–gated channels play a key role in photoreceptor responses to light. The conventional kinase-dependent pathway is shown in the bottom panel. This type of arrangement mediates the well-known ability of sympathetic stimulation to speed the heart rate via activation of b-adrenergic receptors.

In this regard, it is interesting to note that the generalization that cyclic nucleotides always act via kinases has also been debunked by studies in sensory neurons demonstrating that these signaling molecules interact directly with ion channels, without kinases acting as intermediaries. These alternate arrangements emphasize the notion that intracellular signaling cascades have evolved in ways that heighten their versatility, with each of the components having multiple signaling capacities. Tyrosine Phosphorylation The landmark discovery that viral oncogenes were mutant versions of cellular genes that had been hijacked by tumor viruses has had a major impact on the entire field of tumor biology. In addition, characterization of the mode of action of several of these proto-oncogenes yielded another surprise—they represent a novel class of kinases that phosphorylate tyrosine residues, rather than serine or threonine residues that are targeted by all previously described mammalian kinases. Since the late 1970s intense exploration of this novel form of phosphorylation has provided compelling evidence that it can exert powerful influences on neuronal function. Initially it was assumed that because tyrosine kinases were proto-oncogenes involved in regulating cellular proliferation, this type of phosphorylation would have little relevance to the nervous system, which has extremely low levels of cellular proliferation. Contrary to this presumption, surveys of the level of tyrosine phosphorylation present in various tissues revealed that the brain has one of the highest concentrations of phosphotyrosine-containing proteins as well as of tyrosine kinases. Studies of tyrosine kinase signaling cascades have provided important new sights into the mode of action of nerve growth factor and other neurotrophins. Binding of growth factors to the extracellular portion of these receptors leads to activation of a tyrosine kinase domain located in the cytoplasmic tail of the receptor protein. It is thought that growth factor binding brings together two receptor molecules that then phosphorylate each other on tyrosine residues. This simple modification of the cytoplasmic tail converts it into a magnet for an array of signaling proteins that are brought together at the inner surface of the membrane. This arrangement triggers multiple divergent signaling cascades from this nidus. One of these branches can lead to activation of the PI system, as one of the isoforms of phospholipase C contains a domain that is attracted to the activated growth factor receptor. Another branch leads to activation of ras, a proto-oncogene that has G-protein–like properties. Another family of tyrosine kinases has been identified that differs from the receptor tyrosine kinases in that it contains only the cytoplasmic domain. The absence of an extracellular ligand binding domain has prompted questions about how members of this family are regulated; these questions are still largely unresolved. Nevertheless, evidence is accumulating that these non-receptor tyrosine kinases, such as fyn, src, and yes play a critical role in multiple neuronal responses, including ion channel regulation. The organization of the tyrosine kinase pathways provides an interesting contrast to the classical, second–messenger-based pathways outlined previously. First, the tyrosine kinase pathways do not utilize small, diffusible second messengers. In theoretical terms, this may have the advantage of maintaining a restricted spatial domain of signal propagation, as opposed to the classical second messenger systems, which have a larger sphere of influence. Second, the ability of multiple adapter proteins to interact with the activated cytoplasmic tail of tyrosine kinase receptors confers a remarkable degree of divergence as multiple signaling pathways can be engaged simultaneously. Thus, the importance of tyrosine phosphorylation signaling does not reside simply in the availability of another residue that is amenable to modification by phosphorylation; rather, it represents an intracellular signaling system built on an alternative set of architectural principles. Identification of the signaling pathway downstream of Ras has opened up a new avenue to understanding the mechanism of action of growth factors and neurotransmitters. Members of the Ras family are referred to as small G proteins because of their lower molecular weight compared to their large G protein relatives linked to the cyclic AMP and PI systems. Like their cousins, Ras and other small G proteins bind GTP following activation of growth factor receptors and slowly hydrolyze it to GDP with the help of accessory proteins called GTPase-activating proteins (GAP). In contrast to the large G proteins that are involved in regulating the synthesis of small second messenger molecules or in regulating ion channel activity, activated ras has the ability to stimulate a cascade of kinases arranged in series, that lead to activation of mitogen-activated protein (MAP) kinase ( Fig. 1.8-5). Unlike protein kinase A (PKA) or protein kinase C (PKC), each of these kinases is regulated by phosphorylation by an upstream activator kinase, instead of by small second messengers. However, like PKA or PKC, this kinase cascade has numerous targets within the cell ranging from influencing the organization of the cytoskeleton in the cytoplasm to control of gene expression in the nucleus. The pervasive influence of this signaling pathway helps to explain many of the remarkable effects of neurotrophins on neuronal growth and differentiation.

FIGURE 1.8-5 Kinase cascade activated by Ras. Ras, a member of the small G protein family, has been identified as an important mediator of growth factor responses. Activation of Ras stimulates a kinase, Raf, which regulates a series of downstream kinases. In contrast to the “classical” second messenger systems described above, these kinases are directly regulated by upstream kinases rather than by second messengers.

MAP kinase is particularly interesting from the perspective of neuronal signal transduction because it was initially identified using MAP-2, a neuron-specific cytoskeletal protein, as a preferred substrate. Once investigators realized that the kinase was widely distributed and also activated by mitogens and other extracellular agonists, its name was changed from MAP-2 kinase to mitogen activated protein kinase (MAP kinase) or extracellular agonist regulated kinase (ERK). Recent studies have demonstrated that MAP kinase in neuronal dendrites is associated with microtubules and indicate that MAP-2 is a physiological substrate of this kinase in vivo. Other substrates that have been identified include tyrosine hydroxylase and transcription regulatory factors, as well as another downstream kinase referred to as Rsk-2, which is capable of phosphorylating and activating CREB. The length of the kinase cascade distal to MAP kinase has also been stretched to add yet another kinase called (glycogen synthase kinase-3), which is downstream of Rsk-2. GSK-3 has received attention recently as the target of lithium, accounting for its teratogenic effects in several model systems of development. Further studies are needed to help elucidate whether this kinase may also play a role in mediating lithium's therapeutic action in mood disorders. Cross-Talk Among Signaling Pathways The organization of intraneuronal signaling pathways allows for a high degree of interaction or cross-talk among pathways. For example, growth factor receptor activation can also engage the PI system initially identified as a target of neurotransmitter receptors. Conversely, activation of neurotransmitter receptors can also stimulate MAP kinase initially linked to growth factor receptor activation. Thus, neurotransmitters have the ability to influence the response to neurotrophins and vice versa. In this context it is noteworthy that neurotransmitters can also regulate the MAP kinase pathway. This interplay among signaling pathways increases their versatility by providing alternative routes for regulating many of the same effector proteins. Although kinase regulation has been focused on, it is important to emphasize that there are analogous regulatory cascades involved in controlling dephosphorylation. In this way, the longevity of phosphorylation on a specific residue can vary dramatically depending on the substrate protein involved and the context it which it occurs. For example, PKA phosphorylation of dopamine regulated phosphoprotein-32 (DARPP-32), a protein phosphatase inhibitor that is highly enriched in neurons that receive dopaminergic innervation, is required for it to be functional. Thus, if a neuron receives simultaneous stimulation of both a calcium-dependent kinase and PKA, activation of DARPP-32 may greatly prolong the duration of phosphorylation of residues normally removed by the phosphatase inhibited by DARPP-32. An analogous cascade involves another phosphatase inhibitor, referred to as I-2, which is inhibited by GSK-3. Thus, in this case, activation of the MAP kinase/GSK-3 pathway would also affect the longevity of phosphorylation on residues regulated by the I-2–sensitive phosphatase. As a result of cross-talk between systems, coordinate activation of multiple pathways can have important synergistic effects. Another level of cross-talk has been observed at the level of specific target proteins ( Fig. 1.8-6). Rather than being substrates for specific kinases, the more common situation is that a given target is phosphorylated by multiple kinases. This overlapping of substrate specificity allows for complex patterns of regulation. For example, phosphorylation of a specific substrate by both protein kinase A and protein kinase C may have qualitatively different effects than modification by either alone. In addition, there are intriguing examples of conditional phosphorylation in which a protein only becomes a substrate for a protein kinase when it is first phosphorylated on a nearby residue by a distinct kinase. This sequential form of interaction confers a conditional switching mechanism that will only allow a substrate protein to be modified when a specific pre-condition is met. Furthermore, there are situations that represent the equivalent of “or” operations, when multiple kinases can substitute for each other in phosphorylating a specific residue. Therefore, if any one of the corresponding pathways is activated, the response will be triggered. A specific example of the “or” situation is presented by CREB. Phosphorylation on serine 133 by PKA converts this transcription factor into its active form. In addition, this same residue can be phosphorylated by calcium on calmodulin-dependent kinases, as well as Rsk-2, a kinase downstream of MAP kinase. Thus, activation of any one of these signaling pathways is sufficient to trigger CREB activation, allowing these distinct pathways to converge on CREB to induce changes in gene expression. In summary, multiple levels of cross-talk between signaling pathways transforms them from isolated pathways into a highly integrated network that possesses a high degree of sophistication and versatility in detecting and responding to incoming stimuli.

FIGURE 1.8-6 Cross-talk between kinases. As multiple kinases target individual protein substrates, multiple types of interaction can occur at this level. As shown in the top panel, there are instances where multiple kinases are capable of targeting the same residue. This arrangement is analogous to an “or” circuit, since activation of either kinase 1 or kinase 2 is sufficient to influence the target protein. In contrast, phosphorylation of a substrate by two different kinases on distinct residues may be needed to elicit a functional change in activity of the substrate (middle panel). As both kinases are necessary, this configuration is analogous to an “and” circuit. As illustrated in the bottom panel, the sequence of phosphorylation can also be crucial. In the example shown, both kinases are necessary, but they must be activated in the correct order because kinase 2 cannot act on the target unless it has already been phosphorylated by kinase 1.

SYNAPTIC PLASTICITY In its simplest form, the postsynaptic response to neurotransmitter release can be mediated by a single protein complex. For example, nicotinic acetylcholine receptors are self-contained stimulus-response modules that both detect a stimulus, acetylcholine, and generate a response, passage of ion currents. In a similar vein, other members of this superfamily of ionotropic receptors, including g-aminobutyric acid (GABA) and glutamate receptors, have the ability to function in a manner that is independent of the intracellular signaling pathways discussed. Thus, in contrast to growth factor or G-protein–coupled receptors, which often recruit elaborate cascades to elicit a response, the simplicity of self-sufficient ionotropic receptor complexes represents an optimal design for achieving reliability, precision, and speed. However, this view of ionotropic receptors as insulated from their social environment has had to be abandoned in the face of overwhelming evidence that this class of receptors is dynamically regulated by intraneuronal signaling pathways. Although these receptors do not rely on intraneuronal signaling pathways to operate ion channels, because these channels are an intrinsic feature of the receptor complex the linkage between ligand binding and ion channel gating is nevertheless subject to regulation by the network of intraneuronal signaling pathways just described. For example, phosphorylation of the GABA or glutamate receptors modulates their response to ligand exposure. Long-Term Depression The principle that ion channels are regulated by second messenger pathways is of central importance in considering how neuronal responses are altered by experience. Perhaps, one of the best examples for which the intracellular pathways involved have been worked out is the paradigm of long-term depression induced in Purkinje cells of the cerebellum. In this model of synaptic plasticity, the responses of Purkinje neurons to activation of ionotropic glutamate receptors is reduced for extended periods of time, by coincident activation of multiple signaling pathways. Even though the direct response to glutamate receptor activation does not rely on second messenger systems, its amplitude is indirectly modulated by a network of intraneuronal signaling pathways. This arrangement appears to be a general feature of synaptic transmission in which slower, second-messenger–based signaling pathways have a major impact on the fast modes of synaptic transmission. In the specific example of long-term depression in cerebellar Purkinje cells, the plasticity observed is triggered by coordinate activation of two distinct classes of afferents to these neurons. Purkinje cells receive a major input from both climbing fibers arising from the inferior olive and parallel fibers that emanate from granule cells of the cerebellum. The parallel-fiber response in an individual Purkinje cell is decreased if that cell is coincidentally activated by a climbing fiber input. Analysis of this phenomenon has revealed that it is dependent on coincident activation of two distinct types of glutamate receptors: an a-amino-3-hydroxyl 5-methyl-4-isoxazole propionic acid (AMPA) type of ionotropic glutamate receptors and a G-protein–coupled (metabotropic) glutamate receptor that linked to the PI system. In addition, the climbing fiber input produces a massive depolarization of the Purkinje cell that opens voltage gated calcium channels. The coordinated presentation of these three signals: (1) depolarization with subsequent calcium entry, (2) activation of the PI/PKC system, and (3) AMPA receptor stimulation conspire to produce a prolonged decrease in responses elicited by AMPA receptor stimulation. Any combination of only two of these signals is insufficient to trigger this form of synaptic plasticity. The exact mechanism by which these signals are integrated or detected simultaneously has not yet been worked out. However, the requirement for simultaneous

activation of multiple pathways provides a compelling example of how these pathways can act synergistically to modulate neuronal responses. This example also underscores the importance of intraneuronal signaling pathways in regulating the responsiveness of ionotropic receptor channels. Long-Term Potentiation The notion that coactivation of multiple second messenger pathways can have a qualitatively different impact than any one individually is also borne out in another well-known model of synaptic plasticity, long-term potentiation. In this paradigm, which has received intense attention because it provides a model of associative learning, modification of the synaptic responses to glutamate are also dependent on co-activation of multiple second messenger pathways. This requirement for coordinate activation of multiple pathways presumably represents a form of safeguard against changing synaptic weight inadvertently, which could have devastating effects on the nervous system. Accordingly, the requirements for synapse modification that underlie learning appear to have evolved in a way that entails the approval of multiple branches of the signaling network as a means of checking that the pattern of synaptic activity is of sufficient importance to warrant a long-term change in the synapses to be modified. Role of NMDA Receptor Activation Prior to outlining the intracellular signaling pathways involved in long-term potentiation, it is first important to understand the key synaptic events that trigger plasticity in this paradigm. Studies of long-term potentiation of inputs to CA1 hippocampal neurons have highlighted the role of N-methyl-D-aspartate (NMDA) receptors as coincidence detectors. In this system basal levels of synaptic activity are mediated by activation of AMPA receptors. Even though the same synapses also express NMDA receptors, under quiescent conditions these do not open in response to glutamate because NMDA receptors have an additional requirement that must be met before they open. Unlike AMPA receptors, NMDA receptors will only pass current if they detect glutamate and membrane depolarization simultaneously. Thus, NMDA receptors represent an unusual hybrid between ligand-gated ion channels and voltage-gated ion channels. In contrast to AMPA glutamate receptors or nicotinic acetylcholine receptors, which open automatically whenever they detect glutamate or acetylcholine, NMDA receptors are indifferent to the presence of glutamate unless they simultaneously detect that the neuronal membrane is depolarized. Only when both these conditions are met does the NMDA receptor open its channel, allowing influx of depolarizing current. This unusual property of NMDA receptors provides a molecular mechanism for conferring associative properties on long-term potentiation. When a glutamatergic input is of sufficient strength to meet both requirements of NMDA receptor activation, (i.e., glutamate and depolarization), then it will trigger a persistent potentiation of the response to that input. In contrast, an input that is too weak to elicit sufficient depolarization for NMDA receptor activation on its own will not undergo potentiation, unless it is presented simultaneously with other inputs that induce depolarization. Thus, the special requirements of the NMDA receptor allow weak inputs to be strengthened as long as they are presented simultaneously (i.e., associated) with strong stimulation of other inputs. This associative property of long-term potentiation has many of the same formal features as classical associative conditioning. For example, the conditioned stimulus, a bell in Pavlov's famous experiment, when presented by itself is insufficient to trigger a response, salivation. However, when the bell is sounded together with an unconditioned stimulus, such as food, then the temporal pairing of the two is capable of altering the response to the weak bell stimulus. Role of Phosphorylation The associative property of this model of synaptic plasticity has focused attention on deciphering the intraneuronal signaling pathways that mediate the long-term change in synaptic transmission triggered by NMDA receptor stimulation. NMDA receptor activation leads to transient rises in intracellular levels of calcium making this second messenger an attractive candidate. Experiments demonstrating that intracellular calcium chelators block this form of long-term potentiation corroborated the critical role of calcium in this process. Subsequent studies investigated whether either of the calcium-sensitive kinases that are highly enriched in neuronal dendrites, calcium/calmodulin-dependent kinase II and protein kinase C, were critical for this process. Unexpectedly, inhibition of either kinase blocked long-term potentiation, indicating that activation of both is necessary to trigger this persistent change in synaptic responsiveness. Thus, in both long-term potentiation and long-term depression simultaneous activation of multiple signaling pathways is used to detect unusual forms of stimulation that warrant an adjustment of synaptic responses. To underscore this general point, subsequent studies have also demonstrated that activation of the cyclic AMP system is also necessary for long-term potentiation to occur. The role of cyclic AMP in this paradigm may be related to its ability to suppress phosphatase activity. A key effect of PKA is to phosphorylate and thereby inactivate phosphatase inhibitors, such as DARPP-32. In this way, PKA on the one hand phosphorylates effector substrates and at the same time inactivates the phosphatase that erases its effects or the effects of other kinases. Given the data linking phosphorylaton or dephosphorylation to synaptic plasticity, there is intense interest in defining the substrates involved. Evidence suggesting that the potentiation of synaptic responses reflects an increase in responsiveness of AMPA receptors located in the postsynaptic membrane has focused attention on these receptors themselves as candidate substrates. In this regard, it is interesting that the AMPA receptor is a substrate for PKA, PKC, and calcium/calmodulin-dependent kinase. On the other hand, there are those who subscribe to the alternate view that long-term potentiation may reflect a presynaptic alteration in transmitter release that is produced by a retrograde messenger, such as nitric oxide, generated postsynaptically. Although the formal similarities between the associative properties of long-term potentiation and classical conditioning have provided compelling support for the hypothesis that this form of synaptic plasticity underlies associative learning, it has been difficult to gain experimental support linking this electrophysiological response to the behavioral phenomena. An important breakthrough in this area has been the utilization of transgenic animals with targeted mutations in genes encoding signaling molecules involved in long-term potentiation. The ability to examine the effect of these genetic alterations on behavior in the intact animal as well as on long-term potentiation in vitro has provided a means of bridging the gap between intraneuronal signaling pathways and behavior. Ongoing experiments in this area have validated the hypothesis that long-term potentiation and long-term depression represent the synaptic counterparts of learning. Application of this powerful genetic strategy to analysis of behavior provides an unprecedented means of dissecting the signaling pathways involved in modifying behavior in response to naturally occuring stimuli as well as to psychiatric drugs. As the technology employed by this approach is still developing rapidly, its application can be expected to become more widespread in the near future and provide a wealth of insights into the molecular substrates of a wide variety of behavioral responses. Actions of Psychotropic Drugs In addition to providing insight into the molecular mechanism underlying synaptic plasticity, studies of intraneuronal signaling pathways are also directly relevant to deciphering the mode of action of psychotropic drugs. Modern psychopharmacology has made tremendous advances in defining the primary site of action of the major classes of psychiatric drugs. For example, benzodiazepines act via GABA receptors, cocaine blocks the reuptake of monoamines, and opioids act via an array of opiate receptor subtypes. However, these important advances have not always provided an adequate explanation of the delayed effects elicited by these agents. For example, the primary site of action of the most widely used class of antidepressant drugs is the serotonin uptake site. However, it is clear that blockade of this uptake pump is not sufficient to elicit an antidepressant effect because this blockade occurs rapidly whereas the therapeutic response is delayed. This paradox has focused attention on the neuronal adaptation to serotonin uptake blockade to look for clues to the basis for the antidepressant response. A leading hypothesis to account for the delay in antidepressant response hinges on the observation that prolonged uptake blockade leads to downregulation of inhibitory presynaptic receptors on serotonin nerve terminals. This adaptation may then allow for increased release of serotonin, with each action potential invading the serotonin nerve terminals. According to this theory, the intracellular signaling pathway regulating the responsiveness of presynaptic receptors is the critical determinant of the antidepressant response. Another example is provided by recent studies implicating the cAMP system in mediating responses elicited by long-term opiate administration. Many of the acute effects of opiate receptor activation on ion channel function are mediated directly by G i proteins, independent of cAMP. However, in parallel with these electrophysiological effects, opioid receptor activation also suppresses cAMP concentrations. With long-term administration of opioids, neurons adapt to this persistent suppression of cAMP concentrations by altering the expression of several components of the cAMP system, yielding a net increase in cAMP tone to compensate for the chronic negative influence of opioids. This adaptive shift in the cAMP system brings the system back into balance as long as opioid stimulation persists. However, if opioids are withdrawn, the neuron is left with an overly active cAMP system that may underlie many of the behavioral phenomena of withdrawal. Although it is unclear how long-term suppression of cAMP concentrations leads to a compensatory upregulation of this system, available evidence suggests that CREB, a transcription factor sensitive to cyclic AMP, mediates this response. Evidence supporting this theory has been provided by recent studies demonstrating that opiate withdrawal is attenuated in transgenic animals that are deficient in CREB. These landmark results provide important confirmation that intraneuronal signaling pathways play a central role in this important aspect of opiate action. In addition, these findings exemplify how application of molecular biological approaches to deciphering intraneuronal signaling pathways will provide important insights into the mode of action of currently used psychiatric drugs and pave the way for a new generation of improved treatment approaches.

SUGGESTED CROSS-REFERENCES The role of intraneuronal signaling pathways in mediating the effects of neurotransmitters on ion channels and gene expression are also discussed in Section 1.3, Section 1.4, Section 1.7, and Section 1.14; the cellular events underlying memory are discussed in Section 3.5.

SECTION REFERENCES *Bear MF, Malenka RC: Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 4:389, 1994. Bear MF, Abraham WC: Long-term depression in hippocampus. Ann Rev Neurosci 19:437, 1996. Berridge MJ: Inositol trisphosphate and calcium signaling. Nature 361:315, 1993. Blenis J: Signal transduction via the MAP kinases: Proceed at your own RSK. Proc Natl Acad Sci USA 90:5889, 1993. Blier P, De Montigny C: Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220, 1994. *Bliss TVP, Collinridge GL: A synaptic model of memory: Long-term potentiation in the hippocampus. Nature 361:31, 1993. Blitzer RD, Wong T, Nouranifar R, Iyengar R, Landau E: Postsynaptic cAMP pathway gates early LTP in hippocampal CA1 region. Neuron 15:1403, 1995. Chen C, Tonegawa S: Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning and memory in the mammalian brain. Annu Rev Neurosci 20:157, 1997. Dohlman HG, Thorner J: RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem 272:3871, 1997. Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597, 1997. Exton JH: Regulation of phosphoinositide phospholipases by hormones, neurotransmitters and other agonists linked to G proteins. Ann Rev Pharmacol Toxicol 36:481, 1996. Frank DA, Greenberg ME: CREB: A mediator of long-term memory from mollusks to mammals. Cell 79:5, 1994. *Ghosh A, Greenberg ME: Calcium signaling in neurons: Molecular mechanisms and cellular consequences. Science 268:239, 1995. Greengard P, Valtorta F, Czernik AJ, Benfenati F: Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 259:780, 1993. Gudermann T, Kalkbrenner F, Schultz G: Diversity and selectivity of receptor-G protein interaction. Ann Rev Pharmacol Toxicol 36:429, 1996. Hedgepeth CM, Conrad LJ, Zhang J, Huang H-C, Lee VMY, Klein PS: Activation of the Wnt signaling pathway: A molecular mechanism for lithium action. Dev Biol

185:82, 1997.

Huang C, Hepler JR, Gilman AG, Mumby SM: Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells. Proc Natl Acad Sci USA

94:6159, 1997.

Huganir RL, Greengard P: Regulation of neurotransmitter receptor desensitization by protein phosphorylation. Neuron 5:555, 1990. *Hyman SE, Nestler EJ: Molecular Foundations of Psychiatry. American Psychiatric Press, Washington, DC, 1993. Jaffrey SR, Snyder SH: Nitric oxide: A neural messenger. Ann Rev Cell Dev Biol 11:417, 1995. Jope RS, Williams MB: Lithium and brain signal transduction systems. Biochem Pharmacol 47:429, 1994. Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93:8455, 1996. Linden DJ: Long-term synaptic depression in the mammalian brain. Neuron 12:457, 1994. Maldonado R, Blendy JA, Tzavara E, Gass P, Roques BP, Hanoune J, Schutz G: Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB. Science 273:657, 1996. Mansuy IM, Winder DG, Moallem TM, Osman M, Mayford M, Hawkins RD, Kandel ER: Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron 21:257, 1998. Mauk MD, Garcia KS, Medina JF, Steele PM: Does cerebellar LTD mediate motor learning? Toward resolution without a smoking gun. Neuron 20:359, 1998. Mulkey RM, Endo S, Shenolikar S, Malenka RC: Involvement of a calcineurin/inhibitor-1 phosphatase cascade in long-term depression. Nature 369:486, 1994. Nestler EJ: Under siege: The brain on opiates. Neuron 16:897, 1996. *Nester EJ, Aghajanian GK: Molecular and cellular basis of addiction. Science 278:58, 1997. Nicoll RA: The coupling of neurotransmitter receptors to ion channels in the brain. Science 241:545, 1988. Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607, 1992. Schlessinger J: SH2/SH3 signaling proteins. Curr Opin Genet Dev 4:25, 1994. Segal RA, Greenberg ME: Intracellular signaling pathways activated by neurotrophic factors. Ann Rev Neurosci 19:463, 1996. Sunahara RK, Dessauer CW, Gilman AG: Complexity and diversity of mammalian adenylyl cyclases. Ann Rev Pharmacol Toxicol 36:461, 1996. *Takahashi M, Terwilliger R, Lane C, Mezes PS, Conti M, Duman RS: Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms. J Neurosci 19:610, 1999. *Vanhoutte P, Barnier JV, Guibert B, Pages C, Besson MJ, Hipskind RA, Caboche J: Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Mol Cell Biol 19:136, 1999. Yang X, Diehl AM, Wand GS: Ethanol exposure alters the phosphorylation of cyclic-AMP-responsive element-binding protein and cyclic-AMP-responsive element-binding activity in rat cerebellum. J Pharmacol Exper Ther 278:338, 1996. Zheng F, Gingrich MB, Traynelis SF, Conn PJ: Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition. Nature Neuroscience 1:185, 1998.

Textbook of Psychiatry

1.9 BASIC ELECTROPHYSIOLOGY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 1. NEURAL SCIENCES

1.9 BASIC ELECTROPHYSIOLOGY CHARLES F. ZORUMSKI, M.D., AND KEITH E. ISENBERG, M.D. Principles of Cellular Electrophysiology Ion Channels Neurotransmitters and Ion Channels Psychiatric Aspects of Ion Channels Suggested Cross-References

Neurons use electrical signals to send and receive information. These electrical signals determine local and network properties of the central nervous system (CNS) and result from the flow of ions across cell membranes through macromolecular pores called ion channels. Neurons possess two classes of ion channels, gated and nongated. Nongated ion channels open spontaneously and contribute to the cellular resting membrane potential. The opening and closing of most ion channels is regulated (gated) by changes in transmembrane voltage or neurochemicals. Certain voltage-gated sodium channels allow very rapid movement of ions and provide the basis for communication within and between neurons. These rapid signals (action potentials) are generated at or near the neuronal cell body and are transmitted to nerve terminals with little decrement in amplitude. The high-fidelity propagation of action potentials results from saltatory conduction, which is the ability of electrical signals to “jump” rapidly between axonal nodes of Ranvier. At a nerve terminal an action potential causes a depolarization that opens voltage-gated calcium channels. The influx of calcium promotes the release of a chemical neurotransmitter into the extracellular space where the transmitter is able to influence a receiving cell. Neurotransmitters bind to specific protein receptors and alter neuronal excitability via actions on ion channels. There are two broad classes of neurotransmitter receptors: ligand-gated ion channels are directly opened by the binding of a transmitter whereas G-protein–coupled receptors influence the function of ion channels indirectly via guanine nucleotide binding proteins (G proteins) or chemical second messengers.

PRINCIPLES OF CELLULAR ELECTROPHYSIOLOGY Resting Membrane Potential In nerve cells, potassium ions (K +) are at higher concentration inside the membrane than outside whereas the opposite is true for sodium (Na+), calcium (Ca2+), and chloride (Cl –) ions (Fig. 1.9-1). The bulk solutions on either side of the membrane are electrically neutral, with most of the intracellular negative charge being contributed by large organic anions (acids and proteins). The differential distribution of ions across neuronal membranes results in part from the action of membrane pumps that use energy from adenosine triphosphate (ATP) to drive ions against a concentration gradient into or out of the cell. The best characterized pump is the Na +-K+ adenosine triphosphatase (ATPase) that transports 3 Na + out of and 2 K+ into the cell during each cycle. Because an unequal amount of charge is moved during each cycle, the pump is electrogenic and produces an electrochemical potential across the membrane that makes the inside of the membrane negative with respect to the outside. Na +-K+ ATPase activity is a major contributor to brain energy utilization, with as much as 40 percent of brain oxygen consumption resulting from pump activity required to reestablish ionic homeostasis following action potential firing and synaptic transmission. The cardiac glycosides digoxin (Lanoxin) and ouabain are effective inhibitors of Na +-K+ ATPase in the heart and improve myocardial contractility by depolarizing cardiac myocytes and increasing intracellular Ca 2+.

FIGURE 1.9-1 The distribution of Na +, K+, Ca2+, and Cl – across the membrane of a typical neuron. Using these ion concentrations, the equilibrium (Nernst) potentials for these ions at 37°C are shown at the lower right.

At rest, neuronal membranes are permeable to K + and Cl– and to a lesser extent to Na +, partly because of the flow of ions through nongated leakage channels. K + and Cl– flow down their concentration gradients making the inside of the neuronal membrane negative with respect to the outside. The separation of charge establishes a voltage, called a (potential difference) across the membrane. The presence of a transmembrane potential difference creates an electrical gradient for the movement of ions in addition to the concentration gradient established by the differences in ion concentrations inside and outside the cell. By convention, the bulk extracellular solution is at 0 mV, making the resting membrane potential about –70 mV inside the neuron. The bulk extracellular and intracellular solutions are electrically neutral and the charge separation that produces the membrane potential occurs in the immediate vicinity of the membrane. The number of ions needed to change the membrane potential is very small relative to concentrations in the bulk solutions. For example, a potential change of 100 mV across a 1 cm 2 area of membrane requires the movement of only about 10 –12 moles of a monovalent ion. By comparison, Na + and K+ are present at about 10 –1 M in the extracellular and intracellular fluids, respectively. For each ion in solution there is a specific membrane potential at which the opposing forces of the electrical gradient and concentration gradient are balanced. This potential (known as the Nernst potential or equilibrium potential) can be calculated based on the ion concentrations on either side of the membrane. For K +, the Nernst potential (designated E K) is expressed as: EK = (RT/zF) · ln([K] o/[K]i ), where R is the ideal gas constant (8.31 joules/degree/mole), T is the temperature in degrees Kelvin, z is the valence of the ion, F is Faraday's constant (96,500 coulombs/mole, the charge on a mole of monovalent ions), and [K] o and [K]i are the concentrations of K+ outside and inside the cell. At 37° C, the Nernst potential for K + is –96 mV, while ENa is +67 mV, ECl is –81 mV and ECa is greater than +97 mV. The importance of these equilibrium potentials comes from the fact that when an ion channel that is permeable to a specific ion opens, it drives the membrane potential towards the equilibrium potential for that ion. For example, when K +-selective ion channels open, the neuronal membrane potential moves toward –96 mV. This makes the inside of the cell more negative, an effect that is termed hyperpolarization. Na+ and Ca2+ channel opening has the opposite effect, making the inside of the cell less negative (depolarization). At any time, the membrane potential is a weighted average of the equilibrium potentials of the ions to which the membrane is permeable. Passive Membrane Properties To understand how ion concentration gradients, electrical gradients, ion channels, and the distribution of charges across the membrane are related, it is helpful to describe the cell membrane as an electrical circuit consisting of resistors (conductors), batteries, and capacitors. Because ions do not directly penetrate the lipid membrane but rather flow through ion channels, the ion channels can be thought of as variable resistors. Physiologists describe ion channels in terms of their ion selectivity (which ions flow through the channel) and their conductance (relative ease of passing ions). Conductance (g) is the inverse of resistance (R) in an electrical circuit (g = 1/R). The presence of a voltage across the membrane provides an electrical driving force for the flow of ions through ion channels resulting in a transmembrane current. The relationship among voltage (V), ionic current (I), and resistance (conductance) is given by the physiologists version of Ohm's law: Iionic = g · (Vm– Erev) where Vm is the membrane potential, Erev is the Nernst potential for the ions flowing through the channel, and (V m– Erev) represents the driving force for ion flow. Another important passive electrical property is capacitance. A capacitor is an electrical device consisting of two conductors separated by an insulating material that is

capable of storing charges of opposite sign on the two conductors. In the case of neurons, the conductors are the extracellular and intracellular fluids while the lipid membrane is the insulator. Whenever current flows through the membrane, some current must flow to charge the membrane capacitance (C m). The expression describing this capacitive current is: I cap = Cm · (dV/dt). Note that capacitive current flows only when the membrane potential is changing (i.e., there is some change in voltage [dV] as a function of time [dt]. The total current flowing across a membrane at any given time is a sum of I cap and Iionic. One of the major tools used by physiologists to study ionic currents is a voltage clamp (or more recently a patch clamp). These techniques employ electrical devices to keep the membrane potential constant and eliminate the contribution of capacitive currents during physiological studies, thus making it possible to measure ionic currents directly. One way to view the operation of an ion channel is as a battery (voltage source) in series with a conductor (resistor). The different types of ion channels can be viewed as being in parallel with each other and with the membrane capacitance. The net result is that the neuronal membrane can be represented by an equivalent electrical circuit ( Fig. 1.9-2), which can be used to describe how current flows when ions enter and exit the cell in response to various stimuli.

FIGURE 1.9-2 Ion channels form proteinaceous pores that traverse the lipid bilayer of the cell membrane. Because of the action of membrane pumps, the extracellular surface of the membrane has a net positive charge with respect to the intracellular surface. As a result of the transmembrane potential and the presence of ion channels, the neuronal membrane can be depicted as an equivalent electrical circuit in which each ion channel is a resistor (conductor, G x) in series with a battery (Ex). Different ion channels are shown parallel with each other and parallel with the membrane capacitance (C m).

Active Membrane Properties: Action Potentials Changes in membrane potential have important effects on excitability because certain ion channels are activated (gated) by voltage changes. When neurons are depolarized with respect to the resting potential, specific Na + channels open rapidly and drive the membrane potential towards the Na + equilibrium potential (+66 mV). Because of the leakage channels that are open at rest, there is initially a balance between the leakage currents and the currents flowing through Na + channels that are opened by depolarization. However, at a certain membrane potential the current flowing through Na + channels exceeds the current through the leakage channels. The membrane potential at which Na + currents exceed the leakage currents is called the threshold potential. Importantly, at potentials that are depolarized with respect to threshold the entry of more Na + into the neuron produces further depolarization, which in turn opens more Na+ channels in a regenerative fashion. During this process the neuronal membrane potential depolarizes to potentials >0 mV but never reaches the Na + equilibrium potential for two reasons. First, during the depolarization, Na + channels not only activate but they also rapidly inactivate. Inactivation refers to a process by which voltage-gated ion channels enter a nonconducting state despite the continued presence of the activating stimulus (depolarization). Second, the depolarization produced by Na + entry also opens voltage-gated K + channels, which drive the membrane potential towards the K + equilibrium potential (–96 mV). The net effect of the activation and inactivation of Na + channels and the delayed opening of K + channels is that the neuronal membrane potential rapidly changes to values >0 mV and then returns rapidly to the resting membrane potential. This rapid sequence occurs over several milliseconds and is referred to as an action potential (or spike) (Fig. 1.9-3). The fact that the membrane potential transiently exceeds 0 mV is called an overshoot. Action potentials represent all-or-none increases in electrical excitability and are important contributors to information transfer within and between neurons, allowing the neuronal cell body to communicate rapidly with its terminals, and in the terminals providing the depolarization that promotes the Ca 2+-dependent release of neurotransmitters.

FIGURE 1.9-3 A. A neuronal action potential as recorded by an intracellular microelectrode. The portions of the action potential are described in the text. B. The sequence of events underlying the action potential.

In most neurons the K+ equilibrium potential is negative with respect to the resting membrane potential. Thus, the action potential is often followed by a transient afterhyperpolarization (or undershoot) that decays back to the resting potential as the voltage-sensitive K + channels responsible for action potential repolarization close (Fig. 1.9-3). Following an action potential, there is a time during which stimulation either cannot elicit an action potential or during which it takes a very strong stimulus to evoke an action potential. These are called the absolute and relative refractory periods, respectively. The absolute refractory period results from the increased K + conductance that repolarizes the action potential and produces the undershoot; the relative refractory period reflects the time it takes for Na + channels to recover from inactivation. Action Potential Conduction in Axons Action potentials are typically generated in the neuronal cell body or in the initial segment of the axon (also called the axon hillock) where Na+ channels are densely collected. Because action potentials are generated at a distance from the nerve terminals where neurotransmitters are released, an important question concerns how action potentials are transmitted to the synaptic terminals. In a strictly passive nerve fiber, leakage of current across the membrane results in decremental conduction with the signal fading over a distance that is determined by the longitudinal (axial) resistance of the fiber, the membrane capacitance, and the transmembrane resistance. Decremental conduction is more typical of the spread of electrical signals along dendrites back to the neuronal cell body, although recent studies have shown that dendrites also have voltage-gated ion channels that play important roles in modifying electrical synaptic inputs to the dendrites. Many axons are encased in myelin sheaths that allow them to send action potentials over longer distances. As a result of myelination, axons are electrically insulated except at Ranvier's nodes where there are collections of voltage-gated Na + channels involved in action potential generation ( Fig. 1.9-4). The myelin sheath greatly increases the transmembrane resistance and diminishes current leakage from the axon, making it easier for current to flow down the length of the axon. Once generated, action potentials propagate rapidly and the wave of depolarization jumps from node to node in a form that transmits the signal faithfully to the nerve terminals. This process of action potential spread through axons is referred to as saltatory conduction (derived from the Latin word saltare meaning “to jump”) and is important because of the speed and fidelity with which electrical information is passed from a nerve cell body to its terminals. The importance of saltatory conduction can be readily appreciated when considering the distances over which impulses must travel from the CNS to cause movement in the toes. In several human illnesses, including multiple sclerosis and Guillain-Barré syndrome, demyelination of axons produces changes in axon conduction and specific neurological defects.

FIGURE 1.9-4 An example of saltatory conduction of an action potential in a neuron with a myelinated axon. The action potential is generated in the initial segment of the axon. As the signal moves along the axon, current tends to leak from the cell diminishing the amplitude. However, myelin insulates the axon and markedly diminishes current leakage out of the axon, thus enhancing flow down the axon to the first node of Ranvier. At the node of Ranvier, Na + channels of the type involved in action potentials open in response to the wave of depolarization and reproduce the all-or-none action potential. The sequence is repeated at subsequent nodes of Ranvier until the action potential reaches the nerve terminal.

ION CHANNELS Structure and Function of Voltage-Gated Ion Channels Voltage-gated ion channels allow the flow of ions in response to changes in membrane voltage and are key elements in neuronal excitation and inhibition. Although ion channels can usually pass more than a single type of ion, voltage-gated channels are named according to the predominant ion that flows when the channel is open. Ion channels that are selective for Na +, K +, Ca2+, or Cl– have been described in neuronal membranes. Certain ion channels that are gated directly by chemical neurotransmitters such as glutamate and acetylcholine are selective for Na +, K+, and Ca2+ but exclude Cl – and are called nonselective cationic channels. Sodium (Na+) Channels Na+ channels are primarily responsible for the fast upstroke of action potentials, although in some neurons Na + channels also contribute to lower-level depolarizations and pacemaker firing. Pacemaker activity refers to the ability of certain neurons to depolarize spontaneously and to drive activity in a system of connected cells. Na + channels activate (open) rapidly in response to depolarization and also inactivate rapidly and nearly completely in response to prolonged depolarizations. Cloning studies have provided important information about the structure of Na + channels. Na + channels cloned from rat brain contain three protein subunits—a main (or a) subunit with a molecular weight of 240 to 280 kd and two minor subunits with molecular weights of 30 to 40 kd (termed b 1 and b2) that appear to assemble in a 1:1:1 ratio. The a-subunit is a glycoprotein consisting of four structurally similar ( homologous) domains that each have six proposed membrane spanning regions, referred to as S1 through S6 ( Fig. 1.9-5). The properties of voltage dependence, ion permeation, activation, and inactivation are conferred by specific regions of the Na+ channel protein. However, the exact manner in which the proteins assemble in the lipid membrane remains a matter of active study.

FIGURE 1.9-5 A. The diagram shows the proposed secondary structure of voltage-gated Na +, Ca2+, and K+ channels based on analysis of the primary amino acid sequences. Na+ and Ca2+ channels consist of four homologous domains (I,II,III, and IV), each of which has six membrane spanning regions (S1-S6). Both the amino (NH2) and carboxy (COOH) terminals are located intracellularly. A stretch of amino acids between S5 and S6, called the p-loop, is believed to form two antiparallel b-sheets that line the channel pore. Positive charges in the S4 region are believed to comprise the voltage sensor. B. Some K+ channels also have 6 transmembrane regions but lack the four homologous repeats seen in Na + and Ca2+ channels. C. Inwardly rectifying K + channels, including K-ATP channels, have a structure that differs from the scheme described above. These channels have two membrane spanning regions and a pore-lining p-loop. In contrast to channels gated by extracellular ATP (Fig. 1.9-7C), the bulk of the protein is located intracellularly.

Relations between primary protein structure and ion channel function in Na + channels have been examined using mutations of specific amino acid residues. It appears that both the amino- and carboxy-terminals of the a-subunits are located intracellularly. The fourth membrane spanning region (S4) plays a key role in sensing the transmembrane voltage changes that allow channel gating. Between the S5 and S6 membrane spanning regions there is a segment of hydrophobic amino acids that does not completely cross the lipid membrane bilayer. This reentrant loop of amino acids (called a p loop) is a feature shared by other voltage-gated ion channels and appears to form the lining of the ion channel pore. Na+ channels contain several sites at which neurotoxins and drugs act to influence excitability. Most but not all Na + channels contain an extracellular site at which tetrodotoxin (TTX) and saxitoxin (STX) act to block ion flow. TTX is a neurotoxin isolated from puffer fish that is used experimentally to block Na + channel function. At a site on Na+ channels that is distinct from the TTX site, certain scorpion and sea anemone toxins act to modify gating properties. The a-scorpion toxin slows inactivation of Na + channels while b-scorpion toxins shift the voltage of activation and allow channels to open at voltages closer to the resting membrane potential. The net effect of the scorpion toxins is to enhance excitation, contributing to the increased firing in pain fibers and paralysis (tetany) that are associated with a scorpion sting. Mutations in the a-subunit of skeletal muscle Na + channels cause the human disorder hyperkalemic periodic paralysis. Like the anemone and a-scorpion toxins, these mutations slow channel inactivation. Other toxins isolated from the buttercup family (aconitine), the lily family (veratridine), and frogs that are used for arrow poisons in South America (batrachotoxin) promote the direct opening of Na + channels and prolong the duration that the channels stay open. The net effect is similar to the scorpion toxins. Finally, certain local anesthetic drugs, including lidocaine and procaine, block Na + channels by binding reversibly to sites within the hydrophobic regions of the ion channel. The blockade of Na+ channels is likely to contribute to local anesthetic effects as well as to the antiarrhythmic effects of these drugs in the heart. The rich pharmacology of voltage-gated Na + channels provides a means for understanding how certain neurotoxins act as well as a means by which Na + channel function can be manipulated therapeutically. It is important to emphasize that not all Na + channels in neurons are sensitive to all these agents. It is clear that TTX-insensitive Na + channels exist in a variety of excitable cells, although their function is not well understood at present. Potassium (K+) Channels K+ channels represent the most diverse family of voltage-gated ion channels in excitable cells and are important participants in determining the firing properties of neurons. For example, the fast repolarization of neurons produced by certain K + channels allows an increased rate of action potential firing, which can then be used in frequency-dependent information coding. Most neurons express multiple types of K + channels that differ in their activation and inactivation kinetics, voltage dependence, and pharmacology. Because the equilibrium potential for K + is about –90 mV in most neurons, the opening of K + channels allows K + to flow out of the cell, resulting in membrane hyperpolarization and a decrease in excitability. The first K + channel to be identified was called a

delayed rectifier. These channels derive their name from the experiments of Hodgkin and Huxley on squid giant axons and are so named because the currents gated by these channels activate more slowly than the Na + channels that produce the upstroke of the action potential (i.e., the K + channel opening is delayed). A rectifier (or diode) is an electrical device that passes current better in one direction than another. The K + current is described as a rectifier because the channel is more effective in allowing K + ions to exit than to enter the cell. Delayed-rectifier channels open slowly and show little inactivation during prolonged depolarizations. It appears that these channels help to determine the frequency with which neurons fire action potentials. Early experiments in squid giant axons indicated that delayed rectifier currents were the primary K + currents involved in action potential repolarization. However, in neurons the situation is more complex, with several more rapidly activating K + channels contributing significantly. These include two classes of calcium-activated K + channels that are opened by increases in intracellular Ca 2+ and are called SK small conductance Ca2+-activated K+ (SK) channels and big conductance (BK) channels, based on the relative ease (conductance) with which they pass K + when open. SK channels activate with relatively small intracellular Ca 2+ increases to levels on the order of 100 nM whereas BK channels require Ca 2+ levels to rise to 1 to 10 µM. In neurons, intracellular Ca 2+ buffering mechanisms usually keep free Ca 2+ concentrations 30 percent above baseline; blood pressure >140/90 mm Hg). Indeed, ECG monitoring has been shown to be an important laboratory tool for assessing compliance and assessing cardiac toxicity. A significant relationship has been shown between maintenance plasma levels of some tricyclic drugs and clinical response. For instance, for imipramine, the authors of one study recommended a therapeutic blood concentration discriminating cut-off value of 150 ng/mL. In another study with nortriptyline, plasma levels between 60 and 100 ng/mL were associated with a positive clinical response in prepubertal children with depression. However, more research is necessary to determine meaningful therapeutic blood concentrations for antidepressant medications in children. The clinical laboratory will be essential to the development of effective pharmacotherapy for prepubertal depression and management of these children. At a minimum, blood concentration tests will help to determine compliance and dosage regulation. LITHIUM Although lithium is clearly effective in the treatment of bipolar I disorder, the therapeutic and toxic blood levels of this agent are very close to one another, and in certain individuals even seem to overlap. Additionally, lithium has effects on a number of organ systems of which the clinician should be aware. Lithium therapy is associated with a benign elevation of the white blood cell count (WBC), which can range to about 15,000 cells per mm 3. This WBC elevation can sometimes be mistaken for signs of infection, or wrongly be attributed to lithium in the context of other signs of infection (e.g., fever, cough, discomfort on urination, malaise). Furthermore, lithium can have adverse effects on electrolyte balance (especially in patients on thiazide diuretics), thyroid function, the kidney, and the heart. Hence, common lithium pretreatment tests include serum electrolytes, BUN serum creatinine, urinalysis, thyroid function tests (TFTs) (e.g., TSH, T 4, T3RU), and an ECG. In patients with a history suggestive of possible kidney problems, a 24-hour urine test for creatinine and protein clearance is recommended, although some clinicians routinely order this test in patients about to begin lithium therapy. Some have argued that antithyroid antibody testing is helpful in assessing the potential of lithium-induced hypothyroidism. Because of the potential cardiac teratogenicity of lithium, a pregnancy test in potentially child-bearing women should be ordered. Periodic follow-up of serum electrolytes, BUN, creatinine, TFTs, ECG, and 24-hour urine for creatinine and protein clearance are recommended. The frequency and exact makeup of the follow-up testing battery should be dictated by the patient's medical condition. Suggested therapeutic blood concentrations for the lithium ion in acute mania range from 0.8 to 1.5 mEq/L, although a range where potential toxicity might be manifest is 1.2 to 1.5 mEq/L (a “warning range” where the risk of developing toxicity rises rapidly). The serum lithium concentrations of patients with lithium levels above 1.0 mEq/L should be carefully monitored. Maintenance therapeutic blood concentrations of lithium are around 0.6 to 0.9 mEq/L. Lithium concentrations for therapeutic blood-level monitoring are drawn as close to 12 hours after the last dose of lithium as possible. Steady-state concentrations in patients without renal dysfunction are reached about 5 to 8 days after initiation of lithium treatment or after a dosage change. Patients with evidence suggestive of lithium toxicity should have a concentration measured immediately. These patients might need close medical attention, including hemodialysis when the lithium levels exceed 2 to 4 mEq/L (especially in the patient in poor medical condition with poor lithium excretion). Lithium levels are often measured every 1 to 2 weeks during the first 2 months of treatment. Unless there are indications to do otherwise, follow-up testing for patients on lithium includes lithium concentrations obtained every 3 to 6 months, yearly thyroid function testing (e.g., T 4 and TSH), serum BUN, and creatinine. Serum electrolytes are measured every 6 to 12 months, with a 24-hour urine for volume and glomerular filtration rate (GFR) in patients with suspected renal disease. Changes in lithium dosing would necessitate more frequent blood level monitoring. Antipsychotics Except for the antipsychotic clozapine (Clozaril), no clear pretreatment and follow-up laboratory and diagnostic evaluation strategy exists. Additionally, no specific therapeutic blood levels for these agents have emerged although some suggested therapeutic blood concentrations for several antipsychotic agents exist in the psychiatric literature. For instance, some studies have suggested that a therapeutic window for treatment efficacy exists for haloperidol (Haldol), and clinically meaningful responses to clozapine have been associated with blood concentrations between 200 and 450 ng/dL; one study noted the greatest benefit with blood concentrations greater than 350 ng/dL. For haloperidol, gross toxic adverse effects, including neuroleptic malignant syndrome, confusion, seizures, or catatonia, have been associated with blood concentrations greater than 30 ng/mL; blood-level reductions were associated with a reduction in these toxic adverse effects. There is also significant dose-to-blood-level variability between individuals. Blood concentrations for antipsychotic agents have been described as useful for assessing medication noncompliance or perhaps in treatment-refractory patients who might be very rapid metabolizers of the antipsychotic agent being used. Blood concentrations testing can also be utilized to determine if a drug interaction is lowering the blood level of an antipsychotic drug. Additionally, some clinicians have advocated the use of at least a single blood level in patients who do not respond to an antipsychotic agent. Clinicians need to be aware of the potential toxicities of the antipsychotic agents that they use, and order laboratory and diagnostic tests accordingly. For instance, clinicians using clozapine need to be aware of its potential to cause fatal agranulocytosis and seizures (although these risks exist with all antipsychotic agents, albeit to a lesser extent). With clozapine the risk of agranulocytosis (defined as an absolute neutrophil count [ANC] of less than 500/mm 3) appears to be about 1.3 percent per year; the risk of seizures reaches approximately 5 percent of persons treated with higher dosages. Other potential adverse effects of antipsychotic medication include melanism from phenothiazines (especially chlorpromazine [Thorazine] related), abnormal lactation, and gynecomastia. It is also probably advisable to establish the childbearing status of at-risk women prior to the use of antipsychotic medications. Serious cardiac arrhythmias have been reported associated with antipsychotic use (e.g., thioridazine [Mellaril]); hence, patients with preexisting cardiac disorder might need careful ECG follow-up when these agents are used. In patients about to start on antipsychotic agents with known cardiac effects, obtaining a baseline ECG is prudent. Note that in patients over the age of 50, the frequency of ECG abnormalities is considered significant enough to warrant such screening. ECG screening is

indicated in persons with a history of cardiac disease, regardless of age. Clinicians should also be aware that significant orthostasis can be associated with some antipsychotic agents. Patients with concomitant hepatic or renal disease require periodic monitoring of these organ systems (e.g., with periodic physicals, LFTs, BUN, and creatinine tests). Neuroleptic Malignant Syndrome The diagnosis and follow-up of this potentially fatal adverse reaction to antipsychotic medications can be assisted by the laboratory. This disorder typically consists of varying degrees of hyperpyrexia, autonomic instability (e.g., pulse greater than 100), severe extrapyramidal dysfunction (95 percent with “lead-pipe” rigidity) and delirium. Laboratory abnormalities often include creatine phosphokinase, WBC elevations, myoglobinuria, and liver enzyme elevations. Patients with neuroleptic malignant syndrome are at risk for serious medical complications including renal failure, pneumonia, respiratory arrest, and cardiovascular collapse. Laboratory and diagnostic testing for these conditions should be ordered as indicated. Clozapine-Induced Agranulocytosis The agranulocytosis that develops in clozapine-treated patients often occurs within the first 18 weeks of treatment. Although the drop in the WBC is usually gradual, the progression to agranulocytosis can be rapid and can occur within a few days. Fever, flu-like symptoms, sore throat, or petechiae and ecchymosis (i.e., from thrombocytopenia) on any part of the body may be a sign of granulocytopenia in patients taking clozapine. At this time there is no way to predict who will develop this potentially fatal adverse event. Prior to initiating clozapine therapy, a WBC count should be obtained. It has been recommended that patients with a WBC count of less than 3500/mm 3 not be treated with clozapine. If during treatment with clozapine the WBC falls below 3500/mm 3, or there is a significant decrease from a higher WBC baseline that does not fall below 3500 (i.e., a single drop of 3000 or more or a cumulative drop of more than 3000 over a 3-week period), or immature white cell forms are detected, a repeat WBC with differential should be obtained immediately. If the count is between 3000-3500/mm 3, the ANC should be above 1500/mm 3 for therapy to continue (and follow-up WBC counts should be done twice weekly). WBCs below 3000/mm 3 or ANCs below 1500/mm3 are typically indications to discontinue clozapine therapy, and WBC counts with differentials should be obtained daily. Clozapine therapy can be resumed when WBC counts are over 3000/mm 3 and ANC concentrations are over 1500/mm3. Twice-weekly WBC counts with differentials should be obtained until the WBC reaches 3500/mm 3. At WBCs below 2000/mm3 and ANCs below 1000/mm3, bone marrow studies are recommended. It is now also recommended that patients who have total WBC counts that fall below 2000 mm 3 during clozapine therapy or ANCs that drop below 1000/mm3 should not be rechallenged with clozapine ( Table 7.7-6).

Table 7.7-6 Clinical Management of Reduced White Blood Cell (WBC) Count, Leukopenia, and Agranulocytosis in Patients Taking Clozapine

Clozapine-Related Seizures The risk of seizure from clozapine rises with increasing dosage, and reaches approximately 5 percent of persons treated with high doses of clozapine (between 600 to 900 mg a day). Although most of the clozapine-related seizure events are of the generalized tonic-clonic type, myoclonic seizures and cataplectic-like events have also been described. Before raising clozapine doses above 600 mg a day, the clinician should consider obtaining an EEG; however, according to some reports an abnormal EEG might predict therapeutic response to clozapine. In treating suspected or confirmed clozapine-related seizures, phenytoin (Dilantin) is avoided because of its ability to lower serum clozapine levels and its association with agranulocytosis. Carbamazepine can also cause agranulocytosis and should not be used in patients taking clozapine. Anticonvulsants Valproate Valproic acid and divalproex (Depakote) are now commonly used in the management of bipolar I disorder. They have also been used to treat agitation in patients with dementia, depression, and borderline personality disorder. In adults, serum concentrations above 45–50 µg/mL are described as the most effective in managing bipolar I disorder. Serum concentrations above 125 µg/mL are associated with a greater frequency of adverse effects, including thrombocytopenia. Acutely manic patients appear to have the greatest therapeutic response and the fewest adverse effects with valproic acid blood concentrations between about 45 and 100 µg/mL (although therapeutic concentrations up to 125 µg/mL are described). Caution should be exercised when using valproic acid and divalproex sodium in patients with liver disease. These medications are typically discontinued when liver enzyme elevations exceed three times the upper limit of normal. Serious adverse reactions that have been reported during valproic acid therapy include hepatitis, liver failure, hematological abnormalities (e.g., decreased platelets, bone marrow suppression) and acute hemorrhagic pancreatitis. Finally, these agents should not be used during the first trimester of pregnancy because of their association with birth defects. During the first 2 months, serum valproic acid levels can be obtained as often as every 2 weeks; CBC and LFTs should be obtained monthly. During long-term use, serum valproic acid levels can be obtained every 3 to 6 months, and CBC and LFTs every 6 to 12 months. Any changes in valproic acid or divalproex dosing would necessitate more frequent monitoring of blood levels. Carbamazepine Carbamazepine has been used as the sole or adjunctive medication in various psychiatric disorders, especially bipolar I disorder. When utilized for the treatment of psychiatric disorders, therapeutic blood levels for carbamazepine have not been clearly established. However, many clinicians aim for carbamazepine blood concentrations between 4 to 15 µg/mL (the blood concentrations with established therapeutic efficacy in the treatment of seizures). Carbamazepine has been associated with aplastic anemia in up to 1 in 10,000 patients treated with the agent, although more recent research has revised the occurrence of severe hematological adverse effects to about 1 in 125,000. However, decreases in the WBC count are common in patients taking this medication. In addition, a benign drop in the red blood cell count may occur within the first week of treatment, which reverts to normal without the drug having to be discontinued. Recommendations for the discontinuation of carbamazepine treatment have included WBC counts less than 3000 per mm 3, erythrocyte counts less than 4.0 × 10 6/mm3, hemoglobin less than 11 mg/dL, platelet counts less than 100,000 per mm 3, or reticulocyte counts less than 0.3 percent. A conservative plan for the laboratory monitoring of patients taking carbamazepine is provided in Table 7.7-7.

Table 7.7-7 Laboratory Monitoring of Patients Taking Carbamazepine

Other less stringent recommendations for laboratory follow-up have suggested that during the first 2 months of carbamazepine treatment, serum carbamazepine concentrations be obtained every 1 to 2 weeks, and a CBC and LFTs be obtained monthly. Clinicians should be aware that carbamazepine induces liver enzymes that increase its own metabolism and lower blood concentrations during the initial 2 to 3 weeks of its use. Hence, some clinicians recommend more careful monitoring of carbamazepine blood levels during the first month of treatment. During long-term treatment, serum concentrations can be obtained every 3 to 6 months, and CBC and LFTs every 6 months. Carbamazepine can also have effects similar to the tricyclic antidepressant drugs on the ECG. Like valproic acid and divalproex sodium, carbamazepine is potentially teratogenic; hence, pretreatment pregnancy testing is advised in women of childbearing potential. Carbamazepine has also been reported to reduce haloperidol blood levels with clinical deterioration of the patient. Concurrent use of carbamazepine and clozapine has been associated with reductions in plasma clozapine concentrations approaching 50 percent. Finally, carbamazepine has also been associated with lowering serum sodium concentrations, potentially progressing to hyponatremia and even water intoxication (syndrome of inappropriate antidiuretic hormone secretion). Hence, some clinicians recommend a baseline serum sodium determination in patients who are going to be started on carbamazepine, as well as periodic follow-up determinations.

BRAIN IMAGING Computed Tomography CT is used by neuropsychiatrists to exclude the presence of brain lesions in their patients. There is no evidence in support of making functional psychiatric diagnoses based on CT findings. There has been some controversy in the medical literature regarding the use of this diagnostic procedure as a screening tool. Most physicians would agree that psychiatric patients with focal neurological findings, a past history suggestive of brain insult (e.g., a history of head trauma or seizures), an abnormal EEG, or delirium should be seriously considered for a CT scan of the head. Others have proposed that CT scans should be obtained in psychiatric patients who evidence either confusion, dementia, delirium, movement disorder, anorexia nervosa, prolonged catatonia, or who are psychotic for the first time. Some also recommend a CT scan in patients over the age of 50 who show a personality change or who are having their first episode of mood disorder. A normal CT scan result oes not entirely rule out the possibility of organic brain syndrome or insult. Magnetic Resonance Imaging MRI visualizes brain structures with remarkable clarity and offers better resolution of brain structure than CT. The indications for using MRI in a psychiatric patient are similar to those for CT scans. MRI is perhaps superior to CT scans when the suspected CNS disease process includes white matter demyelinating disease, nonmeningeal neoplasm, vascular malformation, degenerative disease such as Huntington's disease, and when a seizure focus is suspected. The MRI technique is also useful in patients unable to tolerate iodine-based contrast materials or intravenous procedures that might be needed during a CT scan evaluation. Additionally, the MRI can be used to clarify ambiguous CT scan findings. The MRI technique is typically contraindicated in patients with pacemakers, aneurysm clips, pregnant women, and patients with potentially magnetic foreign bodies. Additionally, the CT scan is often recommended over MRI when the disease process suspected involves the pituitary gland, calcified brain lesions, meningeal tumors, and acute parenchymal infarction or hemorrhage. The clinician should be aware that a variety of anxiety reactions can occur during MRI scanning, requiring that some patients be carefully screened prior to scanning in the more claustrophobic MRI scanners and prepared for the experience (perhaps with friends and family on hand, with prescanning behavioral desensitization, or premedication with a short-acting antianxiety agent).

ELECTROPHYSIOLOGY Electroencephalogram In patients with a possible organic CNS component to their psychiatric disturbance, an EEG can be useful. The clinician should realize that a single normal EEG result does not rule out organic pathology. Diffuse slowing is perhaps the most common EEG abnormality in psychiatric patients, constituting about 40 percent of abnormal EEGs in psychiatric populations. EEG slowing in psychiatric patients has been associated with diminished cognitive functioning, being on a larger number and higher doses of medications, increased length of hospital stay, and greater illness severity. If a seizure disorder is strongly suspected, “sampling errors” can be corrected by repeat EEGs or 24-hour ambulatory recording (often accompanied by video recordings of the patient's behavior to further document potential seizure activity). Sleep-deprived EEG recordings further increase the likelihood of unmasking latent abnormal EEG activity. Some clinicians use nasopharyngeal (NP) leads to increase the diagnostic yield. However, NP leads can be quite uncomfortable for patients and can keep them from falling asleep during EEG recording. The failure to sleep during the EEG recording can significantly diminish the usefulness of the EEG as a diagnostic tool because it is during sleep that latent abnormal EEG activity is often best detected. Clinicians should also remember that a seizure diagnosis is typically made on clinical grounds and is not entirely dependent on abnormal EEG findings. Finally, EEG monitoring is also used by some clinicians and researchers during the administration of electroconvulsive therapy (ECT). Such EEG monitoring assures the clinician that a fully therapeutic seizure has been induced. Polysomnography This procedure is used in the evaluation of various sleep disorders (e.g., insomnia, sleep apnea, parasomnias, narcolepsy, male erectile disorder). Polysomnography involves the assessment of multiple physiological parameters while the patient sleeps (or attempts to sleep); the parameters include EEG, electro-oculogram (EOG), electromyogram (EMG), ECG, blood oxygen saturation, blood pressure, respiratory effort, and body temperature. A special daytime polysomnographic evaluation called the multiple sleep latency test is used in the evaluation of narcolepsy. Evoked Potentials Evoked potentials refer to brain electrical activity elicited by stimuli. Exogenous, or sensory, evoked potentials (visual, auditory, and somatosensory) have great utility in detecting peripheral and central neural conduction abnormalities. Evoked potential testing can be used in the differentiation of certain organic versus functional complaints (e.g., the visual evoked potential [VEP] can be used to evaluate hystorical blindness). Other forms of evoked potential studies include the brainstem auditory evoked potential (BAEP). When neuropsychiatric symptoms of unclear etiology are present, certain evoked potential findings can be useful for detecting possible underlying neurological dysfunction (e.g., evoked potential testing might suggest an underlying demyelinating condition such as multiple sclerosis as a cause of what was previously regarded as “functional” symptoms). Genetic Testing Clinical chromosome analysis usually takes place in the context of a prenatal analysis of genetic disorders. Possible clinical indications for ordering a cytogenetic analysis in a psychiatric patient who is not in a gynecologic or obstetric setting might include the psychiatric patient with congenital anomalies or nonspecific mental retardation. If a patient has cytogenetic analysis performed for some reason (e.g., as part of the workup of infertility, habitual abortion, amenorrhea, or ambiguous external genitalia), careful attention needs to be paid to the potential adverse psychological impact of the result on the patient and family.

AMOBARBITAL INTERVIEW The amobarbital interview involves the slow intravenous infusion of sodium amytal, with careful attention to avoid oversedation and respiratory depression. Reports exist describing the amobarbital interview as a useful aide in differentiating certain functional versus organic conditions. For instance, in certain stuporous patients with schizophrenia or major depressive disorder, amobarbital has been described as making the patient more verbal and less guarded. Patients whose stuporous state is secondary to a neuromedical condition (e.g., brain tumor, stroke) typically become more confused, with clear deterioration on cognitive examination. An alternative medication that has been proposed as perhaps better than amobarbital for drug-assisted interviewing is the high-potency benzodiazepine midazolam (Versed); for safety, pulse oximetry has been used in conjunction with midazolam administration.

NEW CLINICAL AND RESEARCH TOOLS Biological Markers There has been a great deal of interest in finding neurophysiological markers of psychiatric disorders. Such biological markers would not only reveal underlying pathophysiologies for psychiatric disorders, but they could also serve as diagnostic tests. Biological markers could assist in: (1) making accurate psychiatric diagnoses, (2) identifying patients at risk of developing a psychiatric disorder (e.g., so preventive steps could be implemented), and (3) predicting treatment response. Biological markers currently being investigated encompass a wide range of procedures, some of which are listed in Table 7.7-8. Difficulties that have arisen for many of the proposed markers include problems with sensitivity, specificity, reliability, and contamination from artifactual influences (e.g., concurrent medical illnesses, medication effects, and normal individual variation). None of these markers have clearly established themselves as useful for routine clinical practice. More precise biological markers for idiopathic psychiatric conditions of greater clinical and research utility will be most forthcoming when the underlying pathophysiologies of these conditions are determined. Because the etiologies and genetic contributions of psychiatric disorder largely remain unknown, biological marker research in psychiatry often takes on the character of a fishing expedition with better fishing spots suggested by earlier encouraging findings or intriguing hypotheses.

Table 7.7-8 Some Biologic Markers Under Investigation

Brain Imaging Techniques An exciting area of biological marker research involves several brain imaging techniques that have become available to neuropsychiatrists and it is understandable that tests that directly measure and image brain structure and function are of interest in psychiatry. Electroencephalography Computerized topographic mapping of electrophysiological data represents an enhancement of conventional EEG and evoked potential (EP) testing. In this brain-imaging tool, a computer is used to amass and process large quantities of EEG and EP data from a patient. The computers analyze the data in various ways and graphically present the data as two-dimensional, typically color-coded maps of brain electrical activity. The newer technology of computerized topographic mapping of EEG and EP data has not found a clear niche in the diagnostic assessment of the psychiatric patient. There has also been the hope that the computerized EEG would help in the development of the EEG as a functional measure of the therapeutic activity of various psychiatric drugs. Recent EEG work in patients with schizophrenia treated with clozapine has suggested that clozapine “responders” demonstrate increased EEG photic driving compared to nonresponders. The increase in photic driving was positively correlated with clinical improvement. Indeed, patients with schizophrenia who develop abnormal EEGs while on clozapine tend to evidence a better clozapine response compared to those patients whose EEGs are unaffected by clozapine. Even when not taking any psychiatric medications, patients with schizophrenia tend to display EEG changes compared to normals, such as lower alpha frequencies (which have been shown to correlate negatively with total positive symptom scores in these patients). Sleep EEG (Polysomnography) A potentially powerful biological marker of psychiatric illness uses EEG obtained during sleep. Sleep EEG abnormalities described in major depressive disorder include an increase in the overall amount of rapid-eye movement (REM) sleep and a shortened period before the onset of REM sleep (shortened REM latency). Neuromedical conditions giving rise to psuedodepressive presentations are typically associated with decreased REM sleep (e.g., patients with dementia usually have increased amounts of non-REM sleep). In schizophrenia, decreased slow-wave sleep and increased sleep latency and fragmentation have been reported, especially during relapse. Computerized analyses of the sleep EEG, with the generation of topographic maps of sleep EEG activity, are also available. Computed Tomography Researchers continue to study possible useful subcategories of psychiatric diagnoses that could be based on CT findings (e.g., schizophrenia with or without ventricular enlargement). For instance, there has been the suggestion that certain patients with schizophrenia who have enlarged ventricles might be more resistant to treatment with antipsychotic agents. For instance, increased prefrontal cortical sulcal widening has been associated with a poor response to clozapine. In patients with chronic alcohol dependence, a relationship between severity of frontal atrophy and negative symptoms (as measured with the Scale for the Assessment of Negative Symptoms) has been reported, although the ability of such atrophy to predict future abstinence and treatment response has not been examined. However, there is currently no evidence that supports making functional psychiatric diagnoses based on CT scan abnormalities. Magnetic Resonance Imaging Various neuropsychiatric studies using the MRI technique have yielded some interesting findings. Patients with schizophrenia have been reported to have smaller frontal lobes, cerebrums, craniums, and hippocampi (but larger lenticular nuclei and thalami) than normal controls. Differences in the symmetries of various brain structures have also been noted when subjects with schizophrenia and normal control subjects are compared. In elderly depressed patients, MRI signal hyperintensities in subcortical gray matter have been reported to be more common than in nondepressed comparison subjects. The full utility of MRI in neuropsychiatry, with its many different scanning modes, has not yet been completely explored. Functional MRI Although traditional MRI provides anatomical images of the brain, the functional MRI (fMRI) technique might ultimately provide the researcher and clinician images of brain activity that rival the clarity of MRI anatomical images. fMRI can be directly correlated with high-resolution, three-dimensional anatomical MRI images. In a recent fMRI study it was reported that patients with schizophrenia demonstrated less frontal lobe activation and greater temporal lobe activation on the left during a word fluency task compared to comparison subjects. The utility of this technique for informing researchers about brain functioning in psychiatric illnesses is in its infancy, but it is expected that there will be many indications for this procedure in the future. Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy (MRS) is related to MRI but uses more powerful magnetic fields to evaluate certain aspects of brain function and metabolism. Information about brain phospholipid, carbohydrate, protein, amino acid, and high-energy phosphate metabolism, brain intracellular pH, as well as information about lithium and fluorinated psychopharmacological agents, can be obtained by this technique. For instance, using phosphorus-31 nuclear magnetic resonance ( 31P NMR) spectroscopy, metabolism of brain high-energy phosphate and membrane phospholipids was studied in the dorsal prefrontal cortex of drug-naive patients with schizophrenia. Significant differences were found between the patients and controls, with dorsal prefrontal cortex hypoactivity in patients suggested by decreased adenosine triphosphate and inorganic orthophosphate levels. Alterations in membrane phospholipid metabolism were suggested by lower levels of phosphomonoesters and higher levels of phosphodiesters compared to the control subjects. Technological improvements in MRS should further the contributions of this functional brain-imaging technique to neuropsychiatric research. Positron Emission Tomography PET allows for the direct visualization of cortical and subcortical brain functioning. Depending on the type of positron-emitting isotope used, different aspects of brain functioning can be studied, including brain glucose metabolism, cerebral blood flow, brain oxygen use, and binding parameters of specific neurotransmitter receptors. PET findings include abnormalities of the anteroposterior gradient of glucose utilization and higher subcortical-to-cortical glucose metabolism ratios in patients with schizophrenia compared to normal controls. PET findings in schizophrenia, as well as in other psychiatric disorders such as bipolar I disorder, substance use disorders, obsessive-compulsive disorders, and panic disorders, have not always been replicated by other investigators. PET remains a research tool available at only a few research centers. Single Photon Emission Computerized Tomography Like PET, SPECT visualizes both cortical and subcortical brain activity. Because of certain technical differences, the image resolution is typically not as good with SPECT as compared to state-of-the-art PET scanners. Depending on the radioisotope employed, different aspects of brain function can be studied, such as brain blood flow. SPECT may also be utilized to image the distribution of neurotransmitter receptors in vivo. SPECT scanning defects have been described in a wide variety of neuropsychiatric conditions. For instance, one study reported an average of 7.3 SPECT defects in patients with chronic fatigue syndrome versus a mean of 0.4 defects in controls. Additionally, SPECT changes were reported to correlate with changes in clinical status. Another study reported a similar number of SPECT scan defects in a group of patients with chronic fatigue syndrome and a group of patients with major depressive disorder (6.5 defects per patients versus 1.7 in healthy controls). Magnetoencephalography Conventional and computerized EEG gather data based on measurements made of cortical brain activity. Magnetoencephalography (MEG) detects the magnetic fields associated with neuronal electrical activity in both cortical as well as deeper brain tissues. MEG is noninvasive and does not expose the patient to harmful radiation; MEG is available in only a few research centers. Regional Cerebral Blood Flow Regional cerebral blood flow (rCBF) is a nuclear medicine technique involving the introduction of metabolically inert radioactive substances into the body. These substances arrive at the brain via the blood, and radiation emanating from the brain is picked up by detectors surrounding the skull. rCBF can delineate blood flow in cortical structures. Using rCBF, there have been reports of decreased blood flow to certain frontal regions of the brain in patients with schizophrenia as well as in patients with other neuropsychiatric disorders. Other Neurophysiological Markers

Eye Movement Deficits (EMD) A deficit in smooth pursuit eye movement (SPEM) performance has been described in up to 85 percent of patients with schizophrenia (versus approximately 10 percent in control populations). The SPEM deficit has been proposed to be a biological marker of schizophrenia. Another EMD involves an antisaccade deficit, which has been described in a number of neuropsychiatric conditions, including in patients with frontal cortical and basal ganglia lesions, schizophrenia, and obsessive-compulsive disorder. The antisaccade performance deficit includes a decreased ability to inhibit reflexive glances toward stimuli that subjects are instructed to look away from. Schizophrenia patients with greater smooth pursuit deficit tend to show more antisaccade performance deficits. EMDs can be measured using a number of different techniques, including electrooculography (EOG) and infrared scleral reflectance techniques. Electroretinogram The electroretinogram (ERG) measures electrical changes produced in the retina by flashes of light. ERG amplitudes are reduced in certain diseases (e.g., retinitis pigmentosa and myotonic dystrophy), and also during the prodromes for these disorders. Decreased ERG amplitude has been reported in cases of thioridazine toxicity. In neuropsychiatric conditions, ERG amplitude reductions (specifically beta-wave amplitude) have been described in some patients with autistic disorder and those with various types of dementia, such as dementia of the Alzheimer's type and Creutzfeldt-Jakob disease. Pupillometry It has been reported that persons with dementia of the Alzheimer's type have an exaggerated pupil dilation response to the ophthalmic administration of the anticholinergic medication tropicamide (Mydriacyl) compared to persons without the disease. The pupil dilation response of individuals with forms of dementia other than of the Alzheimer's type was reported as similar to that of the healthy controls, suggesting that this pupillary marker might be more specific for Alzheimer's disease than for other forms of dementia. The pupil dilation response was also reported as more sensitive for the presence of premorbid and morbid Alzheimer's disease than conventional neuropsychological testing. However, these findings based on pupil size measures have recently been challenged. One recent report suggests that increases in pupillary oscillation might accompany prodromal mania, supporting other suggestions that pupillometry might be useful for clinical psychophysiological diagnosis and management of psychiatric patients. Quantitative Measures of Visual Scanning Such quantitative visual scanning procedures are performed on data obtained while patients view various visual stimuli. One method of quantitative visual scanning assessment is based on eye movement research suggesting that it takes at least approximately 40 to 50 milliseconds (ms) to fully scrutinize and cognitively process a single image element. Hence, visual fixations of shorter duration are thought to subserve more automatic or preattentive cognitive processes. In schizophrenia, such quantitative assessments of eye movements while patients viewed slides of faces were reported to correlate with symptom severity. In cocaine addicts, quantitative visual scanning measures while viewing cocaine cues have been shown to correlate with measures of cocaine craving. Endocrine Stimulation Techniques Dexamethasone Suppression Test (DST) There was the hope that this laboratory test would prove useful for the diagnosis and management of psychiatric patients. While a version of this test is used routinely by endocrinologists in the evaluation of Cushing's disease, the test was found by research psychiatrists to be a possible marker of major depressive disorder. There was initial enthusiasm that the test would be useful in assisting with psychiatric differential diagnosis (e.g., differentiating dementia from the pseudo-dementia of depression; differentiating schizoaffective disorder from schizophrenia) and in the prediction of treatment response and suicidal risk. Although many of the research findings have proved interesting, it has been argued that overall they do not support the routine clinical use of this test. However, although pretreatment baseline DST results are of questionable value, many agree that posttreatment DST cortisol nonsuppression predicts a poor outcome in depressive disorders, with a higher risk of early relapse. A common version of the DST as employed by psychiatrists involves the administration of a 1-mg dose of dexamethasone (Decadron) at 11 PM with a serum cortisol concentration determination prior to dexamethasone administration (to assess baseline cortisol concentrations) and other serum cortisol determinations at various points over the next 24 hours (typically 8 AM, 4 PM, and 11 PM). The DST result is considered abnormal if the postdexamethasone serum cortisol concentration exceeds about 5 µg/dL. However, the reliability of many commercial assays at about the 5 µg/dL cut-off value is questionable; hence, there is a recommendation that plasma cortisol concentrations between 4 and 7 µg/dL be interpreted cautiously. Additionally, many other limitations to the routine use of the DST have emerged, including significant potential artifactual contamination from concomitant medical conditions (e.g., diabetes mellitus), medications (e.g., carbamazepine) and the potential that the test results will direct the clinician's attention away from other more important clinical issues for the patient. If the DST is used, the psychiatrist should be attentive to the possible causes of false-positive or false-negative DST results outlined in Table 7.7-9.

Table 7.7-9 Causes of False-Positive or Negative Results on the Dexamethasone-Suppression Test (DST)

Thyrotropin-Releasing Hormone Stimulation Test Endocrinologists use a version of this test in the evaluation of hypothyroidism. The hypothyroid patient has an augmented TSH response to an intravenous (IV) injection of thyrotropin (Thytropar). The test has also been proposed as useful in grading different forms of hypothyroidism. In Grade 1 hypothyroidism the diagnosis is obvious based on clinical and biochemical grounds (e.g., elevated serum TSH and low serum T 4). Grade 2 hypothyroidism is less obvious and without clear clinical features of hypothyroidism (except perhaps depression), but serum TSH is elevated. Grade 3 hypothyroidism is characterized by normal baseline TSH and thyroid hormone values, but the results of the TRHST are abnormal. It has been argued that Grade 3 hypothyroidism can also present with or accompany depression in some patients, and would be missed if only the conventional serum thyroid hormone assays are used (i.e., serum TSH and T4). Furthermore (and perhaps confusingly so) a blunted TRHST result (i.e., a result more common to hyperthyroidism) has been proposed as a biological marker of major depressive disorder with diagnostic and prognostic meaning. Although a blunted TRHST result has been reported in up to 30 percent of depressed patients, the result does not appear specific to major depressive disorder (e.g., blunted results have been reported in patients with other affective spectrum disorders such as alcoholism, panic disorder, bulimia nervosa, and borderline personality disorder). Provocative Tests of Panic Disorder These tests challenge patients with various agents such as carbon dioxide (via inhalation), lactate (via IV infusions) or IV infusions of such substances as caffeine, isoproterenol (Isuprel) b-carboline and flumazenil (Romazicon)—all of which have been noted to be capable of inducing panic attacks in patients so predisposed (and less so in individuals without a history of panic disorder). Lactate infusion is the most extensively studied provocative test for panic disorder, and up to 72 percent of panic disorder patients have been reported as experiencing a panic attack after the IV infusion of sodium lactate. Anxiogenic responses to lactate or fenfluramine provocation have been described as greater in patients with higher panic attack frequencies. In patients with posttraumatic stress disorder, IV infusions of lactate have been demonstrated as capable of triggering flashbacks of the traumatic event, with at times dramatic affective displays in response to the flashback. Panic attacks precipitated by IV lactate infusion have been shown to be inhibited by tricyclic antidepressant medication and alprazolam (Xanax), which are psychotherapeutic agents of demonstrated efficacy in the treatment of panic disorder. Responses to challenge tests for anxiety disorders might lead to useful subtyping paradigms for these disorders. The specificity of lactate infusions for panic disorder is unclear, as patients with primary depressive disorder with secondary panic attacks have similar rates of lactate-induced panic attacks as those patients with primary panic disorder. Simple hyperventilation procedures have also been reported as capable of precipitating panic attacks in patients so predisposed, although hyperventilation appears to be a less potent stimulus of panic attacks than IV infusions of lactate. The clinician should note that hyperventilation procedures should be used with caution because of their ability to trigger seizures. At this time, these provocative tests are more useful as research tools to study various paroxysmal anxiety disorders than they are as diagnostic tests.

Biochemical Markers From blood, CSF, and urine, the clinician and researcher can obtain many potential biochemical markers, including neurotransmitter substances and their metabolites (e.g., dopamine, homovanillic acid [HVA], norepinephrine, its metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and amino acids such as tryptophan, tyrosine, glycine, and glutamate). Studies involving most of these markers and many other proposed markers have yielded mixed results. What follows are some interesting recent highlights regarding this area of research. Plasma Homovanillic Acid The measurement of homovanillic acid in plasma (pHVA), a major acidic metabolite of dopamine, may reflect changes in the activity of dopamine in the brain. The measurement of pHVA may have a practical clinical application in the identification of schizophrenia patients responsive to antipsychotic medications. For instance, some reports suggest that responders to these drugs are characterized by antipsychotic-induced reductions in pHVA. The time-dependent decreases in pHVA in treatment responders further suggest that the ability to dampen presynaptic dopaminergic activity is related to the therapeutic efficacy of antipsychotic medications. 3-Methoxy-4-Hydroxyphenylglycol When measured in 24-hour urine collections, MHPG has been reported to be lower in patients with bipolar I disorder than in patients with bipolar II disorder. Low urine MHPG might predict imipramine (Iofranil) response in depressed patients with bipolar disorder but not in depressive disorder (unipolar) patients. High urinary MHPG concentrations have also been associated with a subtype of depressed patients more likely to show cognitive features of learned helplessness. Low CSF MHPG (along with decreased 24-hour urinary norepinephrine-epinephrine ratios) has been proposed as a measure of a decreased noradrenergic activity that could suggest an increased predisposition to suicidal behavior. 5-Hydroxyindoleacetic Acid Associations have been reported between low CSF 5-HIAA and suicidal behavior, aggression, poor impulse control and impulsive suicidal acts, disturbed behavior in childhood, violent suicide attempts, and depression in patients with diagnoses including major depressive disorder, schizophrenia, alcohol use disorders, and adjustment disorder. Hence, although this marker might not have nosological specificity, it might mark problematic behaviors across a wide variety of psychiatric diagnoses. There have also been reports of an association between elevated CSF 5-HIAA concentrations and anxious, obsessional, or inhibited behaviors. Markers of Alzheimer's Disease SPECT and PET are emerging as useful tools in the detection and evaluation of patients with dementia of the Alzheimer's type. When SPECT and PET are used, these patients typically show decreased perfusion in temporoparietal areas bilaterally, while patients with ischemic brain changes (vascular dementia) more often demonstrate single focal perfusion defects or multiple areas of patchy hypoperfusion. The presence of an ApoE allele has also been associated with an increased risk of Alzheimer's disease. Individuals with two copies of the ApoE-e4 allele appear to have an especially increased risk. By late middle age, persons who are cognitively normal but who are homozygous for the e4 allele for ApoE have been reported to show evidence of reduced glucose metabolism on PET in the regions of the brain as do patients with dementia of the Alzheimer's type. These findings have been interpreted as being supportive of the notion that ApoE-e4 is a risk factor for this disorder. A variety of other biological markers of Alzheimer's disease are currently under examination. One test for neural thread protein (NTP) from CSF is now being marketed for assisting in the diagnosis of these patients. The test measures the brain protein 21 kD NTP that is reported to be increased in patients with dementia of the Alzheimer's type as compared to normal controls. Other potential CSF tests for this disorder include measurement of CSF-tau (increased) and CSF-amyloid (decreased). One proposed biochemical marker of blood-brain barrier damage in dementia caused by cerebrovascular pathology is the CSF albumin-to-serum albumin ratio. The CSF albumin-to-serum albumin ratio is normal in patients with dementia of the Alzheimer's type but elevated in vascular dementia. The hope is that all these emerging diagnostic tests will be able to diagnose the disease early in its course. Clinicians would then be able to start drug treatments early, when such interventions would have the greatest potential of being effective. Persons with vascular dementias can be identified by CT, MRI, SPECT, or PET scan. Inflammatory mechanisms have been implicated in the pathogenesis of dementia of the Alzheimer's type, and certain biochemical and genetic markers of inflammation may serve as diagnostic aids in the identification of persons affected with the disease or at risk of developing it. For instance, there have been reports of elevations of acute-phase reactive proteins in sera and CSF (e.g., a 1-antichymotrypsin) of patients and unaffected first-degree relatives of patients with this disorder. These markers of inflammation may become targets for novel pharmacotherapy and laboratory indices to monitor therapeutic response to treatment with anti-inflammatory medications. Additionally, knowledge of the normal handling of proteolytic products of amyloid precursor protein (APP) and factors mediating inflammation in brain of these patients may help to identify targets for novel pharmacotherapy and genetic markers of the disease. For instance, measurements of (1) apolipoprotein J and allelic variants (apolipoprotein J has been shown to be the predominant binding protein for the b-amyloid split product in CSF), (2) complexes of apoJ with soluble b-amyloid and soluble complement membrane-attack complex (MAC), and (3) low-density lipoprotein receptor (LRP-2) and allelic variants, may serve as potential risk markers for Alzheimer's disease. Genetic Testing In theory, markers for the defective genes in the heritable neuropsychiatric disorders ultimately will be identified; these markers should prove to be powerful diagnostic tests for these diseases. At this time no functional (idiopathic) psychiatric disorder has been associated clearly with a specific chromosome or gene location. Using new molecular biology techniques, studies are beginning to suggest chromosomal loci for a host of neuropsychiatric problems. For instance, independent groups have provided evidence for a vulnerability locus for schizophrenia and associated disorders on chromosome 8p. This vulnerability locus on 8p was likely to segregate in about 10 to 25 percent of the multiplex families studied. Data from this series have also shown potential linkage between schizophrenia and a vulnerability locus on chromosome 6p in about 10 to 30 percent of the multiplex families. Thus, there is an interesting possibility that epistasis or gene-gene interaction can take place between the 8p and 6p regions in at least some patients. Another interesting allelic marker whose absence in patients and mothers of offspring with schizophrenia may be associated with schizophrenia is the locus (DRB1*04) encoding the class II human leukocyte antigen (HLA) DR4 on chromosome 6p. There have also been reports of an association between schizophrenia and the absence of DQB1*0602, another class II HLA gene, in African-Americans and Chinese men from Singapore. Evidence has been collected suggestive of a susceptibility gene for bipolar I disorder in the pericentrometric region of chromosome 18. Candidate genes in this region that may have some etiological or pathological association with bipolar I disorder include Golf, the a subunit of a heterotrimeric GTP-binding protein, and a corticotropin receptor gene. The lithium ion influences the affinity of the a subunit for GTP, antidepressant medications modulate expression of GTP-binding proteins, and the function of the hypothalamic-pituitary-adrenal axis is altered in mood disorders. In Alzheimer's disease, genetic defects on chromosomes 21, 14, and 19 have been implicated. The presence of an ApoE allele has also been associated with an increased risk of the disease, but the presence of the allele is not considered diagnostic. ApoE maps to a region on chromosome 19 that has been implicated in linkage studies of the disease. Recent evidence suggests that genetic screening of mutant presenilin alleles (presenilin genes located on chromosomes 14 and 1 have been designated as PS1 and PS2, respectively) might also lead to possible diagnostic genetic tests of persons at risk. Ultimately, batteries of tests might be needed to fully determine the at-risk profile of an individual for a particular neuropsychiatric disease. The further extension of genotypic analyses, including restriction fragmentation length polymorphism, polymerase chain reaction amplification, and sequence-specific oligonucleotide probe analysis, and specialized statistical procedures to assess linkage to complex traits will undoubtedly result in the identification of genetic risk factors for neuropsychiatric illnesses such as schizophrenia, bipolar I disorder, and dementia of the Alzheimer's type. The discovery of genetic defects responsible for neuropsychiatric disease, along with the uncovering of their roles in the diseases and biological products, will revolutionize laboratory testing of these conditions. At this time these genetic procedures and markers remain only research tools. However, there is a substantial effort to identify genes responsible for specific diseases sponsored by the federal government's human genome project, which involves the mapping of the entire human genome (composed of over 100,000 genes, of which approximately 80,000 are represented in the brain). The mapping of the human genome should enhance the clinician's ability to diagnose neuropsychiatric disease and will result in new conceptualizations of psychiatric disorders. It is hoped that this project will lead to better preventive and therapeutic measures for these disorders. Nevertheless, a host of clinical and ethical issues pertaining to the interpretation of these genetic risk factors and the counseling of patients and families will be raised by this promising area of research.

SUGGESTED CROSS-REFERENCES Assessment is also discussed in Section 2.1, the other sections of Chapter 7, Chapter 32, Chapter 33, Chapter 34, Chapter 35, Chapter 36, Chapter 37, Chapter 38, Chapter 39, Chapter 40, Chapter 41, Chapter 42, Chapter 43, Chapter 44, Chapter 45, Chapter 46, Chapter 47, Chapter 48 and Chapter 49 on child psychiatry, and

Chapter 51 on geriatric psychiatry. Neuroimaging is discussed in Section 1.15 and Section 1.16. Substance-related disorders are discussed in Chapter 11, schizophrenia in Chapter 12, mood disorders in Chapter 14, and anxiety disorders in Chapter 15. Endocrine and metabolic disorders are discussed in Section 25.6; dementia of the Alzheimer's type is discussed in Chapter 10. SECTION REFERENCES Ananth J, Gamal R, Miller M, Wohl M, Vandewater S: Is the routine CT head scan justified in psychiatric patients? A prospective study. J Psychiatry Neurosci 18:69, 1993. *Anfinson TJ, Kathol RG: Screening laboratory evaluation in psychiatric patients: A review. Gen Hospital Psychiatry 14:248, 1992. Bonne O, Krausz Y, Lerer B: SPECT imaging in psychiatry: A review. 14:296, 1992. Bouman WP, Pinner G, Johnson H: Incidence of selective serotonin reuptake inhibitor (SSRI) induced hyponatraemia due to the syndrome of inappropriate antidiuretic hormone (SIADH) secretion in the elderly. Int J Geriatr Psychiatry 13:12, 1998. Boutros NN: Diffuse electroencephalogram slowing in psychiatric patients: A preliminary report. J Psychiatry Neurosci 21:259, 1996. Bowden CL, Janicak PG, Orsulak P, Swann AC, Davis JM, Calabrese JR, Goodnick P, Small JG, Rush AJ, Kimmel SE, Risch SC, Morris DD: Relation of serum valproate concentration to response in mania. Am J Psychiatry 153:765, 1996. Burke MJ, Preskorn SH: Short-term treatment of mood disorders with standard antidepressants. In Psychopharmacology: The Fourth Generation of Progress, Bloom FE, Kupfer DJ, editors. Raven Press, New York, 1995. Denburg SD, Carbotte RM, Ginsberg JS, Denburg JA: The relationship of antiphospholipid antibodies to cognitive function in patients with systemic lupus erythematosus. J Int Neuropsychol Soc 3:377, 1997. *D'Ercole A, Skodol AE, Struening E, Curtis J, Millman J: Diagnosis of physical illness in psychiatric patients using Axis III and a standardized medical history. Hosp Comm Psychiatry 42:395, 1991. Elia J, Gulotta C, Rose SR, Marin G, Rapoport JL: Thyroid function and attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 33:169, 1994. Expert Consensus Panel for Bipolar Disorder: Treatment of bipolar disorder. J Clin Psychiatry 57:12A, 1996. Expert Consensus Panel for Schizophrenia: Treatment of Schizophrenia. J Clin Psychiatry 57(Suppl):12B, 1996. Freeman DJ, Oyewumi LK: Will routine therapeutic drug monitoring have a place in clozapine therapy? Clin Pharmacokinet 32:93, 1997. Giedd JN, Rapoport JL, Leonard HL, Richter D, Swedo SE: Case study: Acute basal ganglia enlargement and obsessive-compulsive symptoms in an adolescent boy. J Am Acad Child Adolesc Psychiatry 35:913, 1996. Goldenberg DL: Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 7:127, 1995. Greenwald BS, Kramer-Ginsberg E, Krishnan RR, Ashtari M, Aupperle PM, Patel M: MRI signal hyperintensities in geriatric depression. Am J Psychiatry 153:1212, 1996. Grunberger J, Linzmayer L, Grunberger S, Saletu B: Pupillometry in clinical psychophysiological diagnostics: Methodology and proposals for application in psychiatry. Isr J Psychiatry Relat Sci 29:100, 1992. *Hollister LE: Electrocardiographic screening in psychiatric patients. J Clin Psychiatry 56:26, 1995. Keshavan MS, Kapur S, Pettegrew JW: Magnetic resonance spectroscopy in psychiatry: Potential pitfalls and promise. Am J Psychiatry 148:976, 1991. Hughes JR: A review of the usefulness of the standard EEG in psychiatry. Clin Electroencephalogr 27:35, 1996. Kahn EM: Imaging of brain electrophysiologic activity: Applications in psychiatry. Gen Hosp Psychiatry 14:99, 1992. Kronig MH, Munne RA, Szymanski S, Safferman AZ, Pollack S, Cooper T, Kane JM, Lieberman JA: Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 152:179, 1995. Levin JM, Ross MH, Renshaw PF: Clinical applications of functional MRI in neuropsychiatry. J Neuropsychiatry Clin Neurosci 7:511, 1995. Maier M: In vivo magnetic resonance spectroscopy. Applications in psychiatry. Br J Psychiatry 167:299, 1995. Marcum JM: The use of midazolam with pulse oximetry in the drug-assisted interview. J Clin Psychiatry 57:111, 1996. Mookhoek EJ, Sterrenburg VD, Nieuwegiessen IM: Screening for somatic disease in elderly psychiatric patients. Gen Hosp Psychiatry 20:102, 1998. Moseley ME, deCrespigny A, Spielman DM: Magnetic resonance imaging of human brain function. Surg Neurol 45:385, 1996. *National Institutes of Health Consensus Development Panel: Differential diagnosis of dementing disease. Nat Inst Health Consens Dev Conf Consens Statement 6:1, 1987. Nilsson K, Gustafson L, Faldt R, Anderson A, Vaara I, Nilsson R, Alm B, Hultberg B: Plasma methylmalonic acid in relation to serum cobalamin and plasma homocysteine in a psychogeriatric population and the effect of cobalamin treatment. Int J Geriatr Psychiatry 12:67, 1997. Perry JC, Jacobs D: Overview: Clinical applications of the amytal interview in psychiatric emergency settings. Am J Psychiatry 139:552, 1982. Ribeiro SCM, Tandon R, Grunhaus L, Greden JF: The DST as a predictor of outcome in depression: A meta-analysis. Am J Psychiatry 150:1618, 1993. Rosse RB, Giese AA, Deutsch SI, Morihisa JM: A Concise Guide to Laboratory and Diagnostic Testing in Psychiatry. American Psychiatric Press, Washington, DC, 1989. Sachdev P, Mason C, Hadzi-Pavlovic D: Case-control study of neuroleptic malignant syndrome. Am J Psychiatry 154:1156, 1997. Scinto LFM, Daffner KR, Dressler D, Ransil BI, Rentz D, Weintraub S, Mesulam M, Potter H. A potential noninvasive neurobiological test for Alzheimer's disease. Science Siegler EL, Tamres D, Berline JA, Allen-Taylor L, Strom BL, et al: Risk factors for the development of hyponatremia in psychiatric inpatients. Arch Intern Med

266:1051, 1994.

155:953, 1995.

Sloan EP, Fenton GW, Kennedy NS, MacLennan JM: Electroencephalography and single photon emission computed tomography in dementia: A comparative study. Psychol Med 25:631, 1995. Small GW, Rabins PV, Barry PP, Buckholtz NS, DeKosky ST, Ferris SH, Finkel SI, Gwyther LP, Khachaturian ZS, Lebowitz BD, McRae TD, Morris JC, Oakley F, Schneider LS, Streim JE, Sunderland T, Teri LA, Tune LE: Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association of Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA 278:1363, 1997. Swedo SE, Leonard HL, Mittleman BB, et al: Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 154:110, 1997. Tiihonen J, Vartiainen H, Hokola P: Carbamazepine-induced changes in plasma levels of neuroleptics. Pharmacopsychiatry 28:26, 1995. *Wahlsten D: Single-gene influences on brain and behavior. Annu Rev Psychol 50:599, 1999. *Weinberger DR: Brain disease and psychiatric illness: When should a psychiatrist order a CT scan? Am J Psychiatry 141:1521, 1984. Work Group on Bipolar Disorder: Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 151(Suppl):1, 1994. Zametkin AJ, Ernst M, Silver R: Laboratory and diagnostic testing in child and adolescent psychiatry: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 37:464, 1998.

Textbook of Psychiatry

7.8 PSYCHIATRIC RATING SCALES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 7. DIAGNOSIS AND PSYCHIATRY: EXAMINATION OF THE PSYCHIATRIC PATIENT

7.8 PSYCHIATRIC RATING SCALES DEBORAH BLACKER, M.D., SC.D. Potential Benefits and Limitations of Rating Scales in Psychiatry Types of Scales and What They Measure Assessment of Rating Scales Selection of Psychiatric Rating Scales Suggested Cross-References

A variety of questionnaires, interviews, checklists, outcome assessments, and other instruments are available to inform psychiatric practice, research, and administration. These instruments, which are grouped here under the term psychiatric rating scales, are used with increasing frequency in the practice of psychiatry. Psychiatrists must be aware of rating scales for several reasons. Most critically, many such scales are useful in practice for monitoring patients over time or for providing information that is more comprehensive than that generally obtained in a routine clinical interview. In addition, scales are sometimes required administratively to justify the need for services or to assess quality of care. Last, but equally important, these scales are used in the research that informs the practice of psychiatry, so familiarity with them provides a deeper understanding of the results of that research and the degree to which it applies to psychiatric practice.

POTENTIAL BENEFITS AND LIMITATIONS OF RATING SCALES IN PSYCHIATRY Rating scales in psychiatry serve to standardize the information collected across time or observers. This standardization ensures a comprehensive evaluation that may aid treatment planning by establishing a diagnosis, ensuring a thorough description of symptoms, identifying comorbid conditions, and characterizing other factors affecting treatment response. In addition, it can establish a baseline for follow-up of the progress of illness over time or in response to specific interventions. This is particularly useful when several clinicians are involved, for instance in a group practice or clinic setting, or in the conduct of psychiatric research. In addition to standardization, most rating scales also offer the user the results of a formal evaluation of their performance characteristics. This means that the clinician can know to what extent a given scale produces reproducible results ( reliability) and how it compares with more definitive or established ways of measuring the same thing (validity). Rating scales also offer some practical advantages. First, they can save valuable physician time: self-administered rating scales can be administered in the waiting room, or a nurse or technician can administer an interview prior to a session with the physician. In addition, rating scales may make it easier to obtain information about sensitive areas such as cognitive decline or sexual functioning in which direct questioning is sometimes experienced as more intrusive. However rating scales are not a panacea. They can provide erroneous measurements because of difficulties in administration or limitations in the underlying construct. In this respect they do not differ from clinical assessments, but they may appear to provide more definitive information and thus give a spurious sense of security. At the practical level, they take time that might better be devoted to other pursuits. The critical decision about using a formal assessment tool in clinical practice is whether on balance it contributes useful information in an efficient manner. This decision depends on the specific clinical setting and goal, the practical attributes of the scale, and its psychometric properties.

TYPES OF SCALES AND WHAT THEY MEASURE Scales are used in psychiatric research and practice to achieve a variety of goals. They also cover a broad range of areas and use a broad range of procedures and formats. Measurement Goals Most psychiatric rating scales in common use fall into one or more of the following categories: making a diagnosis (e.g., the Structured Clinical Interview for DSM-IV [SCID] or the Diagnostic Interview Schedule for Children [DISC]); measuring severity and tracking change in specific disorders (e.g., the Hamilton Rating Scale for Anxiety [HAM-A] or the Mini-Mental State Examination [MMSE]) or general symptoms (e.g., the Symptom Checklist-90) or in overall outcome (e.g., the Behavior and Symptom Identification Scale [BASIS-32]); screening for conditions that may or may not be present (e.g., the CAGE or the Zung Self-Rating Depression Scale). Constructs Assessed Psychiatric practitioners and investigators assess a broad range of areas, referred to as constructs to underscore the fact that they are not simple, direct observations of nature. These include diagnoses, signs and symptoms, severity, functional impairment, quality of life, and many others. Some of these constructs are fairly complex and are divided into two or more domains (e.g., positive and negative symptoms in schizophrenia, or mood and neurovegetative symptoms in major depression). Many scales yield separate scores, or subscales, for each domain. Especially when these domains are seen as substantially independent, they may be referred to as dimensions (e.g., Axis I and Axis II in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders [DSM-IV], multidimensional personality traits). Categorical Versus Continuous Classification Some constructs are viewed as categorical, or classifying, while others are seen as continuous, or measuring. Categorical constructs describe the presence or absence of a given attribute (e.g., competency to stand trial) or the category best suited to a given individual among a finite set of options (e.g., assigning a diagnosis). Continuous measures provide a quantitative assessment along a continuum of intensity, frequency, or severity. In addition to symptom severity and functional status, multidimensional personality traits, cognitive status, social support, and many other attributes are generally measured categorically. The distinction between categorical and continuous measures is by no means absolute. Ordinal classification, which uses a finite, ordered set of categories (e.g., unaffected, mild, moderate, severe), stands between the two. In addition, a cutpoint is frequently used with a continuous or ordinal scale to indicate a threshold for membership in a corresponding category. For instance, individuals with Mini-mental State Examination scores below 24 may be considered to have a dementia, or those with Hamilton Rating Scale for Depression (HAM-D) scores above 8 may be considered to have an episode of major depression. Measurement Procedures Rating scales differ in measurement methods. Issues to be considered include format, raters, and sources of information. Format Rating scales are available in a variety of formats. Some are simply checklists or guides to observation that help the clinician achieve a standardized rating. Others are self-administered questionnaires or tests. Still others are formal interviews that may be fully structured (i.e., specifying the exact wording of questions to be asked) or partly structured (i.e., providing only some precise wording, along with suggestions for additional questions or probes). Whether fully structured or not, instruments may be written so that all questions are always included, or they may have formal skip-out sections to limit administration time. Individual items also vary in their format. Most commonly, scales use yes-no or multiple choice questions. Often, answers are graded on a Likert scale, an ordinal scale with three to seven points that measures severity, intensity, frequency, or other attributes. Likert scales are most often partially or fully anchored, assigning a meaning to each numeric level. The same anchors can apply to all items or the instrument may provide specific anchors for each. Occasionally, questionnaires include open-ended questions, especially at the beginning, which may be used to help establish rapport. In semistructured or unstructured interviews, this information also serves to guide the rest of the interview and aids in forming a clinical impression about the patient. Raters Some instruments are designed to be administered by doctoral-level clinicians only, while others may be administered by individuals such as psychiatric nurses or social workers with more limited clinical experience. Still other instruments are designed primarily for use by lay raters with little or no experience with psychopathology. In general, more training is required to administer less-structured scales. In addition, some scales require extensive training, even for experienced clinicians, to master the appropriate procedures and achieve a good result. Virtually all scales perform better when raters are familiar with their format and specific content.

Source of Information Instruments also vary in the source of information used to make the ratings. Information may be obtained solely from patients, who generally know the most about their condition. In some instruments, some or all of the information may be obtained from a knowledgeable informant. When the construct involves limited insight (e.g., cognitive disorders or mania) or significant social undesirability (e.g., antisocial personality, substance abuse), other informants may be preferable. Informants may also be helpful when the subject has limited ability to recall or report symptoms (e.g., delirium, dementia, or any disorder in young children). Some rating scales also allow or require inclusion of information from medical records or patient observation.

ASSESSMENT OF RATING SCALES In clinical research, rating scales are mandatory to ensure interpretable and potentially generalizable results and are selected on the basis of coverage of the relevant constructs, expense (based on the raters, purchase price, if any, and necessary training), length and administration time, comprehensibility to the intended audience, and quality of the ratings provided. In clinical practice, one considers these factors and also whether a scale would provide more or better information than would be obtained in ordinary clinical practice or contributes to the efficiency of obtaining that information. In either case, the assessment of quality is based on psychometric, or mind measuring, properties. Psychometric Properties The two principal psychometric properties of a measure are reliability and validity. Although these words are used almost interchangeably in everyday speech, in the context of evaluating rating scales they are distinct. To be useful, scales should be reliable, or consistent and repeatable even if performed by different raters, at different times, or under different conditions, and they should be valid, or accurate in representing the true state of nature. Relation Between Reliability and Validity Establishing a measure's reliability is generally considered primary, since it is difficult to reach valid judgments without first achieving consistency. However, problems with reliability can be overcome to an extent by combining information from several assessments. Unfortunately, improved reliability does not guarantee improved validity, and some efforts to improve reliability may actually limit validity. For example, a personality disorder instrument might focus on overt behaviors rather than inner thoughts and feelings to achieve higher reliability but at the cost of losing some of the most valid information about personality. Even with clinically trained raters, it is particularly difficult to achieve reliability on items requiring subjective clinical judgment (e.g., feelings evoked in the examiner): nonetheless, when used by experienced diagnosticians, such items may contribute substantially to valid diagnoses. Reliability Reliability refers to the consistency or repeatability of ratings and is largely empirical. In the categorical context, it refers to whether agreement can be reached on the classification of each individual. In the continuous context, it refers to whether agreement can be reached on the assignment of a given score. It can also be seen as precision; that is, whether a measure yields a ballpark estimate or a finely graded score. An instrument is more likely to be reliable if the instructions and questions are clearly and simply worded and the format is easy to understand and score. There are three standard ways to assess reliability: internal consistency, interrater, and test-retest. INTERNAL CONSISTENCY Internal consistency assesses agreement among the individual items in a measure. This provides information about reliability because each item is viewed as a single measurement of the underlying construct; thus, the coherence of the items suggests that each of them is measuring the same thing (and hence all of them are). Internal consistency is measured most often with coefficient alpha (also known as Cronbach's alpha), which ranges between 0 and 1; values of .75 or above are considered good. However, the internal consistency of a measure depends on the internal consistency of the construct that the measure purports to assess and is higher for unidimensional constructs than those with two or more relatively independent domains. INTERRATER AND TEST-RETEST RELIABILITY Interrater (also called interjudge, or joint) reliability is a measure of agreement between two or more observers using the same information to evaluate the same subjects. Estimates may vary with assessment conditions; for instance, estimates of interrater reliability based on videotaped interviews tend to be higher than those based on interviews conducted by one of the raters. Interrater reliability tends to be higher than test-retest reliability, a measure of agreement between evaluations at two points in time, in which the information obtained may differ (e.g., be associated with differences in interviewer skill, interviewer mood, room conditions, or subject's attitude). In addition, test-retest evaluations measure reliability only to the extent that the subject's true condition remains stable in the time interval, which is problematic for many conditions but virtually impossible for rapidly fluctuating conditions like state anxiety. However, because the test-retest situation more closely reflects the clinical problems associated with serial evaluations by multiple clinicians, to the extent that concerns about interval change can be eliminated, it is generally a more useful indicator of reliability in practice. Interrater reliability and test-retest reliability of continuous constructs are measured with the intraclass correlation coefficient (ICC), while those of categorical constructs are measured with the kappa coefficient (k). A weighted version of k is available to penalize large disagreements more than small ones (e.g., between schizophrenia and psychotic depression compared with schizophrenia and schizoaffective disorder). Both k and the ICC are measures of agreement corrected for the agreement expected by chance alone and both range from 0 to 1. As a rule of thumb, a k or ICC above .8 is considered excellent, those in the .7 to .8 range are considered good, and those in the .5 to .7 range are considered fair. However, the degree of reliability required varies with the clinical purpose; extremely reliable ratings are required before administering potentially dangerous treatments, while more modest reliability may suffice for estimating rates in a population. ISSUES IN INTERPRETING RELIABILITY DATA When interpreting reliability data, remember that reliability estimates published in the literature may not generalize to other settings. Factors to consider are the nature of the sample, the training and experience of the raters, and the test conditions. Issues regarding the sample are especially critical. In particular, reliability tends to be higher in samples with high variability, in which it is easier to discriminate among individuals. Thus, for continuous measures, reliability tends to be higher when the sample includes individuals with a wide range of scores. For categorical measures, reliability tends to be higher when the prevalence of the attribute being measured is fairly high. Reliability estimates also depend on the fraction of difficult cases (e.g., individuals near a diagnostic threshold or those resistant to being interviewed), since large numbers of these tend to diminish observed reliability. Validity Validity refers to conformity with truth or a gold standard that can stand for truth. In the categorical context, it refers to whether an instrument can make correct classifications. In the continuous context, it refers to accuracy, or whether the score assigned represents the true state of nature. While reliability is empirical, validity is partly theoretical; many constructs measured in psychiatry have no absolute truth. Even so, some measures yield more useful and meaningful data than others. Validity assessment is generally divided into face and content validity, criterion validity, and construct validity. FACE AND CONTENT VALIDITY Face validity refers to whether the items appear to assess the construct in question. Although a rating scale may purport to measure a construct of interest, a review of the items may reveal that it embodies a very different conceptualization of the construct. For instance, an “insight” scale may define insight in either psychoanalytic or neurological terms. However, items with a transparent relation to the construct may be a disadvantage when measuring socially undesirable traits such as substance abuse or malingering. Content validity is similar to face validity but describes whether the measure provides good balanced coverage of the construct and is less focused on whether the items give the appearance of validity. Content validity is often assessed with formal procedures such as expert consensus or factor analysis. CRITERION VALIDITY Criterion validity (sometimes called predictive or concurrent validity) refers to whether or not the measure agrees with a gold standard or criterion of accuracy. Suitable gold standards include the long form of an established instrument for a new shorter version, a clinician-rated measure for a self-report form, and blood or urine tests for measures of drug use. For diagnostic interviews, the generally accepted gold standard is the longitudinal, expert, all data (LEAD) standard, which incorporates expert clinical evaluation, longitudinal data, medical records, family history, and any other sources of information. When comparing continuous measures with a gold standard, a correlation coefficient is the statistic most often reported. For categorical variables such as diagnoses (or continuous measures with a cutpoint), sensitivity and specificity are the statistics of choice. Sensitivity refers to the test's ability to identify true cases, or its true positive rate. Specificity is the test's accuracy in identifying noncases, or one minus the false positive rate. In general, the more sensitive a test, the less specific it is. If the threshold for diagnosis, for example, is lowered, more cases are detected but at the expense of some false positives; if the threshold is raised to decrease the number of false positives, true cases are inevitably missed. The optimal threshold depends on the consequences of false positives and false negatives. CONSTRUCT VALIDITY When an adequate gold standard is not available—a frequent state of affairs in psychiatry—or whenever additional validity data are desired, construct validity must be assessed. To accomplish this, one can compare the measure with external validators, attributes that bear a well-characterized relation to the construct under study but are not measured directly by the instrument. External validators used to validate psychiatric diagnostic criteria and the diagnostic instruments that aim to operationalize them include course of illness, family history, and treatment response. For example, when compared with schizophrenia measures, mania measures are expected to identify more individuals with a remitting course, a family history of major mood disorders, and a good response to lithium. Two special cases of assessing validity using external validators have particular relevance for clinical psychiatry. One is discriminant validity, which examines a

measure's ability to discriminate between populations that are expected to differ on the construct of interest. For example, does a sociopathy measure correctly separate individuals in jails from those living in the community? Although such discriminations are important in clinical practice, the true test of a measure is its ability to discriminate at the margins. A study of discriminant validity is more clearly relevant if it includes the types of cases encountered in clinical practice (e.g., psychotic depression versus schizoaffective disorder) rather than more-easily discriminated populations (e.g., psychotic depression versus normal). Another special case is sensitivity to change; the fact that a measure shows expected changes (e.g., an improvement with an efficacious treatment or a decrement with a progressive disease) can be a strong validator. When assessing validity in areas with few established measures and no gold standard or criterion of accuracy can be established, the assessment of the validity of the measure is limited by the validity of the construct itself. Nonetheless, by triangulating between a better definition of the construct, better ways to measure it, and better exploration of how it operates in clinical practice and research, the field moves to greater validity over time.

SELECTION OF PSYCHIATRIC RATING SCALES The rating scales used in psychiatric practice and research presented below are grouped by topic, beginning with such general issues as diagnosis, functioning, symptom severity, and side effects and then proceeding to specific diagnostic groups, organized according to the section of DSM-IV. The selection was made on the basis of coverage of major areas and common use in clinical research, current (or potential) use in clinical practice, or both. A brief discussion of measurement issues for each area is followed by a description of each instrument, its psychometric properties, and its potential uses. Whenever possible, a brief, clinically useful instrument is provided in each area. References for each measure, organized by topic, are listed in Table 7.8-1. These references include more-detailed information about each measure and its psychometric properties and may also provide either the measure itself or instructions for obtaining a copy.

Table 7.8-1 Key References for Measures Included

Functional Status, Impairment, and General Symptom Severity The broad area of functional status, impairment, and general symptom severity cuts across a variety of diagnoses and is thus useful for grading patients by functional status or overall severity without reference to specific symptomatology. The instruments presented here have a strong mental health focus and often include items on psychiatric symptomatology. Instruments focused on more-global functioning or domains such as mobility and self-care are not generally included here. Global Assessment of Functioning (GAF) Scale and Social and Occupational Functioning Scale (SOFAS) The GAF, shown in Table 7.8-2 was developed in the early 1990s to rate Axis V of DSM-IV and provides a measure of overall functioning related to psychiatric symptoms. The GAF is extremely similar to the Global Assessment Scale (GAS) used for the same purpose in the third edition of DSM (DSM-III) and the revised third edition (DSM-III-R), from which it was derived. A related instrument is the SOFAS, proposed as a new axis in Appendix B of DSM-IV, which focuses only on functioning and not on symptoms and does not try to discriminate between functional changes related to psychiatric and nonpsychiatric causes ( Table 7.8-3). Both scales are clinician rated on a 100-point scale based on all available information, with clear descriptions of each 10-point interval. Ratings are generally made for the past week, but longer intervals (e.g., highest during the past year) can be used. Instructions for rating the GAF and SOFAS are included in DSM-IV; clinician raters do not require additional training to use these scales. The GAS has received more extensive evaluation and shows fair-to-good reliability and good validity judged against clinician ratings of the degree of impairment. GAF or GAS ratings are often required for billing purposes. In addition, the scales have been used to track change with treatment in inpatient and outpatient practice and in multiple research studies. The major criticism of the GAS and GAF is that they tend to confound symptoms and functioning, so that individuals with significant symptomatology (e.g., fixed delusional system) score low even when their social and occupational functioning is relatively spared.

Table 7.8-2 Global Assessment of Functioning (GAF) Scale

Table 7.8-3 Social and Occupational Functioning Assessment Scale (SOFAS)

Global Assessment of Relational Functioning The GARF (Table 7.8-4) was developed in the late 1980s to provide a measure of the quality of functioning in relationships analogous to the measure of individual functioning provided by the GAF or SOFAS. It was subsequently included in Appendix B of DSM-IV as an additional axis for further consideration. It provides a global rating on a 100-point scale based on a review of three major areas: problem-solving, organization, and emotional climate. Anchors are provided for each quintile of each domain. The GARF is focused on the particular needs of family and couple therapists but can be

rated by any clinician. Ratings are generally based on the present, but alternate periods (e.g., the past year, or in the period following a major stressor) can be implemented. The GARF has not been extensively evaluated, but preliminary evidence suggests that clinician and even nonclinician raters can achieve good to excellent reliability with only minimal training. The validity of the GARF is supported by expected correlations with other measures of family and couple distress and functioning. The GARF shows promise for rating relational functioning but only time will tell whether it will prove useful in clinical or research practice.

Table 7.8-4 Global Assessment of Relational Functioning (GARF)

Behavior and Symptom Identification Scale The BASIS-32 (Table 7.8-5) was developed in the early 1990s to provide a broad but brief overview of psychiatric symptoms and functional status from the patient's point of view for use in assessing the outcome of psychiatric treatment. The instrument assesses a wide range of areas, including family and work relationships; ability to complete regular tasks at home, work, or school; and symptoms of anxiety, depression, psychosis, and substance abuse. Each item is rated on a five-point scale focused on the degree of difficulty during the preceding week. BASIS-32 can be completed as a paper and pencil test (requiring 5 to 20 minutes) or the questions can be read aloud with the patient selecting the best answer from a laminated card (requiring 15 to 20 minutes). It can be scored readily by hand. A computerized scoring system is also available. BASIS-32 generates an overall score and five subscales: relation to self and others, daily living and role functioning, depression and anxiety, impulsive and addictive behavior, and psychosis. Good reliability and validity have been demonstrated. Its simple administration, brevity, and broad coverage make it well suited to its original task, and it is frequently used at baseline, during, and after treatment to monitor progress. It can provide valid ratings across a wide range of psychiatric impairment but is not generally suitable for individuals with substantial cognitive impairment. It is also not suitable for children under age 14.

Table 7.8-5 BASIS-32

Symptom Checklist-90 Revised (SCL-90-R) and Brief Symptom Inventory (BSI) The SCL-90-R was developed in the mid-1970s from the older Hopkins Symptom Checklist, a multidimensional measure of the severity of psychopathology. ( SCL-90 refers to a very similar earlier version but is frequently used to denote the current version as well.) The BSI was developed in the early 1980s as a short form of the SCL-90-R. Both cover the following domains: depression, anxiety, phobia, psychoticism, paranoia, obsessive-compulsive, hostility, somatization, and interpersonal sensitivity. Even the longer SCL-90-R fits on two sides of a single sheet of paper and can be completed in 20 minutes or less. The SCL-90-R is a self-report measure with 90 items Likert-scaled from 0 to 4 on the basis of the distress caused over the past week. The BSI is very similar, but has 53 items. Hand scoring is relatively simple, and computerized scoring is available. Both yield t scores based on extensive normative data for each subscale, a Global Severity Index, a Positive Symptom Distress Index, and a Positive Symptom Total. Reliability is fair to good, depending on the subscale, and most subscales appear reasonably valid when assessed against more specific measures (e.g., the depression scale against a HAM-D). The principal use of the SCL-90-R and BSI has been in characterizing psychopathology in treatment and other studies, but they have sometimes been used in primary care clinics as a screening tool for psychopathology. However, caution may be warranted in this setting because their sensitivity may be limited in some areas. In addition, the subscales bear only a modest relation to the corresponding DSM-IV disorders. Side Effects The instruments described below are used to detect and quantify side effects from psychiatric medications, specifically motor effects of antipsychotics. Because of the focus on motor symptoms, these scales include a brief, focused physical examination as well as questions posed to the patient. Abnormal Involuntary Movement Scale (AIMS) The AIMS (Table 7.8-6) is a clinical examination and rating scale that was developed in the 1970s to measure dyskinetic symptoms in patients taking antipsychotic drugs. The AIMS has 12 items, each of which is rated on an item-specific five-point severity scale ranging from 0 to 4. Total scores are not generally reported. Instead, changes in global severity and individual areas can be monitored over time. Ten items cover the movements themselves, divided into sections rating global severity and those related to specific body regions; two items concern dental factors that can complicate the diagnosis of dyskinesia. In the presence of extended neuroleptic exposure and the absence of other conditions causing dyskinesia, mild dyskinetic movements in two areas or moderate movements in one area suggest a diagnosis of tardive dyskinesia. The AIMS was developed for clinician raters, but lay raters can be trained to use it. It can be completed in under 10 minutes. Excellent reliability has been demonstrated, especially for experienced raters, and the instrument appears valid. In many clinical settings, the AIMS is considered standard clinical practice for patients receiving long-term neuroleptic drugs and is useful in clinical practice and research, both for monitoring patients for the development of tardive dyskinesia and for tracking changes in tardive dyskinesia over time.

Table 7.8-6 Abnormal Involuntary Movement Scale (AIMS) Examination Procedure

Simpson-Angus Rating Scale for Extrapyramidal Side Effects The Simpson-Angus scale was developed to monitor the effects of antipsychotic drugs. It has 10 items, each of which is rated on an item-specific, five-point severity scale ranging from 0 to 4. Scores are reported as the mean on all 10 items, with 0.3 considered the upper limit of normal. It is strongly focused on parkinsonian symptoms, particularly rigidity, but includes one akathisia item. It is designed for clinician use but can be administered by trained lay raters and takes about 10 minutes to administer. Good reliability has been reported, and validity is supported by the correlation of scores with antipsychotic drug dose. The scale is useful in a wide variety of clinical settings to monitor parkinsonian adverse effects and the impact of interventions to treat these effects. Psychiatric Diagnosis Instruments assessing psychiatric diagnosis are central to psychiatric research and may have utility in clinical practice as well. However, they tend to be rather long, especially for individuals reporting many symptoms, who may require many follow-up questions. When evaluating such instruments, one must be sure that they implement current diagnostic criteria and cover the diagnostic areas of interest. For instance, few cover personality disorders (with the exception in some cases of antisocial personality), and not all cover disorders that typically begin in childhood. Structured Clinical Interview for DSM-IV The SCID was developed in the early 1990s to provide a standardized DSM-III-R Axis I diagnosis based on an efficient but thorough clinical evaluation. It has since been updated for DSM-IV. The semistructured diagnostic interview begins with a section on demographic information and clinical background. Then there are seven diagnostic modules focused on different diagnostic groups: mood, psychotic, substance abuse, anxiety, somatoform, eating, and adjustment disorders. Both required and optional probes are provided, and skip-outs are suggested when no further questioning is warranted. All available information, including that from hospital records, informants, and patient observation, should be used to rate the SCID. The SCID is designed to be administered by experienced clinicians and is generally not recommended for use by lay interviewers. In addition, formal training in the SCID is required, and training books and videos are available to facilitate this. In individuals without symptoms, the interview takes approximately 1 hour, but it may take up to 3 hours in individuals with extensive symptomatology. Although the primary focus is research with psychiatric patients, a nonpatient version (with no reference to a chief complaint) and a more clinical version (without as much detailed subtyping) are also available. Reliability data on the SCID suggest that it performs better on more-severe disorders (e.g., bipolar I disorder, alcohol dependence) than on milder ones (e.g., dysthymia). Validity data are limited, as the SCID is more often used as the gold standard to judge other instruments. It is considered the standard interview to verify diagnosis in clinical trials and is extensively used in other forms of psychiatric research. It can also be used to ensure a systematic evaluation in psychiatric patients; for instance, on admission to an inpatient unit or at intake into an outpatient clinic. It is also used in forensic practice to ensure a formal and reproducible examination. Diagnostic Interview Schedule (DIS) and Composite International Diagnostic Instrument (CIDI) The DIS and CIDI are fully structured diagnostic interviews designed for lay administration. The DIS was developed in the 1980s for use in the Epidemiologic Catchment Area (ECA) study in the United States, which aimed to assess rates of current and lifetime psychiatric illness according to DSM-III in a large and diverse community sample, and has since been updated for DSM-III-R and DSM-IV criteria. In 19 diagnostic modules, it covers a broad range of Axis I conditions in adults, plus several childhood disorders and antisocial personality. The most recent version also includes more information about symptoms, impairment, and treatment. The CIDI was developed from the DIS for international use and covers both ICD and DSM criteria in 11 diagnostic modules; the CIDI does not cover antisocial personality or childhood disorders. The instruments are fairly similar, and both involve verbatim reading of questions with little or no rewording allowed; only specified probes may be used for follow-up. The DIS takes 90 minutes to 2 hours; the CIDI may be somewhat shorter. Both can be scored by computer, yielding diagnoses and symptom profiles. A computerized, self-administered version of the CIDI is also available. The instruments are designed for use by lay interviewers with extensive training in their use: formal training is recommended. Reliability appears to be good for both, at least for more-severe disorders. Validity appears problematic for the DIS; studies of agreement with clinician diagnoses have yielded inconsistent results, with marked discrepancies often observed for psychotic disorders. The validity of the CIDI is still being evaluated. Both instruments have been used extensively in psychiatric research, particularly in epidemiological settings and provide valuable data. However, some caution is warranted in interpreting these data, given concerns about the instruments' validity. Primary Care Evaluation of Mental Disorders (PRIME-MD) The PRIME-MD was developed in the mid-1990s to provide an efficient screening and evaluation tool for common mental disorders seen in the primary care setting. The instrument has two parts: a 25-item patient questionnaire that screens for a range of symptoms and a structured interview designed to follow up on any symptoms identified in the patient questionnaire or through other means. The interview has five modules covering mood, anxiety, alcohol, somatoform, and eating disorders. The patient questionnaire is very brief and can be completed in under 5 minutes. If follow-up is required, a primary care practitioner can complete the structured questionnaire in about 10 minutes. Training in the use of the instrument or careful review of the instruction manual is recommended. A self-report version of the structured interview is in development. Reliability appears to be fair to good, better for more severe diagnoses. Validity judged against psychiatrist evaluations is quite good. The screening instrument has appropriately high sensitivity, and the follow-up interview provides reasonable specificity. The PRIME-MD appears to be useful for primary care settings and may also be useful in psychiatric practice when a quick screen is desired. However, its utility for the latter purpose is limited by its lack of coverage of the more-severe psychopathology not typically seen in primary care (e.g., psychotic symptoms, mania). Psychotic Disorders A variety of instruments are used for patients with psychotic disorders. Those reported here are symptom severity measures. A developing consensus suggests that distinguishing positive and negative symptoms in schizophrenia is worthwhile, and more-recently developed instruments implement this distinction. Because patients with psychotic disorders often lack insight and are sometimes agitated, patient observation is required in addition to direct questioning. Thus, most instruments in this domain must be administered by psychiatrists or others with clinical training. Brief Psychiatric Rating Scale (BPRS) The BPRS (Table 7.8-7) was developed in the late 1960s as a short scale for measuring the severity of psychiatric symptomatology. Developed primarily to assess change in psychotic inpatients, it covers a broad range of areas including thought disturbance, emotional withdrawal and retardation, anxiety and depression, and hostility and suspiciousness. Its 18 items are rated on a seven-point item-specific Likert scale from 0 to 6, with the total score ranging from 0 to 108 (in some scoring systems, the lowest level for each item is 1, and the range is 18 to 126). Because the ratings include observations as well as patient reports of symptoms, the BPRS can be used to rate patients with very severe impairment. It is intended for use by experienced clinicians and can be administered in 30 minutes or less, including patient interview and observation. Reliability of the BPRS is good to excellent when raters are experienced but is more difficult to achieve without substantial training; anchored versions and a semistructured interview have been developed to increase reliability. Validity is also good as measured by correlations with other measures of symptom severity, especially those assessing schizophrenia symptomatology. The principal use of the BPRS is as an outcome measure in treatment studies of schizophrenia, and it functions well as a measure of change in this context. However, it has been largely supplanted in more-recent clinical trials by the newer measures described below. In addition, given its focus on psychosis and associated symptoms, it is only suitable for patients with fairly significant impairment. Its use in clinical practice is less well supported, in part because considerable training is required to achieve the necessary reliability.

Table 7.8-7 Brief Psychiatric Rating Scale

Positive and Negative Syndrome Scale (PANSS) The PANSS was developed in the late 1980s to remedy perceived deficits in the BPRS in the assessment of positive and negative schizophrenia and other psychotic disorders by adding additional items and providing careful anchors for each. The PANSS includes 30 items on three subscales: 7 items covering positive symptoms (e.g., hallucinations and delusions), 7 covering negative symptoms (e.g., blunted affect), and 16 covering general psychopathology (e.g., guilt, uncooperativeness). Each item is scored on a seven-point item-specific Likert scale ranging from 1 to 7; thus the positive and negative subscales each range from 7 to 49, and the general psychopathology scale from 16 to 112. The PANSS requires a clinician rater because considerable probing and clinical judgment are required. A semistructured interview guide is available. The ratings can be completed in 30 to 40 minutes. Reliability for each scale

is fairly high, with excellent internal consistency and interrater reliability. Validity also appears good based on correlation with other symptom severity measures and factor analytic validation of the subscales. The PANSS has become the standard tool for assessing clinical outcome in treatment studies of schizophrenia and other psychotic disorders and is sensitive to change with treatment. Its high reliability and good coverage of both positive and negative symptoms make it excellent for this purpose. It may also be useful for tracking severity in clinical practice, and its clear anchors make it easy to use in this setting. Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) The SAPS and SANS were designed to provide a detailed assessment of positive and negative symptoms of schizophrenia and may be used separately or in tandem. The domains assessed include hallucinations, delusions, bizarre behavior, and thought disorder for the SAPS and affective flattening, poverty of speech, apathy, anhedonia, and inattentiveness for the SANS. Each instrument consists of 30 fully anchored items each scored 0 to 5; thus the total score ranges from 0 to 150 for each. Each must be rated by an experienced clinician and requires approximately 30 minutes to complete. Good-to-excellent interrater reliability exists if trained interviewers are used, and each scale has high internal consistency as well. Validity is supported by correlation with other symptom severity instruments. The SAPS and SANS are principally used to monitor treatment effects in clinical research and have also been used to help characterize positive and negative symptoms in studies of schizophrenia phenomenology. The comprehensive characterization of symptomatology provided might also be useful in clinical practice, but there is little experience in this area at the present time. Mood Disorders The domain of mood disorders includes both depressive and bipolar disorders. The issues for mania are similar to those for psychotic disorders, in that limited insight and agitation may hinder accurate symptom reporting, so clinician ratings including observational data are generally required. Rating depression, on the other hand, depends substantially on subjective assessment of mood states, so interviews and self-report instruments are both common. Because depression is common in the general population and involves significant morbidity and even mortality, screening instruments, especially those using a self-report format, are potentially quite useful in primary care and community settings. Hamilton Rating Scale for Depression (HAM-D) The HAM-D was developed in the early 1960s to monitor the severity of major depression, with a focus on somatic symptomatology. The version in most common use has 17 items, although versions with different numbers of items, including the 24-item version ( Table 7.8-8), have been used in many studies as well. Most versions do not include some of the symptoms used to diagnose depression in DSM-III and its successors, most notably increased sleep and increased appetite. Items on the HAM-D are scored 0 to 2 or 0 to 4, with total scores on the 17-item version ranging from 0 to 50: scores of 7 or less may be considered normal; 8 to 13, mild; 14 to 18, moderate; 19 to 22, severe; and 23 and above very severe. The HAM-D was designed for clinician raters but has been used by trained lay administrators as well. Ratings are completed by the examiner on the basis of patient interview and observations. A structured interview guide has been developed to improve reliability. The ratings can be completed in 15 to 20 minutes. Reliability is good to excellent, including internal consistency and interrater assessments. Validity appears good based on correlation with other depression symptom measures. The HAM-D has been used extensively to evaluate change in response to pharmacological and other interventions. It is more problematic in elderly and medically ill persons, in whom somatic symptoms may not indicate major depression.

Table 7.8-8 Hamilton Rating Scale for Depression

Beck Depression Inventory (BDI) The BDI was developed in the early 1960s to rate depression severity, with a focus on behavioral and cognitive dimensions of depression. The current version, the Beck Depression Inventory–II (Beck-II), has added more coverage of somatic symptoms to be compatible with DSM-IV and covers the most recent 2 weeks. Earlier versions focus on the past week or even shorter intervals, which may be preferable for monitoring treatment response. The BDI includes 21 self-report items, each of which has four statements describing increasing levels of severity; the total score ranges from 0 to 84. Scores of 0 to 9 are considered minimal; 10 to 16, mild; 17 to 29, moderate; and 30 to 63, severe. The scale can be completed in 5 to 10 minutes. Internal consistency has been high in numerous studies. Test-retest reliability is not consistently high, but this may reflect changes in underlying symptoms. Validity is supported by correlation with other depression measures. The principal use of the BDI is as an outcome measure in clinical trials of interventions for major depression, including psychotherapeutic interventions. Because it is a self-report instrument, it is sometimes used to screen for major depression, for instance in medical outpatients. Various cutoffs have been suggested for a diagnosis of major depression, but even a cutoff of 9 has only fair sensitivity, at a cost of considerable nonspecificity, suggesting that the instrument has limited use for screening. The instrument's strength lies in measuring the depth of depression; it is not suitable for making a diagnosis. Zung Self-Rating Depression Scale The Zung scale was developed in the 1960s to provide a self-report measure of major depression with broad coverage of depression symptomatology. It has 20 items, each of which is scored from 1 to 4, based on the fraction of time in which it occurs. Half of the items are scored positively, and half negatively; positive items must be reversed to obtain a total severity score, which is then converted by formula to a scaled score. Scaled scores under 50 are considered normal; 50 to 59, minimal depression; 60 to 69, moderate depression; and over 70, severe depression. Most individuals can complete the Zung scale in 5 to 10 minutes. The Zung scale has been in use for many years but has not been extensively evaluated. However, reliability is good based on split-half and internal consistency studies. Validity also appears good based on correlations with other depression measures and the ability to discriminate between depressed and nondepressed outpatients. The Zung scale has been used to follow depressed patients in treatment studies; however, there is less variation in Zung scale scores than some other measures, which limits its utility as a change measure. It has also been used to screen for depression in medical outpatients or community interventions, including National Depression Screening Day, in which a threshold score of 50 was used to identify potential cases of depression requiring follow-up by a clinician. Young Mania Rating Scale (YMRS) The YMRS is a checklist developed in the late 1970s to provide a brief but thorough evaluation of the severity of mania that could be used to monitor treatment response or detect relapse. It consists of a checklist of 11 items rated either 0 to 4 (seven items) or 0 to 8 (four items). Each item has five item-specific anchors. The total score ranges from 0 to 60. Ratings include clinical observation, so it must be rated by a clinician, but reliable ratings have been obtained by nurses on inpatient units and beginning psychiatric residents. Reliability is good, based on interrater reliability and internal consistency studies. Validity also appears good, based on correlation with other mania measures. The YMRS is useful for evaluating response to treatment in clinical research, and it is sensitive to change in this setting. It might also be used to assess treatment response or monitor for relapse in treated or untreated patients, although extensive experience with this use has not been reported. Anxiety Disorders The anxiety disorders addressed by the measures below include panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder. When examining anxiety measures, one must be aware that their definitions have changed significantly over time. Both panic and obsessive-compulsive disorder are relatively recently recognized, and the conceptualization of generalized anxiety disorder has shifted over time. Thus, older measures have somewhat less relevance for diagnostic purposes, although they may identify symptoms causing considerable distress. Whether reported during an interview or on a self-report rating scale, virtually all measures in this domain, like the measures of depression discussed above, depend on subjective descriptions of inner states. Hamilton Rating Scale for Anxiety The HAM-A (Table 7.8-9) was developed in the late 1950s to assess anxiety symptoms, both somatic and cognitive. Because conceptualization of anxiety has changed considerably, the HAM-A provides limited coverage of “worry” required for DSM-IV diagnosis of generalized anxiety disorder and does not include the episodic anxiety found in panic disorder. There are 14 items, each of which is rated 0 to 4 on an unanchored severity scale, with the total score ranging from 0 to 56. A score of 14 has been suggested as the threshold for clinically significant anxiety, but scores of 5 or less are typical in individuals in the community. The scale is designed to be administered by a clinician, and formal training or the use of a structured interview guide is required to achieve high reliability. A computer-administered version is also available. Reliability is fairly good, based on internal consistency, interrater, and test-retest studies. However, given the lack of specific anchors, reliability should not be assumed to be high across different users in the absence of formal training. Validity appears good, based on correlation

with other anxiety scales, but is limited by the coverage of domains critical to the modern understanding of anxiety disorders. Even so, the HAM-A has been used extensively to monitor treatment response in studies of generalized anxiety disorder and may also be useful for this purpose in clinical settings.

Table 7.8-9 Hamilton Rating Scale for Anxiety

Panic Disorder Severity Scale (PDSS) The PDSS is a recently developed, brief rating scale aimed at measuring the severity of panic disorder. It was based on the Yale-Brown Obsessive Compulsive Scale (YBOCS) and has seven items, each of which is rated on an item-specific five-point Likert scale. The seven items address frequency of attacks, distress associated with attacks, anticipatory anxiety, phobic avoidance, and impairment. The items are scored 0 to 4, and the total score ranges from 0 to 28. The instrument was designed for use by clinicians, but a patient-scored computerized version is in development. Reliability is excellent, based on interrater studies, but, in keeping with the small number of items and multiple dimensions, internal consistency is limited. Validity is supported by correlations with other anxiety measures, both at the total and item level, and lack of correlation with the HAM-D. Because the PDSS has been available for a fairly short period of time, there is limited experience with its use. However, it appears to be sensitive to change with treatment and is thus likely to prove useful as a change measure in clinical trials or other outcome studies for panic disorder, as well as for monitoring panic disorder in clinical practice. Yale-Brown Obsessive Compulsive Scale (YBOCS) The YBOCS (Table 7.8-10) was developed in the late 1980s to measure the severity of symptoms in obsessive-compulsive disorder. It has 10 items rated on the basis of a semistructured interview. The first five items concern obsessions: the amount of time they consume, the degree to which they interfere with normal functioning, the distress they cause, the patient's attempts to resist them, and the patient's ability to control them. The remaining five items ask parallel questions about compulsions. Each item has a set of item-specific anchors scored 0 to 4, so total scores for obsessions and compulsions each range from 0 to 20, and overall total score ranges from 0 to 40. Typical scores for patients with obsessive-compulsive disorder are in the 16 to 30 range, and a threshold of 16 is typically used for inclusion in drug trials. The semistructured interview and ratings can be completed in 15 minutes or less. A self-administered version has recently been developed and can be completed in 10 to 15 minutes. Computerized and telephone use also provide acceptable ratings. Prior to the first use of the YBOCS, an associated 64-item checklist is administered to provide a more detailed assessment of the specific content of the patient's obsessions and delusions. Reliability studies of the YBOCS show good internal consistency, interrater reliability, and test-retest reliability over a 1-week interval. Validity appears good, although data are fairly limited in this developing field. The YBOCS has become the standard instrument for assessing obsessive-compulsive disorder severity and is used in virtually every drug trial. It may also be used clinically to monitor treatment response.

Table 7.8-10 Yale-Brown Obsessive-Compulsive Scale

Substance Use Disorders Substance use disorders include both abuse and dependence on both alcohol and drugs. These disorders, particularly those involving alcohol, are common and debilitating in the general population, so screening instruments are particularly helpful. Because these behaviors are socially undesirable, underreporting of symptoms is a significant problem. Validation against drug tests or other measures is of great value, particularly when working with patients who have known substance abuse. CAGE The CAGE was developed in the mid-1970s to serve as a very brief screen for significant alcohol problems in a variety of settings, which could then be followed up by clinical inquiry. CAGE is an acronym for the four questions that make up the instrument: (1) Have you ever felt you should cut down on your drinking?; (2) Have people annoyed you by criticizing your drinking?; (3) Have you ever felt bad or guilty about your drinking?; (4) Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover ( eye-opener)? Each “yes” answer is scored as 1, and these are summed to generate a total score. Scores of 1 or more warrant follow-up, and scores of 2 or more strongly suggest significant alcohol problems. The instrument can be administered in a minute or less either orally or on paper. Reliability has not been formally assessed. Validity has been assessed against a clinical diagnosis of alcohol abuse or dependence, and these four questions perform surprisingly well. Using a threshold score of 1, the CAGE achieves excellent sensitivity and fair to good specificity. A threshold of 2 provides still greater specificity, but at the cost of a fall in sensitivity. The CAGE performs well as an extremely brief screening instrument for use in primary care or in psychiatric practice focused on problems unrelated to alcohol. However, it has limited ability to pick up early indicators of problem drinking that might be the focus of preventive efforts. Alcohol Use Disorders Identification Test (AUDIT) The AUDIT (Table 7.8-11) was developed by the World Health Organization in the late 1980s as a brief screening instrument designed for the early detection of hazardous (i.e., involving the risk of harm) and harmful (i.e., involving the presence of harm) alcohol use in a variety of settings. It focuses on both the past year and current drinking. It includes a 10-item core screening instrument covering alcohol consumption, drinking behaviors, and alcohol-related problems. Each item is rated using item-specific anchors scored 0 to 4 and summed for a total score of 0 to 40. The AUDIT can be administered and scored in less than 5 minutes and does not require professional training. The AUDIT also offers a Clinical Screening Procedure involving a physical examination and blood tests, which adds no more than 5 to 10 minutes to a routine medical examination. Reliability of the AUDIT appears good, based on internal consistency data. Validity judged against a clinical diagnosis of alcoholism is also good; using a threshold score of 8 is quite sensitive but somewhat nonspecific. A score of 10 is more specific but at a cost in specificity. Validity also appears good, based on correlation with other alcohol self-report measures and risk factors for alcoholism. The AUDIT provides an excellent brief screen for alcohol problems and is particularly good for detecting problem drinking at a fairly mild stage. However, its focus on early detection of hazardous and harmful drinking makes it less suited for use as a diagnostic instrument.

Table 7.8-11 AUDIT

Drug Abuse Screening Test (DAST) The DAST was developed in the early 1980s to serve as a screening and assessment instrument for drug abuse. The DAST is an adaptation of the Michigan Alcohol Screening Test (MAST), used to screen for alcoholism. It focuses on lifetime drug use, so it is not designed to measure changes over time. The current version of the DAST has 20 items, all of which are answered “yes” or “no,” and can be given orally or as a paper and pencil questionnaire. An earlier version had 28 items, so the 20-item version is sometimes called the Brief DAST. The positive items can be summed to form a 20-point scale. The DAST can be administered and scored in less than 10 minutes. Reliability is very good, based on internal consistency. Validity based on ability to detect drug abuse disorder also appears high, with excellent sensitivity and fairly good specificity using a threshold score of 5. The DAST is useful as a screening device for drug abuse problems in patients with other mental disorders, particularly alcohol abuse. It also provides an overview of problem severity that may be useful in guiding treatment choices. Addiction Severity Index (ASI) The ASI was developed in the early 1980s to serve as a quantitative measure of symptoms and functional impairment caused by alcohol or drug disorders. It covers demographics, alcohol use, drug use, psychiatric status, medical status, employment, legal status, and family and social issues. Frequency, duration, and severity are assessed. It has 142 items in varying formats including yes-no, multiple choice, and scaled items. They include both subjective and objective items reported by the patient and observations made by the interviewer. In each area, the ASI yields the rater's global assessment of severity along with a computer score on a 0 to 1 scale. The 142-item version includes information on the past 30 days and lifetime status, but a shorter version is available for use at follow-up. The instrument is designed for clinician administration but has been used successfully by trained lay raters. Training is recommended, and both manuals and formal training programs are available. A computerized version is also available. The standard ASI requires 45 to 75 minutes to complete, but the follow-up version can be completed in 15 to 20 minutes. Very good to excellent reliability has been demonstrated for the overall composite score, with somewhat lower reliability for severity ratings in each area. Validity has also been demonstrated, based on correlation with other measures and discrimination of patient and nonpatient populations. Normative data are available for a range of populations of alcohol and drug abusers, including alcohol clinic patients, drug abusers, homeless persons, and prisoners. The principal use of the ASI is as an aid to treatment planning and the assessment of treatment outcome in clinical and law enforcement settings. It is relatively time consuming to administer but performs well for this purpose. It is also used in clinical research as a sensitive indicator of baseline severity and change over time, which allows comparison between clinical research and clinical practice. Eating Disorders Eating disorders include anorexia nervosa, bulimia nervosa, and binge-eating disorder, which is included in Appendix B of DSM-IV and is gaining acceptance among eating-disorders clinicians and researchers. A wide variety of instruments, particularly self-report scales, are available. Because of the secrecy that may surround dieting, bingeing, purging, and other symptoms, validation against other indicators (e.g., body weight for anorexia, dental examination for bulimia) may be very helpful. Such validation is particularly critical for patients with anorexia, who may lack insight into their difficulties. Eating Disorders Inventory (EDI) The EDI was developed in the early 1980s to provide a multidimensional self-report assessment of eating disorder symptomatology and related psychological attributes. The current version of the EDI, the EDI-2, has 91 items in 11 subscales: Drive for Thinness, Bulimia, Body Dissatisfaction, Ineffectiveness, Perfectionism, Interpersonal Distrust, Interoceptive Awareness, Maturity Fears, Asceticism, Impulsive Regulation, and Social Insecurity. Each item is rated on a six-point frequency-based Likert scale. The two ratings at the symptomatic end of the scale are scored 2; the middle two, scored 1; and the last two, scored 0; then the items in each subscale are added to generate a subscale score. Instrumentwide total scores may also be obtained but are not considered meaningful. Norms for each subscale are available for a variety of eating-disordered and nonclinical populations. The EDI can be completed in less than 20 minutes. Easy-reading and childhood versions are available. A computerized version is also available. Reliability data indicate very good internal consistency and test-retest reliability for virtually all EDI subscales. Validity of the EDI subscales is supported by correlation with related eating disorder measures and discrimination between patient and nonpatient samples. The EDI subscales also correlate moderately with ratings of these domains by trained clinicians. The EDI has several uses that apply in both clinical and research practice. Its principal use is in providing a range of data that may help in treatment planning. For instance, body dissatisfaction is an important predictor of prognosis and treatment response in bulimia nervosa. Some of the subscales, particularly the Bulimia scale, have also been shown to be sensitive to change with treatment and thus may be used to monitor patients over time. The EDI has also been used for screening purposes in primary care or other settings to identify individuals at high risk for eating disorders. The Drive for Thinness, Bulimia, and Body Dissatisfaction scales are probably the most useful in this regard. For instance, scores of 14 or above on the Drive for Thinness scale suggest an increased risk for anorexia nervosa and warrant further evaluation. Bulimia Test-Revised (BULIT-R) The BULIT-R was developed in the mid-1980s to provide a categorical and continuous assessment of bulimia nervosa. The current version, while designed for DSM-III-R criteria, has been validated for DSM-IV as well. The BULIT-R has 36 self-report items, each scored on an item-specific five-point Likert scale. Of these items, 8 provide descriptive information, and the remaining 28 are summed to provide the total score, which ranges from 28 to 140. Young women with bulimia nervosa typically score above 110, while young women without disordered eating typically score below 60. The instrument can be completed in about 10 minutes. The BULIT-R shows high reliability, based on studies of internal consistency and test-retest reliability in multiple studies. Validity is supported by high correlations with other bulimia assessments. The recommended cutoff of 104 suggested to identify probable cases of bulimia shows high sensitivity and specificity for a clinical diagnosis of bulimia nervosa. Using cutoffs between 98 and 104, the BULIT-R has been used successfully to screen for bulimia nervosa. As with any screening procedure, follow-up by clinical examination is indicated for individuals scoring positive; clinical follow-up is particularly critical because the BULIT-R does not distinguish clearly between different types of eating disorders. The BULIT-R may also be useful to track symptoms over time or in response to treatment, in both clinical and research practice, although more detailed measures of the frequency and severity of bingeing and purging may be preferable in research settings. Cognitive Disorders Dementia is becoming an increasing focus of psychiatric practice. A wide variety of measures are available. Most involve cognitive testing and provide objective, quantifiable data. However, scores vary by educational level in subjects without dementia, so these instruments tend to be most useful when the patient's baseline score is known. Other measures focus on functional status, which can be assessed on the basis of a comparison with a description of the subject's baseline function; these types of measures generally require a knowledgeable informant and may thus be more cumbersome to administer, but they tend to be less subject to educational biases. Mini-Mental State Examination The MMSE (Table 7.8-12) is a 30-point cognitive test developed in the mid-1970s to provide a bedside assessment of a broad array of cognitive functions including orientation, attention, memory, construction, and language. It can be administered in under 10 minutes by a busy doctor or a technician and scored rapidly by hand. The MMSE has been extensively studied and shows excellent reliability. Validity appears good, based on correlations with a wide variety of more comprehensive measures of mental functioning and clinicopathological correlations. One common use of the MMSE is in screening for dementia, in both office practice and epidemiological or clinical research. For this purpose, a cutoff of 24 for identifying cases of dementia has been suggested, but it is probably more accurate to use age- and education-adjusted norms to interpret the results. For patients with extensive education, who may score 30 out of 30 despite clear evidence of functional decline, a more difficult cognitive test, full neuropsychological battery, or clinical interview may be required to detect dementia. The other principal use of the MMSE is in following the progression of dementia over time. As a rule of thumb, mild dementia ranges from a score of 20 to 24, moderate from 11 to 19, and severe from 0 to 10. However, these figures do not take the educational differences noted above into account. In addition, the MMSE does not do as well tracking progression of dementia in the lower ranges, as many patients become untestable.

Table 7.8-12 Mini-Mental State Examination

Blessed Information Memory Concentration Test (IMC) The IMC, sometimes called the Blessed IMC after its developer, was developed in the late 1960s for studies of the relationship between dementia severity and neuropathological changes. The original version of the scale, developed in Britain, had 29 items, the current American version has 26. Areas assessed include information (date, time, place, name, age, remote personal information, dates of the world wars, name of governmental leaders), memory (a name and address for 5-minute recall), and concentration (counting forward and backward from 1 to 20). A six-item version, sometimes called the short form of the Blessed or the Orientation Memory Concentration (OMC) test, is also available: it asks only the time of day, month, year, the 5-minute recall of the address, and counting backward from 20 and is highly predictive of total IMC score. IMC scores on individual items are weighted; on the 26-item IMC they range from 0 (no errors) to 33 and on the six-item version, scores range from 0 to 28. The IMC can be administered in person or over the phone by a trained clinician or lay rater. Based on internal consistency and test-retest studies in demented subjects over a 1- to 6-week interval, reliability of the 26-item and 6-item IMC both appear very good. Validity also appears good, based on clinicopathological correlations and correlations with other dementia severity measures. Studies of changes with time in patients with Alzheimer's disease show an average annual increase of 3 to 4 points on the 26-item version and 2.5 points on the 6-item version. The principal use of the IMC is assessing dementia severity over time, either through the natural course of the disease or in response to treatment interventions. The IMC is also sometimes used as a screening instrument in clinical practice or community research studies. A cutoff score of 10 has been recommended for the 6-item version, but no standard cutoff is recommended for the 26-item version. In any case, very limited population data exist, and norms are not available by age or education, which are very likely to affect test results. Because of its focus on memory items, the IMC may perform better as a severity or screening measure in patients with Alzheimer's disease than in those with other dementing illnesses. Global Deterioration Scale (GDS), Brief Cognitive Rating Scale (BCRS), and Functional Assessment and Staging Tool (FAST) The GDS, BCRS, and FAST are a group of measures designed to provide ordinal staging of cognitive and functional status in patients with dementia, particularly those with Alzheimer's disease. The three instruments use a consistent seven-point scale. The GDS is a simple rating scale that describes seven stages from normal aging to severe dementia: (1) normal, (2) subjective complaints only, (3) subtle deficits with little or no functional decline except in very demanding tasks (e.g., managerial tasks at work, or preparing an elaborate social event like a holiday meal), (4) definitive deficits that interfere with complex activities of daily living (ADLs) (e.g., balancing a checkbook), (5) deficits that interfere with independent living in the community, (6) deficits that interfere with basic ADLs (e.g., dressing, toileting), and (7) profound deficits leading to the need for continuous assistance. The BCRS focuses on cognitive issues and describes the same seven levels in five different domains referred to as axes: (I) concentration, (II) recent memory, (III) remote memory, (IV) orientation, and (V) self-care. The FAST focuses on functional status, again in seven stages, but it adds substages within stages 6 and 7. All three scales should be completed by an individual with clinical experience (physician, psychologist, nurse, or trained technician) after a review of all available information from the patient, informants, and medical records. The FAST can generally be completed in as little as 10 to 15 minutes, but the GDS and especially the BCRS may require 30 to 45 minutes. Reliability of these scales is excellent, based on interrater and test-retest studies. Validity of all three measures is supported by correlations with other cognitive and functional status scales. GDS and BCRS stages have also been validated against neuropathological data. FAST stages correspond closely to typical progression in Alzheimer's disease. The GDS, BCRS, and FAST are useful in staging dementia, especially Alzheimer's disease, which is much more likely to follow the described ordinal stages closely. Such staging may be used to provide a concise description for patients referred to other clinicians or settings or to track changes over time or in response to treatment. The FAST is especially useful in staging severe dementia and has been used extensively to assess the need for services. The GDS and BCRS are both sensitive to change, with average declines of approximately 0.5 GDS or BCRS subscale points per year in Alzheimer's disease patients. Personality Disorders and Personality Traits Personality may be conceptualized categorically as personality disorders or dimensionally as personality traits, which may be viewed as normal or pathological. The focus here is on personality disorders, and the traits are generally viewed as their milder forms. DSM-IV defines 10 personality disorders in three clusters, and an additional two disorders (passive-aggressive and depressive personality) are proposed in Appendix B for further study. Patients tend not to fall neatly into DSM-IV personality categories; instead, most patients who meet criteria for one personality disorder also meet criteria for one or more others, particularly within the same cluster. This and other limitations in the validity of the constructs themselves makes it difficult to achieve validity in personality measures. Personality measures include both interviews and self-report instruments. Self-report measures are appealing in that they require less time and may appear less threatening to the patient. However, they tend to overdiagnose personality disorders. Because many of the symptoms suggesting personality problems are socially undesirable, and because patients' insight tends to be limited, clinician-administered instruments, which allow for probing and patient observation, may provide more accurate data. Structured Clinical Interview for DSM-IV Axis-II Personality Disorders (SCID-II) The SCID-II is the counterpart of the SCID for making DSM diagnoses of personality disorders. The initial version was developed for DSM-III-R in the mid-1990s, and the current version makes diagnoses according to DSM-IV. The SCID-II is organized by disorder and includes all 10 DSM-IV personality disorders plus the two proposed in Appendix B. A 119-item self-report screening questionnaire is generally given first to eliminate sections not needing further exploration: each of the items corresponds to a specific criterion for a DSM-IV personality disorder. The SCID-II proper includes one or two yes-no items for each criterion, with each affirmative answer to be followed-up by examples from the person's life. Based on these answers each criterion is scored 1 for false, 2 for subthreshold, and 3 for present, allowing criteria scores to be summed for a dimensional measure of each disorder or combined following the DSM-IV diagnostic rules for a categorical approach. The screening questionnaire can be completed by the patient in about 20 minutes; the interview generally requires about an hour. The SCID-II must be administered by doctoral-level clinicians, and training in the SCID-II is also required. A computerized administration and scoring program is available. Reliability is good for the presence or absence of any disorder but only fair for specific personality disorders; the reliability of dimensional assessment is somewhat better. Validity is somewhat harder to determine, as agreement with clinician assessment tends to be modest, but given its comprehensiveness and strict adherence to DSM-IV criteria, the SCID-II may actually be more valid. The SCID-II is most useful to provide a standardized, comprehensive assessment of personality disorders, whether in research, forensic, or clinical settings. Personality Disorder Questionnaire (PDQ) The PDQ was developed in the late 1980s as a self-report questionnaire designed to provide categorical and dimensional assessment of DSM-III-R personality disorders and was subsequently revised for DSM-IV. An alternate version includes the two disorders in Appendix B as well. Another alternate version allows for ratings within the last few weeks and is designed to serve as a change measure. The current PDQ, the PDQ-IV, includes 85 yes-no items, designed primarily to assess the diagnostic criteria for DSM-IV personality disorders. Within the 85 items are embedded two validity scales to identify underreporting, lying, or inattention. There is also a brief clinician-administered Clinical Significance Scale to address the impact of any personality disorder identified by the self-report PDQ. The PDQ can provide categorical diagnoses with a scaled score for each or an overall index of personality disturbance based on the sum of all the diagnostic criteria. Overall scores range from 0 to 79; patients with personality disorders generally score above 30, psychotherapy outpatients without such disorders tend to score in the 20-to-30 range, and normal controls tend to score below 20. The PDQ can be completed in under 30 minutes. Computerized administration and scoring are available. Reliability is fair to good for dimensional assessment and quite variable for categorical assessment, with good reliability for obsessive-compulsive and antisocial personality, and inadequate reliability for many disorders. Validity judged against semistructured clinician-administered interviews is also variable. The PDQ, like other self-report instruments, tends to overdiagnose personality disorders, with many false positives and few false negatives. Its brevity, excellent sensitivity, and poor specificity make it most useful as a screening device, with a follow-up semistructured interview for patients screening positive. Childhood Disorders A wide variety of instruments is available to assess mental disorders in children. Despite a rich array of instruments, the evaluation of children remains difficult for several reasons. First, the child psychiatric nosology is at an earlier stage of development, and construct validity is often problematic. Multiple changes in diagnostic criteria from DSM-III to DSM-III-R to DSM-IV complicate the choice of measures. Second, because children change markedly with age, it is virtually impossible to design a measure that covers children of all ages. Finally, because children, particularly young children, have limited ability to report their symptoms, other informants are necessary. This often creates problems because child, parent, and teacher reports of symptoms frequently disagree, and the optimal

way to combine information is unclear. Child Behavior Checklist (CBCL) The CBCL is a family of self-rated instruments that survey a broad range of difficulties encountered in children from preschool age through adolescence. One version of the CBCL, designed for completion by parents of children aged 4 to 18, is shown in Table 7.8-13. Another version is available for parents of children ages 2 to 3. The Youth Self Report is completed by children ages 11 to 18, and the Teacher Report Form is completed by teachers regarding school age children. The scale includes not only problem behaviors, but academic and social strengths as well. Each version includes approximately 100 items scored on a 3-point Likert scale. Scoring can be done by hand or computer, and normative data are available for each of the three subscales: problem behaviors, academic functioning, and adaptive behaviors. A computerized version is also available. The CBCL does not generate diagnoses, but instead suggests cutoff scores for problems in the “clinical range.” Parent, teacher, and child versions each show high reliability on the problem subscale, but the three informants frequently do not agree with one another. The CBCL may be useful in clinical settings as an adjunct to clinical evaluation: they provide a good overall view of symptomatology and may also be used to track change over time. They are used frequently for similar purposes in research involving children and thus can be compared with clinical experience. The instrument does not, however, provide diagnostic information, and its length limits its efficiency for tracking purposes.

Table 7.8-13 Child Behavior Checklist for Ages 4–18

Diagnostic Interview Schedule for Children (DISC) The DISC was originally developed in the early 1990s as a fully structured diagnostic interview for making DSM-III diagnoses in children. It has since been revised for DSM-III-R and DSM-IV. The current DISC, the DISC-IV, covers a broad range of DSM-IV diagnoses, both current and lifetime. It has nearly 3000 questions but is structured with a series of stem questions that serve as gateways to each diagnostic area, with the remainder of each section skipped if the subject answers “no.” Subjects who enter each section have very few skips, so both symptom scales and diagnostic information can be obtained. Child, parent, and teacher versions are available. Computer programs are available to implement diagnostic criteria, to generate severity scales based on each version, or to combine parent and child information. A typical DISC interview may take more than an hour for a child, plus an additional hour for a parent, but because of the stem question structure, the actual time varies widely with the number of symptoms endorsed. The DISC was designed for lay interviewers. It is fairly complicated to administer, and formal training programs are highly recommended. Reliability of the DISC is only fair to good and generally is better for the combined child and parent interview. Validity judged against a clinical interview by a child psychiatrist is also fair to good, better for some diagnoses and better for the combined interview. The DISC is well tolerated by parents and children and can be used to supplement a clinical interview to ensure comprehensive diagnostic coverage. Because of its inflexibility, some clinicians find it uncomfortable to use, and its length makes it less than optimal for use in clinical practice. However, it is used frequently in a variety of research settings. Children's Depression Inventory (CDI) The CDI is a 27-item self-report measure of mood symptoms in children aged 7 to 17. A 10-item screening version is also available. The instrument may be administered as a simple pen-and-pencil test using a special easily scored form or by computer. The CDI has a first-grade reading level, so even young children can generally complete it on their own. Good reliability has been demonstrated, and good validity is suggested by its ability to distinguish currently depressed children from those with partially remitted depression or with other psychiatric disorders, along with its correlation with other measures of childhood depression. The principal uses of the CDI are in screening for depression in psychiatric patients or epidemiological surveys: it works fairly well for this purpose but tends to miss a substantial fraction of cases because children are not always good reporters. The other use is as a change measure in office practice or clinical trials. It appears to have adequate sensitivity to change for this purpose but has not been subjected to extensive evaluation. Conners Rating Scales The Conners Rating Scales are a family of instruments designed to measure a range of childhood and adolescent psychopathology, but are most commonly used in the assessment of attention-deficit/hyperactivity disorder. There are teacher, parent, and self-report (for adolescents) versions and both short (as few as 10 items) and long (as many as 80 items, with multiple subscales) forms. Extensive normative data drawn from an ethnically diverse population are available for each sex across a broad age range. Even the longer forms can be completed in 15 to 20 minutes, and scoring can be accomplished rapidly. Rater training is not required. Reliability data are excellent for the Conners Rating Scales. However, teacher and parent versions tend to show poor agreement. Validity data suggest that the Conners Rating Scales are excellent at discriminating attention-deficit/hyperactivity disorder patients and normal controls. It has more difficulty separating attention-deficit/hyperactivity disorder from other disruptive behavioral disorders such as conduct disorder, but this may substantially relate to the genuine clinical difficulties separating these syndromes. Newer versions of the Conners have been developed that aim to improve these discriminations, but they have not yet been subjected to extensive testing. The principal uses of the Conners Rating Scales are in screening for attention-deficit/hyperactivity disorder in school or clinic populations and following changes in symptom severity over time; sensitivity to change in response to specific therapies has been demonstrated for most versions of the Conners.

SUGGESTED CROSS-REFERENCES Section 5.2 discusses statistics and experimental design. Section 7.1 discusses the psychiatric interview, history and mental status examination; 7.5 the personality assessment of adults and children; 7.4 neuropsychological assessment of adults; and 9.6 neuropsychological assessment of children. Section 11.1 discusses the classification of mental disorders. SECTION REFERENCES *Carmines E, Zeller R: Reliability and Validity Assessment, publ no. 17. Sage, Beverly Hills, CA, 1979. Hulley SB, Cummings SR: Planning the measurements: Precision and accuracy. In Designing Clinical Research: An Epidemiologic Approach, SB Hulley, SR Cummings, editors. Williams & Wilkins, Baltimore, 1987. Kendler KS: Toward a scientific psychiatric nosology: Strengths and limitations. Arch Gen Psychiatry 47:969, 1990. McDowell I, Newell C: Measuring Health: A Guide to Rating Scales and Questionnaires. Oxford University Press, London, 1996. Murphy J: Diagnostic schedules and rating scales in adult psychiatry. In Textbook in Psychiatric Epidemiology, MT Tsuang, M Tohen, GEP Zahner, editors. Wiley, New York, 1995. Murphy JM, Berwick DM, Weinstein MC, Borus JF, Budman SH, Klerman GL: Performance of screening and diagnostic tests: Application of receiver operating characteristic (ROC) analysis. Arch Gen Psychiatry 44:550, 1987. *Nunnally JC: Psychometric Theory, ed 2. McGraw Hill, New York, 1978. Regier DA, Kaelber CT, Rae DS, Farmer ME, Knauper B, Kessler RC, Norquist GS: Limitations of diagnostic criteria and assessment instruments for mental disorders: Implications for research and policy. Arch Gen Psychiatry 55:109, 1998. *Robins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. Am J Psychiatry 126:983, 1990. Robins L: Epidemiology: Reflections on testing the validity of psychiatric interviews. Arch Gen Psychiatry 42:918, 1985.

Schutte NS, Malouff JM: Sourcebook of Adult Assessment Strategies. Plenum, New York, 1995. *Sederer L.L, Dickey B: Outcomes Assessment in Clinical Practice. Williams & Wilkins, Baltimore, 1996. Shrout PE, Spitzer RL, Fleiss JL: Quantification of agreement in psychiatric diagnosis revisited. Arch Gen Psychiatry 44:172, 1987. *Spitzer RL: Psychiatric diagnosis: Are clinicians still necessary? Compr Psychiatry 24:399, 1983. Spitzer RL, Fleiss JL: A re-analysis of the reliability of psychiatric diagnosis. Br J Psychiatry 125:341, 1974. Sudman S, Bradburn NM, Schwarz N: Thinking About Answers: The Application of Cognitive Processes to Survey Methodology. Jossey-Bass, San Francisco, 1996. Winokur G, Zimmerman M, Cadoret R: 'Cause the Bible tells me so. Arch Gen Psychiatry 45:683, 1988. Zarin DA, Earls F. Diagnostic decision making in psychiatry. Am J Psychiatry 150:197, 1993.

Textbook of Psychiatry

7.9 COMPUTER-BASED TESTING OF THE PSYCHIATRIC PATIENT Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 7. DIAGNOSIS AND PSYCHIATRY: EXAMINATION OF THE PSYCHIATRIC PATIENT

7.9 COMPUTER-BASED TESTING OF THE PSYCHIATRIC PATIENT MARVIN J. MILLER, M.D. Computer-Based Testing Future Directions Suggested Cross-References

Twenty-five years of advances in personal computers and software have begun to affect how patients are evaluated and treated and how information about them is stored. Few clinicians have managed to avoid the impact of computers entirely. New tools will be widely used only if they are tested, validated, confirmed, and publicized throughout the professional community. Computer applications have slowly gone through this process and have gained acceptability. Insurance and managed-care companies lead the way in implementing computers for accounting, monitoring, and practice-shaping tools. Hospitals generally introduce computers through the business office and bring them no further into the health care process. A few computer applications, however, have gained rapid acceptance and use. The Internet is a worldwide communication network of cables, software, and computers that has rapidly gained popularity in psychiatric education, communication, and program distribution. The Internet is a decentralized tool and thus amenable to rapid growth unfettered by rigid rules and constraints. Considerable caution is therefore required on the part of the clinician because there is little regulation or supervision. Individual clinicians browsing the Internet can explore applications and Web sites of value and can benefit from them immediately if they are of demonstrated quality. Computers equipped with appropriate cameras and software can transmit video and audio over telephone lines at low cost. This opens rich opportunities for the mental health clinician to consult with colleagues, receive education, and evaluate and treat patients. It also raises many new questions of reimbursement, supervision, licensure, and efficacy. However, the power of the technology is setting the pace and more than fifteen states have some telemedicine projects in place. Some computerized evaluation tasks (quantitative electroencephalogram (EEG) and magnetic resonance imaging) are readily accepted as computerized tools because they would be impossible or impractical without the computational power of computers. Other tasks such as computer-based testing of patients have experienced slow but gradual acceptance. Computer education, therapy, or both of patients has proceeded even more slowly. The area of mental health computing with the most untapped potential is the computerized evaluation of patients.

COMPUTER-BASED TESTING In the past 30 years of computerized testing in the mental health field there has been a steady increase in the quality and quantity of test instruments available and a steady decrease in the costs of these tests. The earliest computerized interviews were done at the University of Wisconsin on a LINC computer provided by the National Institute of Mental Health. The initial computerized interviews gathered a medical history that was then printed out for the physician to use. The interview was branching and would select a maximum of 320 questions out of a library of more than 500 questions in the program. Progress in the development of computerized testing remained very slow until the arrival of the microcomputer in 1980 changed the rate of development. Individual clinicians could more easily justify the cost of the equipment and could dedicate it to a task of computer testing. The hardware capabilities available expanded rapidly to include color graphics, photos, sound, and even physiological modalities. Early attempts at computerizing psychiatric tests involved slavish attempts to mimic the traditional tests exactly. One early investigator devised a computerized version of an intelligence test on a PDP-8 computer with a concrete replication of the original formats. When different sections of the tests were presented, drawers would open and close to present the proper test material to a patient. The same investigator also developed one of the earliest computerized therapy programs; a group of patients eager to lose weight were treated with either a computerized program, a peer group, or a control group—all lost significant amounts of weight at an equal rate. Dimensions of Computerized Testing The gradual realization of the many advantages of computer-based testing prompted the gradual move toward computerized testing of the psychiatric patient. Answers can be gathered from the patient more quickly and more accurately by the computer. One question presented on the screen at a time helps the patient to focus and answer that question more quickly than if presented on paper. Accuracy is enhanced because there is less chance that the patient will record answers incorrectly and there is less chance that the psychometrist will record or key punch the answers incorrectly. Computer-based testing also is less threatening and encourages patients to reveal sensitive material more readily. The computer summarizes the responses to the questions more quickly and more accurately than humans do. Interpretation of the raw data is still a difficult task. Various studies show that a combination of computerized summary and human interpretation provides the most reliable and most comprehensive evaluation of the test results. Neither the human nor the computer can do as well individually as the two combined. However, acceptance of computerized testing remains mixed. Various evaluations show that patient acceptance (even among seriously ill patients) is higher than clinician acceptance. Some clinicians reject computer-based testing entirely. Others accept the testing results in an uncritical way, as if the computer were infallible. Proper use of computer-based testing avoids both these extremes; the use of these tests is recommended only after careful development and assessment of test results in conjunction with other tests in the battery and other clinical information gathered in more traditional ways. Early Developments John Greist was an early pioneer in computerized testing in mental health. He developed an early program to assess suicidality that showed that patients will reveal sensitive information about suicidal impulses to the computer. The computer program could predict the probability of a suicide gesture as well as clinicians could. His group went on to develop a variety of computerized tests for diagnostic purposes and symptom assessment in a variety of areas. The first psychological test to be widely computerized was the Minnesota Multiphasic Personality Inventory (MMPI). The volume of test questions and the large number of experimental scales dictated the use of the computer as a time-saving measure for test administration and test scoring. Ethical and Professional Concerns Computer-based testing is only one component of a professional evaluation of mental illness. The mental health professional must be the main source of quality assurance during the evaluation and needs to integrate the computer-based testing with all the other aspects of the evaluation. Psychiatrists and other professionals are bound by strict guidelines about initial specialty training, certification in the specialty, continuing medical education, and general ethical conduct. The highly trained professional signing the evaluation of a patient assumes the ultimate responsibility for the content and quality of an evaluation. Persons constructing a computerized test need to be concerned about various aspects of reliability and validity. They need to ensure that the test will produce similar results at various points in time. Use of the computer can often enhance standardization of a test because the conditions under which the test is administered can be more precisely regulated. The validity of a test also needs to be addressed by the test designer or developer. Tests need to demonstrate content validity by proving that adequate aspects of the topic in question are sampled. Computerized tests also need to show criterion-related validity. A test to measure attention-deficit/hyperactivity disorder should show a high correlation with an expert clinician making the same diagnosis; computer-based testing should also show predictive validity if possible. The computer evaluation of attention-deficit/hyperactivity disorder should show change and correlation with medication used to treat the disorder. The computer-based testing should also demonstrate construct validity by showing that a carefully defined theoretical construct is measured and described. For some tests the issue of reliability can be addressed by comparing the paper-and-pencil form of the test with the computerized version; these comparisons

generally show a very high correlation. Some tests, however, are designed specifically for the computer and measure things that cannot be easily measured without a computer. Testing for reliability and validity becomes more complex for these tests. The results of reliability and validity studies should be published in the professional literature and should be reviewed by clinicians attempting to use a specific test in their practice. Some tests enjoy wide popularity among the public and among some clinicians despite the lack of evidence in the literature of concurrent or predictive validity. Careful clinicians will ask for a bibliography regarding a test before purchasing and using that test. Taking clinical action on a set of numbers or phrases derived from computerized testing is similar to getting numbers back from a clinical laboratory report of a blood test. The clinician must first have a measure of confidence in the clinical laboratory or the person developing the computerized test. The individual numbers, however, mean nothing unless they are evaluated within the context of the total patient condition and are integrated with other complementary or contradictory findings. The clinician's skill in using computer-based testing is the most central part of the overall ability to evaluate a patient. Does Computerized Testing Work? Patient acceptance of computerized testing has been very rapid and clinician acceptance is gradually increasing. Studies that have compared old (usually paper-and-pencil) versions of tests with computer-based tests have generally shown very good equivalence. However, when a group of 188 psychiatric patients were given a standard verbal digit span test as well as a computerized (visual) version of the verbal digit span the patients performed more poorly on the computerized test. The State Trait Anxiety Inventory and the Beck Depression Inventory (BDI) were administered in paper-and-pencil and computerized formats. The study also evaluated the amount of computer anxiety or computer phobia present among the students and found that those with greater computer anxiety also had high BDI scores. The study was not designed to find out why the depression scores were higher or whether they more accurately revealed the amount of a depression present in the subject. A study of alcohol consumption seemed to show that patients were more willing to divulge sensitive information about alcohol consumption to the computer than they were to the human interviewer. There are also valid questions concerning the tendency of computerized test subjects to respond in socially desirable ways. One study of 162 college students tested with the MMPI, the Research Evaluation Form, and the Drinking Habits Questionnaire supported the hypothesis that subjects reveal less damaging information to a human interviewer. Another study used the Paulhus Balanced Inventory of Desirable Responding (BIDR) on a group of 241 university students. The subscale evaluating responses in the socially desirable direction was higher in the computer-tested group as compared with the group administered this test by paper and pencil. However, a more refined version of the socially desirable subtest revealed no significant differences between computer and paper-and-pencil administration. Students who took these tests anonymously reported more pathology than they did in the nonanonymous situation. Using a later version of the BIDR test in an effort to replicate these results in a sample of 246 naval recruits revealed similar effects for anonymity but different effects for method of administration, which supports the idea that the initial version of the social desirability scale contains some confounding factors that did not properly evaluate the question of truthful responding. Deliberate Faking An evaluation of 100 college students taking a test by computer compared with 100 students taking the same test by paper and pencil revealed that 10 percent of the former group gave random responses and 4 percent of the latter group gave random responses. However, the random responders could be identified in both groups by inclusion of a scale that consisted of statements that could not possibly be true. Response latency also identifies faking. Latency is the number of milliseconds required to answer each question and the shortest response latencies are noted in random responding; this is followed by faking good responses, followed by honest responses, followed by faking bad patterns. There is a suggestion, however, that latency scores regarding questions evaluating medical problems are not as predictable. Another effort evaluated malingering. The addition of response latency as a measure of malingering increased the correct classification of malingerers by 30 percent as compared with traditional methods of detection. An extensive evaluation of patient acceptance in computerized testing situations revealed very good acceptance. The three main dimensions of this study compared traditional testing versus keyboard testing versus touch screen testing. Three hundred and sixty-seven psychiatric patients were tested on a variable number of eight computerized tests available. The standardized test was preferred in one case and the computerized test was preferred in another. In one other test the standard approach was preferred over the keyboard approach but was no different from the touch screen approach in terms of patient preference. There were, however, frequent differences between the touch screen approach—four tests were more easily or enjoyably performed on the touch screen as compared with the keyboard and only in one situation was the keyboard preferable to the touch screen to a significant degree. The researchers concluded that computerized testing was widely accepted. Cost Impact of Computerized Testing Potential cost savings exist in many aspects of computerized testing but surprisingly little has been done to document this. Administration of a test by a microcomputer, if amortized over the life of the computer, will probably be less than $1 per hour. This compares very favorably with what it costs when a psychometrist or a psychologist administers the same test. Test scoring by computer saves additional time and money. The computerized printout of test scores takes less time than the human typing of test results would require. Test royalties, if applicable, would be the same in both cases. Clinicians who have computerized testing readily available tend to perform more tests and to do a broader evaluation of the patient. This does have implications for quality of care. Computerized testing can be summarized and available for the clinician to view much earlier than testing done by conventional means. In some hospital settings this can make a difference of 1 day of hospital care. More thorough assessment and more focused treatment also has the potential to reduce the length of stay for a patient or to reduce the number of outpatient visits, which can reduce total health care costs. More studies need to be done to show the potential savings. It is estimated that more than 500 computerized tests are now available for use within the mental health field. Tests for Children and Adolescents A community center offering crisis and counseling services for children and adolescents can administer a screening battery to help with evaluation. Self-administered tests can evaluate family structure, family satisfaction, and drug use. This system can help to summarize the initial evaluation, provide a storage medium for problem lists, maintain notes of treatment sessions, and keep records for billing purposes. Diagnosing and monitoring attention-deficit disorders in children and adolescents is a very important task. Many different investigators have computerized this task and it does seem sensitive to treatment with methylphenidate (Ritalin). Some have started programs to measure these disorder via a microcomputer or on dedicated equipment. The computerized continuance performance test has been significantly correlated with teacher ratings of school performance, subtests of the Wechsler Intelligence Scale for Children-Revised that relate to attention, and some scales from the Conner Parent and Teacher Rating Scales. Parents of children with problems fill out the computerized version of the Child Behavior Checklist and report preferring it to the paper-and-pencil version. Respondents further displayed this preference by providing significantly more information about their child's difficulties on the computerized version. An evaluation of the paper-and-pencil versus the computer-administered version of the Piers Harris Children's Self Concept Scale revealed no significant differences between the means of the scales derived from each version. The scale summarizing behavioral problems did show significantly more variance on the paper-and-pencil test as compared with the computerized version. Personality Tests The Minnesota Multiphasic Personality Inventory (MMPI) are the most widely used assessments of personality and have good equivalence between the computer version and the traditional version. One study compared 80 community volunteers under one of four testing conditions: computer-computer, traditional-traditional, computer-traditional, or traditional-computer. These four sequences revealed no significant differences on any of the traditional scales and on 27 special scales. Another study used 150 college students to compare computer versus traditional administration of the MMPI. This study revealed more differences in the time of testing variable as compared with the format of testing. An evaluation of computer versus traditional testing of the MMPI in a group of 77 substance abusers also found no significant differences between formats. The computerized version versus the paper-and-pencil version of another popular test of personality, the Personality Research Form-E, was compared and showed good test-retest stability. Surprisingly, the infrequency scale (used to detect careless responding) was the only scale that did not show good levels of reliability. The sample population of 55 subjects was quite small and probably not sufficient to warrant discarding the Infrequency scale as has been suggested. The Jenkins Activity Survey helps to detect the type-A personality style associated with specific physiological responses to stress. Computerized and paper-and-pencil versions were compared in a group of 60 college students. There were no significant differences in the two forms when comparing method of administration or time (first or second) of testing. Reaction time for each question was also measured and was found to be significantly associated with the Speed and Impatience Scale on the second testing but not on the initial testing.

Obsessive-Compulsive Disorder Computerized tests assess the severity of symptoms of obsessive-compulsive disorder very well. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) evaluates the presence and severity of symptoms of this disorder and was computerized with high reliability results. The total Y-BOCS score correlated at r = .88 between the clinician-administered and the computer-administered forms and the subscales correlations were almost as high. Preference of the patient regarding form of testing was evenly split between the computer and the clinician versions. A version of the Y-BOCS has also been designed for administration by touch-tone telephone hooked up to a talking computer. This method was compared with a live telephone interview and a paper-and-pencil version. The agreement among the three methods was very high (r = 0.99) but more of the patients (44 percent) preferred the live interview and none preferred the talking computer. Depression The most widely used self-rating scale for depression is the BDI. This was computerized and administered to 330 inpatients. There was no paper-and-pencil comparison group but total scores and coefficient alpha were very similar to other published studies of the BDI. The scores on the BDI also correlated strongly with the clinical diagnosis of depression. The most frequently used depression rating for use by clinicians is the Hamilton Rating Scale for Depression (HAM-D). A self-administered version of the Hamilton scale that was developed for computer administration required 37 questions to cover the original 17 items. The mean difference in total score for the total sample was only 0.1 (17.29 for the clinical version and 17.19 for the computerized version). The correlation with the BDI was r = 0.925. Using a cutoff score of 17, the clinician-administered version showed a specificity of 100 percent and a sensitivity of 100 percent in identifying patients with major depressive disorder whereas the computer version showed a specificity of 100 percent and a sensitivity of 94 percent. Anxiety The Hamilton Rating Scale for Anxiety (HAM-A) has been one of the instruments most frequently used to evaluate anxiety, which is among the most frequent of the mental disorders in the United States. The HAM-A contains 14 items designed to be administered by a trained clinician. The computerized version of the HAM-A designed for self-administration contains 31 questions and was tested in a group of 292 adults including persons diagnosed as having a generalized anxiety disorder, panic disorder with or without agoraphobia, social phobia or obsessive-compulsive disorder, major depressive disorder, and community controls with no current diagnosis. The computer and the clinician versions of this test were administered in a counterbalanced form 1 week apart. The scores in the patients with anxiety disorder correlated very highly between the computer and clinician versions (coefficient alpha r = .92). The computer and the clinician versions of the test in a group of anxiety disorder patients were different at a significance of P < .05. This, however, translated to a difference of about one point in the total scale score, which may not translate to a clinically meaningful difference. On each occasion the scores on the computer were slightly higher than the scores of the clinician rater. Neuropsychology and Psychophysiology One large category of computer programs exploits the unique abilities of the microcomputer to administer tests consistently and in a very carefully timed pattern. Neuropsychological tests are very expensive to administer, score, and interpret. The digit span test, used to evaluate attention and memory, is simple enough so that the computerized version is fairly straightforward. The digit substitution test is a more complex evaluation of logic in addition to memory and can help to evaluate the effects of research medications on cognition. Patients with schizophrenia who were tested on a computerized version of the Tower of London test showed a slow and inefficient pattern of problem solving. The patients were slower in moving the pieces of the puzzle and required more moves to solve a particular problem. Schizophrenia patients also tend to do poorly in a specially modified version of the continuous performance test. These patients show a greater drop in performance over a 10-minute task than do normal controls. The evaluation of memory is an important part of the psychiatric evaluation. Recently, a comparison of eight different implementations of a memory test was conducted. The Halstead category test is a test that measures abstracting ability and is very sensitive to various kinds of brain damage. The test has been successfully computerized with good replication of the traditional testing method. The Cognitive Neuromotor Testing Battery includes five different tasks designed to measure speed of processing, vigilance, memory, and visuomotor skills. This test was originally designed to measure skills needed to drive but it was also found to be sensitive to the adverse effects of medications such as those accompanying treatment with benzodiazepines. The test was found to have a good correlation with an existing neuropsychological test. Investigators have also noted the sensitivity of computerized testing in detecting neurobehavioral toxicology and a series of computerized tests are available for this purpose and are reviewed in the literature. Psychiatric Diagnosis The Diagnostic Interview Schedule is a diagnostic instrument used by psychiatrists and lay interviewers in several large epidemiological studies. Its reliability as a valid diagnostic tool is established and several investigators have computerized this tool. The reliability of these computerized tests has generally been modest—the kappa values for the Levitan study ranged from .17 to .92 with a mean of .46. These values show the need to regard the computerized diagnostic instrument as suitable for screening only; they also point out the need for correlation of computer testing with the remainder of the clinical evaluation. Anorexia Nervosa A self-administered test for anorexia nervosa was computerized and is correlated highly with the standard paper-and-pencil version according to a recent sample of 47 subjects. Posttraumatic Stress Disorder Approximately 15 to 20 percent of war veterans report this disorder; civilians who experience a severely traumatic event are also at high risk. A semi-structured clinical interview was computerized for more efficient administration; the computerized version includes 34 questions and takes about 15 minutes to administer. The kappa for diagnosis of the disorder was .90 with a sensitivity of .95 and a specificity of .95, indicating excellent validity. Alcoholism Because treatment costs for alcohol and substance abuse problems have surpassed treatment costs for all the other mental illnesses since the mid-1980s, careful and efficient detection of these disorders of abuse is extremely important. Computerized screening and follow-up instruments have shown good validity and reliability. The self-administered Alcoholism Screening Test is a 35-item test in its long form and a 9-item test in its short form and it has demonstrated validity. The computerized version showed excellent correlation with the paper-and-pencil version. The differences in regard to format and order of administration were both nonsignificant. Agreement between the two forms was 95 percent. A follow-up instrument, the Substance Use Disorder Diagnostic Schedule, showed a similarly high agreement with the interviewer-administered format. k values were .86 for presence or absence of alcohol abuse and .86 for presence or absence of other drug abuse. These two computerized tests reported mild but nonsignificant increases in the amount of alcohol consumption as compared with reports from the interviewer-administered forms. Vocational Testing This testing can advance the process of making a career choice by identifying particular interests and aptitudes. The array of interests can then be compared to the responses of persons in particular fields and can help to achieve a compatible career choice. Computerized batteries have been developed to test an individual's aptitudes and interests and each of these tests has shown increased efficiency and reliability in the testing process. Behavioral Assessment Careful evaluation of potential reinforcers for a behavior therapy program conducted in a computerized evaluation was found to save time in identifying the optimal set of behavior reinforcers. Adaptive Testing Adaptive testing consists of a computerized method for selecting the optimal questions to be presented to a patient. These consist of branching patterns that depend on a screening question to decide the particular branches taken for a particular patient. The advantages of this method are that it saves the patient testing time and energy. Application of this method to lengthy tests such as the MMPI show substantial correlation with the full administration of the MMPI. Shortening the testing time is a dubious achievement because the computer-administered testing is extremely inexpensive. Development and validation of subscales of the MMPI or other tests is also hindered when only a subset of the test is administered to any particular patient, making it very difficult to develop norms. Questions that serve to screen patients and determine the choice of branches are sometimes too brief and too superficial to make a sensitive determination of the branching, which reduces the overall validity of the test; it is therefore wise to be cautious when using adaptive testing methods. Legal Aspects of Computerized Testing Computerized testing is similar to any other kind of psychological evaluation in the legal arena. The expert clinician on the witness stand is the one who is under scrutiny and must use these evaluation tools within the proper context and must have information about their development and validity. The expert must then consolidate all the available structured and clinical evaluation in order to form an opinion with “reasonable certainty.” Because the computerized testing can be subjected to measures of validity and reliability, the expert witness must be prepared to document knowledge of the development of a test. The clinical opinion of an expert witness is also subject to cross-examination and will almost certainly have less documented evidence of accuracy or validity. Computer-Based Test Interpretation Simple computerized scoring of test results is rapid, precise, and efficient. Computer scoring of tests such as the MMPI-2 with its many research scales is almost a necessity and is well accepted. Computer-based test interpretation of the test results is much more controversial. Validation of computer-based test interpretation has lagged behind the validation of

the test in question. Many computer-based test interpretation systems had attempted to generate interpretive statements for the MMPI-2. These statements were generally compared with statements by expert clinicians who looked at their own interpretation of the MMPI-2 but these were rarely compared with direct clinical observation of patients for cross-validation. Some interpretive systems make public the decision rules or the mathematical formulas that govern the generation of specific statements appearing on the interpretive summary. Other systems, however, keep the decision-making process secret and thus the clinician has no specific basis on which to judge the legitimacy of the derived interpretation, which makes it very difficult to use interpretive statements in court when the basis of those interpretations has not been revealed. Users of computer-based test interpretation products deserve to know the research underlying interpretive statements. Legitimate arguments exist about the optimal mathematical approaches to use in modeling the process of psychiatric diagnosis. The cookbook approach used in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders is easy to understand conceptually but is too simplistic to reflect accurately how human beings actually make diagnostic decisions and act on them. Some computerized systems use the logical decision tree, the Bayesian model, cluster analysis, multiple discriminate functions, or even neural networks. In fact, different clinicians may use different models successfully. Some clinicians are able to define the models they use whereas others cannot reduce these models to specific algorithms, which helps to explain why the field of computer-based test interpretation continues to evolve and must be approached cautiously.

FUTURE DIRECTIONS The rapid proliferation of the Internet has attracted the attention of those interested in public education and in the assessment of psychiatric illnesses. Several Internet sites now offer the public a chance to answer a select group of questions on a particular illness and receive feedback about the presence or absence of the illness in themselves. Referral sources are offered so that the individual can follow up on the situation. A recent World Wide Web search using the words “test” and “mental” found three Web sites (among the first 30 listed) offering online testing. One additional site offered a free test for depression that could be downloaded and used. Clinicians can also obtain tools to construct their own computerized questionnaires. This, along with the availability of numerous commercial testing programs, allows clinicians to use computerized testing of psychiatric patients in more extensive and comprehensive ways than ever before.

SUGGESTED CROSS-REFERENCES Statistics and experimental design are covered in Section 5.2. Psychiatric rating scales are discussed in Section 7.8. The psychiatric report and medical record is covered in Section 7.2. SECTION REFERENCES *Allen CC, Ellinwood EH, Logue PE: Constructive validity of a new computer-assisted cognitive neuromotor assessment battery in normal and inpatient psychiatric samples. J Clin Psychol 49:784, 1993. Baer L, Brown-Beasley MW, Sorce J, Henriques A: Computer-assisted telephone administration of a structured interview for obsessive-compulsive disorder. Am J Psychiatry 150:1737, 1993. Booth-Kewley S, Edwards JE, Rosenfeld P: Impression management, social desirability, and computer administration of attitude questionnaires: Does the computer make a difference? J Appl Behav Sci 77:562, 1992. Bucholz KK, Robins LN, Shayka JJ, Przybeck TR, Helzer JE, Goldring E, Klein MH, Greist JH, Erdman HP, Skare SS: Performance of two forms of a computer psychiatric screening interview: Version I of the DISSI. J Psychiatr Res 25:117, 1991. Choca J, Morris J: Administering the Category Test by computer: Equivalence of results. Clin Neuropsychol 6:9, 1992. Conoley CW, Plake BS, Kemmerer BE: Issues in computer-based test interpretive systems. Comp Hum Behav 7:97, 1991. Davis LJ, Hoffman NG, Morse RM, Luehr JG: Substance Use Disorder Diagnostic Schedule (SUDDS): The equivalence and validity of a computer-administered and an interviewer-administered format. Alcohol Clin Exp Res 6:250, 1992. Davis LJ, Morse RM: Self-administered alcoholism screening test: A comparison of conventional versus computer-administered formats. Alcohol Clin Exp Res 15:155, 1991. Faust D, Ziskin J: Computer-assisted psychological evaluation as legal evidence: Some day my prints will come. Comput Hum Behav 5:23, 1989. Fekken GC, Holden RR: Psychometric evaluation of the microcomputerized personality research form. Educ Psychol Measure 49:875, 1989. *Finger MS, Ones DS: Psychometric equivalence of the computer and booklet forms of the MMPI: A meta-analysis. Psychol Assess 11:58, 1999. Flowers JV, Booraem CD, Schwartz B: Group therapy client outcome and satisfaction as a function of the therapists' use of rapid assessment instruments. Small Group Res 24:116, 1993. French CC, Beaumont JG: The reaction of psychiatric patients to computerized assessment. Br J Clin Psychol 26:267, 1987. French CC, Beaumont JG: Microcomputer version of a digit span test in clinical use. Interacting Comput 4:163, 1992. *Glover G: Mental health informatics and the rhythm for community care: Information systems in psychiatry must be released from the asylums and updated. BMJ 311:1038, 1995. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL Heninger GR: The Yale-Brown Obsessive Compulsive Scale: I. Development, use and reliability. Arch Gen Psychiatry 46:1006, 1989. Greist JH, Klein MH, Erdman HP, Bires JK, Bass SM, Machtinger PE, Kresge DG: Comparison of computer- and interviewer-administered versions of the Diagnostic Interview Schedule. Hosp Community Psychiatry 38:1304, 1987. Harrell TH, Honaker LM, Hetu M, Berwager B: Computerized versus traditional administration of the Multidimensional Aptitude Battery—Verbal scale: An examination of reliability and validity. Comput Hum Behav 3:129, 1987. Hedlund JL, Vieweg BW: Automation in psychological testing. Psychiatr Ann 18:217, 1988. Honaker LM, Harrell TH, Buffaloe JD: Equivalency of microtest computer MMPI administration for standard and special scales. Comput Hum Behav 4:323, 1988. Kane RL, Kay GG: Computerized assessment in neuropsychology: A review of tests and test batteries. Neuropsychol Rev 3:1, 1992. Kobak K, Reynolds WM, Greist JH: Development and validation of a computer-administered version of the Hamilton Anxiety Scale. Psychol Assess 5:487, 1993. Kobak KA, Reynolds WM, Rosenfeld R, Greist JH: Development and validation of a computer-administered version of the Hamilton Depression Rating Scale. Psychol Assess 2:56, 1990. Kobak KA, Taylor L, Dottl SL, Greist JH, Jefferson JW, Burroughs D, Katzelnick DJ, Mandell M: Computerized screening for psychiatric disorders in an outpatient community mental health clinic. Psychiat Serv 48:22, 1997. Levitan RD, Blouin AG, Navarro JR, Hill J: Validity of the computerized DIS for diagnosing psychiatric inpatients. Can J Psychiatry 36:728, 1991. Mattila MJ, Aranko K, Mattila ME, Paakkari I: Effects of psychotropic drugs on digit substitution: Comparison of the computerized symbol digit substitution and traditional digit symbol substitution tests. J Psychopharmacol 8:81, 1994. Miller MJ: Computerized models of psychiatric diagnosis. In Using Computers in Clinical Practice. EM Schwartz, editor. Haworth Press, New York, 1984. *Miller MJ, Hammond KW, Hile MG, editors: Mental Health Computing. Springer-Verlag, New York, 1996. Neal LA, Busuttil W, Herapath R, Strike PW: Development and validation of the computerized clinician administered Post Traumatic Stress Disorder Scale-1-Revised. Psychol Med

24:701, 1994.

Nestor PG, Faux SF, McCarley RW, Shenton ME, Sands SF: Measurement of visual sustained attention in schizophrenia using signal detection analysis and a newly developed computerized CPT task. Schizophr Res 3:329, 332, 1990.

Rosenfeld R, Dar R, Anderson D, Kobak KA: A computer-administered version of the Yale-Brown Obsessive Compulsive Scale. Psychol Assess 4:329, 1992. Steer RA, Rissmiller DJ, Ranieri WF, Beck AT: Use of the Computer Administered Beck Depression Inventory and Hopelessness Scale with psychiatric inpatients. Comput Hum Behav 10:223, 1994. Vansickle TR, Kapes JT: Comparing paper-pencil and computer based versions of the Strong-Campbell Interest Inventory. Comput Hum Behav 9:441, 1993. *Vaterott M, Callier J, Hile M: The development of the Missouri Automated Reinforcer Assessment (MARA): An update. In Computer Applications in Mental Health: Education and Evaluation, MJ Miller, editor. Haworth Press, New York, 1992. Vieweg BW, DiFranco B: The use of automated assessment with seriously mentally ill clients. Behav Health Tomorrow 4:37, 1995.

Textbook of Psychiatry

CHAPTER 8. CLINICAL MANIFESTATIONS OF PSYCHIATRIC DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 8. CLINICAL MANIFESTATIONS OF PSYCHIATRIC DISORDERS JOEL YAGER, M.D., AND MICHAEL J. GITLIN, M.D. Predisposing Vulnerabilities Characteristics of Psychiatric Signs and Symptoms Somatic Manifestations of Psychiatric Disorders Disturbances in Thinking Thought Disturbances Thought Content Disturbances in Perception Disturbances of Mood Disturbances in Motor Aspects of Behavior Language Disorders Disturbances in Interpersonal Relationships Future Directions Suggested Cross-References

Like other medical disorders, psychiatric disorders express themselves in characteristic ways. Deviations from normal, from mild to severe, may occur in the intensity, duration, timing, and content of thoughts, emotions, and behaviors. Inquiring about subjective complaints and clinical symptoms and observing and eliciting the clinical signs of psychiatric disorders parallels taking a history and conducting a physical examination in general medicine. Many psychiatric complaints and disorders have to be understood in a broad context, requiring a more thorough evaluation and comprehension of the patient's interpersonal world, work role, family life, and culture than is typical in general medical practice. The nature and expression of psychiatric signs and symptoms are profoundly altered by the patient's strengths, coping capacities, and psychological defenses, so that the clinical picture ultimately represents a balance between psychopathology and psychological strengths. The most important distinction between typical presentations of medical diseases and those of psychiatric disorders is the greater importance in psychiatric disorders of the patients' sometimes idiosyncratic descriptions of their qualitative internal states, subjective experiences that are often difficult to describe in words. Poets and novelists are often more capable than clinicians at characterizing and delineating the precise quality and experience of many psychiatric symptoms. Many patients and clinicians often find it difficult to accurately communicate a fully comprehensible and reliable description of even familiar, somewhat universal feeling states. An usually articulate woman, a published writer, tried to relate the differences she felt between the fatigue she associated with her disabling Lyme disease and the fatigue she experienced during a previous bout of atypical depression. Although unusually gifted in her capacity to form images in words, she found that her capacity to express exactly what she meant was not up to the task. She remained frustrated, knowing that she had not been able to adequately describe or convey the subtle but real distinctions in how she had experienced these two states. Subjective descriptions of psychiatric symptoms are inherently less reliable, or at least less objective, than more directly measurable and quantifiable data such as blood pressure, temperature, and laboratory test results. A great deal of the research in psychiatric diagnosis over the last 25 years has been concerned with increasing the reliability of observer-rated clinical symptom assessments. In many ways this research has had the desired impact—clinicians and researchers using a variety of structured interviews can come to reasonable agreement on what symptoms patients are experiencing and whether these patients meet the criteria for most of the specific psychiatric disorders in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). However, one of the costs of this increasing reliability has, in many instances, been the narrowing of the field of clinical vision. Clinicians who rely predominantly on structured interviews and checklists may become somewhat closed-minded and risk ignoring clinical phenomena that are very important, but that may not be part of the structured interview framework or mental set. Furthermore, the quest for reliability can go only so far in describing phenomena that are difficult to express in words. Despite these difficulties, a thorough assessment of the clinical history and description of the psychopathology and a detailed account of the patient's subjective experiences are important because: 1. Significant diagnostic distinctions are made primarily on the basis of the historical information and elicited phenomenology. The more detailed, complete, and correct the diagnosis, the more rational and precise the treatment planning and the more reliable the prognosis. Consider, for example, the importance of accurately distinguishing between antipsychotic-induced akathisia and anxiety symptoms related to psychotic thinking. On the basis of the diagnosis made, opposite therapeutic strategies may be attempted. 2. The clinician's capacity to fully hear and communicate a comprehensive understanding of a patient's internal experiences helps to diminish the patient's sense of isolation, so characteristic of many of these disorders, and fosters the growth of a therapeutic alliance, increasing the likelihood of compliance with treatment.

PREDISPOSING VULNERABILITIES Genetic and Intrauterine Factors Genetic vulnerabilities play an important role in the expression of many psychiatric disorders. Prominent among these are dementia of the Alzheimer's type, schizophrenia, mood disorders, anxiety disorders, and alcohol dependence. For virtually all these disorders, the nature of the inherited vulnerabilities is still largely unknown. Intrauterine processes contribute to many psychiatric disorders. For example, maternal starvation and influenza infections during the second trimester of pregnancy have been implicated in the pathogenesis of schizophrenia. Maternal smoking and low birth weight may be risk factors in the pathogenesis of attention-deficit disorders in children. Maternal alcohol abuse or dependence may lead to the fetal alcohol syndrome, a major cause of developmental disability. Constitutional Factors Considerable research demonstrates that by birth and shortly afterward infants differ widely in temperament—in their spontaneous activity levels and thresholds, intensity, and duration of their reactions to external stimuli; the regularity or irregularity of certain biological rhythms such as sleep; tendencies to approach or withdraw from new stimuli; the speed and degree of adaptation; attention span and distractibility; the persistence of behavior; and qualities of mood. Based on such early behaviors, children may be described as having easy or difficult temperaments, as being quick or slow to warm up. Temperament, however, is not immutable. There are discontinuities over time, and the development of temperament and its lasting impact on personality development is at least in part a function of the goodness of fit with a child's family. Nevertheless, these temperamental qualities correlate somewhat with behavioral problems, especially through early childhood. Aside from temperament, other persistent normal variations in personality development seem to be constitutionally related, and may influence subsequent resilience or vulnerability. Traits such as introversion, extroversion, and neuroticism appear to be relatively enduring and stable personality dimensions. Other temperamental qualities that endure include tenacity, novelty-seeking, and being relatively open to new experiences. Subtypes of intelligence, such as those related to conceptual, mathematical, musical, kinesthetic, and interpersonal abilities have been postulated as having separate genetic determinants and patterns of development. The type A and B personality patterns, hardy and resilient personalities, highly strung, sensitive, fussy, irritable, and pessimistic characteristics have all been described as generally lifelong qualities that originate in early childhood. Physiological Stressors Physiological vulnerability may result from long-standing problems or from newly acquired ones. All the metabolic, toxic, infectious, and other causes of physical illness produce increased vulnerability to psychiatric disturbance. Studies have shown higher utilization of psychiatric services by those who are physically ill, and higher than expected prevalence of physical disease among the psychiatrically impaired. Some children with prepubertal onset, obsessive-compulsive disorder and tic disorders that have an episodic symptom course have been found to have pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A b-hemolytic streptococcal) infections (PANDAS). Accompanying symptoms during episodes of exacerbation are emotional lability, separation anxiety, nightime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity. In PANDAS patients flareups of behavioral problems are commonly associated with documented group A b-hemolytic streptococcal infections or symptoms of pharyngitis and upper respiratory infections. Human immunodeficiency virus (HIV) infection leading to seropositivity and acquired immune deficiency syndrome (AIDS) vividly illustrates the multiple and complex ways in which stressors can lead to psychiatric disturbances. These patients' psychiatric symptoms may represent organic changes that are the direct effects of the

virus on the central nervous system (CNS), producing changes in cognition, personality, and mood; understandable psychological adjustment responses of patients in response to an overwhelming life-threatening disorder; or the emergence of latent or quiescent primary psychiatric problems provoked by the psychological stress of the viral illness. A 55-year-old successful businessman with a strong family history for unipolar depression started to feel mentally sluggish, and developed depressed mood, psychomotor retardation, and ruminative self-doubts. A medical work-up revealed high serum calcium that led to a diagnosis of hyperparathyroidism, which was ultimately treated surgically. Once the parathyroid problem was corrected, the mood disorder disappeared without further treatment. Environmental Stressors Complex relationships exist between various life events, particularly threatening, unpredictable, and uncontrollable negative events, and the development of psychiatric symptoms. In general, such undesirable life events predispose individuals to develop psychiatric symptoms, especially if they already have a preexisting psychiatric disorder. After exposure to the same negative stressors such as a serious accident or act of violence, individuals who previously had anxiety disorders are more prone than those without such histories to subsequently develop symptoms of posttraumatic stress disorder. Although individual responses vary widely, truly catastrophic events, such as incarceration in a concentration camp, cause enduring psychiatric disturbances in a high percentage of survivors whether or not they had prior psychiatric problems. Similarly, the stress-related consequences of combat also vary widely, so that some veterans exposed to combat develop long-lasting posttraumatic stress disorder whereas others develop very few persistent symptoms. The death of a parent or spouse, divorce, and major physical injury affect some people profoundly and others hardly at all in the long run. Significant stressors are likely to be more traumatic during early development rather than later, or at certain critical developmental periods compared to other times. For example, the loss of a parent at a very young age is likely to be more traumatic and have more profound and lasting effects than the loss of a parent as an adult. The combined impact of negative life events and poor emotional and practical social supports is important in the pathogenesis of at least some psychiatric disturbances. One British study found that women who were depressed were much more likely to have lost a parent at an early age, to be relatively housebound with three or more young children, and to lack a good confiding relationship with a spouse or other confidant. In that study biological vulnerability to depression seemed less important than the accumulation of negative life circumstances in the development of the disorder. People who are usually competent in all role functions may fall apart completely when a supportive spouse who has bolstered them and taken care of many of their needs dies suddenly. Patients presenting with a major depressive episode have experienced more uncontrollable actual and threatened losses such as the death of a spouse in the year prior to onset. Nevertheless, not all psychiatric disturbance is attributable to easily identified provoking negative life events; indeed, some major negative life events that seem to have preceded the onset of a serious psychiatric disturbance may in fact have occurred only after the psychiatric disturbance actually began. For example, someone who attributes the onset of depression to having been fired from a job several months previously may already have been functioning suboptimally and may have been fired as a consequence of a depression-induced decline in role function. Certain environmental features can counter the effects of environmental stressors and protect against breakdowns. Stable families and friends, good financial circumstances, and supportive churches and communities offer some protection. Research has shown that individuals with psychiatric disturbances have fewer social supports than normal controls. This may be caused by friends' and relatives' withdrawal from deviant behaviors or by the disturbed individual's withdrawal from deleterious family and social relationships. In contrast, physically ill persons have more social supports than others, perhaps reflecting their ability to recruit help in times of need. The quality as well as the quantity of social supports is important too. As has been demonstrated in schizophrenia and mood disorders, for example, even in close families negative relationships may have deleterious effects in initiating and in sustaining psychiatric disturbance. The negative impact of a physiological or environmental stressor is closely related to its personal meaning to the individual in question. For example, the loss of a spouse who has been chronically demented, disabled, and burdensome will have a very different impact than the loss of vital, supportive, loving spouse.

CHARACTERISTICS OF PSYCHIATRIC SIGNS AND SYMPTOMS Signs and symptoms form the two major categories of clinical phenomena. Classically, as for most medical disorders, the distinction between the two is clear. Symptoms are subjectively experienced disturbances that are not necessarily observable by others. Patients complain of symptoms—for example, chest pain, headache, and tingling sensations. Signs are abnormalities that are observable by an examiner, including those that are easily evident in the course of a routine encounter with the patient as well as those elicited only through specific physical, mental status, or laboratory examinations. In psychiatry the line between symptoms and signs is often more blurred than in general medicine. For instance, many phenomena often considered to be symptoms of psychiatric disorders may not be experienced as psychiatric problems by patients. Hearing an angel's voice may represent a manifestation of a psychotic disorder, yet the patient may vigorously dispute that the experience is a psychopathological symptom. Additionally, auditory hallucinations are often considered to be signs of a psychotic disorder even though, by their very nature, they are subjective internal experiences (symptoms). Further complicating the distinction, some psychiatric phenomena, such as the classical psychological defense mechanisms, may only be inferred from speech and behaviors but are not directly observable. Signs and symptoms are said to be present when the limits of normal variability are surpassed. Abnormalities may manifest as alterations in amplitude (e.g., excesses or deficits), duration, intensity, timing, and modifiability of physiological events, perceptions, emotions, thoughts, and motor activities. These limits are often arbitrary. Examples include the number of hours of sleep, the intensity of anger, or the extent of mood lability. However, for other experiences the distinction between normal and abnormal is qualitative, not quantitative. However, for some phenomena, any is too much. In mainstream American culture, for instance, any experience of thoughts being broadcast out loud is considered pathological. These signs and symptoms must all be considered in context because exactly what constitutes “normal” varies from culture to culture and from situation to situation. A behavior or subjective experience that may be defined as symptomatic in one context may be perfectly acceptable and within normal bounds in another. A phenomenon should be considered abnormal only if it seems deviant within the patient's unique culture after its full physiological and environmental context is taken into account, and if it causes personal or interpersonal impairment. Too often, phenomena prematurely mislabeled as psychopathological turn out to be perfectly understandable and nonpathological once the whole situation is appraised. Conversely, some examiners are reluctant to label certain phenomena as psychopathological even when they clearly are, for fear of stigmatizing the patient. Within cultures, most interpersonal interactions are carefully regulated by tight sets of rules and controls, and constrained by reasonably well defined sets of expectations and acceptable limits. Even slight deviations from these acceptable limits are quickly perceived by lay persons as well as professionals, because behavioral deviances are often experienced as threats. Deviations in amplitude, duration, and intensity can occur in facial expressions, gestures, postures, vocalizations, language, and other expressions of emotion and thought. A small increase in the rate of speech, an intrusion into one person's conversation by another who does not allow proper pauses, a gesture that comes just a bit too close to a face, an excessively rigid or distant stance, or a gaze that is too staring or too avoidant—each signals social insensitivity and alerts the observer to deviant behavior. Reliability Problems Among the core difficulties in psychiatric evaluation has been that multiple observers may note different symptoms or interpret signs differently when interviewing the same patient. These discrepancies may be caused by differences in the patient's status or in information imparted by the patient from examination to examination, in the observers' definitions of the symptoms or signs in question, and differences in perceiving and interpreting the patient's responses to general presentation or questions within the interview. These three types of reliability problems are called information variance, criterion variance, and observation bias. Although good interrater reliability can be achieved for most symptoms of Axis I disorders, this may not hold true for personality disorders or for some specific symptoms. Furthermore, good interrater reliability may occur consistently only under optimal circumstances and may not be as common in clinical practice. Even when simply responding to direct questions about symptoms, patients may answer differently depending on the interviewer's manner, how the questions are asked, their personal sense of trust or safety, whether they have answered these questions before, the amount of cuing that may signal the desired response fatigue, or a host of other variables. Most clinicians still rely heavily on their own clinical intuition and subjective responses to patients as part of a diagnostic assessment. Unfortunately, whether accurate or not, these clinical judgments are often based on nonconscious assumptions, comparisons with other patients not well remembered, or distortions based on the clinician's own personal experiences. When the bases for these intuitions can be identified and described clearly, they may prove to be reliable and valid. However, intuitions are often wrong—simple trust in intuition alone is not sufficient. Thus, a clinician's sense that a patient is angry and potentially violent may result from the patient's subtle (but verifiable) body language and tone of voice—or it may represent a countertransference distortion that is not prompted by any observable patient

behavior. Clinicians often too quickly label behaviors as inappropriate when they fail to appreciate and understand contextual or cultural considerations. Appropriateness depends heavily on context, and definitions of what is proper in a given context may also be highly subjective. Appropriate behavior or clothing in some parts of California may be inappropriate in Boston. A low intensity of emotional expression leading to a clinical description of “constricted affect” may reflect cultural norms or a psychopathological state. Nonspecific Nature of Signs and Symptoms Until psychiatry discovers reliable diagnostic laboratory tests to define clinical syndromes, the field will continue to construct diagnostic categories based on the clustering of signs and symptoms within specific time frames. Unfortunately, pathognomically specific signs or symptoms rarely exist in psychiatry; virtually all psychiatric symptoms are nonspecific and are usually seen in a many different disorders. Depressed mood, for example, occurs in a wide variety of diagnostic groups—including major depressive disorder, schizophrenia, some personality disorders, and mood disorder due to a general medical condition. Even the so-called first-rank symptoms of schizophrenia described by Kurt Schneider are diagnostically nonspecific and are seen with some frequency in otherwise classic depressive and bipolar disorders. In general medicine, symptoms not recognized as part of a clearly defined syndrome are often described as being of unknown origin. Thus, a fever that cannot be ascribed to a known disorder, such as pneumonia, is described as a fever of unknown origin. Given the nonspecific nature of psychiatric symptoms, it would seem wise to use similar conventions, referring to hallucinations of unknown origin or depressed mood of unknown origin when a symptom cannot be clearly linked to a well-described syndrome. Even though individual signs and symptoms may be organized into syndromes and disorders, they often have courses of their own. Thus, in the appearance or the resolution of a disorder, certain associated signs and symptoms may appear very early or may persist after all the others have waned. For example, in the restricting form of anorexia nervosa, excessive exercise is often the first symptom to appear and the last to abate even after dieting has stopped. In some cases, certain signs and symptoms that are commonly associated with a given disorder may fail to appear. Each sign and symptom may have its own pattern and variable response to treatment. In the treatment of schizophrenia, for example, some patients experience rapid resolution of hallucinations but have persistent delusions without ever having any other thinking disorders, whereas others may have no residual hallucinations or delusions but still have prominent thinking disorders. Sign and Symptom Categories Signs and symptoms have been categorized in a variety of ways: state versus trait, primary versus secondary, and form versus content. The state versus-trait distinction refers to whether the sign or symptom is an enduring characteristic of the person (‘traits”) or time-limited. Phenomena associated with specific Axis I disorders are usually state-associated phenomena. However, some enduring traits may also be symptoms. A person who always worries a great deal, chronically exhibits catastrophic thinking, and feels subjectively nervous in many different circumstances since early childhood may have trait anxiety. However, if such symptoms of anxiety are present only during a specific time frame, for example, over a 9-month period in conjunction with a full depressive syndrome, they are best described as state-related symptoms. During the acute stages of psychiatric disorders marked by dramatic state characteristics, it is unwise to infer that any of the prominent signs or symptoms are enduring traits, even those usually associated with personality. Thus, a diagnosis of dependent personality traits based on an acutely depressed patient's behavior is often incorrect. Similarly, manipulative behavior in the midst of a hypomanic or manic episode should not be considered evidence for enduring manipulative traits unless these behaviors are also present when the mania has clearly resolved. Distinctions between primary and secondary symptoms have been blurred by varying definitions of these terms. The distinction may refer to causal relations between what is primary and secondary, temporal sequence between the two symptom sets, or inability to more clearly understand the origin of the various symptoms. Basing the distinction between primary and secondary upon causality implies that the terms cause and effect are clearly understood. In attention-deficit/hyperactivity disorder, for instance, the attention deficit is thought to be primary whereas the hyperactivity is thought to be secondary, caused by the inability to attend. Patients who develop severe dependent personality traits and chronic demoralization only after experiencing several incapacitating psychotic mood episodes might be described as having primary mood disorders and secondary personality disorders. Conceptual models of psychopathology in which some signs and symptoms are seen as restitutive albeit ineffective attempts to cope with more fundamental psychopathological deficits use a primary-secondary model. For example, Eugen Bleuler viewed thought disorder as a primary symptom in schizophrenia, but viewed hallucinations and delusions as secondary symptoms that developed to help the patient cope with the chaos of the primary symptoms. These models must be viewed as hypothetical constructs only and applied with great caution because in the vast majority of clinical phenomena little evidence indicates that one symptom is more primary than another. Temporal sequence in the appearance of certain symptoms is regularly used as the basis for deciding the primacy of certain symptoms, behaviors, or disorders, such as in trying to determine what is primary and what is secondary when substance abuse occurs in conjunction with depression or anxiety. These differences are not trivial but often have strong treatment implications, because for example, treating a primary mood disorder in a substance-abusing patient (with a long course of medication) is quite different from expecting that with prolonged sobriety a secondary mood disorder will resolve on its own. Furthermore, it is becoming increasingly clear that the presence of certain preexisting psychiatric conditions, such as personality disorders, increases one's vulnerability for the subsequent development of other psychiatric disorders, such as major depressive disorders. Unfortunately, establishing temporal sequence with any certainty is usually difficult. Although there is a high comorbidity between bulimia nervosa and major depressive disorder, in excess of 50 percent according to some studies, attempts to establish which disorder is primary have been inconclusive. Even with careful historical analysis, major depressive disorder precedes bulimia nervosa, bulimia nervosa precedes major depressive episodes, and the two conditions start concurrently in about equal percentages. Making simple categorical distinctions between primary and secondary signs, symptoms, and disorders is less important than understanding the contribution of each element as a thread in the evolution and development of a given clinical presentation. From this perspective, each element can be viewed as dynamically affecting the appearance, manifestations, and course of the others and as exerting its own influence on the pathogenesis and treatment of the specific syndromes and associated disorders. For example, the onset, specific nature, and independent time course of sleep disturbances and insomnias may prove to be important in understanding the appearance, manifestations, and sequence of other prominent signs and symptoms of the mood disorders of which they are a part, and in their treatment. This view is particularly important because despite the excellent conceptual contributions made by categorical diagnostic systems such as the American Psychiatric Association's DSM-IV, distinctions are often fuzzy in clinical practice and comorbidity among so-called categorically distinct disorders is often the rule rather than the exception. For example, data from the National Comorbidity Study show that 14 percent of the population experience three or more comorbid psychiatric disorders. In such individuals the dynamic interactions and mutual influences of various signs and symptoms, and their biological underpinnings, becomes impossible to disentangle. Furthermore, the categories that currently comprise DSM-IV are not going to be the last word in the evolving history of psychiatric diagnosis. Recent studies show that psychiatric signs and symptoms may be usefully grouped into psychotic syndromes that differ in some respects from current DSM-IV categories. In a large family study of probands with broadly defined schizophrenia and affective illness and their first degree relatives, using a sophisticated statistical technique called latent class analysis Kenneth Kendler and his colleagues found six classes of psychosis including classic schizophrenia, major depression, schizophreniform disorder, bipolar-schizomania, schizodepression, and hebephrenia. While these classes bore substantial resemblance to current or historical nosological constructs, several of them differ from DSM-IV nosological constructs. In another study the three factors ordinarily associated with symptoms of schizophrenia, representing positive, negative and disorganized symptom domains, were found not to be specific to schizophrenia but were found in other schizophrenia-spectrum psychoses and in nonschizophrenia-like psychotic conditions as well. Context Signs and symptoms are usually not static entities; depending on the context, they often vary in intensity or even in their existence. The depressed mood of a melancholic depression may persist regardless of the external situation whereas the depressed mood of milder depression may vanish completely during certain situations—including a psychiatric interview—only to reappear at other times. Signs and symptoms that occur only in specific settings or with certain internal states are referred to as state-dependent. For example, certain hallucinations or memories may be present only during states of drug or alcohol intoxication; in some patients, hives may erupt as a psychophysiological response only during states of anger. Interpersonal context is also important. Some persons become violent only when involved in sadomasochistic relationships or in certain group settings, such as within adolescent gangs. In gangs, social pressures for conformity and expectations for aggressive behavior may provoke or release pathological behaviors that might otherwise never be expressed by gang members individually. Problems and Impairments Beyond the classic signs and symptoms of psychiatric disorders, recent attention has focused on the problems and impairments that psychiatric signs, symptoms, and disorders generate in affecting specific role functions and in causing social and economic burdens for the patient and others. These problems and impairments often cut across traditional sets of signs and symptoms of which categorical diagnoses are composed, affecting, for example, basic abilities to care for oneself and one's family, marital functioning, child rearing, wage earning, school performance, and social behavior. They constitute the issues with which

patients and families contend, and they need to appear on the problem lists that treatment plans and specific interventions target. Studies reveal that the impairments imposed by major depression are considerable with regard to physical functioning, role limitations, and social functioning. Problems such as violent temper outbursts, sexual aggression, or lack of job skills, which may impair role functioning in several spheres, must be directly addressed in their own right regardless of the associated DSM-IV diagnoses. These impairments enter determinations of ratings for Axis V of DSM-IV, which addresses the global assessment of functioning, and are of considerable importance in evaluating treatment outcomes. Table 8-1 lists some examples of critical impairments that have been recognized as often requiring urgent or intensive levels of care.

Table 8-1 Signs, Symptoms, and Impairments Requiring Immediate Care

Need for a Comprehensive Perspective A psychiatric disorder may be characterized by disturbances involving a wide variety of areas in the patient's life, including the biological, psychological, behavioral, interpersonal, and social spheres. In practice, common psychiatric syndromes often manifest in each of these dimensions. (Table 8-2). Viewing the patient from multiple perspectives, using the so-called biopsychosocial model (similar to the multiaxial approach of DSM-IV) enables clinicians to consider psychopathology and its effects on a patient's life in the broadest possible manner. To illustrate, Figure 8-1 lists some clinical hypotheses commonly used by clinicians as they link collections of signs and symptoms into syndromes and consider the treatment options that would logically follow.

Table 8-2 Common Current Clinical Hypotheses Used to Assess Signs and Symptoms: Ways of Understanding the Patient's Problems

FIGURE 8-1 Biological, psychological, and social forces interact and effect the psychiatric health of a person. (Adapted from Richmond JB, Lustman SL: Total health: A conceptual visual aid. J Med Educ 29:23, 1954.)

Because the amount of information gathered in a thorough assessment of a psychiatric disorder is potentially overwhelming, clinicians often tend to limit their fields of vision and appreciate only part of the available information; the clinician's theoretical orientation and other personal and cultural factors also limit what is perceived. Research has demonstrated that clinicians tend to perceive primarily those signs and symptoms that are most in accord with their own opinions and with the tools they have to treat psychiatric disorders, a phenomenon known as concept-driven perception. The theoretical biases of clinicians seem to be related both to the microcultures of their training programs and to their own personality traits. Such differences may lead one clinician to see a major mood disorder, to be treated with medication, where another sees a pervasive personality problem with dysthymic disorder, to be treated with psychotherapy, and to use different technical terms to label the same phenomenon. A psychodynamic psychiatrist might see psychomotor retardation where a neuropsychiatrist sees bradykinesia; a psychodynamicist might see depressed mood and muted speech where a neuropsychiatrist sees mask-like facies and aprosodic speech; the psychodynamicist might see ruminative thought where a neuropsychiatrist sees forced thinking; a psychodynamicist might see a grimace where a neuropsychiatrist sees a tic. Given the extent to which words themselves shape our concepts of reality, the consequences of using these different labels for very similar phenomena may be significant. Figure 8-1 illustrates concept-driven perception in which each clinician who adheres to a prominent contemporary point of view perceives only some of the potentially available phenomena related to a psychiatric disorder. Although there is overlap, each observer also perceives information that other observers do not notice. Also, some information that may be highly relevant to diagnosing or treating the disorder may be overlooked by all the observers. The intermittent nature of many psychiatric signs and symptoms; the potential unreliability, selective recall, and false recall of patients and others in reporting symptoms and events; differing interpretations of elicited information or observations; and subjective theoretically driven biases that influence the clinician's perception of signs and symptoms, all contribute to potential errors in data collection. To help guard against misinformation and simplistic understandings and formulations, wherever possible complete assessment of a psychiatric patient requires consultation with family, friends, co-workers, and other professional observers to enrich the history and to provide supplemental observations of the patient over time.

SOMATIC MANIFESTATIONS OF PSYCHIATRIC DISORDERS Virtually all Axis I, symptom-based disorders and most other psychiatric disorders are characterized by disturbances in at least some basic physiological functions. Although frequently nonspecific in nature, the severity of these somatic signs and symptoms provides markers as to the amount of biological disruption seen in the disorders that cause them. Furthermore, somatic symptoms can also cause exacerbations of some disorders. If untreated, these processes can create destructive feedback loops in which the disorder causes symptoms, which then exacerbates the disorder, which increases the symptoms, and so on. For example, the insomnia of manic or hypomanic episodes will, if untreated, cause a marked worsening of the mania; similarly, the weight loss of anorexia nervosa causes starvation effects such

as a preoccupation with food, thus exacerbating one of the hallmark features of the underlying disorder. Sleep Disturbances Abnormalities of sleep may manifest in the amount, quality, and timing of sleep, as well as by the presence of abnormal events during sleep. Insomnia is usually defined by its subjective component as the sensation of sleeping poorly. Most but not all patients complaining of insomnia will demonstrate some sleep abnormality if examined in a sleep laboratory. Insomnia is a common, often chronic symptom or sign of many different psychiatric disorders and conditions including substance abuse, depressive disorder, generalized anxiety disorder, panic attacks, manic episodes (in which the diminished sleep does not always provoke a complaint), and acute schizophrenia. It may also occur as a consequence of aging or as a symptom or disorder not associated with other psychopathology. Insomnia may also result from the ingestion of substances that alter the normal sleep-wake cycle, including alcohol or stimulants, and by the discontinuation of sedative-hypnotics. Although much attention is often paid to distinguishing patterns of insomnia, such as difficulty falling asleep versus middle or terminal insomnia (early-morning awakening), or linking specific patterns linked to specific conditions (e.g., major depressive episode with melancholic features and associated terminal insomnia) the clinical utility of these distinctions is unclear. A 62-year-old woman presented with new-onset primary insomnia. In spite of an extensive medical work-up by her primary physician, and equally extensive psychiatric examination, no other medical, psychiatric, iatrogenic, or substance-related problems usually causing or associated with insomnia could be identified. She was treated for her symptoms with hypnotic agents and experienced partial improvement. The insomnia persisted for more than a year before spontaneously remitting as mysteriously as it initially appeared. Hypersomnia, characterized by either excessive nighttime sleep or excessive sleepiness during the day, is less common than insomnia. However, it too may reflect a number of different pathological states. Some depressed patients, especially those with a history of mania or hypomania, may exhibit hypersomnia. Hypersomnia may also be seen during amphetamine withdrawal, excessive use of sedatives or anxiolytics, or in conjunction with a variety of medical disorders. In narcolepsy, the patient has sudden attacks of irresistible sleepiness, a symptom that may be part of a broader syndrome that includes cataplexy (sudden attacks of generalized muscle weakness leading to physical collapse in the presence of alert consciousness), sleep paralysis (waking from sleep with a sensation of being totally paralyzed that may persist for minutes), and hypnagogic hallucinations (vivid visual hallucinations that occur at the point of falling asleep). Narcoleptic attacks are often precipitated by unusual states of arousal (e.g., cataplexy may immediately follow unrestrained laughter or orgasm). Daytime sleepiness may reflect sleep apnea. In this disorder, middle-aged patients demonstrate severe snoring—often first reported by their bed partners—and periods when breathing stops. The condition results from soft-palate abnormalities that cause intermittent airway obstruction throughout the night; patients awaken repeatedly to find themselves gasping for air. Associated daytime fatigue is common in sleep apnea. Periodic hypersomnia also occurs in the Kleine-Levin syndrome, a condition that typically affects young men, in which periods of sleepiness alternate with confusional states, ravenous hunger, and protracted sexual activity. Intervals of days, weeks, or months may pass between these episodes. Sleep drunkenness is characterized by excessive sleep and great difficulty awakening completely, with confusion and motor incoordination soon after arising. Excessive daytime sleepiness may also occur secondary to abnormalities to the brainstem, hypothalamus, or thalamus. Sleepwalking disorder (somnambulism) and sleep terror disorder are two sleep disorders characterized, respectively, by aimless wandering with incomplete arousal, and by acute anxiety and physiological arousal without awakening. Although both disorders typically begin in childhood, sleepwalking may be also be initially precipitated by some psychotropic medications. Nightmares are a common complaint, often associated with traumatic events, anxiety disorders, and mood disorders, but are also not uncommon as an occasional event in otherwise healthy individuals. Vivid dreams and nightmares may also be an adverse effect of medications. A 24-year-old Peace Corps volunteer started to experience frequent, vivid, and disturbing nightmares shortly after arriving at her placement in South America. She mentioned these symptoms to other volunteers with whom she was traveling and learned that several of them were also having similar nightmares. All had recently started courses of mefloquine (Lariam) for malarial prophylaxis, and one had been forewarned to expect vivid nightmares as a commonly occurring adverse effect of this medication. Sensory symptoms during sleep, typically described by patients as peculiar feelings in their legs causing an irresistible need to move around, are characteristic of restless legs syndrome. The motor abnormality of repetitive myoclonic jerking of the legs, awakening both patients and their partners, is known as nocturnal myoclonus. Appetite and Weight Disturbances Aside from the anorexia of medical illnesses, especially in their later stages, loss of appetite is most commonly seen in depressive disorders, grief, and anorexia nervosa, and is also commonly seen in conjunction with significant anxiety. Anorexia is often accompanied by changes in taste (e.g., foods begin to taste bitter or flat or have an unpleasant aroma). Patients with eating disorders may resist hunger to restrict food intake in order to achieve a physiologically unrealistic low weight. Hyperphagia (increased appetite) occurs in some depressed patients, both with and without a history of mania bipolar I or bipolar II disorder. Binge eating, of up to several thousand calories per episode, may occur as an attempt to self-soothe and emotionally self-regulate during times of increased tension and anxiety, and as a key feature of bulimia nervosa or of binge-eating disorder. Increased appetite may be seen, albeit rarely, in some hypothalamic disorders or in bilateral temporal lobe dysfunction, such as the Kluver-Bucy syndrome, in which it occurs in association with emotional placidity, hypersexuality, hyperorality, and other symptoms. Other Ingestive Disturbances—Substance Abuse The use of chemicals such as alcohol, opioids, marijuana, cocaine, amphetamines, hallucinogens, and other drugs to change one's inner emotional and tensional state is well known. Used at inappropriate times and in excess, such ingestions may culminate in various syndromes of abuse and dependence and may complicate other psychiatric disorders. Use of nonnutritious substances for their presumed psychoactive effects has even been reported to occur in the wild among elephants and baboons. Energy Disturbances Normal energy levels vary considerably among people. Some people fatigue easily and are perceived by themselves and others as having weak constitutions, whereas others appear to have almost boundless energy and much less need for sleep. Fatigue is a common nonspecific symptom that occurs in both medical and psychiatric disorders. It is also frequently seen as an unexplained complaint in primary-care practices; in one study 24 percent of patients complaining of fatigue received no medical or psychiatric diagnosis. Historically, fatigue not caused by another disorder, typically in association with “nervousness,” has been described by terms such as asthenia, neurocirculatory asthenia, neurasthenia, and psychasthenia. Consistent with this tradition, many fatigued patients, having been labeled depressed or neurotic by their physicians, are referred to psychiatrists after routine work-up has ruled out anemia, hypothyroidism, sleep apnea, and other frequent somatic causes. Recently, patients with primary complaints of tiredness have been most commonly diagnosed as having chronic fatigue syndrome, incorrectly labeled Epstein-Barr viral syndrome. This disorder is characterized by fatigue lasting months to years, typically beginning soon after a viral syndrome. In addition to the fatigue, chronic fatigue syndrome is characterized by myalgias and cognitive changes, such as forgetfulness and poor concentration. Although controversy still exists on the extent to which cases of chronic fatigue syndrome represent discrete postviral diagnostic syndromes, mislabeled cases of depression, or modern versions of neurasthenia, evidence continues to mount to suggest that this syndrome is a discrete postinfectious entity, and is not simply a variant of or a disguised mood or anxiety disorder. A highly accomplished, energetic 40-year-old woman was referred for psychiatric consultation after her physicians were unable to offer a definitive physiological diagnosis despite extensive medical work-up following the acute onset of profound fatigue occurring in the wake of a mild viral illness. This fatigue caused her to be totally incapacitated and bedridden for many months, and left her feeling helpless and distraught. Her condition was exacerbated by even small amounts of alcohol. Two independent psychiatric evaluations concluded that the patient had no psychiatric disorder. The patient developed this syndrome after jogging near Lake Tahoe. Epidemiological studies were found that reported several other cases of profound fatigue originating in this particular area after vigorous exercise. She was treated for symptoms of fatigue and gradually made an almost full recovery after about 2 years. Disturbances in Sexual Drive As with energy, the normal range of sexual drives is great. Some individuals are naturally lusty, whereas others have limited sexual desire. Diminished sexual drive with impotence or decreased libido is seen in a wide variety of neurological, metabolic, and other somatic syndromes. Among neurological disorders, complex partial seizures are commonly associated with hyposexuality, occurring in 50 percent of patients. Psychiatric disorders known for diminished sexual drive include depressive disorders, schizophrenia, substance-related disorders, and marital conflict. Diminished libido, impotence, and anorgasmia are also common sequelae of many pharmaceutical agents, including psychotropic medications.

A 24-year-old woman, treated for depression with a selective serotonin reuptake inhibitor by her primary physician, developed profoundly diminished sexual sensation and anorgasmia in the course of treatment. In order to increase her sexual feelings as her dating and sex life resumed, she stopped taking her medication without first discussing this decision with her physician. Several months later, when her depression returned, she revealed what she had done and was effectively started on a different class of medication that lacked these adverse effects. Increased sexual activity may be seen in some neurological, substance-induced, and psychiatric disorders. Manic patients frequently exhibit hypersexual interests and behaviors to an unusual degree compared to their euthymic interests and behaviors. Hypersexuality is occasionally seen in conjunction with epileptic syndromes or in patients who have suffered diencephalic injuries. Altered sexuality, including fetishism, sadomasochism, and pedophilia, may be seen as isolated psychiatric syndromes. In individuals whose previous sexual behaviors were within the bounds of social propriety for their groups, inappropriate sexual behaviors may signal early brain disease or psychosis. Cross-dressing may occur in transvestites, transgenderists, transsexuals, or occasionally in psychiatric conditions such as schizophrenia. A 36-year-old former Marine pilot became psychotic several years after being discharged from active duty. During the next several years while being successfully treated for schizophrenia, he started to cross-dress in a garish, almost cartoonish manner, and sought hormone treatment in Mexico to reduce his secondary male sex characteristics and to foster the development of breasts. Although he considered undergoing a genital amputation and having a plastic surgeon build a vagina-like vault, he hesitated to do so, describing how he really enjoyed shocking the men he took home from bars by revealing that he had a penis. On several occasions these men, outraged and humiliated, physically attacked him and hurt him badly. Appearance Studies show that clinicians often formulate an initial psychiatric diagnosis within 30 seconds of seeing a patient. Although approximately half of such initial impressions prove to be incorrect, the remainder are validated by psychiatric history and mental status examination, revealing just how much information is communicated by appearance and body language. Among the physical disorders whose appearance suggest coexistent psychiatric conditions are acromegaly, Cushing's disease, Down syndrome, systemic lupus erythematosus, fetal alcohol syndrome, Klinefelter's syndrome, and Wilson's disease. The general appearance of the skin may suggest the presence of occult psychiatric problems. Skin condition and tone may reveal hypervascularity and ruddiness suggestive of alcoholism, abscesses are indicative of hypodermic needle abuse, tattoos are indicative of certain group affiliations, or weathering and wasting indicative of self-neglect and malnutrition. Healed scars on the wrists and arms suggest a pattern of self-mutilation from depression, personality disturbance, or both. Patchy baldness, especially in conjunction with torn or infected cuticles, indicate trichotillomania, a syndrome of compulsive hairpulling. Psychophysiological symptoms reflecting psychiatric disturbance include urticarial reactions and neurodermatitis, the latter resulting in part from self-excoriation, destructive scratching secondary to compulsions, and unrelenting sensations of discomfort. Examination of the head and neck may reveal exophthalmos or puffy eyelids suggesting thyroid disease, the marked pupillary dilation of anxiety or amphetamine abuse, the miosis of narcotic abuse, the abnormal pupillary pigments of Wilson's disease, the salivary gland enlargement of bulimia nervosa, or the necrosis of the nasal septum seen in cocaine abuse, among other signs. Frequent sighing is a common respiratory sign in depression. Simple sighing must be distinguished from respiratory dyskinesia in psychotic patients who have been treated with neuroleptic agents. The latter may occur as an acute dyskinesia resulting from antipsychotic medication or it may be a late manifestation and component of tardive dyskinesia. Deviant appearance is quickly perceived by lay persons as well as professionals, and may contribute to the frightened and stigmatizing social withdrawal by strangers and acquaintances so often experienced by psychiatric patients. Akathisia and dystonic movements and Parkinsonian shuffling gait in patients taking neuroleptic agents, as well as the dilapidated, unkempt appearance of some psychiatric patients can immediately signal psychiatric patient status to observers. The term Diogenes syndrome has been used to describe old people who have a filthy personal appearance that demonstrates severe self-neglect about which they have no shame.

DISTURBANCES IN THINKING Normal Thinking Thinking refers to the ideational components of mental activity, processes used to imagine, appraise, evaluate, forecast, plan, create, and will. Most thought involves complex rules that are best approximated by fuzzy logic decision-making algorithms that use neural net technology, increasingly applied by scientists and engineers in situations where all-or-none, black-or-white thinking does not apply, and where multifaceted, contradictory, and competing possibilities and biases are the rule. Most of what is known about thinking derives from the study of language as the product and reflection of thought; yet a great deal of thinking takes place preverbally and nonverbally. Thinking occurs in images, music, kinesthetic sensations, and in symbols other than linguistic ones. Attempts to transmit preverbal and nonverbal thought using only words are frustrating and unsatisfactory. Creative artists have considerable difficulty describing the inner states of tension and inchoate awareness from which ideas are distilled. Ordinary thought is far from logical. Streams of conscious thought are intruded upon by competing thoughts and associations, and by outside stimuli, and attention is easily distracted. Ordinary conversation is marked by recurring asides, interruptions, delays, and the loss of ideas. Decisions are often made on the basis of very few cues and inadequate evidence: people jump to conclusions and beliefs that are not supported by evidence are zealously held. Thinking in stereotypes is more common than thinking in logical categories; from an evolutionary perspective, thinking in stereotypes and by approximation has probably been more adaptive than thinking in strictly defined categories. This tendency helps to account for clinicians' tendencies to make diagnoses by approximation and intuition based on prototypes, and to feel less comfortable using formal lists of criteria found in statistical manuals, such as DSM-IV. Individuals vary greatly in their predominant cognitive styles, and a given individual's style of thinking will also shift considerably from time to time. Cognitive style is one's predominant manner of information processing and decision making, the particular biases and distortions that thinking processes make by means of augmenting, elaborating, or minimizing incoming information, and the extent to which careful and deliberate logic versus intuition versus thoughtless, anxiety-induced impulsivity is used to guide the decision-making process. A particular cognitive style may come to dominate a person's repertoire so completely as to interfere with the flexible, adaptive responses required to deal with the usual variety of daily needs. An obsessional style of thinking is marked by attention to detail and hypervigilance concerning the possible implications of a particular thought or event. This may take the form of preoccupation with strict adherence to established rules, values, or beliefs. An obsessional style may be highly adaptive in certain situations, as in professions requiring meticulous detail such as library science, computer programming, and surgery. However, excessively rigid obsessionality may be maladaptive, as when someone scrupulously sticks to the rules even when such adherence is self-destructive and short-sighted. A hysterical style of thinking is characterized by global, diffuse, impressionistic, emotionally laden evaluations of situations where lack of attention is given to details and nuances. This style is poorly adaptive to detail-oriented work, but may be useful in the arts, certain aspects of marketing and sales, and in some social situations. Two brothers watched Kramer vs. Kramer, a film about the dissolution of a marriage and the struggles of caring for the couple's only child after the divorce. In discussing the movie afterwards, one brother, a business lawyer specializing in writing complex contracts, remembered the plot in detailed linear sequence. However, he had great difficulty explaining the underlying feelings and motivations of any of the characters. The other brother, an artist, could not remember details of the plot and confused the sequence of scenes. However, he could easily and accurately explain the relationships between the characters and their feelings. Types of Thinking Because of the different ways in which normal and abnormal thinking expresses itself, attempts have been made to subtype thinking by the extent to which logical versus nonlogical thought is utilized. Freud's division of thought into primary and secondary process thinking is still widely used. PRIMARY PROCESS Primary process thinking, the more primitive type, is typically seen in dreams, but also prominent in young children and in psychotic states. This type of thinking disregards logic, permits contradictions to exist simultaneously, disregards the linear notion of time, and is dominated by wish and fantasy. It uses symbol, metaphor, imagery, condensation, displacement, and concretism in its organization, creating the jumbled and incoherent style of thinking characteristic of dreams. Primary process thinking represents what has been loosely and metaphorically called right brain thinking, associated with visual images and creative thought. SECONDARY PROCESS Secondary process thinking is characterized by logic. Unlike primary process thinking, the secondary process uses linear notions of time, clearly delineated abstract categories, and deductive rules of logic. The ability to think abstractly and to think in detail about future plans is characteristic of secondary process thinking. Normal secondary process thinking is also characterized by predictability, coherence, and redundancy. Words, vocal inflections, and gestures provide important contextual cues and create a sense of overall coherence to the communication. Ideas follow one another in a sequence that is understandable to

the listener. A non-Freudian typology of thought divides thinking into three types: fantasy thinking, imaginative thinking, and rational or conceptual thinking. Fantasy thinking allows the person to escape from, or deny, reality, and can be seen in normal as well as pathological thinking. Everyone occasionally uses fantasy thinking when daydreaming. Some dissociative and psychotic phenomena illustrate the most pathological manifestations of fantasy thinking. Imaginative thinking merges fantasy and memory in order to generate plans for the future. Rational or conceptual thinking uses logic to solve problems. Regardless of how one categorizes thought, people can fluidly shift from linear, secondary process or rational thought to fantasy, primary process or nonlogical thought, as in the free associative method used in psychoanalysis. During this process, individuals willfully surrender the controls that maintain secondary process thinking and switch to the less controlled modes of primary process thinking in which thoughts are loosely associated by emotional associations or based on peripheral, concrete, coincidental, loosely similar, or trivial aspects of a thought. Additionally, the fact that increases in primary process thinking can be induced in normal people under experimental conditions or with fatigue suggests that more primitive thought processes, such as those seen in psychosis, are usually inhibited by higher-order processes, and that their appearance may be release phenomena; that is, nonlinear or psychotic thinking may indicate the functional absence of those overriding control systems that ordinarily sift, evaluate, and regulate the form and flow of thought before it reaches consciousness.

THOUGHT DISTURBANCES Flow and Form Disturbances Because the underlying processes that govern thought are not understood, current systems for classifying thought abnormalities are primarily descriptive. Conventional classification separates form and flow from the content of thought. Yet, many types of abnormal thinking include both form and content abnormalities. Thus, whereas delusions are usually classified as thought content disturbances, they are also marked by formal abnormalities such as rigidity and imperviousness of thought to external influence or to information that clearly contradicts the delusional idea. Although formal thought disorder typically refers to marked abnormalities in the form and flow or connectivity of thought, some clinicians use the term broadly to include any psychotic cognitive sign or symptom. As with energy and sexuality, normal variations in the flow and form of thought are considerable. For some people, thinking appears to be effortless—rapid and productive, exhibiting linear, goal-directed thoughts and creativity, with digressions and occasional leaps but always controlled and comprehensible. For others thinking is a difficult exercise—a slow, painstaking process with low output compared to other people, or scattered, with difficulty staying with a topic or finishing a single thought. Most people experience mixtures of these extremes. Disturbances in the flow and form of thought occur with regard to rate, continuity, control, and complexity. Thinking can be unusually slow or accelerated. Slowed (or retarded) thought, (e.g., as seen in depression), is typically goal directed but characterized by little initiative or planning. Patients experiencing retarded thought often describe feeling that even simple thought requires monumental effort, as if molasses were cluttering their thinking. These difficulties are expressed as slowness in decisionmaking and as long latency of response, increased pause times when speech is initiated and during speech. Thought blocking, seen in schizophrenia, is experienced as the snapping off or as a sudden break in a train of thought, as if a wall suddenly came down interrupting thinking (and speaking) in midsentence. To an outside observer, without further explanation from the patient, thought blocking may appear identical to thought withdrawal, a disturbance in the control of thought in which the patient feels as if some alien force has intentionally withdrawn the thoughts from consciousness. The patient's further description and explanation of the inner experience is necessary to distinguish these two symptoms. A 26-year-old man with paranoid schizophrenia frequently broke off his conversation in mid-sentence. To the puzzled examiner he explained that the mysterious force that controlled him with a computer chip in his brain closely monitored his thought and speech, and would shut him down whenever it was concerned that he might inadvertently say something that was classified information. Accelerated rates of thinking, typically accompanied by fast talking, can be seen as a normal variant. Rapid rates of speech, influenced heavily by cultural and situational factors, only sometimes reflects truly rapid thought. (For example, it is not at all clear that New Yorkers, who characteristically speak more quickly than people from some other cities, actually think at a faster rate. Similarly, auctioneers and some radio and television announcers can speak with astonishing rapidity, probably reflecting both innate capacities as well as learned psychomotor skills.) Pressure of speech—speech that is rapid, excessive, and typically loud—is characteristic of mania (or hypomania), stimulant intoxication and, occasionally, anxiety. Flight of ideas occurs when the flow of thought increases to the point where the train of thought switches direction frequently and rapidly. The associative links between conceptual topics during flight of ideas are comprehensible to the listener, sometimes with considerable effort! Listening to a flight of ideas that is not overwhelmingly fast can be both a dizzying and enjoyable experience for the listener, as exemplified by the successful performance style of certain contemporary comedians, notably Robin Williams. Continuity Disturbances in the continuity of thought may take several forms. In circumstantiality the flow of thought includes many digressive turns and associations, often including a great deal of unnecessary detail. Transcripts of circumstantial thought or speech are marked by multiple commas, subclauses, and parenthetical asides. Nonetheless, in circumstantial thought or speech the speaker eventually returns to the point that was initially intended without having to be prompted by the listener. In contrast, in tangentiality, the person's thought wanders further and further away from the intended point, without ever returning, so that the person may not even remember what the original point was supposed to be. In vorbeireden, a form of tangentiality, the person talks past the point and never quite gets to the central idea. Tangentiality is a mild form of derailment, in which there is a breakdown in associations. Loose associations exemplify more severe derailment, in which the flow of ideas is no longer comprehensible to the listener because the individual thoughts seem to have no logical relation to one another. Loose associations are classically a hallmark feature of schizophrenia. In extreme cases, the associations of phrases and even individual words are incomprehensible, and syntax—the rules of grammar by which phrases are organized into sentences and words into phrases—may be disrupted. Word salad describes the stringing together of words that seem to have no logical association, and verbigeration describes the disappearance of understandable speech, replaced by strings of incoherent utterances. Clang association refers to a sequence of thoughts stimulated by the sound of a preceding word. For example, a patient with mania said, “I'll kill with a drill or a pill—God, I'm ill—what swill.” In echolalia the patient repeats a sentence just uttered by the examiner. Repetition of only the last uttered word or phrase is called palilalia, a symptom found most often in patients with chronic schizophrenia. Perseveration and stereotypy are two other associative abnormalities in which the flow of thought or speech appears to get stuck. In perseveration, a sentence or phrase is repeated, sometimes several times over, after it is no longer relevant; perseveration is commonly seen in delirium and other organic mental disorders. Stereotypy refers to the constant repetition of a phrase or a behavior in many different settings, irrespective of context. Disturbances in the control of thought include delusional passivity and obsessional thinking. In delusional thought passivity, patients experience their own thoughts as being under the control of other forces. Thought passivity may take several forms: in thought insertion thoughts are experienced as having been placed within the patient's mind from the outside; in thought withdrawal thoughts are whisked out of the mind; in thought broadcasting patients experience their thoughts as escaping their minds to be heard by others. These experiences are often combined with specific delusions of control, seemingly to explain the passivity experiences. Several of these phenomena were included by Kurt Schneider among the first-rank symptoms of schizophrenia. Today, these symptoms are viewed more broadly as nonspecific psychotic symptoms, and are no longer considered to be pathognomonic of schizophrenia. A 40-year-old man who had been living in a state hospital for many years described how he was the outer shell in a set of nested beings. A homunculus-like figure in the center controlled another being surrounding him, and the patient himself was simply the outer wrapping. The inner homunculus made all the decisions, and pulled all the strings, so that the patient was simply a passive recipient of his thoughts and of the instructions that ordered him to carry out each and every act in his life. Obsessional thinking is stereotyped, repetitive, persistent thinking that is recognized as one's own thoughts. In contrast to patients with delusional thought passivity, obsessional patients do not experience their thoughts as being controlled by outside forces. Nonetheless, they experience only partial control over the obsessional thoughts. They can, with great effort, stop thinking the obsessional thoughts but cannot prevent them from recurring. Thus, characteristic of obsessions is the subjective experience of compulsion, the resistance to it, and the preservation of insight. As bizarre as some obsessions are, patients know that these thoughts are irrational and their own. At times, obsessions may be pervasive enough to dominate the patient's consciousness. Obsessions may be simple—a sequence of words—or elaborate—such as enumerating the possible consequences of a past behavior and elaborating a cascading sequence of typically catastrophic events. Typical obsessional themes in obsessive-compulsive disorder involve preoccupations with dirt and contamination, fear of harming others, symmetry, and those related

to health and appearance. A 24-year-old woman was preoccupied with the fear that she would be contaminated by germs that were all around her. These thoughts were inescapable, and led her to narrow her range of activities considerably, to the point of being nearly housebound. She had to comply with a series of ritualistic acts to ward off contamination in her house. Obsessional thoughts are usually seen in conjunction with compulsive behaviors, which are rituals linked to the obsessions, typically constructed to undo the effects of the thought. The most prominent disturbance of thinking complexity is an impaired capacity to think abstractly. Abstract thinking is the ability to assume a mental set, to keep simultaneously in mind all the aspects of a complex situation, to move from feature to feature as indicated by the situation, and to abstract common properties. Complex thinking also concerns the ability to simultaneously consider many different, vague, and subtle aspects of situations; to appreciate differing and contradictory points of view; and to integrate these multiple dimensions to form opinions that are marked by differentiatedness and nuance. Normal individuals vary greatly in their abilities to engage in abstract thinking—geniuses in mathematics and theoretical physics leave most mortals far behind. Concrete thinking is a disturbance in the ability to form abstract concepts, generally illustrated by literal-mindedness and the inability to abstract the commonality of members of a group, for example, the fact that a flea and a tree are similar in that they are both living things. Concrete thinkers seem unable to free themselves from the literal or superficial meanings of words. Concrete thinkers may be more prone to prejudice and stereotypic thinking, more likely to manifest unidimensional or all-or-none reactions to complex situations. Concrete thinking can be seen in individuals with lower intelligence, organic mental disorders, and schizophrenia. Patients with schizophrenia may also exhibit highly selective disturbances of abstraction.

THOUGHT CONTENT The normal content of thought, the buzzing, booming stream of consciousness that constitutes the stuff of everyday life, is composed of awareness, concerns, beliefs, preoccupations, wishes, and fantasies occurring with various degrees of clarity, vividness, differentiation, imagination, and strength. Normal thought is often illogical, containing many beliefs and prejudices that, although clearly contradictory, are nevertheless held with passion and conviction. Belief systems are the scaffolding of thought, chains of impressions, and expectations around which plans and behaviors are organized. Belief systems may be attitudinal, setting general expectations and biases about the world that inform how incoming information is processed; examples of belief systems are optimism, pessimism, and paranoia. Some beliefs are effervescent and fleeting, whereas others are pervasive, tenacious, enduring, and influential. Some beliefs are unique and private, whereas many are shared by others. Imaginative fantasy is an important component of normal thought. The vivid, eidetic imaginations of young children can produce fantasies in which children become fully immersed, almost as if in hypnotic states. During latency many children develop imaginary companions as playmates. In later years, imaginative thinking in which previously separate streams of thought playfully interact with one another to produce new ideas may be the essence of the creative reverie. Artists, writers, and creative scientists may retain access to these forms of thinking more readily than others. Meditative states of mind may facilitate the emergence of imaginative insights. Such thinking may also occur in dreams. Intrusive reveries are normal and common components of the usual adult stream of consciousness. During periods of specific deprivation, such as starvation or sexual deprivation, elaborate wish-fulfilling daydreams frequently occur. Ideas are the contents of the stream of thought. Those that are consistent with one's sense of self, compatible with the individual's self image, are called ego-syntonic. Other thoughts that conflict with one's central values are called ego-alien or ego-dystonic. An ego-dystonic impulse to kill someone, inconsistent with one's predominant value systems, may generate a counteractive ego-syntonic thought such as, “You really don't mean it.” Disturbances in Thought Content Abnormal beliefs and convictions form the core of thought content disturbances. Considerations of abnormality regarding beliefs and convictions must take the person's culture into account. Beliefs that may seem abnormal in one culture or subculture may be commonly accepted in another. For example, religious hallucinations, attributed to psychological or biological factors by contemporary Western societies, are routinely attributed to religious and spiritual causes by many other cultures. With regard to intensity of conviction, distorted beliefs range on a continuum from overvalued ideas to the determined, unshakable belief that is characteristic of fixed delusions. Abnormal beliefs and delusions are, in most circumstances, diagnostically nonspecific. Delusions are commonly seen in mood disorders, schizoaffective disorder, delirium, dementia, and substance-related disorders, as well as in schizophrenia and delusional disorders. Overvalued ideas are unreasonable and sustained abnormal beliefs that are held beyond the bounds of reason. Patients with overvalued ideas have little or no insight into the fact that their ideas are very unlikely to be valid; however, the ideas themselves are not as patently unbelievable as most delusions. The distorted body images of body dysmorphic disorder exemplify overvalued ideas. Morbid jealousy and preoccupation with a spouse's possible infidelity may constitute an overvalued idea if no real evidence has ever existed to warrant such suspicion. A 32-year-old woman, fatigued for many months, complained of being “allergic to everything.” She initially associated her fatigue with eating certain foods, then with using certain cosmetics and soap products, then with wearing certain types of clothing, and then with being around certain types of housepaints, carpets, and draperies. These beliefs resulted in severe restrictions and functional limitations in her work and social life. Ideas of reference are false personalized interpretations of actual events in which individuals believe that occurrences or remarks refer specifically to them, when in fact they do not. Ideas of reference may be less firmly held than delusional beliefs. A psychotic young man came to the emergency room in a state of severe water intoxication. He had been sitting at home drinking gallons and gallons of ginger ale, after having seen a television advertisement that said “Drink Gingerale!” He believed this message was specifically addressed to him, and that dire consequences would result if he disobeyed. Delusions Delusions are fixed, false beliefs, strongly held and immutable in the face of refuting evidence, that are not consonant with the person's education, social, and cultural background. Thus, delusional thoughts can only be understood or evaluated with at least some knowledge of patients' interpersonal worlds, such as their involvements with religious or political groups. One of the mind's primary functions is to generate beliefs, including myths and meaning systems. These beliefs provide the individual with a sense of personal and group identity and with ways of understanding reality. They are most noticeable when shared untestable beliefs form the basis for group cohesion as in religions and cults. Some groups adhere to their cherished beliefs despite the abundance of plausible contrary evidence, for example, some fundamentalist sects take the biblical creation story literally. In the face of contrary evidence or grave personal threat, individuals often cling to their primary beliefs as matters of faith (i.e., alternative, nonrefutable bases for understanding). The strong faith with which religious, political, and nationalistic convictions are held, even at the cost of death, shows the power that untestable beliefs can have on behavior. Potential mental health advantages of religious beliefs have been demonstrated in epidemiological studies showing that those with a sense of personal devotion report fewer depressive symptoms. Subjectively, delusions are indistinguishable from everyday beliefs. Therefore, the subjective experience of a delusion is no different from the subjective experience of believing that the earth is round or that my spouse is the same person I married on my wedding day. Because of the identical experience of delusions and other strongly held beliefs, it is generally impossible to argue a patient out of a delusional belief. The content of delusions is highly influenced by culture. Whereas centuries ago delusions of persecution often concerned persecution by the devil and had religious connotations, persecutory delusions today often take on contemporary political and social perspectives. A 42-year-old Native American Vietnam veteran fled to a remote area of the Rocky Mountains to escape a world-wide conspiracy that he believed was trying to control each and every individual, including him. He was aware of this conspiracy because when he lay on the ground at night he could see countless stars and knew that they, and everything on earth, were all connected by “the Web.” Confirming this belief, he heard the murmurings of all computer messages, radio and television transmissions, phone calls, and even face-to-face conversations as part and parcel of this web. Although delusions are diagnostically nonspecific, some specific types of delusions are more prevalent in one disorder than another. For example, although delusions of control and delusional percepts are often seen in schizophrenia, they also occur, albeit less frequently, in psychotic mood disorders. Similarly, classic

mood-congruent delusions with grandiose themes seen in mania or delusions of poverty characteristic of depression may also be seen in schizophrenia. Table 8-3 lists some characteristics by which delusions have been classified. Simple delusions contain relatively few elements, whereas complex delusions may contain extensive elaborations of people, spirits, motives, and situations.

Table 8-3 Characteristics of Delusions

Systematized delusions are usually restricted or circumscribed to well-delineated areas, and are ordinarily associated with a clear sensorium and absence of hallucinations. They are often isolated from other aspects of behavior. In contrast, nonsystematized delusions usually extend into many areas of life, and new data—new people and situations—are constantly incorporated to further support the delusion. The patient usually has concurrent mental confusion, hallucinations, and some affective lability. Whereas the patient with a closed systematized delusional system may go about life relatively unperturbed, the patient with a nonsystematized delusion frequently has poor social functioning and often behaves in response to the delusional beliefs. Complete delusions are those held utterly without doubt. In contrast, partial delusions are those in which the patient entertains doubts about the delusional beliefs. Such doubts may be seen during the slow development of a delusion, as the delusion is gradually given up, or intermittently throughout its course. Delusions have also been categorized into primary and secondary forms. Unfortunately, these terms have been used in a variety of ways, such that the distinctions are confused in the literature. According to one definition primary delusions are those that are not further understandable in terms of the patient's specific context, such as culture or mood, whereas delusional beliefs that could be understood or appreciated as an extension of a cultural belief or of a mood are secondary. In this framework, a mood-congruent psychotic delusion with themes of worthlessness or guilt would be a considered a secondary delusion. According to a different definition, a primary delusion refers to and is synonymous with an autochthonous delusion, one that takes form in an instant, without identifiable preceding events, as if full awareness suddenly burst forth in an unexpected flash of insight, like a bolt from the blue. These delusions may be quite elaborate. An 18-year-old young man from a middle-class Jewish family who had become increasingly socially isolated and withdrawn over a 2-year period presented to an emergency room in an utter panic, with his penis taped to his thigh, believing that his penis had started to shrink into his body and would disappear. No other delusional beliefs or hallucinations were evident. Aside from the autochthonous types, three other types of delusions have been described as primary. Delusional percept refers to the experience of interpreting a normal perception with a delusional meaning, one which has enormous personal significance to the patient. Delusional atmosphere or delusional mood is a state of perplexity, a sense that something uncanny or odd is going on that involves the patient, but in unspecified ways. Ordinary events may take on heightened significance but the delusional interpretations are fleeting whereas the uncanny feeling lingers. Typically, after a period of time full-blown delusions develop, replacing the delusional mood. Delusional memory is the memory of an event that is clearly delusional. As an example, a patient “remembered” his fourth-grade teacher slipping lysergic acid diethylamide (LSD) into his apple juice; this memory served to explain his psychotic disorder. The elaboration of false memories and their subsequent fixed beliefs may assume delusional proportions. A young woman with schizophrenia attended a trauma group with her roommate and gradually came to believe that she had been repeatedly sexually assaulted by her father, from the time she was in the crib. What started out as vague dream-like images gradually coalesced into a series of “sensed” memories that then took on specific visual images of her father's fingers penetrating her, and of his leering down at her in the crib. Her parents were horrified by these accusations, and there was not a shred of evidence to corroborate her increasingly venomous accusations. Patients vary considerably in the extent to which they take action in response to delusional thoughts. Just as patients can experience delusions of their thoughts being controlled (thought passivity), they may similarly experience their feelings, behaviors, and will as controlled by outside forces. These delusions of control (or passivity experiences) occasionally, albeit uncommonly, result in dramatic self-destructive or aggressive behaviors, as illustrated by the murderer who called himself Son of Sam. This psychotic killer murdered several people in New York and claimed that he was the powerless agent of a force that required him to commit the acts. To defend themselves and others against delusional anticipated events, some patients may take bold and occasionally destructive actions. A 36-year-old man with schizophrenia was brought to the hospital after enucleating one of his eyes with a pencil. He believed that he had to sacrifice his eye in order to avert world destruction. In an elaborate delusional scheme, he was convinced that the evil he saw in the world was going to lead God to bring destruction upon all mankind, and he hoped that by sacrificing his eye God would see less of the evil in the world. Table 8-4 lists some classic types of delusions. Although less common than those involving paranoia, grandiosity, and influence, delusions of misidentification are prominently reported because of their inherently intriguing nature. In Capgras's syndrome the patient believes that someone close to him has been replaced by an exact double. In Fregoli's phenomenon strangers are identified as familiar persons in the patient's life. In the delusion of doubles, patients believe that another person has been physically transformed into themselves.

Table 8-4 Some Classic Types of Delusions

Delusions are not only seen in isolated individuals. Shared delusional disorder may occur in couples (folie a deux) and in families (folie en famille). Many psychiatrists consider group delusions to be present in some cults, however, the exact distinction between delusions and other zealous beliefs held by larger, more traditional, and

well-organized religious, political, and other groups, is arguable. Self-Mutilatory, Suicidal, Aggressive, and Homicidal Preoccupations Other disturbances in the content of thought include maladaptive, self-destructive, and other-directed destructive thoughts. In some individuals, such thoughts occur only during times of acute distress, in reaction to specific stressful situations. In others, these thoughts may be chronically present, like background music in the stream of consciousness, varying in the frequency and intensity of their presence, in the specificity and vividness of their accompanying images, and in how compelling they are. A 36-year-old unemployed man with alcoholism became increasingly preoccupied with the idea that his wife was unfaithful. He accused and threatened her, stalking her whenever she left the house, filled with rage and entertaining fantasies of killing her and her presumed lover if he found them together. After months of trying to appease and reason with her husband, and after several instances of being beaten, the wife finally left him. She took their child to a shelter, hoping that he would leave them alone, but constantly feared for their safety. Disturbances of Judgment Judgment involves a complex and diverse group of mental functions that includes analytic thinking, social and ethical action tendencies, and depth of understanding or insight. Analytic thinking includes the capacity to discriminate and to weigh the pros and cons of alternatives. Social and ethical action tendencies are closely related to culture and upbringing. The evidence for genetic factors in antisocial personality disorder (defined primarily by judgments that lead to criminal behaviors) points to the additional role of constitutional factors. Insight may reflect intelligence, learning, cognitive style, and the capacity to integrate intellectual knowledge with emotional awareness. Impairments of judgment occur in many psychiatric disturbances. Anxiety states, intoxications, fatigue, and even group pressures may cause temporary impairments of judgment in otherwise normal individuals. Organic brain damage, cognitive disorders, and psychotic disorders may chronically impair any aspect of judgment in any person regardless of premorbid character. Poor role models and deviant social backgrounds may lead to social and ethical action tendencies quite different from those of the examiner. Thus, someone raised in a criminal environment may have superb analytic judgment and self-awareness, which are, however, put to illegal use. Judgment may be impaired in one dimension and spared in others. Individuals may retain sound ethical judgment when their analytic capacities fail or they may retain excellent analytic abilities for nonpersonal matters while lacking insight into personal situations or behaviors. Thus, some people who can provide socially appropriate responses to traditional mental status examination questions such as what one would do in a movie theater if a fire broke out, or what one would do with a stamped and sealed addressed envelope found in the street, might at the same time be incapable of accurately assessing crucial clinical information or more personal matters specifically related to the capacity to provide informed consent, such as the pros and cons of receiving a medication or electroconvulsive therapy; or regarding judgments necessary to provide oneself with food, clothing, and shelter; or insight into one's state of health or illness. The apocryphal story about the delusional patient who was able to accurately evaluate and fix a broken-down car that had stymied the mechanics, ending with the patient's declaring “I may be crazy, but I'm not stupid” indicates the selective nature of poor judgment within psychiatric disorders. The term insight, usually applied in the context of self-awareness, has been used in a variety of ways. Basic insight refers to a superficial awareness of one's situation, (e.g., that one is ill). A deeper level of insight is operating when the patient has an intellectual appreciation of what is going on (e.g., “I have hallucinations and delusions, and my doctors have told me that I have schizophrenia and must take medication”). Still deeper levels of insight reflect more complete cognitive and emotional appreciation of a situation (e.g., “I realize that I have schizophrenia, that it impairs my judgment and social function at times, and that I will have to take medications if I am to minimize my symptoms and try to make the most of my life. I feel profoundly disappointed about this affliction because it prevents me from achieving some of the goals I've always wished for. Nevertheless, I have do my best to get over my disappointment and hurt feelings so that I can get whatever I can out of life.”) Judgment may be impaired by several factors, including cognitive clouding (as in disturbances of consciousness, such as intoxication that impairs one's usual analytic abilities), self-deception, and impulsivity. Self-deception refers to the almost universal tendency to hide certain issues about the external world or about ourselves from various levels of one's own awareness. Self-deception functions as a coping strategy, fostering or maintaining comfortable perspectives about the world, and avoiding confrontation with issues and realities that would inevitably stir up painful conflicts or the need for difficult actions; it thereby helps an individual to preserve emotional calm. In addition, studies suggest that self-deception enables one to act and to be perceived as more convincing in the service of particular goals, as in romantic relationships or business dealings. Therefore, while kidding oneself may sometimes reflect impaired judgment, it may also yield certain important strategic advantages. Impulsive judgment describes a tendency to avoid taking the time to fully understand and integrate all the facts and levels of awareness required for optimal decisionmaking. Impulsive judgment may occur only with certain issues or situations (such as how one picks investments), may signal an impaired state (such as substance intoxication), or may reflect a pervasive character trait. Rapidly made judgments, and even so-called “snap” judgments, are not all maladaptively impulsive, even when they involve very important areas of life. Rapid decisions can be very accurate, highly adaptive, and even life-saving, especially if made against a background of great experience, wisdom, and forethought concerning the area requiring the decision. Disturbances of Consciousness Consciousness can be defined as subjective awareness of the self and environment. Biologists increasingly believe that a continuum of consciousness exists, extending from lower animals through Homo sapiens. However, consciousness is subject to conflicting definitions and conceptualizations, and exactly where consciousness begins in evolution remains unclear. Philosophers agree that it is the subjectivity of experience, the so-called qualia of consciousness, that clearly distinguishes living consciousness from the 1990s' best versions of self-regulating automata, elegant computers, and robots. All current attempts even to approach an understanding of consciousness are very unsatisfying; consciousness remains unexplained and as yet unexplainable from a scientific point of view. Consciousness has been viewed as an emergent property of complex biological nervous systems, as a poorly understood general property of an even more mysterious and complex universe, or as a phenomenon to be understood only in religious and spiritual terms. One of the best analyses to date of possible relationships between the construction of a brain and the possibility of consciousness has been set forth by Gerald Edelman, who believes that reflective consciousness cannot occur until complex higher-order brain systems evolve whose major functions are to monitor the experiences, activities, and results of activities of those lower-order brain systems that deal directly with appraising and responding to the external and internal environments. Such higher-order meta-systems require the presence of memory, so that current and immediate impressions can be checked and compared against past experiences. These meta-systems may use a variety of sensor mechanisms to detect and signal their sensations or perceptions of various events. Some of these sensors may correspond to feeling states and some may correspond initially to preverbal thought-like mechanisms that contain the capacity to develop and recognize abstract categories, and ultimately conceptual language-based thought. Clinically, consciousness can be considered from both qualitative as well as quantitative viewpoints. Qualitatively, consciousness does not seem to be an all-or-none phenomenon. Rather, conscious experiences may gradually and phasically shift in focus, intensity, and clarity; altered states of consciousness may occur in which some aspects of consciousness, such as sensation, perception, memory, orientation, and judgment are enhanced or impaired relative to other aspects. Quantitatively, crude divisions can be made between states depending on the relative presence, impairment, or total absence of consciousness. Even within a single individual consciousness is not a unitary phenomenon. Multiple streams of thought, operating at multiple levels of preconsciousnesses, appear to exist in all of us almost all the time, with various elements in these coexisting streams constantly shifting into higher or lower levels of conscious awareness. In pathological states, even more remarkable properties of consciousness are seen; for example, the existence of co-consciousness in humans who have had commissurotomies, and of seemingly multiple discrete consciousnesses in patients with dissociative identity disorders. Experiments involving patients with commissurotomies of the corpus callosum have shown the existence of two virtually separate systems of consciousness that seem to operate simultaneously. For example, when in the course of an experiment the picture of a nude woman was flashed only to the right brain (the left visual field) of a commissurotomized patient, the subject verbally denied being aware of anything unusual (i.e., the left brain—the verbal brain—was unaware). However, the patient started to squirm and blush, blurting out, “Oh, you have some machine!” Similarly, when a cup was presented to the right brain (left visual field) only, the patient denied seeing anything (the left brain was unaware and the language output of the left brain indicated no awareness), but he was able to pick out the cup from an assortment of objects with his left hand (right brain control). This literal splitting of verbal awareness from visual-spatial awareness in the brain produces behavior that is at least superficially similar to that of patients who deny being consciously upset by an event, but who react with strong visceral responses. Although this formulation is simplistic, the separate consciousness for logical-verbal and for spatial-visual awareness demonstrated in split-brain experiments may be crude analogues for more highly differentiated and discrete types of awareness and modes of information processing. Furthermore, the very fact that there are separate and

even competing modes of consciousness may increase the likelihood of psychological distress, because the various modes are capable of yielding internally conflicting views of reality. Psychological and Physiological Factors In ordinary states of alert consciousness individuals are able to pay an adequate amount of attention to their surroundings and to reflective thought. Normal people vary enormously in their ability to pay careful attention in different settings without being distracted; individual variations may reflect temperamental and cognitive style differences as well as physiological shifts within the individual. Many functions of attentive consciousness including attention, planning, and the capacity to switch appropriately between mental tasks have recently been linked to the activity of specific neurons in area 46 of the prefrontal cortex. A sense of increased consciousness with heightened alertness, awareness, and sharper thinking may be experienced in highly aroused emotional states such as threat, sexual attraction, falling in love, or other high-stakes events such as hunting (in primitive peoples), sporting competitions, or performing in front of an important audience. High levels of arousal do not necessarily guarantee effective attention because optimal consciousness depends on optimal arousal. Too little arousal, caused by illness or fatigue, may result in insufficient stimulation and mental lethargy, diminishing the sense of alertness and attentiveness; too much arousal may result in hyperintense alertness but distractibility and scattered attention. Consciousness involves, among other things, the experience of a continuous sense of self and of the environment, existing coherently in time and space. The experience of time and its passage may be altered by shifts in the level of awareness and by emotional states such as boredom, concentration, pain, and discomfort. The experience of time and space may be altered by hypnosis, cannabis, psychoactive and psychedelic drugs, and other events that directly affect brain physiology. Disturbances in the Level of Consciousness Levels of consciousness (i.e., alertness, awareness, and attentiveness) may be pathologically increased or decreased. Such changes are diagnostically nonspecific and can occur in many different disorders. When levels of arousal and alertness are mildly elevated, as in hypomania or with the ingestion of small amounts of psychostimulants, subjective experiences are typically positive. In these situations the person experiences intense alertness, prolonged concentrating ability, and hyperesthesias in which perceptual vividness is heightened: colors are brighter, sounds are sharper, and touch is more intense than usual. With further increases in arousal and consciousness as seen in mania, more severe intoxications with amphetamines and cocaine, and catatonic excitement, attention deteriorates. Heightened alertness transforms into hypervigilance and paranoia, and hyperesthesias become unpleasant. Diminished levels of consciousness can be described on a continuum. Clouding of consciousness is marked by diminished awareness of sensory cues and diminished attentiveness to the environment and to the self. Secondary-process thinking is most notably compromised, and more primary-process thinking emerges into consciousness. In this state, one's ability to appreciate subtleties and to think in a nuanced manner is diminished, and is replaced by more dichotomous all-or-none, stereotypic thinking. The level of consciousness may fluctuate rapidly in relation to the internal physiological state or to the degree of external stimulation. In alterations of consciousness, confusion may occur with disorientation to time, place, or person. The patient is usually highly distractible and unable to pay sustained attention to a single stimulus. Torpor is a condition in which the patient is drowsy, falls asleep easily, and shows a narrowed range of perception and slowed thinking. Stupor is a state of diminished consciousness in which the patient remains mute and still although the eyes are open and may follow external objects. In the most extreme impairment of consciousness, coma, there is no evidence of mental activity at all. The patient appears essentially to be functioning on a decorticate or decerebrate level. In akinetic mutism or coma vigil, patients with profound brainstem lesions appear to be awake with their eyes open, but there is in fact no evidence of consciousness. Delirium, an acute confusional state, is usually characterized by a relatively abrupt onset and a short duration of clouded, reduced, and fragmented attention; impaired memory and learning; perceptual and cognitive abnormalities such as hallucinations and delusions; disrupted sleep; and other autonomic dysfunction. The level of consciousness may be consistently diminished or may fluctuate. The electroencephalogram (EEG) usually shows diffuse slowing. Typical motor abnormalities include an increase in general restlessness, fine and coarse tremors, and myoclonic jerks. Autonomic disturbances commonly include tachycardia, fever, elevated blood pressure, diaphoresis, and pupillary dilatation. The causes of delirium are legion, including systemic medical disorders such as metabolic imbalances or infections; intracranial disorders caused by traumatic, structural, and electrical causes; and substance intoxication and withdrawal states. Attentional difficulties are manifest by impairments in the person's ability to deploy, focus, and sustain attention. Some attentional difficulties first appear in early childhood as developmental problems of uncertain cause, and are described as attention-deficit disorder. Secondary attention-deficit difficulties may appear de novo in adulthood from a variety of exogenous agents, psychiatric disorders, and late-life developmental and degenerative factors. In narcolepsy, which is characterized by sudden lapses into sleep, one's usual ability to stay alert and maintain consciousness is impaired. At times the onset of profound sleepiness is gradual, accompanied by hypnogogic phenomena, in which dreamlike images invade the consciousness; at other times the shift in consciousness appears to be almost instantaneous. This syndrome, occurring in about 1 in 10,000 persons, is thought to be the second most frequent cause of automobile accidents after alcohol intoxication. Altered States of Consciousness Consciousness may also be qualitatively changed with the production of altered states. Drugs such as scopolamine (Transderm) with strong central anticholinergic properties, some seizures, and on occasion other conditions associated with delirium can induce twilight states, dream-like states of wakeful consciousness in which attention is poor, a mixture of primary and secondary process thinking appears, and patients fade in and out of alertness. Dream-like experiences intrude into the stream of conversation. Emotional outbursts or violent acts may occur during twilight states. Mystical states of consciousness may occur in normal and pathological conditions. Intense meditation and peak or epiphanic experiences, reported by more than 10 percent of normal individuals in community surveys, may produce a sense that the self dissolves or expands, that the self fuses mystically with the cosmos, that time stops, and that universal meaning becomes clear. These perceptions may be accompanied by a sense of rejuvenation and renewed personal identity, ineffability, intense emotionality, and concurrent perceptual changes. Such experiences do not ordinarily last more than a few minutes. Many people have achieved these states through the use of psychedelic agents such as mescaline and LSD. Reports of a white light at the end of a tunnel, described by individuals using psychedelics and during near-death experiences, have been linked to specific neurophysiological pathways thought to be stimulated under these conditions. Although hypnosis lacks a consensually accepted definition, its hallmarks are selective attention, suggestibility, and dissociation. Most people, but not all, can be hypnotized to some degree. Up to 90 percent of people are capable of achieving a light trance, whereas 10 to 20 percent are capable of entering a deep trance and exhibiting remarkable hypnotic phenomena. Hypnosis occurs when the subject is in a state of heightened, not diminished, attention. EEG studies have shown hypnotized subjects to be fully awake and alert. The heightened concentration probably accounts for the unusual levels of sensory and motor performance often seen under hypnosis and self-hypnosis. Hypnotic phenomena include hypnotically induced hallucinations (including negative hallucinations in which the subject selectively fails to perceive sights, sounds, or other stimuli), anesthesia, sustained motor behaviors and acts of strength ordinarily beyond the individual's capacity, and distortions of memory (both hypermnesias and amnesia). Several phenomena that reveal the multiple nature of consciousness, for example, co-consciousness, are also demonstrable. Experiments have shown that even when a subject in a deep trance has achieved profound hypnotic anesthesia and can, for example, keep a hand submerged in ice water for longer periods of time than usual, part of the hypnotized subject's consciousness continues to register exactly how painful the experience actually is and can signal the researcher about the pain by finger movements without the subject having any conscious awareness or disturbance. This phenomenon, called the hidden observer, has also been seen in postsurgical patients who, under hypnotic trance after surgery, have been able to accurately recall conversations in the operating room that occurred while they were under general anesthesia. Dissociative and psychosomatic phenomena have also been induced with hypnosis. With posthypnotic suggestion, subjects may carry out complex actions without any hint that they are actually doing so because they were previously instructed to act that way under hypnosis. When asked why they are carrying out these activities, such subjects will usually make up reasons, while seemingly unaware of the real reasons for their actions. It has been suggested, not entirely facetiously, that many normal daily activities are conducted in a trance-like posthypnotic state, and although these activities are attributed to conscious intention, they may in fact be carried out as a result of previous suggestion. Advertisers know this well. Urticaria (hives) can be hypnotically induced and hypnotically made to disappear. Plantar warts have been successfully treated with hypnosis, and in these conditions diminished blood supplies to their bases have been demonstrated. It has recently been appreciated that yoga masters can exert remarkable control over basic bodily functions through self-hypnosis. As yet, little is known of the full extent to which heightened concentration may influence physiological regulation. Suggestibility Pathological suggestibility may be seen in several clinical conditions. Automatic obedience has been described in echolalia (the automatic repetition of a sentence or phrase just uttered by another person), echopraxia (the automatic mimicking of a movement performed by another person), and waxy flexibility (maintaining for a prolonged period of time a posture in which one is placed), symptoms common in catatonic states. In situations of group delusions, and sometimes

in cults, passive individuals adopt the delusional beliefs of stronger ones. In epidemic hysteria, as described so beautifully among young women at the Salem witch trials in Arthur Miller's The Crucible, distorted and even delusional perceptions and beliefs may sweep over a group that has been highly aroused by a charismatic leader. Autosuggestibility can be seen in the constructions of false memories, in which an individual progressively comes to believe that something that never happened in fact occurred. Such false memories may be held with such great conviction that they are indistinguishable from the memories of real events. Various types and degrees of self-deception may be more common in individuals who are more suggestible. DISSOCIATIVE PHENOMENA Dissociation refers to the splitting off from one another of what are ordinarily closely connected behaviors, thoughts, or feelings. Dissociative states are those in which there is a disturbance or alteration in the normally integrated functions of identity, memory, or consciousness and include trances, fugues, blackouts, multiple personalities ( dissociative identity disorder), and dissociative frenzies. Although dissociative states are ordinarily thought to be functional in nature, arising as an adaptive defense in individuals subjected to a great deal of trauma, particularly at early ages, they occur regularly with a variety of neurological disorders, particularly with partial complex seizures. In one series, one third of patients with complex partial seizures had dissociative phenomena including multiple personality. In these patients the dissociative phenomena were not related to the seizure activity, but to interictal alterations. As in posthypnotic amnesia, elaborate activities can occur in dissociative states for which the subject will have no conscious memory. This amnesia is functional in nature and may be reversed by hypnosis or drug-facilitated disinhibition, for example, with amobarbital (Amytal) infusion. In many of the functional dissociative states, amnestic episodes may occur for years or decades before the patient seeks medical or psychiatric attention. Blackouts are periods of amnesia in alcoholism, other intoxications, or following head trauma. An alcoholic blackout period may last for hours to days, after which the person has no recollection of what transpired although other observers will attest to the fact that during this period the individual carried out multiple complicated behaviors. Although memory of the blackout is lost to the predominant consciousness, during subsequent reintoxication memories of events occurring during the previous blackout may be reawakened. This phenomenon, known as state-dependent memory, occurs in many other conditions as well, signifying that one's ability to retrieve specific memories may be highly influenced by specific physiological alterations caused by external intoxicants or other unusual physiological states. When he was questioned during an initial psychiatric interview, a 28-year-old euthymic man with a history of severe bipolar I disorder could not recall the content of his thinking during any of his manic episodes. However, at the beginning of his next manic period he reminded his psychiatrist about this question, and was able to describe the grandiose delusions and hallucinations he had experienced during his previous manic states. Dissociative fugue is characterized by prolonged periods in which individuals carry out very complex activities without having any recollection of their previous lives, identities, or even names. They often travel away from customary locales and assume entirely new identities. By definition, psychogenic fugue cannot result from a neurological disorder. In comparison, the discontinuity of experience in dissociative amnesia is typically more circumscribed and does not involve assuming an entirely new identity. The dissociated memories and moods often reveal themselves in disguised form as nightmares, intrusive visual images, and conversion symptoms. Typically, in psychogenic amnesia an individual may not be able to recollect what transpired during a specific period of time, for example, before the age of 9 or 10 in the context of a traumatic childhood, or catastrophic events such as traumatic, gruesome combat, or less momentous events that a person prefers to forget in order to preserve self-esteem by denying shameful, immoral, or illegal activities. A 42-year-old man who had been in an automobile accident several months previously, without any clear report of head injury at that time, was seen in a hospital claiming that he was unable to remember any of the events of the accident or any events for a week prior to or subsequent to the accident. After several interviews conducted after he had been administered amobarbital he was able to recall that although formal police charges had never been filed against him, the accident had been his fault and that a passenger in the other car had been killed as a result of the accident. His memories evoked a great deal of psychological pain, grief, and remorse. Dissociative identity disorder is a chronic, dissociative state in which two or more separate ongoing identities or personalities alternate in consciousness. It usually occurs in persons who as young children were severely and repeatedly brutalized. The number of identities is variable, with some cases reporting 25 or more identities. The development of dissociated alter personalities is thought to be a last-ditch, primitive psychological defense against inescapable and unbearably traumatic situations. The personalities may be of different ages and even different sexes. Typically, the presenting identity is dysphoric, anxious, and constricted, may suffer headaches and periods of blackout or amnesia, and is not aware of the other personalities. A second identity is typically vivacious and uninhibited. Another identity may know all about the other personalities and has a wise perspective on the life events leading to the problems and on possible solutions. A classic case is described in a popular book and film, The Three Faces of Eve. In so-called channeling, dissociated complex part-personalities are produced in trance states, in which fictitious past lives or spirit lives are created. In Ganser's syndrome the patient responds to questions by giving approximate or patently ridiculous answers, for example, in response to the question “What sound does a dog make?” the patient answers “moo.” Additional features of the syndrome include alterations in consciousness, hallucinations (or pseudohallucinations), conversion phenomena, and amnesia for the episode during which these symptoms were manifest. This syndrome has most commonly been reported in prisoners, and is generally thought to be a dissociative state, although organic features may contribute. Depersonalization refers to an alteration in one's experience and awareness of the self, leading to feelings of being unreal or detached from one's own body, of feeling like an automation; it is often accompanied by the complaint that the individual lacks all feelings and sensory experiences. Those experiencing depersonalization frequently fear that they are going crazy. Because of this fear, patients often endure depersonalization experiences for long periods of time before describing them to a mental health professional. Depersonalization is also characterized by frequent internal nonaudible dialogues between the participating self and the observing self, but with full awareness that both parties are the same person (a feature that distinguishes it from hallucinations.) Mild sensory distortions, but not hallucinations, are commonly associated with the experience. Depersonalization is seen in a variety of neurological and psychiatric disorders and is common in complex partial seizures. It may occur in the context of depression, anxiety disorders, or certain personality disorders or as an entity by itself (depersonalization disorder). In derealization, individuals know themselves to be real, but feel that the world around them has suddenly become unreal. Derealization often but not always accompanies depersonalization. Transient episodes of depersonalizaiton and derealization occur frequently in normal persons, particularly during states of fatigue, sleep deprivation, or stressful situations such as bereavement, learning of a terminal diagnosis, or sudden awareness that one is about to be in an inescapable vehicle accident. A 27-year-old man described driving in his car when he realized that he was about to be hit by a huge tractor trailer and had no way of avoiding the collision. During the seconds prior to impact, at the moment of impact itself, and for minutes following the impact when he sat, dazed and thankful to be alive, in his totally destroyed car, he felt completely estranged from events, saying to himself, “This can't be real; this isn't happening to me; I'm going to wake up and things will be normal.” Disturbances of the Self At the most basic level, the key components of self-awareness are the reality and integrity of the self (that I am one person), the continuity of self (that I am the same person now that I was in the past and that I will be in the future), the boundaries of self (that I can distinguish between myself and the rest of the world as not-self), and activity of self (that it is I who is thinking, doing, feeling). Additional components of a sense of self include body image, and various self-evaluations including self-esteem and ego ideal (ideal self). Body image is an individual's mental representation of his or her own body. Self-esteem is thought to reflect how one measures up to the desired self-image. To the extent that what one sees in oneself approximates what one would like to be, elf-esteem is positive. Ego ideals are fantasies of the optimum person one could ever wish to be. Any of these qualities may be disturbed in psychiatric disorders. Within each individual is a group of social selves composed of the roles and identities that the person assumes and that are evoked in various contexts. The presenting “self” varies depending on the persons with whom we are interacting, for example, parent, romantic partner, child, friend, or employer, and depending on what role we are assuming, for example, child, parent, colleague, or lover. Accompanying each of these “selves” are various levels of objective and subjective self-awareness and self-understanding. Disturbances in Sense of Self Disturbances of the basic elements of self-awareness may be seen in a variety of disorders. Discontinuity phenomena are characteristic of dissociative disorders, such as dissociative amnesias and dissociative fugue. Depersonalization reflects a mild disturbance in the awareness of self as the agent of activity. More severe disturbance is characteristic of the psychotic passivity phenomena seen in schizophrenia. Boundary disturbances may be

considered characteristic of all psychotic states, regardless of diagnosis. Disorders of self-integrity are characteristic of dissociative identity disorders as well as severe borderline personality disorders in which a person's self-concept and expression of this concept to others is erratic, leading to a sense of unstable identity. The as-if personality typically adopts characteristics of those who are particularly important to the individual, like a personality chameleon. In adopting these characteristics, the as-if personality does not appear to be acting, but seems to experience and manifest the assumed traits in a very genuine manner, at least for a while. A change in relationships and situations usually prompts the as-if personality to summarily discard previously held traits and to assume new ones that better fit with the new circumstances. False self describes a persona or a faulty and limited superficial aspect of the personality that an individual builds up as a mechanism for adapting to a hostile world—to please, control, or negotiate with others and with himself or herself. However, the false self fails to incorporate, integrate, or validate important fundamental needs, wants, values, and beliefs. Through self-deception and denial the individual may consciously believe that this “self” constitutes his or her entire being. However, the false self is a relatively fragile construction that has usually warded off and denied fundamental strivings, which may include needs for autonomy, acting with integrity, expressing certain desires, beliefs or talents, or other unacknowledged aspects of the self. When these warded-off needs finally break through and demand expression at various points in development, the defective false self may collapse, leading to a period of distress and identity confusion which individuals sometimes describe as a “nervous breakdown.” Patients with pseudologia fantastica and the impostor syndrome demonstrate extreme examples of inconsistency in the sense of self. Patients with pseudologia fantastica compulsively spin out webs of lies, ordinarily self-aggrandizing ones, and also appear to be trying very hard to deceive themselves into believing that they are true. In the impostor syndrome, such fantasies are acted out by liars and impostors who seem to fervently wish that these fantasies were their reality, as if they cannot accept themselves and would be overwhelmingly ashamed to be known for who they actually are. The impostor compulsively adopts the identities of others and may, for example, show up properly attired at diplomatic functions and society galas and interact with the other guests under the assumed identity. Some famous impostors have repeatedly insinuated themselves into inner circles of high society and government. Transsexualism is a syndrome characterized by the feeling that one was born into a body of the wrong sex and marked by the desire, starting at an early age, to be a person of the opposite sex. Male-to-female transsexualism is reported more often than female-to-male transsexualism. Both psychodynamic and biological theories have been advanced to explain these phenomena. Such persons seek procedures to change their anatomy with hormones or surgery. Self-esteem is a measure of one's self-appraisal in relation to one's values and ego-ideals. Negative self-esteem is characteristic of depressive disorders, many personality disorders, and situational failures. Superficially inflated self-esteem may be seen in mania (or hypomania), or, in a fluctuating manner, in narcissistic and other personality disorders. Although some individuals regard their ego-ideals as unattainable and are content to live as imperfect human beings, others strive to approximate their ideals. People who feel driven to achieve unattainable ideal goals or to become their unrealistically perfect ideal selves are likely to be chronically dysphoric and have poor self-esteem, since their attempts to become their ego-ideals are doomed to failure. Disorders of the Will Central to the sense of self is the concept of will or volition. Psychologically, will is linked to the concepts of intentionality and of transforming awareness and knowledge into initiating action, as the bridge between desire and act. To manifest normal will, individuals must be aware and feel desires, and these desires must arise from within themselves. Concepts related to will that may become the focus of clinical attention when disturbed include motivation and decision making (i.e., the capacity to make choices). Pathologically heightened will, seen primarily in manic states, is characterized by excessively intense desires and an overly facile capacity to make decisions, with complex questions being decided on in an instant. With heightened psychological energy, these individuals can start new courses of action with astonishing rapidity. Closer examination of these actions in more extreme cases, however, reveals that they share much in common with decreased will, in that the intense desires and quick decisions often reflect impulsiveness, which can be considered an escape from true willing and decision-making rather than enduring desires or thoughtful decision-making. The term abulia has been used to describe the loss, lack, or impairment of the power to will or to execute what is in mind. Individuals with abulia show a diminished sense of motive or desire and impairment in making the transition from motive and desire to execution of action. Deficiencies in will may be seen in a variety of psychiatric disorders, and at the end of life when patients have surrendered their will to live and are simply waiting to die. In schizophrenia a diminished sense of will can be seen in passivity phenomena, as well as in other negative (or deficit) symptoms that may affect thoughts, feelings, and behaviors. These include lack of drive, impersistence at tasks, and a general inner flatness. Depressed patients also describe volitional disturbances, as in their general apathy and anhedonia. Patients who chronically inhale solvents (e.g., glue, gasoline, toluene), smoke marijuana very heavily, and chronically use hallucinogens have a characteristic amotivational syndrome. The extent to which this lack of motivation results from or contributes to the chronic substance abuse is a matter of debate. In obsessive-compulsive disorder both the obsessional thoughts and the compulsive rituals are experienced as ego-dystonic and not consonant with the patient's conscious desires and will. Similarly, although patients with anorexia nervosa initially have the conscious experience of willing and controlling their intake of food, during the course of the disorder the sense of willfulness is replaced by passivity, of being subjugated by obsessional thoughts and compulsive behaviors that assume control of the eating behavior. A 35-year-old woman with chronic anorexia nervosa felt compelled to cut her food into pieces no larger than rice grains, fearing that larger pieces would make her fat, and that she might choke. She permitted herself no foods that contained any fat. Other compulsions required her to swim eight or sixteen laps in the local pool each day. Failing to do so would result in a masochistic punishment, usually burning her arm with a lit cigarette. Disturbances of volition are among the more common complaints of patients with personality disturbances who request psychotherapy. Individuals with dependent personalities are characterized by difficulties in making decisions by themselves and often engage in courses of action contrary to their own desires. Similarly, individuals with passive-aggressive personality disorder obscure their own desires by being excessively involved in the demands made upon them by others. Their courses of action do not reflect their own decisions so much as the thwarting of others' desires. People with compulsive personalities use inflexible rules, thereby precluding courses of action based on independent evaluation, individual desires, and decisions. In other situations, they are indecisive, sometimes making impulsive decisions at the last minute when forced to decide. Finally, many individuals seek treatment because of self-designated disturbances of willing: they do not know what they want, they are unable to make choices among several options, or they procrastinate excessively. Often these problems may mask other fears—of wanting, commitment, taking initiative, hard work, success, making a mistake, being criticized, angering others, and of all the consequences related to such actions. Disturbances of Orientation Orientation refers to one's awareness of time, place, and person. Accurate orientation requires the integrity of attention, perception, memory, and ideation. Impairments occur primarily in organic mental disorders (i.e., structural and toxic metabolic brain abnormalities) and occasionally in dissociative and psychotic states. Normal individuals vary tremendously in their attention to the details of time, and in the extent to which their bodies automatically keep time. Some people have reliable built-in clocks by which they can awaken themselves at precise times or gauge the passage of time with uncanny accuracy, even in the absence of external cues, as during a psychotherapy session, for example. Others have difficulty making judgments about time and may develop pathological lateness or habitually schedule more activities than could ever be accomplished in the available time. Benign disorientation to time is common. After a few days in a hospital bed, most people do not know exactly what the day or date is because they are not attending to or receiving their usual cues. Pathological time disorientation can be mild or severe, with inaccuracies of estimation ranging from days to years. The dates reported by disoriented individuals may have personal significance, such as those of important births, marriages, or deaths. Because spatial cues are generally more available and obvious than temporal cues, disorientation to place often signifies a greater degree of cognitive impairment than disorientation to time, and therefore rarely occurs in the absence of time disorientation. Disoriented persons may know, more or less, the type of place they are in without knowing the specific place—patients may recognize that they are in a hospital without being able to name the hospital.

A 56-year-old former banking official with advanced Alzheimer's disease demonstrated preserved superficial social graces and was generally in a pleasant mood. When anyone asked him where he was, however, he appeared to become momentarily aware of his profound deficits and became very agitated, developing a marked tremor of his left arm and hand and fearfully looking about. This would last for a few minutes, until he was calmed and reassured that he was all right. Disorientation to person, a lack of awareness of one's own identity, is typically seen only in advanced dementias, such as primary degenerative dementia of the Alzheimer's type or in dissociative states. In postconcussion amnesia, transient global amnesia, and dissociative fugue, knowledge of one's own identity may disappear and a person may remain unidentified for an indefinite period until the memory for self returns. Disturbances of Memory Memory is not a unitary phenomenon. Capacities to remember vary for the different senses and perceptions. One person may have prodigious musical memory, with the capacity to remember and reproduce whole musical pieces after one hearing, but be incapable of remembering people's names or telephone numbers. Exceptionally detailed verbal memories have been associated with obsessional cognitive styles. When individuals with extraordinary memories complain of memory loss, ordinary memory tests may be inadequate to detect their deficits because their relative memory loss may have reduced their capacities to a point within the range of most normal people. Memory functions have been divided into three stages: registration, retention, and recall. Registration or acquisition refers to the capacity to add new material to memory. The material may be sensory, perceptual, or conceptual and may come from the environment or from within the person. In order for new material to be acquired, the person must attend to the information presented, it must then be registered through the appropriate sensory channels, and then be processed or cortically organized. Retention is the ability to hold memories in storage. Large numbers of neurons are thought to be involved in the storage of a specific memory, and it is believed that reverberating circuits are formed in which memory traces are held by means of changes in proteins or synaptic connectivity or both. Recall is the capacity to return previously stored memories to consciousness. Newly registered material is transferred incrementally from immediate to short-term memory to long-term memory. Immediate memory lasts for 15 to 20 seconds; short-term memory (or recent memory) for several minutes up to 2 days (the time involved in new learning and its early consolidation); and long-term (or remote) memory for longer periods of time. Different physiological processes mediate each of these stages of memory. Because of this, processes that affect immediate or short-term memory often spare long-term memory. The processes by which memories are transferred from short-term to long-term stores are unknown. Cognitive scientists now refer to short-term memory as working memory, the system that briefly stores and processes information needed for planning and reasoning. Recent studies suggest that the working memory system consists of at least two short-term memory buffers, one for verbal and another for visual memories, plus a central executive that manipulates and coordinates information stored in the two buffers for problem-solving, planning, and organizing activities. Parallel processing systems involving specific areas of the prefrontal cortex and other brain areas appear to operate separately with respect to various processes concerned with working memory. For example, separate prefrontal areas appear to be involved in working memory functions concerned with object identity and spatial locations. Other studies suggest that different types of memories are stored and retrieved by different brain systems, so that there is at least a dual memory system. The first system, sometimes called a conditioned-emotional system, or system for implicit memory, or perceptual memory, or nondeclarative memory, is present from birth, operational through life, and is addressable by situational, sensory, or affective cues. Past experiences are expressed through images, behaviors, or emotions. These memories need not involve any conscious memories of a past experience. Conditioned fear responses represent examples of memories elicited in this system. The second system, sometimes called narrative-biographical memory, explicit memory, reflective memory, or declarative memory, emerges during the preschool years, and includes information significant to the self. Memories are addressable through intentional retrieval efforts, apart from the original learning conditions. They are identified as representing personally experienced events, and compose the individual's life history, roughly equivalent to memory with consciousness or memory with awareness. Clinical studies suggest that in at least some amnesias implicit and explicit memory functions may become dissociated. Disturbances in memory occur through the interruption of registration, retention, or recall. Disturbances in Registration Registration and short-term memory retention are usually impaired in disorders that affect vigilance and attention such as head trauma, delirium, intoxication, psychosis, spontaneous or induced seizures, anxiety, depression, and fatigue. A variety of other metabolic and structural brain disturbances can affect short-term memory as well, particularly lesions affecting the mammillary bodies, hippocampus, fornix, and closely associated areas. Patients with impaired attention and concentration who are able to demonstrate immediate recall may not be able to retain or recollect these items from short-term memory. Benzodiazepine use has been associated with working memory difficulties, especially in the elderly. Some short-acting high-potency benzodiazepines used as sleeping pills may be particularly troublesome in this regard. Disturbances in Retention The retention of memories is impaired in posttraumatic amnesia as well as in a number of cognitive disorders, such as dementia of the Alzheimer's type and the Wernicke-Korsakoff syndrome. The latter, which ordinarily results from chronic thiamine deficiency seen with alcoholism, is associated with pathological alterations in the mammillary bodies and thalamus. Disturbances in Recall Disturbances in recall can occur even when memories have been registered and are in storage. Research has shown that memories are not passively retrieved but are actively reconstructed. Each act of recollection requires an act of putting the memory together, not simply lifting it ready made from a file. Because memories are often retrieved for specific purposes to meet the individual's particular needs and agendas, this act of reconstruction is often subject to the introduction of distortions and falsification. As a result, memories may fail to truly represent past events. At times, failure to recall may signify that the memory traces themselves have disappeared and are no longer retrievable. However, difficulties in recall can occur separately, as in the everyday event of forgetting the name of a person or object, only to spontaneously remember it hours or days later. In normal forgetting, more remote events are less well remembered than recent ones, and important events are most vividly retained in memory. Some patients with dementia may lose memories for all events occurring after a specific date or event, as if the slate had been wiped clean, but retain earlier memories. Some individuals may progressively erase memories, so that they recall only earlier and earlier events. An 80-year-old patient with Alzheimer's disease initially had no memory for events that occurred after he was 70, a few months later he was unable to recall events that had occurred after he was 60, and several years later, although he could not remember his children who had been born in his 30s, he could still recall his spouse and siblings, from earlier periods of life. At each examination it seemed as if his memories for months' or years' worth of events were simply being erased along the time line of his life. Under usual conditions, forgotten events can be recalled with prompting, associative memories, or other forms of stimulation such as hypnosis. As described earlier, state-dependent memories are recall failures, reversed by reinstituting the context in which the memory was originally formed. Amnestic disorders are syndromes in which short-term and long-term memory is impaired within a state of normal consciousness. Thus, memory disturbances in delirium should strictly speaking not be considered amnestic syndromes. Anterograde amnesia is the inability to register or learn new information (and therefore to form new memories) from a specific event onward; it typically follows head trauma, states of cerebral physiological imbalance, or drug effects. Patients who receive electroconvulsive therapy (ECT) frequently have anterograde amnesias during the course of the treatments; the amnesia gradually fades over numbers of weeks. Retrograde amnesia is an impairment in recalling memories that were established before a traumatic event, extending backwards in time for variable periods. As memory is regained, the more remote memories usually return first. A patient originally amnestic for the 3-month period prior to an accident may ultimately be left with amnesia for events only a day or an hour just prior to the accident. In organically caused retrograde amnesias, remote memories are usually intact while amnesia may exist for more recent events. This contrasts with dissociative amnesia, in which the time periods of forgotten events may be more spotty or selective. Hyperamnesia, unusually detailed and vivid memory, may occur in gifted persons, in association with obsessive-compulsive and paranoid personality traits, and in hypnotic trances. Intrusive memories may occur in posttraumatic stress disorder, signaling failure of the mechanisms that usually keep unwanted memories and information out of working memory. A 36-year-old Hispanic woman who had been brutally raped 3 years before, after which the perpetrator savagely cut her genitals and anus with a razor, experienced frequent intrusive memories of the event, associated with marked anxiety and occasional panic. These memories were most likely to intrude during times of repose, when she was trying to fall asleep, and when she was feeling anxious about other ongoing issues in her life. Although many forgotten memories can be recalled in hypnotic trance, retrospective falsification and distortion may also occur under hypnosis. (Memories recalled under hypnosis usually are not accepted as evidence in court.) Retrospective falsification of memory, the development of false memories, is called paramnesia, also

known as fausse reconnaissance. Confabulation is another common form of paramnesia in which the patient fills in memory gaps with inaccurate information. The responses given to questions by patients who confabulate may reflect past experiences or constitute bizarre, fantastic stories. Confabulation correlates poorly with memory deficit and is thought to reflect frontal lobe dysfunction and a failure of self-monitoring. Confabulation is prominent in certain alcohol amnestic syndromes such as Wernicke-Korsakoff syndrome as well as other disorders of the mammillary bodies, thalamus, or frontal lobes. Dêja vu is the sense that one has previously seen or experienced what is transpiring for the first time; it is a false impression that the current stream of consciousness has previously been recorded in memory. Related phenomena are dêja entendu, a sense that one has previously heard what is actually being heard for the first time, and dêja pensé, a feeling that one has at an earlier time known or understood what is being thought for the first time. Experiences of jamais vu, jamais entendu, and jamais pensé involve feelings that one has never seen, heard, or thought (respectively) things that in fact one has. These phenomena are all common in everyday life but may increase in states of fatigue or intoxication and in association with complex partial seizures or other psychopathological states. Dementia is a syndrome in which the essential feature is an acquired impairment of short- and long-term memory with associated impairments of abstract thinking and judgment, personality changes, and other cortical disturbances. The symptoms always involve more than one sphere of function. In later stages, patients with dementia may become helpless, too confused to use a stove, and incapable of remembering the names of close relatives. They may wander into dangerous situations, oblivious of their surroundings. Dementias are caused by a variety of pathogenic processes, some of which are reversible, such as hypothyroidism and subdural hematoma; others are irreversible, such as dementia of the Alzheimer's type and vascular dementia. Although the characteristic cognitive disturbances seen in severe major depressive episodes are usually called pseudodementias, many neuropsychiatrists believe that profound cognitive dysfunction meeting criteria for dementia associated with depression should properly be labeled a reversible dementia syndrome.

DISTURBANCES IN PERCEPTION Normal perception first requires that the individual be capable of receiving information as sensations. The data must then be organized to make them meaningful and comprehensible, such as distinguishing figure from ground, or focusing attention selectively on some part of the sensory field. The organized entities are called percepts. In states of sensory deficit such as blindness, deafness, and anesthesia perception is impaired but is still possible because individuals generally perceive information about an object through several sensory modalities concurrently. The intensity of sensation and perception is affected by vigilance and attention. Highly focused attention, as in intense concentration or hypnosis, may result in unusually acute sensation and perception—hyperesthesia, hyperacusis, or extraordinary visual acuity. Focused attention may also result in failure to sense or perceive: deep anesthesia and negative hallucinations induced by hypnosis are simply induced failures to perceive what exists in the world. Humans usually operate in an average expectable environment in which certain types and levels of sensory input are expected, and for which the nervous system is primed. Excessive or inadequate stimulation in any sensory modality, levels of input that are extraordinarily intense, or the presentation of novel stimuli that are entirely different from anything previously experienced by the individual can provoke distorted perceptions in most normal people. For example, total sensory deprivation produced in carefully controlled artificial environments may elicit visual and auditory illusions and hallucinations. Individuals generally exhibit selective perception of the world, depending on what is salient at the moment and on their individual memories, emotions, fantasies, and values. Pregnant women are more likely to perceive babies around them than are people who are not as preoccupied with childbearing. The intensity of perceptions depends on individual sensitivities as well as on mood, anxiety, and substance use. Depressed patients often describe that colors look faded, that the world looks washed out or gray, even though their capacity to recognize specific colors is unchanged. Similarly, mania is often characterized by heightened perceptions, hyperesthesia. When extreme, these intense perceptions are uncomfortable. Hyperesthesia can also be seen during benzodiazepine withdrawal, hallucinogen intoxication, and occasionally as part of an epileptic aura. The intensity of perception may vary with cognitive style and other psychological and neurological factors. Some individuals tend to be augmenters and others minimizers of bodily experiences. Chronic pain and some hypochondriacal syndromes may occur more commonly among somatic augmenters. Selective deficits may occur in the perception of emotions. Emotional aprosodies have been described in which patients with specific neurological deficits or depression are selectively unable to recognize the expression of facial emotion. These have been linked by position emission tomography (PET) scan to blunted activity in the right prefrontal cortex and insula. Illusions Perceptual distortions in estimating size, shape, and spatial relations are common even in the absence of psychiatric disorders, especially when one is fatigued or excessively aroused. Illusions are misinterpretations of real sensory stimuli, as when a child in a dark bedroom at night sees monsters emanating from shadows on the walls. Pareidolias are playful and whimsical voluntary illusions that can be seen when one looks at ambiguously defined or evanescent images, such as flames in a fireplace or clouds. Both the onset and termination of these perceptions are entirely voluntary. Trailing, another visual illusion, is the perception that an object moving steadily in space is followed by temporally distinct, after-images of itself. The effect is that of a series of stroboscopic photos. This phenomenon may occur with fatigue and is typically seen with marijuana and mescaline intoxication. Hallucinations are perceptions that occur in the absence of corresponding sensory stimuli. Phenomenologically, hallucinations are ordinarily subjectively indistinguishable from normal perceptions. Hallucinations are often experienced as being private, so that others are not able to see or hear the same perceptions. The patient's explanation for this is typically delusional. Hallucinations can affect any sensory system and sometimes occur in several concurrently. When perception is altered, illusions and hallucinations, and often delusions as well, are frequently experienced together. Some studies have found that 90 percent of patients with hallucinations also have delusions, and about 35 percent of patients with delusions also have hallucinations. About 20 percent of patients have mixed sensory hallucinations (mostly auditory and visual) that may accompany functional as well as organic conditions. A given external stimulus may evoke very different perceptual distortions in different persons. For example, of three scientists who floated in sensory deprivation tanks for long periods of time one experienced a few illusions and no hallucinations; the second had many illusions and a few faint auditory and visual hallucinations; the third had vivid, dramatic, and complex visual and auditory hallucinations. Hallucinations are experienced by many normal people under unusual conditions. It has been estimated that between 10 to 27 percent of the general population have experienced memorable hallucinations, most commonly visual hallucinations. Hypnagogic and hypnopompic hallucinations are common, predominantly visual hallucinations that occur during the moments immediately preceding falling asleep and during the transition from sleep to wakefulness, respectively. Hypnagogic and hypnopompic hallucinations both occur in normal persons and are also characteristic symptoms of narcolepsy. In acute bereavement, up to 50 percent of grieving spouses have reported hallucinating the voice or presence of the deceased, and following amputations, phantom limb hallucinations are common. Patients who become visually impaired often develop pseudohallucinations (i.e., visual hallucinations with preserved insight) with preserved cognitive status, called's Bonnet syndrome. These observations suggest a supersensitivity deprivation hypothesis, that when deprived of important and anticipated perceptual stimuli, the mental apparatus may overinterpret any sensory stimulation as evidence of the presence of the needed objects. A perceptual release theory suggests that hallucinations emerge from the combined presence of intense states of internal arousal and diminished sensory input (including poor attention and poor capacity to sort out relevant from irrelevant input). Thus, diminished input from the environment (as in sensory deprivation) or reduced capacity to attend to and take in the input (as in delirious states) heighten the likelihood that internal sensations, images, and thoughts will be interpreted as originating in the outside environment. Hallucinations vary according to sensory modality, degree of complexity of the hallucinated experience, the levels of conviction about their reality, the clarity of their contents, the location of their sources of origin, the degree of volitional control over them, and the degree to which the hallucination influences the person's behavior. Auditory hallucinations range in complexity from hearing unstructured sounds such as whirring noises or muffled whispers to ongoing multiperson discussions about the patient. Simple auditory hallucinations are more commonly associated with organic psychoses, such as delirium, complex partial seizures, and toxic and metabolic encephalopathies. Deafness can produce hallucinations consisting of noises or of formed music. Auditory hallucinations are classically associated with schizophrenia (seen in 60 to 90 percent of patients) but are also frequently seen in mood disorders with psychotic features; 20 percent of manic patients and less than 10 percent of depressed patients experience auditory hallucinations. Three types of auditory hallucinations commonly associated with schizophrenia (also seen less commonly in patients with psychotic depressions and mania) are: audible thoughts described as hallucinated voices that speak aloud what the patient is thinking; voices that give a running commentary on the patient's actions; and

hearing two or more voices arguing with each other, often about the patient who is referred to in the third person. A 23-year-old woman with schizophrenia heard several choruses of angels and “higher beings” who intermittently argued with each other about how she should be spending her time, and what she should do to hasten the arrival of the Messiah on earth. The multitudes of voices also addressed her directly, but the cacophony was often so great that she could distinguish only one or two voices, belonging to the more powerful or influential angels. She ordinarily took their advice and recommendations to heart, but she was quite perplexed by the fact that the angels often could not agree. Although auditory hallucinations in schizophrenia are frequently mood-neutral, hallucinations in patients with mood disorders are characteristically consistent with their mood. In psychotic depression, the voices may be unrelievedly critical and sadistic; in mania the voices often refer to the patient's specialness. A 50-year-old former schoolteacher with bipolar disorder had characteristic auditory hallucinations during each of her episodes of mania and of melancholia. During manias she heard celestial voices praising her and instructing her to start elaborate international businesses. When melancholic she heard accusatory voices telling her that she had deeply hurt, offended, and harmed many of her students by not grading them accurately, and that as a result the FBI was searching for her and was certain to jail and torture her for the rest of her life. Command hallucinations order patients to do things. Often the commands are benign reminders about everyday tasks: “Pick up your shoes” or “Clean the table.” However, the voices may also be frightening or dangerous, commanding acts of violence toward the self or others, such as “Jump off the roof, you're not worth anything,” or “Pick up the knife and kill your mother.” These voices vary in insistence and persistence, and patients differ in their capacities to ignore these commands. Patients with marked passivity may be helpless in the face of command hallucinations, and may feel impelled to carry out the orders. Even though one study did not find command hallucinations to be associated with a higher risk of harm to the patient or others, the presence of command hallucinations and the patient's ability to resist must be assessed carefully. A young man with schizophrenia heard an insistent voice ordering him to attack his mother with a kitchen knife because she was really an agent of the Devil. He was terrified, and told his mother and his psychiatrist about the voices, assuring them that he was aware that the voices were bad, and that he could resist them. When he stopped taking his medications for a few weeks, he felt that the voices become stronger, more insistent, and was less able to resist obeying them. At one point, immediately after telling his mother about his great anguish in fending off the voices, he grabbed a large kitchen knife and started to slash his own arm in an effort to deflect an attack on her. He was hospitalized and re-medicated, as a result of which the intensity of the voices abated, although they remained constantly in the background. Visual hallucinations occur in a wide variety of neurological and psychiatric disorders, including toxic disturbances, drug withdrawal syndromes, focal CNS lesions, migraine headaches, blindness, schizophrenia, and psychotic mood disorders. Although visual hallucinations are generally assumed to characteristically reflect organic disorders, they are seen in one quarter to one half of schizophrenia patients, often but not always in conjunction with auditory hallucinations. Visual hallucinations range from simple and elemental, consisting of flashes of light or geometric figures, to elaborate visions, such as a flock of angels. Stimulation of one sensory modality sometimes evokes perceptual distortions in another. Marijuana and mescaline intoxication, for example, have been associated with synesthesia, an experience in which sensory modalities seem fused. This is also a normal experience for many people. Music may be experienced visually, the sound fusing with visual illusions; a tactile sensation may be experienced as a color (e.g., a hot surface may feel “red”). In certain religious subcultures visual hallucinations may be experienced as normal. In one fundamentalist Pentecostal Church, worshipers danced themselves into a frenzy and, without using any drugs, several participants shared visions of the Virgin Mary at the altar. During a period of great personal turmoil, a 24-year-old Hispanic woman with great religious conviction and cluster B personality traits, was praying in church when she noticed the Madonna and a host of female angels all smiling at her. She felt as if she were being graced, and experienced a profound sense of peace and relief. On subsequent visits to the same church, these visions returned and were always comforting to her. Autoscopic hallucinations are hallucinations of one's own physical self. Such hallucinations may stimulate the delusion that one has a double (Doppelgänger). Reports of near-death out-of-body experiences in which individuals see themselves rising to the ceiling and looking down at themselves in a hospital bed may be autoscopic hallucinations. In Lilliputian hallucinations, the individual sees figures in very reduced size, like midgets or dwarfs. They may be related to the perceptual distortions of macropsia and micropsia, respectively the perceptions of objects as much bigger or smaller than they actually are. Haptic hallucinations involve touch. Simple haptic hallucinations, such as the feeling that bugs are crawling over one's skin ( formication) are common in alcohol withdrawal syndromes and in cocaine intoxication. When unkempt and physically neglectful patients complain of these sensations, they may be caused by the presence of real physical stimuli such as lice. Some tactile hallucinations, having intercourse with God, for example, are highly suggestive of schizophrenia, but may also occur in tertiary syphilis and other conditions, and may in fact be stimulated by local genital irritation. Olfactory and gustatory hallucinations, involving smell and taste respectively, have most often been associated with organic brain disease, particularly with the uncinate fits of complex partial seizures. Olfactory hallucinations may also be seen in psychotic depression, typically as odors of decay, rotting, or death. The term pseudohallucination has been used in two ways. First, pseudohallucination refers to perceptions experienced as coming from within the mind (i.e., not at the boundary or outside the mind). Using this definition, loud voices that are alien, ascribed to other beings, but that the patient knows are actually within the mind rather than out in space, are pseudohallucinations. The term has also been used to describe hallucinatory experiences whose validity the patient doubts. A better term for this second phenomenon is partial hallucination, analogous to partial delusion. Functional hallucinations are rare hallucinations that occur only in connection with a specific external perception, for example, in the presence of a sound such as running water, or a color, or a particular place. However, unlike illusions, the hallucinated sounds are not elaborations of the perception but are simply triggered only in that specific context. A 25-year-old farmer with schizophrenia told of a talking tree on his property. During previous episodes he had experienced a variety of auditory hallucinations that were generally well controlled with medication. However, each time he came near to this large, old tree, he would hear a profound, wise voice—as if the tree were one with the earth and the universe, and had important guidance for him. He often came to the tree when he was troubled, seeking the hallucinatory experiences. Ictal hallucinations, occurring as part of seizure activity, are typically brief, lasting only seconds to minutes, and sterotyped. They may be simple images—such as flashes of light—or elaborate ones, such as visual recollections of past experiences. During the hallucinations the patient ordinarily experiences altered consciousness or a twilight sleep. Migrainous hallucinations are reported by about 50 percent of patients with migraine. Most are simple visual hallucinations of geometric patterns, but fully formed visual hallucinations, sometimes with micropsia and macropsia, may also occur. This complex has been called the Alice in Wonderland syndrome after Lewis Carroll's descriptions of the world in Through the Looking Glass, which mirrored some of his own migrainous experiences. In turn, these phenomena closely resemble visual hallucinations induced by psychedelic drugs such as mescaline. A flashback is an intense visual reexperience of highly charged past events, which are often replays of hallucinations. They are typically associated with heavy use of hallucinogens such as LSD and mescaline and often occur months after the last drug ingestion. The images may be simple or complex geometric patterns or they may consist of previously experienced elaborate drug-induced hallucinations. Flashback phenomena may be state-dependent. For example, visual hallucinations initially experienced with hallucinogens are more likely to be subsequently experienced as flashbacks when the subject is smoking marijuana. In posttraumatic stress disorder, some complex intrusive flashback-like images may attain an hallucinatory vividness. Images often include horrifying memories of traumatic events that may force themselves repeatedly into consciousness until they are acknowledged and worked through.

A 35-year-old man with a history of polysubstance abuse and who constantly smoked marijuana estimated that he had used hallucinogens including LSD and mescaline more than 100 times before having a series of devastatingly frightening hallucinatory experiences of devils, of his body being consumed and eaten by wild animals, and of burning in hell-fires. These were accompanied by such profound paranoia and panic attacks that he swore off “heavy drugs,” but continued to use alcohol and marijuana. Several months later, during a period of personal crisis during which he smoked an unusually large amount of powerful marijuana he suddenly reexperienced the worst devil-filled flashback; this experience lasted for several hours in spite of the efforts of several of his friends to talk him down. Hallucinosis is a state of active hallucination occurring in someone who is alert and well oriented. This condition is seen most often in alcoholic withdrawal, but it may also occur during acute intoxications and other drug-mediated states. A 30-year-old woman being treated for a depressive disorder with a monoamine oxidase inhibitor snorted cocaine at a party. For the next 3 days she described vivid hallucinatory experiences while in an alert state. She managed to drive her car throughout this time, although with some difficulty. In her psychiatrist's office she alternated between relating coherently to the psychiatrist and responding to her dreamlike complex visual and auditory hallucinations. These phenomena abated within 4 days. Body Image Distortions Body image includes both perceptual and ideational components, and may reflect primarily perceptual distortions or combinations of disturbed perception and self-appraisal. Body image disturbances can occur as normal responses to abrupt changes in the body (e.g., following amputation), in brain disease, and in psychiatric disorders. Phantom-limb phenomena are classic body image problems in which an amputated limb is still felt to be present. The sensation may diminish gradually over time; the patient feels as if the phantom is receding into the stump Agnosias, lack of awareness of some parts of the body, may accompany brain damage, most often of the nondominant parietal lobe. Patients with obvious motor or sensory deficits may deny that any deficit exists at all (anosognosia), or the denial may be limited to half of the body (hemiagnosia), usually the left side. In hemidepersonalization syndromes, a less common disorder (hemisomatognosia), patients feel that one of their limbs is missing, again usually on the left side. Body image distortions in which a limb feels too heavy (hyperschemazia) or weightless (hyposchemazia) can occur as a consequence of neurological conditions such as infarction of the parietal lobe. In duplication phenomena, patients feel as if part or all of them has doubled (e.g., that they have two heads or two bodies). These rare phenomena may occur in schizophrenia, complex partial seizures, and migraine. Dysmorphophobia refers to conditions in which patients distortedly perceive and intensely dislike the shape of a particular body part. As such, these symptoms are misnamed because there is no true phobic component, such as fear or avoidant behavior. Fine lines exist between perceptual distortions and realistic but unhappy appraisals of one's body, given the high social value placed on physical appearance. Dysmorphophobia may occur in the context of some personality disorders or as an isolated disorder, called body dysmorphic disorder. In some ways, dysmorphophobia resembles an overvalued idea. Patients may develop dysmorphophobias in relation to any body part; common concerns are hair, breasts, penis, nose, or the entire body. For some, changing the body part, as in rhinoplasty for those who do not like their noses, seems to effect a lasting positive change in body image, with patients becoming happier with themselves and feeling more attractive for years or a lifetime. Patients with severe dysmorphophobia may undergo multiple plastic surgeries and feel dissatisfied with every result. At times, the condition forms part of a larger and more pervasive syndrome, such as anorexia nervosa. A 24-year-old engineering student from a rigid, devout, and loving home was convinced that his mild pectus excavatum condition was an atrocious deformity that accounted for his never having had a girlfriend. A mild deformity did exist, but his reaction to it was far in excess of the actual problem. He was embarrassed to take showers in the dorm, afraid that other students would see him and make fun of his deformity. He sought the services of a surgeon to fix the deformity; the surgeon sent him for psychiatric consultation prior to performing the surgery. No other psychiatric difficulties were evident, and the results of psychological testing were nonrevealing. His father, a rather literal-minded man, was in full agreement with the son's desires to have the corrective surgery. With no clear contraindication, the surgeon agreed to perform the operation. A 6-month follow-up revealed that the student was much happier, and was now dating for the first time in his life. Hypochondriacal complaints also combine perceptual and ideational distortions. Selective hypervigilance to bodily sensations may result in a higher likelihood of perceptions of unpleasant and potentially pathological body experiences among the worried well, hypochondriacal populations, patients with somatization disorder (Briquet's syndrome), and some patients with a panic disorder. Body image distortions may at times be severe or bizarre. Some psychotic patients with schizophrenia or depression develop somatic delusions. In depression, this often expresses itself as a delusion that part of the body or the entire body is rotting or cancerous. Some culture-bound syndromes in non-Western culture express themselves with body image distortions, such as koro, in which the man fears that his penis is shrinking into his abdomen.

DISTURBANCES OF MOOD Defining, describing, understanding, and categorizing moods has long been among the most important and difficult tasks in psychiatry. The language of feelings is filled with terms that seem to have mostly idiosyncratic meanings as patients, phenomenologists, and psychiatrists all struggle to describe inner emotions and to correlate them with external behavior. Even basic terms such as mood, affect, emotion, and feelings lack universal definition. The most common convention, used here, defines mood as a sustained or prevailing subjective feeling tone or range of tones. Affect is the moment-to-moment feeling state, sometimes rapidly shifting in response to a variety of thoughts and situations, which the clinician can observe. Emotions have been defined as moods and affects that are connected to specific ideas, or to the physical concomitants of moods and affects. Feelings are the most poorly defined of all, leading Karl Jaspers to ultimately describe them as everything for which there is no other name. In common parlance and often professionally as well, these words are sometimes used interchangeably. Moods, affects, and emotions can be described by a number of important qualities: intensity (shallow to deep); range (broad to narrow or flat); stability (rigid to labile); reactivity to external events (none to much); periodicity (periodic to aperiodic); congruence with thought content (congruent or appropriate to incongruent); speed of resolution (rapid to slow); and viscosity (evanescent to persistent). The individual's lifelong predominant mood is one component of temperament. Thus, for example, one may be described as having a calm, buoyant, irritable, depressive, anxious, or sensitive temperament. Moods, affects, and emotions serve as internal and external signal systems. They signal the state of the individual to others, and often elicit the necessary help and support from the environment. A baby's face communicates its state of need, tension, or contentment, thereby recruiting appropriate parental interventions. As adults, much of the most important interpersonal communication is transmitted nonverbally through cues that signal the observer about our moods. Positive words communicated by a scowling or sullen face will lead listeners to perceive an angry message, regardless of the spoken words. Moods also have an infectious quality and serve as important ways of influencing others. A cheerful mood towards others influence their moods toward cheerfulness; they in turn are more likely to reciprocate that cheerfulness. Internally, moods, affects, and emotions let individuals know how well or how poorly they are doing, allowing them, for instance, to gauge the distance between actual self-appraisal and desired self-expectations. For example, individuals who desire to master important goals and feel that they have a reasonably good chance of doing so will ordinarily experience pleasant emotional states in relation to these goals. If something intervenes to prevent them from reaching these goals, so that there is an insurmountable gap between their desires and the likelihood of success, they may feel hopeless. In addition to serving as signal systems, emotional states of nonspecific tension, arousal, or anger usually imply that some action will be necessary to secure their discharge or release. Emotional states and their expression are regulated by biological, psychological, and cultural influences. For example, emotional lability, characterized by rapidly shifting emotions that seem unrelated to the situation, typically occurs premenstrually in some women, with varying periodicity in cyclothymic individuals and in those with cluster B personality disorders, and in relation to need states such as hunger, sleepiness, and sexual frustration. Mood shifts have also been related to environment-related physiological influences such as seasonal changes in light. Psychological regulation of emotions may be related to specific coping mechanisms and the ability to self-soothe, which are developmentally determined. Conscious and preconscious psychological mechanisms, including varieties of self-talk, may help to calm or to inflame the emotions. Cultural factors significantly regulate emotional expression. Although the facial expressions for basic emotions are similar in all cultures studied, the range and style of emotional expression permitted in relation to specific contexts varies greatly from culture to culture, and from family to family. Some cultures and families are stiff-lipped and inhibit the open expression of emotion; others encourage emotional display. Marked differences exist among cultures in the emotional expression of acute grief, fear, pain, and affection.

Depression The term depression has been used variously to describe an emotional state, a syndrome, and a group of specific disorders. When seen as part of a syndrome or disorder, depression has autonomic, visceral, emotional, perceptual, cognitive, and behavioral manifestations, as illustrated in Table 8-1. As a nonpathological ubiquitous mood state lasting from hours to days, but sometimes longer, feelings of depression are synonymous with feeling sad, blue, down in the dumps, unhappy, and miserable. Depressed mood is common and appropriate following a disappointment or loss. For most people, innate psychological resilience, coping options, and supportive social networks help to alleviate these brief depressive states and prevent them from becoming chronic. Some individuals suffer from chronically depressed mood, tend to view the world as a difficult place, filled with obstacles and burdens, see themselves as victimized, and lack hope for the future. The extent to which constitutional, developmental, and ongoing aversive life events contribute to this pervasive worldview is unknown. Persons who in early life were deprived and traumatized may be less resilient and more prone to chronic depressive features than are others. Repeated failures and the impact of unrelenting, uncontrollable, and unpredictable negative life events may set the stage for learned helplessness in humans just as they do in animals. A subset of chronically depressed individuals may also suffer from temperamental, biologically driven depression, often seen in conjunction with strong genetic loading for severe mood disorders. Some depressive states are normal and common reactions to major, unwelcome, and undesirable life events. Normal bereavement best exemplifies this. In bereavement following major losses such as the death of a parent, spouse, or child, people experience sadness, pining, and yearning, but do not ordinarily have the feelings of guilt, unworthiness, and self-reproach that characterize depressive disorders. Feelings of helplessness and hopelessness may be temporarily present in bereavement, but they ordinarily pass with time. In uncomplicated cases, the process of bereavement takes 3 to 6 months in the acute phase, and up to a year for complete resolution. Bereaved persons are more likely to feel physically ill and seek general health care than at other times, and older widowers are more liable to die than age-matched nonbereaved controls. Pathological grief reactions, bereavements that last more than a year, may be seen when the surviving spouse was excessively dependent on the deceased and is unable to obtain emotional and practical (e.g., financial) support elsewhere, or when the survivor is unable to grieve fully because of markedly ambivalent feelings towards the deceased. The inadequate expression of grief because of incomplete bereavement is thought to be pathogenic in many subsequent psychiatric disorders. For example, impulsive acting-out behavior among adolescents who have lost a parent is often assumed to result from unresolved grief. A variety of medical disorders may cause depressive syndromes. Most common among these are endocrine abnormalities such as hypothyroidism and hyperparathyroidism and CNS disorders such as cerebrovascular diseases and Parkinson's disease. Depressions are more common in strokes affecting left anterior lesions than other locations. Some medications, especially antihypertensive agents affecting adrenergic tone such as reserpine (Serpasil) and possibly beta blockers may also trigger depressions. The importance of a genetic diathesis in these iatrogenic depressions is not yet known. Depressive syndromes and disorders in general, however, are unquestionably familial and are likely to have genetic contributions, especially in depressions associated with bipolar I disorder. Cognitive features of depression are prominent. Characterizing the exact nature of the memory impairment using standardized tests has been difficult. Cognitive tasks requiring sustained effort and elaborate cognitive processing may be more disrupted in depression than tasks that can be accomplished more automatically. The so-called cognitive triad of depression consists of pervasive cognitive schema related to feelings of worthlessness, helplessness, and hopelessness—expectations that no one and nothing can or is likely to help now or in the future: “I'm not OK, the world is not OK, and it's never going to get any better.” In geriatric populations the effect of depression on cognition may be so profound as to produce a true dementia syndrome, often called pseudodementia, a misnomer because the dementia is real but reversible. Suicidal phenomena are of particular concern. Suicide is common in severe depressive disorders, with 15 percent of untreated depressed patients ending their lives in suicide. Depressed patients comprise the largest diagnostic group of all completed suicides. However, suicide occurs at high rates in many other conditions as well, notably substance-abuse disorders, schizophrenia, and personality disorders. Suicide may occur in these conditions with or without a diagnosable comorbid depressive disorder. Depressed patients with co-morbid alcohol abuse may be at particularly high risk for suicide. Although consistent, useful, validated predictors of suicide do not exist, certain demographic features are associated with higher risk. These include being white, male, older, and living alone. The single most important factor in the psychiatric history is that of past suicide attempts. A history of violent behavior may also predict suicide. Murderers have a very high suicide rate, especially those who murder family members during episodes of domestic violence. Among clinical signs, hopelessness, anhedonia, and severe anxiety may predict increased suicide risk. Serious physical illness in association with other risk factors such as depression may place a patient at higher risk. A genetic predisposition towards suicidal behavior cuts across diagnostic lines and plays a role in suicide risk. This may reflect a tendency towards impulsive behavior, correlating with low CNS concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin. Suicidal gestures are also common among impulsive, dependent, and self-hating depressed persons, for whom they serve as tension-releasing behaviors and as cries for help that may enlist desired social support. Because such gestures have been associated with an increased risk for subsequently completed suicide, they should not be taken lightly. Nonsuicidal self-destructive behaviors such as self-mutilations and repeated unnecessary risk-taking are also common in depressive syndromes and in personality disorders. Subintentional suicide may result when suicidal gestures go awry or when reckless behavior, such as taking unnecessary risks in combat or driving while drunk, prove fatal. Elated Moods Elated moods include euphoria, elation, exaltation, and ecstasy. They are marked by feelings of well-being and expansiveness, optimism, capability, pleasure, and grace. Such moods are normally experienced when life is going very well, when long-sought-after goals are achieved, and in states of love, religious fervor, and spiritual transcendence. Peak experiences and experiences of mystic fusion are often accompanied by feelings of exaltation and ecstasy. Sexual pleasure and some chemically mediated states of altered consciousness may also induce these feelings. Abnormally elated moods are primarily seen as part of manic states and from the effects of certain medications and street drugs. When subtle, as in hypomania, the mood can be ebullient, and brimming with self-confidence, but with occasional irritability. Other characteristic symptoms of hypomania are increased energy, decreased need for sleep, rapidly flowing thoughts, excessive talking, inflated self-esteem with a demanding nature toward others, and diminished judgment. Mania is a more extreme state in which judgment and sleep are impaired to the point of marked functional disruption. As the mania exacerbates, irritability and anger increase, alternating rapidly with a brittle expansiveness. Cognitions become increasingly disorganized. Psychotic symptoms, usually involving themes of grandiosity or specialness, occur in 50 percent or more of patients with mania. With increasing escalation of the manic state, thinking becomes very fragmented, psychotic symptoms are more prominent, and the syndrome may appear indistinguishable from schizophrenia. These three manic states—hypomania, mania and the psychotic mania, fragmented manic state are often referred to as stage I, II, and III mania, respectively. Manic states occur in bipolar disorders, substance-induced mood disorders, and mood disorders due to a general medical condition. Such secondary manias may follow specific cerebral insults, accompany systemic disorders, or occur following ingestion of some drugs including amphetamines, antidepressants, bromocriptine (Parlodel), decongestants, isoniazid (Nydrazid), and corticosteroids. Mania is the second most common neuropsychiatric disturbance induced by steroids, occurring in 30 to 35 percent of patients who develop steroid-induced behavioral disorders. Up to 12 percent of patients treated with levodopa (Dopar) and bromocriptine for parkinsonism develop mania. Right hemispheric brain lesions are specifically associated with secondary mania. Anxiety Like depression, the term anxiety refers to a number of different entities—a normal transient feeling, often with adaptive functions, a symptom seen in a wide variety of disorders, and a group of disorders in which the symptom of anxiety forms a dominant element. As a transient, disagreeable emotional state, anxiety may be adaptive, signaling anticipated or impending threat and motivating necessary action. In contrast to fear, the emotional state that exists when a source of threat is precise and well known, anxiety occurs when the threat is not well defined. Patients often find it difficult to describe feelings of anxiety precisely; at its core, however, anxiety is characterized by intense negative affect, associated with an undefined threat to one's physical or psychological self. Patients will use words such as tense, panicky, terrified, jittery, nervous, wound-up, apprehensive, and worried to describe their sensations. Anxiety is additionally characterized by somatic, cognitive, behavioral, and perceptual symptoms. The somatic symptoms of anxiety are legion and often dominate the subjective symptoms: a partial list includes twitching, tremors, hot and cold flashes, sweating, palpitations, chest tightness, difficulty swallowing, nausea, diarrhea, dry mouth, and decreased libido. Cognitively, anxiety is characterized by hypervigilance, poor concentration, subjective confusion, fears of losing control or of going crazy, and catastrophic thinking. Behavioral symptoms include fearful expressions, withdrawal, irritability, immobility, and hyperventilation. Perceptual disturbances, including depersonalization, derealization, and hyperesthesia (especially hyperacusis), are also common. Trait anxiety refers to a lifelong pattern of anxiety as a feature of temperament. Individuals with trait anxiety are skittish, hypersensitive to stimuli, and psychophysiologically more reactive than others. In contrast, state anxiety refers to episodes of anxiety that are tightly bound to specific situations and that do not persist after the provoking situation has abated. Free-floating anxiety is characterized by a persistently anxious mood in which the cause is unknown and in which large numbers of diverse thoughts and events all seem to trigger and compound the anxiety. In contrast, situational anxiety occurs only in relation to specific

occasions or external stimuli, as in phobias. Anxiety symptoms can result from numerous physical conditions as well as from other psychiatric disorders. Many endocrine, autoimmune, metabolic, and toxic disorders, as well as medication adverse effects, are known to generate anxiety. The psychiatrist must differentiate the response of the patient to an underlying condition (i.e., secondary anxiety) from symptoms generated by the primary disorder itself. In psychiatric populations, anxiety symptoms are prevalent among patients with psychotic disorders, cognitive disorders, depression, and substance-related disorders, as well as in the specific anxiety disorders. In patients with schizophrenia, anxiety must be differentiated from akathisia, a common and often overlooked syndrome of subjective restlessness, anxiety, and agitation resulting from antipsychotic medication. The coexistence of anxiety symptoms and depression in major depressive disorder is substantial; anxiety symptoms such as anxious mood and irritability are seen in the majority of depressed patients. Additionally, half to two thirds of patients with a panic disorder will experience a major depressive episode during their lifetime. Medication and drug effects—from intoxication, adverse effects, or as part of withdrawal—are also common causes of anxiety. Many patients with severe anxiety become dependent on anxiolytic drugs (e.g., benzodiazepines, and other sedatives) or alcohol for symptom relief. During attempts to discontinue these substances and sometimes during their ongoing use, confusing admixtures of anxiety symptoms, medication effects, and withdrawal symptoms may occur. Although all the anxiety symptoms caused by drug use are also seen in primary anxiety disorders, perceptual disturbances such as depersonalization and hyperaesthesia may be more common in sedative-hypnotic withdrawal than in primary anxiety disorders. Despite the general observation that anxious patients demonstrate increased startle responses, specific consistent differences have not been found in the physiological hyperreactivity of patients with anxiety disorder versus controls. In part, this reflects individual differences in reactivity among anxious patients; one person may respond to a specific stimulus with increased pulse and blood pressure while another might show changes in the opposite direction. Similarly, although patients who suffer panic attacks but not controls tend to experience panic attacks in response to sodium lactate infusion, other biological measures, especially those reflecting the catecholamine system and thought to reflect central noradrenergic activity, have failed to elucidate the biological underpinnings of panic attacks. Despite the lack of consistent findings, a great deal of evidence suggests that biological factors strongly contribute to the appearance of anxiety disorders. Psychological Causes From a psychological point of view, anxiety may signal conflict between opposing desires, wishes, or beliefs on the one hand, and major disequilibria generated by negative life events on the other hand. Role strains, conflicts between the major social roles that form a person's identity—spouse, parent, child, wage earner, professional, community member—are common sources of anxiety. The more important the conflict and the less obvious the resolution, the greater is the associated anxiety. For example, anxiety symptoms may first emerge when an individual is confronted with an unavoidable unhappy choice, such as between sustaining a marriage or accepting a career advancement requiring a major move that is unacceptable to the spouse. At times, these conflicts may escape conscious awareness: the person may feel anxious but not know why. Anxiety disorders frequently result from a combination of several factors. A person in a work conflict facing an important deadline may try to alleviate initial anxiety symptoms by overworking or ingesting caffeine or amphetamines to keep alert, then become exhausted and fatigued, and ultimately use alcohol excessively to calm down, with each of these elements contributing separately to an anxiety state. Certain developmental life situations are associated with anxiety: Stranger anxiety develops when infants 6 to 8 months old begin to recognize the difference between their mother and others. When children first go to school, mild anxiety symptoms are common; if the anxiety is excessive, separation anxiety or school phobia may result. During adult life, anxiety often centers around issues of mastery and accomplishment, both in personal and work life. Performance anxiety, or stage fright, is a specific type of pathological anxiety in which anxiety escalates to panic when public performance is required. In later life, the deterioration of one's body may engender anxiety related to feelings of helplessness and death anxiety. Panic Panic attack is a circumscribed episode of severe state anxiety lasting minutes to hours, with symptoms escalating in a crescendo pattern. The subjective experience is one of utter terror, fears that one will die, go crazy, or lose control, accompanied by many of the somatic symptoms of anxiety mentioned above, including severe chest pains, marked shortness of breath, and exhausting fatigue. Individual isolated panic attacks are common, with up to 30 percent of the general population experiencing at least one attack each year. Panic attacks occur more regularly, and typically more severely, as part of panic disorder or in association with other anxiety disorders. Patients with other psychiatric disorders may experience limited-symptom panic attacks, with episodes characterized by less intense anxiety and by fewer and milder physical symptoms, such as isolated paresthesias or difficulty breathing. These limited-symptom attacks may represent aborted full-blown panic attacks that are not further exacerbated by secondary psychological reactions to the initial symptoms. A 43-year-old Navy Captain began to experience episodes of severe chest pains, profound sweating, and fear that he was about to die. He had gone to the emergency room on several occasions, and each time had a normal electrocardiogram (ECG) and other tests. His capacity to work was impaired, and he started to stay at home rather than drive to work, since all his episodes began while he was driving. Although he had no prior history of significant alcohol abuse, he also began drinking large amounts of wine in an effort to stave off the attacks. The emergency room physician diagnosed panic attacks. A psychiatric interview revealed that the patient's father had died of a heart attack in his mid-40s, and that the patient had never adequately dealt with issues surrounding the death. Although American psychiatry has segregated panic attacks from other forms of anxiety, assuming categorical, phenomenological, and biological differences, these distinctions are far from universally accepted. Some psychiatrists view panic as simply an extreme form of anxiety, to be understood as part of a continuum of intensity. Phobias are irrational fears. In an effort to reduce the intense anxiety attached to phobic objects and situations, patients do their best to avoid the feared stimuli. Thus, phobias consist both of the fears and the avoidance components. The fear itself may include all the symptoms of extreme anxiety, up to and including panic. In specific phobias, persistent, irrational fears are provoked by specific stimuli. Table 8-5 lists some illustrative phobias. Common specific phobias include fear of dirt, excreta, snakes, spiders, heights, and blood.

Table 8-5 Specific Phobias

Behavioral, psychodynamic, and biological theories have all been advanced as causes of phobias. Some well-known phobias, such as fear of animals, may result either from early traumatic events (developing along the paradigm of classical Pavlovian conditioning), or from displacements of early psychodynamic conflicts. Genetic influences may also play a role in the development of phobias. For example, some individuals with blood-injection-injury phobias, which strongly clusters among biological relatives, may be genetically predisposed by vagal responses to certain stimuli. Animal models also indicate possible biological vulnerability. Some monkeys that have never previously been exposed to snakes panic when placed in the presence of a snake. Because such fear responses obviously have adaptive value, it has been suggested that some human phobic responses also represent exaggerations of adaptive behaviors shaped by evolutionary biology. Complex phobias, more elaborate than specific phobias, involve fears related to a broader range of situations. Agoraphobia, the best known, refers to a fear of open spaces. Current thinking suggests that agoraphobia is usually a secondary reaction to panic attacks. According to this view, individuals who have become terrified of having panic attacks in public retreat to the safety of their own homes, hoping to reduce the likelihood of panic attacks by avoiding places where they were once triggered and where they may feel exposed and embarrassed. Patients with social phobia become overwhelmingly anxious and fear situations in which they may be observed. In the limited type, only a few specific situations evoke the fear, such as speaking in public or using a public lavatory. In the general type, broad-based

fears of social situations globally hamper the person's interpersonal life. Aggression, Hostility, Impulsiveness, and Violence The spectrum of aggressive emotions and behaviors is characterized by heightened vigilance in response to a sense of threat and enhanced readiness to attack. Physiological tone may be geared for a fight. Assertiveness, the adaptive aspect of these emotions, includes sensing that something needs to be done and feeling willing and competent to take constructive action. The manner and extent to which aggressive emotions can be expressed varies from society to society and situation to situation. These emotions are among the most carefully regulated because of their potential destructiveness. Acts of aggression may begin with verbal threats and intimidation and extend from physical bullying and assault to homocide, sometimes including acts of calculated violence and sadism. Irritability is an unpleasant feeling state characterized by inner unease. Although minor irritability may abate when the cause is eliminated, escalating irritability has been compared to a psychic itch, begging for discharge via anger outbursts, sometimes leading to temper flareups with verbal or physical lashing out. Unlike anger, irritability does not lessen after an outburst. It is diagnostically nonspecific, seen in a variety of physiological states, anxiety, and mood disorders and as a lifelong temperamental quality. Hunger, sleepiness, sexual frustration, and pain are among the physiological triggers commonly associated with irritability. A 36-year-old woman with bulimia nervosa but no marked mood or anxiety disorder was successfully treated with a selective serotonin reuptake inhibitor (SSRI). During a follow-up visit during which she and her husband were seen conjointly, her husband remarked about her previous irritability, particularly premenstrually, which he saw as a long-standing personality feature that had abated considerably as a result of the treatment. The patient, her husband, and her psychiatrist all attributed the decrease in irritability to the SSRI. The husband, only half-jokingly, remarked “Doc—whatever you decide to do— never take her off that stuff—or if you do, warn me a few days ahead of time and I'll clear out of the house!” Individual differences in the tendency toward experiencing and expressing anger and violence are biological, developmental, and cultural in origin. Some infants are irritable from birth. Subtle early birth injuries and brain anoxia may increase the susceptibility of some persons to be violent. Furthermore, studies of EEG patterns in violent persons show increased abnormalities, especially in those with repeated violence and violence with little or no obvious motive. Soft neurological signs are also seen in violent criminals. Biochemically, low concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF) has been associated with a variety of impulsive behaviors such as violent crimes, recurrent fire-setting, and violent suicide attempts. In support of the hypothesis that an inverse relationship exists between central serotonergic system function and impulsive-aggressive behavior, a recent double-blind placebo-controlled trial demonstrated that pharmacological enhancement of serotonin activity with fluoxetine (Prozac), an SSRI, reduced impulsive aggressive behavior and irritability in subjects in whom such behavior was prominent. The pathological childhood triad of bedwetting past the age of 6, setting fires, and torturing animals has been associated with subsequent violent behavior in adults. Interpersonally, studies show that violence-prone individuals require more personal space around themselves than other people do. Violent individuals feel threatened when approached too closely, particularly from the rear. Psychological and social contributions are also strong. Violence in families breeds violence, and battered children often grow up to be battering adults. Cultural norms for the expression of violence differ considerably. In some socioeconomic and ethnic groups violent gangs organize the energies of many adolescent youth. For some, violent behavior is an adolescent socialization pattern necessary to prove one's manhood. Like other social organizations, violent gangs have detailed rules that inhibit and govern the expression of violence. Some unpredictable and unsocialized violent persons, loners, are too violent to be contained even in gangs. Aggressive and violent behavior is diagnostically nonspecific. Violence in schizophrenia may occur as a consequence of paranoid delusions, in response to command auditory hallucinations, or secondary to passivity experiences. Manic patients and those in mixed states may be violent, often in response to minimal provocation. Violent behavior commonly occurs in patients with antisocial and borderline personality disorders; in the latter the violence is often self-directed as well as other-directed. Violent behavior may occur in epilepsy—although rarely during true ictal periods; in frontal lobe syndromes as a release phenomenon; and in association with abused substances, particularly disinhibiting sedatives such as alcohol or stimulants such as amphetamines and cocaine, which increase irritability, aggressiveness, and paranoia. Impulsive violence may be provoked by a number of stimuli and situations. Alcohol is perhaps the most common disinhibitor of violence. Intrafamilial violence, the most common setting for homicide, is frequently related to alcohol intoxication. In intermittent explosive disorder, violent behaviors typically erupt after a person has ingested alcohol, a phenomenon known as pathological intoxication. In these often ferocious outbursts the individual may confront or provoke any potential target for violence, including total strangers and police, but girlfriends, wives, and parents are frequent victims. Patients with episodic dyscontrol commonly have histories of violent sexual behavior including rape and, often while intoxicated, speeding and reckless driving, sometimes chasing down, stopping, and attacking other motorists who they feel “get in their way.” A 35-year-old man who had a long history of truancy and a poor school record, fighting in school, bar fights, DWIs, and being assaultive while in jail, was seen in a mental health center. Since release from jail, in spite of a diligent attempt on his part to stay out of trouble for the sake of his wife and children, he found himself getting increasingly edgy. He had acquired a job as a short-haul truck driver and had been doing well until the previous day when he felt that someone cut him off on the freeway. In a blind rage he chased down the driver of the other car, attacking him with a tire jack. Luckily, he was restrained by several bystanders and no one was physically hurt. Temper Tantrums Immature individuals with persistent personality problems may fail to develop mechanisms to inhibit the temper tantrums they displayed as children. Particularly if childhood tantrums produced the desired result, learned tantrum behaviors may persist into adult life. Although such individuals may be pleasant and sociable when life is going well, they lack the capacity to tolerate frustration, and are easily provoked by threats to self-esteem and self-image, and by not having their own way. When frustrated or threatened they may act like bullies, glare, snarl, yell, shout, intimidate, pout, sulk, and sometimes be physically violent. Displaced Rage When circumstances prevent the expression of rage directly against the persons or institutions provoking frustration, other outlets for aggression are often found. Acts of violence that are either calculated or wanton may result. Cruelty to animals and fire setting may persist as adult forms of destructive behavior. Rape, an act of control, intimidation, terror, and humiliation, may also displace frustrations that are not expressed more adaptively. Sadism may occur with or without explicit sexual gratification. Calculated cruelty conducted seemingly without anger or emotional arousal may reflect inadequate development of social morality or individual conscience, as in the conduct of torturers and some cold-blooded murderers. In some societies and under specific circumstances at certain times in history, such activity has been socially sanctioned, suggesting at least that some people lack inborn inhibitions against cruelty or violence. A 45-year-old veteran hospitalized for chronic depression and barely contained aggressive outbursts described how as a teenager he had been employed as an enforcer by a drug ring. He and his partners took pleasure in torturing and then killing men they were assigned to murder who failed to make their drug payments—as warnings to others who might try to avoid paying. What bothered him the most was that after a while he too started to enjoy participating in these activities. Self-Mutilation For a variety of reasons, in many different cultures, and in many different disorders people commit acts of violence against themselves ranging from body piercing to cutting and burning to auto-amputation. Psychotic patients may perform extremely self-destructive acts short of actual suicide that often have symbolic import, such as enucleating their eyes or castrating themselves. Patients with borderline personality disorders may cut themselves repeatedly with broken glass or razor blades or burn their arms, legs, breasts, or other body parts with cigarettes. Patients typically deny that these acts are meant to be suicidal, but describe the need to feel external pain to mirror internal suffering, to release tension, or to counteract dissociative-like numbness. A 25-year-old man presented to the emergency room in a deeply suicidal state. Examination revealed his arms to be riddled with cigarette burns of varying ages, from old scars to fresh burns, and he had multiple healing and healed razor and knife cuts on all his extremities. He described how these cuts were not the result of suicidal acts, which he carefully and precisely differentiated from his current mood state, but were the results of rages of self-hatred—he meant to inflict pain upon himself during periods of particular self-hate and frustration.

Trichotillomania is a syndrome of compulsive hair pulling, resulting in bald patches. It is often associated with other self-mutilatory behavior, such as picking the face, nails, or cuticles to the point of infection and bleeding. Trichotillomania may sometimes be related to obsessive-compulsive disorder. Children with Lesch-Nyhan syndrome, a developmental disability syndrome caused by a congenital metabolic abnormality, bite and pick at themselves so compulsively as to do themselves great harm, and routinely require restraint. Occasionally, patients with Tourette's disorder demonstrate compulsive self-harming behavior. Other Disturbances of Feelings Diminished levels of emotional intensity may be seen in anxiety disorders, mood disorders, and schizophrenia. Mild emotional flattening with blunted ability to feel joy is common in dysthymia. Some patients with narcissistic and borderline personality disorders complain of inner emptiness and pervasive boredom and ennui, without demonstrating diminished affect in interviews. Similarly, patients with prominent depersonalization describe numbed emotions. Pathological levels of blunt or flattened affect, indicating markedly diminished affective expression in relation to specific thought content, may be seen in chronic schizophrenia (as part of the deficit syndrome), some organic mental syndromes, and severe depressions. Although the term blunted affect is not classically used to describe the affective flatness of severe depression, it is not always easy to distinguish between schizophrenic and depressive flatness on phenomenological grounds. Anhedonia, the lack of pleasurable feelings from activities that ordinarily provide pleasure, is also seen as part of severe depressions or schizophrenia. Chronically psychotic patients often exhibit emotional deterioration in which affective experience and expression is entirely unrelated to thought content. Inappropriate affect is incongruency of affective expression and thought content. The patient may display loud and raucous laughter or giggling in relation to bland or sad thoughts, or may show grief without apparent reason. Inappropriate affect sometimes indicates that the thoughts have private meaning for the patients; the emotional expression might make better sense if the private meaning was understood. Inappropriate affect must be distinguished from affective expressions that may actually be appropriate in a given subculture or ethnic group that is unfamiliar to the observer, and from defensive affect, such as the nervous laughter used to alleviate tension or ward off crying. Affective lability is characterized by rapid emotional shifts, often within seconds to minutes. It is commonly seen during hypomanic states, late luteal phase dysphoric disorder (premenstrual syndrome), postpartum blues, other states of physiological instability, and in certain personality disorders. Alexithymia is difficulty identifying, describing, and differentiating between feelings or distinguishing between feelings and physical sensations. Alexithymic individuals often have constricted imaginations and fantasies, are preoccupied with objects and events in the outside world, and have a limited private, personal internal life. When distressed, these patients are simply aware of not feeling well and usually complain of somatic symptoms, leading to frustrating interactions with their physicians who are unable to find physical causes for the presenting physical complaints. Some view alexithymia as a condition in which affect is communicated through somatic language.

DISTURBANCES IN MOTOR ASPECTS OF BEHAVIOR Motor behavior is normally finely coordinated, purposeful, and adaptive, and necessary activities are usually carried out efficiently. In psychiatric disturbances motor abnormalities can involve generalized overactivity or underactivity or manifest in a wide range of specific disorders of movement. Overactivity Restlessness and agitation are diffuse increases in body movement, usually noted as fidgeting, rapid and rhythmic leg- or hand-tapping, and jerky start-and-stop movements of the entire body, accompanied by inner tension. Restlessness accompanies psychiatric conditions of high emotional arousal or confusion such as toxic states, deliria, mania, agitated depressive disorders, and anxiety disorders, as well as many medical disorders such as hyperthyroidism. In some depressive states, agitation is often accompanied by pacing and hand wringing. Generalized overactivity, in which patients seem to have increased physical energy, is distinguished from agitation by its lack of inner tension and by more purposeful movements. It is commonly seen in mania, hypomania, anorexia nervosa, and as part of attention-deficit/hyperactivity disorder. In catatonic excitement, less common now than in the era before antipsychotic agents, patients exhibit disorganized and overactive behaviors including frantic jumping, thrashing of limbs, and seemingly senseless menacing or attacking behaviors. Such excitement is seen in mania, periodic catatonia, catatonic forms of schizophrenia, and some culture-bound syndromes such as amok. Confusional excitement is a state of restlessness and generalized purposeless activity seen in ictal states, some acute intoxications, and deliria. Decreased Motor Activity Global reductions in motor activity—motor retardation—are seen in a variety of physical disorders such as hypothyroidism, Addison's disease, some infectious and postinfectious conditions including chronic fatigue syndrome and post-polio syndrome, and other fatiguing conditions, as well as in some organic mental disorders, intoxications, schizophrenias, and depressive disorders. Poverty of movement ( akinesia, or more properly, hypokinesia) may occur in schizophrenia and as an adverse effect of antipsychotic drugs. Changes in the voice frequently accompany the reduced motor activity in schizophrenia and depression, with normal inflection replaced by monotonous tone and prolonged speech latency. In stuporous states patients remain immobile although their eyes are open and they are apparently awake. Conversion reactions are functional, nonphysiological, psychogenic impairments in sensory or motor functions. Common motor forms include various paralyses and pareses, including limb paralyses, ataxias, and aphonias. In globus hystericus the patient is unable to swallow. Patients with astasia-abasia have marked unsteadiness of gait. Sensory conversion reactions include blindness, deafness, anesthesia, and analgesia. Some hyperesthesias and pain syndromes may also originate as conversion symptoms. Mutism may result from a variety of peripheral muscle and CNS conditions and from functional disorders. Mutism may occur in profound depression, catatonic states, and conversion reactions. Selective mutism is occasionally seen in adjustment disorders and some personality disorders. Motor Disturbances Many motor disturbances are seen in psychiatric disorders. Some form part of the core symptoms of the disorders; some occur in disorders that, by their nature, bridge neurology and psychiatry (such as Tourette's disorder); others are acute or chronic adverse effects of medications. Tremor Tremors, involuntary oscillating movements of the limbs or head, may occur at rest or with movement. Physiological tremors, which are minimal at rest and increase with activity, are characterized by small amplitude and high frequency. They are characteristic of anxiety, fatigue, toxic or metabolic disorders such as caffeinism or hyperthyroidism, and are commonly seen in patients taking a number of different psychiatric medications including lithium (Eskalith), valproate (Depakene), and stimulating antidepressants. Coarse tremors with larger amplitude and lower frequency are seen in Parkinson's disease and cerebellar disease. Asterixis is a large-amplitude flapping tremor of the hands seen in hepatic disease. Parkinsonism Parkinsonian symptoms and signs may be seen in psychiatric disorders, particularly in patients taking antipsychotic medications. Symptoms include akinesias with marked decrease in normally spontaneous fidgeting, stiff gait with diminished arm swing, pill-rolling nonintention tremors (which seem to be less common in neuroleptic-induced parkinsonism compared to Parkinson's disease), expressionless soft and monotonous speech, micrographic handwriting, and cogwheel rigidity. Dystonia Although dystonic movements are seen in many neurological disorders, in psychiatric patients they are almost always secondary to the use of antipsychotic medications (neuroleptic-induced acute dystonia). Dystonic reactions consist of intermittent or sustained muscle spasms, typically of the head or neck. Common varieties include tongue spasms causing dysarthria, torticollis (neck spasm), and oculogyric crisis in which there is a forced upward gaze. Opisthotonus (spasms of paraspinal muscles leading to an arched posture) is seen less often. These reactions are most common in young males and typically occur soon after beginning or increasing the dose of a conventional antipsychotic medication. Akathisia Akathisia is a syndrome of motor restlessness seen predominantly in the context of antipsychotic medications and some antidepressant drugs (neuroleptic-induced acute akathisia). It has subjective as well as motor components. Subjectively, patients experience muscle tension, difficulty finding a comfortable body position, and inability to stop moving; they feel as though they were “jumping out of their skin.” Objectively, akathisia classically manifests by rocking from foot to foot while standing, frequently crossing and uncrossing the legs when seated, and pacing. Sleep may be disturbed because of physical discomfort. Subjective components of akathisia may be difficult to distinguish from anxiety caused by the primary disorder (typically schizophrenia). Rarely, the restlessness and inner agitation becomes sufficiently uncomfortable to provoke acts of violence. In pseudoakathisia objective signs of akathisia are present, but the patient denies feeling restless.

A 24-year-old hospitalized man with schizophrenia was given 10 mg of haloperidol (Haldol) daily. Two days after beginning the medication, he became increasingly agitated—pacing around the ward, muttering to himself, and rapidly alternating between sitting and getting up. It was impossible to conduct an interview, in part because he would neither sit nor stand in one place. The staff thought his behavior indicated an escalation of his psychosis, and the dosage of the antipsychotic drug was doubled. Within the next few days the patient became even more agitated and told the staff that he was convinced that a motor inside him would not stop running. (Whether the motor was metaphorical or delusional was unclear.) One of the ward psychiatrists suspected akathisia, lowered the dose of the medication and prescribed anticholinergic medication and a b-adrenergic receptor antagonist to combat the akathisia. Within 2 days the patient became far more relaxed, less restless, and less psychotic. Tardive Dyskinesia Neuroleptic–induced tardive dyskinesia is a movement disorder that occurs only in the context of antipsychotic medication use, occasionally after many months, more commonly after years. The abnormal movements may persist with or without continued medication use or may diminish or disappear over time. The dyskinetic movements occur at rest and can usually be temporarily suppressed volitionally or by purposeful action, distraction, or sleep. The movements are varied. In the most common type, which affects the face, especially the mouth and lips, tongue-thrusting, chewing, lip-smacking, and eye-blinking movements are seen. Another common type is characterized by choreoathetoid movements such as writhing finger motions. In the less common but more severe truncal dyskinesias, the torso moves in thrusting motions, and respiratory dyskinesia is characterized by grunting and irregular breathing patterns. Other tardive (late) syndromes include tardive akathisia and tardive dystonia in which the abnormal movements emerge late in treatment or upon medication discontinuation. Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome, a potentially fatal complication of antipsychotic medication, is characterized by muscle rigidity, fever, diaphoresis, delirium, mutism, and blood pressure abnormalities. Some view neuroleptic malignant syndrome as the most severe end of a spectrum that starts with neuroleptic-induced Parkinsonism, progresses to extrapyramidal syndrome with fever, and then to fulminant neuroleptic malignant syndrome. Rabbit Syndrome This uncommon medication-induced extrapyramidal syndrome is often misdiagnosed as tardive dyskinesia. It most closely resembles a limited expression of a Parkinsonian tremor. Patients make rapid chewing movements similar to those made by rabbits, ordinarily faster and more regular than the orofacial tic of tardive dyskinesia. The tongue is spared. Blepharospasm is a rapid and violent repetitive, spasmodic movement of the eyelids. These movements are often an adverse effect of antipsychotic or other medications but are also common in a variety of neurological disorders, including Meige's syndrome and Tourette's disorder. Tics Tics are rapid, repetitive often spasmodic, jerking involuntary movements that serve no apparent purpose. The person may try to disguise or hide the tic in a seemingly purposive movement, and the movement may ultimately be shaped into a mannerism. Tics are the central feature of tic disorders, are associated with other disorders, and may occur as a consequence of stimulant (e.g., amphetamines) use. Tourette's disorder is characterized by a chronic shifting array of motor and vocal tics. The tics may include grunts, coughs, clicks, or sniffs, while motor symptoms may include eye blinking, tongue protrusions, facial grimacing, hopping, and twitches. Complex tics may merge into complex compulsive behaviors, such as squatting, deep-knee bends, and retracing steps. Coprolalia, characterized by sudden verbal outbursts of obscenities, occurs in fewer than a third of Tourette's disorder patients. Mental coprolalia is an associated feature in which obscene words or phrases suddenly intrude into consciousness in an ego-dystonic manner. Obsessive-compulsive symptoms as well as attention-deficit symptoms are also common in Tourette's disorder. Serotonin Syndrome Serotonin syndrome is a disorder typically caused by the combination of two or more medications with serotonergic properties. It is characterized by restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, and mental status changes, such as confusion. Motor Disturbances of Schizophrenia Many of the abnormal movements ascribed to tardive dyskinesia and other antipsychotic-induced extrapyramidal syndromes had been described in chronically psychotic patients before the introduction of antipsychotic medications. In one series of 100 patients, the large majority of whom were diagnosed as having schizophrenia, a review of medical records prior to 1955 revealed that abnormal purposive movements were found in 83 percent, mannerisms and tics in 71 percent, abnormal eye movements in 27 percent, abnormal postures or facial movements in 42 percent, and gait abnormalities in 10 percent. A recent study that comprehensively assessed hard and soft neurological signs, including motor coordination, involuntary movements, integrative sensory functions, cognitive functions, and primitive reflexes, found abnormalities in each of these areas in 67 percent of schizophrenia patients and 19 percent of their never medicated sibs but not in a matched comparison group. Levels of abnormalities were correlated in patient-sib pairs. In another study spontaneous dyskinesias were present in 12 percent of schizophrenia spectrum subjects (who met 3 of 4 criteria from the revised third edition of DSM [DSM-III-R] for paranoid, schizotypal, or schizoid personality disorder) but not in controls. These findings suggest that many patients with schizophrenia have neurological symptoms not caused by medications, and that severe psychiatric disorders may have a neurological component as well. Catatonia refers to a broad group of movement abnormalities usually associated with schizophrenia, but also found in other disorders such as mania, depression, many neurological disorders (especially those involving the basal ganglia, limbic system, diencephalon, and frontal lobes), systemic metabolic disorders, toxic drug states, and periodic catatonia. Catatonic stupor and excitement have already been noted. Stereotypies are repetitious, bizarre, seemingly non-goal-directed complex organized gestures or postures that are thought to have private meanings to the patient. Examples include continuously and repeatedly crossing oneself or blessing others in a religious gesture, waving in a stylized manner, and making profane gestures. The stereotypic behaviors commonly seen in children with autistic disorder (constant spinning or rocking) may provide self-soothing, steady sensory input that help the patients reduce the degree to which they are disturbed by the ordinarily unpredictable and uncontrollable stimulation coming from the environment. Bizarre posturing may also be seen in catatonia. One patient with chronic catatonic schizophrenia routinely stood for hours on one leg with his arms in the air like a crane. In echopraxia, the patient imitates the examiner's movements, and in echolalia imitates speech, as if in mimicry. Some catatonic patients exhibit waxy flexibility, maintaining unusual postures into which they have been placed for prolonged periods of time. Negativism may take the form of refusing to behave in a prescribed manner, or resisting passive movement. Gait disturbances in patients with psychiatric disorders include a variety of neurogenic gaits consistent with brain disease, intoxications, and medication adverse effects. These include the festinating gait of parkinsonism, spastic and ataxic gaits of neurological disease and psychiatric medications, waddling and reeling gaits associated with intoxications, and the nonphysiological gait disturbances seen in astasia-abasia, a form of conversion disorder. Gait mannerisms include clowning, prancing, military, and effeminate gaits. Bruxism, chronic teeth gnashing, may occur involuntarily during tension states, or as an isolated occurrence during delta sleep in which it has sometimes been associated with benzodiazepine or alcohol use. In severe cases serious damage to dental enamel and temporomandibular joint pain may occur. Myoclonus, characterized by focal muscle jerking, can be caused in psychiatric patients by certain medications, such as serotonin-reuptake inhibitors or monoamine oxidase inhibitors. Myoclonic jerks may be difficult to distinguish from tics, but the latter often represent larger muscle groups and more highly organized motor patterns. Myoclonus may be seen at rest but is more obvious during motor activity. SEIZURE-LIKE BEHAVIORS In addition to the generalized, petit mal, and complex partial seizures seen in some psychiatric patients, a number of nonepileptic seizure-like behaviors must be distinguished. Breath-holding spells, generally innocuous impulsive and tantrumlike phenomena, usually occur in small children who hold their breaths during moments of oppositional rage, and who may faint as a result. Jerking or twitching motor movements may occur. Temper tantrums in young children may look like seizures, especially to the uninformed observer. The children may lie on the floor, screaming and kicking, and fail to respond to the environment. Conversion seizures (hysterical seizures, pseudoseizures) must be differentiated from genuine epileptic seizures. Patients retain consciousness, lack abnormal reflexes, and are not incontinent. However, because so many conversion seizures occur in patients who have genuine epilepsy and who know a good deal about the condition, the differential diagnosis is sometimes difficult. COMPULSIVE BEHAVIORS Compulsive behaviors may occur in relation to everyday activities such as gambling, sexual conquest, shopping, and watching television, or in relation to substances such as alcohol, cocaine, and opioids or food. Other compulsions involve reckless risk-taking behaviors that provide stimulation and dispel dysphoric moods. Sexual compulsive perversions such as exhibitionism and sadomasochism may serve similar purposes. Compulsions are seen in a variety of psychotic and nonpsychotic psychiatric disorders. The cravings that underlie compulsive behaviors are strong motivating forces, and the compulsive behaviors may regulate emotions. As yet unknown similarities may underlie all compulsive and addictive mechanisms. In obsessive-compulsive disorder the compulsions are ritualized, repetitive behaviors that are performed with the goal of satisfying, neutralizing, and undoing obsessional thoughts. Although intended to decrease anxiety, rituals are never more than transiently successful. The most common compulsions involve checking to make certain that gas jets and faucets have been turned off and that windows and doors are locked, hand washing, repeating certain phrases, counting objects, and

placing objects in a prescribed order. A 20-year-old Japanese-American man compulsively touched every electrical socket he passed, washed his hands several times each hour, and spent countless time leaving and returning to his house to check doors and windows. His mother described that these behaviors began when he was 8 or 9, and had been unrelenting ever since. A variety of other subtle neuropsychological deficits have been reported in obsessive-compulsive disorder, including impairments on measures of spatial working memory, spatial recognition, and motor initiation and execution. In one controlled study these impairments were not seen in comparison patients with panic disorder or a depressive disorder.

LANGUAGE DISORDERS Communication difficulties may result from disorders of thinking as previously described, abnormal speech patterns in mood disturbances and schizophrenia; or from primary speech-fluency disorders such as stuttering and stammering; disorders of the articulation and speech apparatus; and CNS disturbances involved in hearing and speech generation (aphasias). Manic patients typically exhibit pressured speech in which the speed of word stream is accelerated. If severe, the speech may be garbled, imprecise, and difficult to understand. Patients with psychomotor retardation depression speak slowly, monotonously, and have a long speech latency in response to questions. Patients with schizophrenia may be difficult to understand because of their disorder or because of the dysarthric effect of antipsychotic medication. Allusory speech is vague, imprecise, and hard to comprehend because too few cues and details are provided for the listener. Such speech may be heard from some patients with schizophrenia, certain personality disorders, or even normal individuals who wish to convey a sense of mystery by just being suggestive, whose suspiciousness causes them to be reluctant to spell things out clearly, or who believe that the listener is more aware of their private codes, meanings, and allusions than is the case. Speech Disorders Stuttering and stammering (ordinarily synonymous), refer to disturbances in the rhythm and fluency of speech due to blocking, convulsive repetition or prolongation of sounds. This disorder affects males two to three times as often as females, and there is a high rate of familial transmission. Aphasias Aphasias, impairments of language produced by brain dysfunction, are ordinarily described as being fluent and nonfluent. In fluent aphasias, which generally reflect dysfunction in the left temporal and parietal area, patients have a normal or even elevated verbal output, sometimes with logorrhea, but they ignore the social conventions of conversation. They produce many well-articulated phrases with normal prosody, but there is little informational content. The fluent aphasias are further divided according to the extent of comprehension by the patient and the ability of the patient to repeat what the examiner says. The principal fluent aphasias are Wernicke's aphasia, conduction aphasia, anomic aphasia, and transcortical sensory aphasia. Nonfluent aphasias are characterized by slow and poor verbal output, difficulty with spontaneous speech, omission of grammatical connecting words, and poor prosody. Patients may produce one-word replies or very short phrases. Brain lesions that cause nonfluent aphasias typically tend to occur in the anterior left hemisphere. The principal nonfluent aphasias are Broca's aphasia, transcortical motor aphasia, global aphasia, and the mixed transcortical aphasias. In aprosodias the nonverbal aspects of speech, the melody, pauses, timing, stress, accent, and intonation, are impaired. Damage to the right prefrontal region has been associated with expressive aprosodias, and damage to the right temporal region and insula has been associated with receptive aprosodias impairments in the ability to understand and interpret the prosodic communications of another person. They are analogous to receptive aphasias, in which the individual is unable to understand another person's words.

DISTURBANCES IN INTERPERSONAL RELATIONSHIPS Normal interpersonal relationships include relationships with parents, children, spouses, lovers, siblings, extended-family members, friends, colleagues, coworkers, and members of the larger community. These relationships ordinarily help provide for the satisfaction of basic drives, for affiliative needs, and for finding purpose and meaning in life. Through stable and satisfying relationships, human needs are met for intimacy, including love, sex, and affection; to be cared for and nurtured, provide care, learn, play, relax, dominate, and be productive through mutual effort. Interpersonal relationships are carefully regulated by means of interpersonal signs and signals. The extent to which deviance from these patterns is tolerated in a given relationship varies from behavior to behavior, relationship to relationship, family to family, and culture to culture. Disturbances in interpersonal relationships may be viewed as characteristics attributable to a single person or as characteristics of an interpersonal system. Individual disturbances are considered to be undesirable or maladaptive personality traits. When these traits are present to a significant extent and interfere with social functioning or cause distress, they may comprise a personality disorder. Disturbances of interpersonal relationships have also been described at a systems level (e.g., as dyadic and family patterns of system disturbance). Personality Traits and Disorders Personality, variably defined, is the characteristic pattern of an individual's attitudes, behaviors, beliefs, feelings, thoughts, and values—the sum of a person's emotional, cognitive, and interpersonal attributes. Personality traits are the prominent and characteristic features of an individual's personality and do not imply psychopathology. Aspects of personality are present from early life, and personality traits are relatively stable from adolescence onward, consistent across different environments, and recognizable by friends and acquaintances. The term personality disorder should be reserved for those consistent patterns of thought, feeling, and behavior that are inflexible and maladaptive. Personality disturbances manifest primarily in interpersonal contexts and can be viewed as interpersonal behavior disorders. The determinants of personality are multiple and varied, and include innate and early biological, developmental, and environmental factors inside and outside the home. Through learning and the environment, temperamental factors (genetic or constitutional) are shaped into character. The dimensional approach to personality and personality pathology characterizes individuals along a continuum of traits. Five dimensions of temperament have been described which appear to be somewhat independent and to have strong genetic contributions: Neuroticism (highly emotional, reactive, and thin-skinned, contrasting with emotional stability), extraversion (contrasting with intraversion), openness (contrasting with discomfort with novel experiences), agreeableness (contrasting with contrariness), and conscientiousness (contrasting with fickleness). These temperamental attributes may have implications for the course of psychotherapies that cut across diagnostic categories. Another dimension of personality not adequately dealt with in the DSM-IV concerns moral behaviors such as honesty and integrity. The extent to which individuals behave honestly and with integrity differs considerably across individuals and in different situations. Deception and lying are common behaviors that occur in benign forms (e.g., in white lies) and in pathological forms, psychiatrically important in antisocial personality disorder and sociopathic behavior, pathological liars, and malingerers. Deception and lying may be difficult to assess clinically in the absence of additional informants. Studies of nonhuman primates indicate that at least among chimpanzees, deception (equivalent to lying and dishonesty) is relatively common and in some situations adaptive. Another recently proposed personality typology characterizes personality along three dimensions related to temperamental characteristics presumed to be strongly influenced genetically— harm avoidance, novelty seeking, and reward dependence. High scores on the three dimensions characterize inhibition and pessimism, impulsive and exploratory behavior, and dependency and sentimentality, respectively. Different personality types can be described according to patterns of scores on the three dimensions. For example, antisocial personalities are characterized by high novelty seeking, low harm avoidance, and low reward dependence, whereas dependent characters have low novelty seeking, high harm avoidance, and high reward dependence. DSM-IV uses a categorical approach to personality. The large overlap among the DSM personality disorders and the clustering of these personality disorders into three broad groups imply a lack of clear boundaries to the currently defined categories. The three DSM-IV clusters describe odd or eccentric types ( Cluster A); dramatic, emotional, and erratic types ( Cluster B); and anxious and fearful types ( Cluster C). The odd or eccentric group includes paranoid, schizoid, and schizotypal personality disorders. Patients with these personality disorders have the core traits of being

interpersonally distant and emotionally constricted. People with paranoid personality disorder are quick to feel slighted and jealous, carry grudges, and expect to be exploited and harmed by others. People with schizoid personality disorder lack friendships or close relationships with others and are indifferent to praise or criticism by others. People with schizotypal personality disorder display odd beliefs, engage in odd and eccentric gestures and practices, and exhibit odd speech. The dramatic, emotional, and erratic group includes borderline, histrionic, narcissistic, and antisocial personality disorders. Patients with these personality disorders characteristically have chaotic lives, emotions, and relationships. People with borderline personality disorder are impulsive, unpredictable, angry, temperamental, unstable in relationships, compulsively interpersonal, and self-damaging with regard to sex, money, and substance use. People with histrionic personality disorder are attention-seeking, exhibitionistic, seductive, and self-indulgent; exhibit exaggerated expressions of emotions; and are overconcerned with physical appearance. People with narcissistic personality disorder tend to be hypersensitive to criticism, exploitative of others, egocentric with an inflated sense of self-importance, feel entitled to special treatment, and demand constant attention. People with antisocial personality disorder are described almost exclusively in behavioral rather than affective or relational terms. They commit truancy, lie, steal, start fights, break rules, are unable to sustain work or school, and shirk day-to-day responsibilities. The anxious and fearful group includes patients with avoidant, dependent, and obsessive-compulsive personality disorders. Patients with these disorders are characterized by constricting behaviors that serve to limit risks. People with avoidant personality disorder avoid relationships, people with dependent personality disorder avoid being responsible for decisions, and people with obsessive-compulsive personality disorder use rigid rules that preclude new behaviors. People with avoidant personality disorders are hypersensitive to rejection and are reluctant to enter close relationships in spite of strong desires for affection. Those with dependent personality disorders show excessive reliance on others to make major life decisions, stay trapped in abusive relationships for fear of being alone, have difficulty initiating projects on their own, and constantly seek reassurance and praise. Individuals with obessive-compulsive personality disorders exhibit restricted expressions of warmth, tenderness, and generosity, and also exhibit stubbornness with a need to be right and to control decisions; indecisive at times, they often apply rules and morals too rigidly, to the point of being inflexible. A characteristic personality disturbance seen with frontal lobe damage is referred to as organic personality disorder in the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10), and as personality change due to a general medical condition in DSM-IV. Its features include irritability, inappropriate jocularity with euphoria, inappropriate socially disinhibited behavior, and impulsiveness. Other patients, with damage to different areas of the frontal lobe, in contrast, exhibit apathy and indifference. Interpersonal Systems Couples and families have been studied as systems in their own right, and many qualities of these systems have been identified as being clinically important. A scheme for categorizing relational disorders has been proposed for future editions of DSM, but so far no single generally accepted typology of family psychopathology or interactional types has been established. However, elements of marital discord and harmony have been operationalized in several standard marital inventories. Characteristics of couples and families that have received the most attention include the rules of communication, such as those governing the directness or indirectness with which disagreement and conflict are addressed; the manner (organized or chaotic) in which communications are conducted; taboo topics and secrets about which no one can openly communicate; the nature and degree of emotional expression including affection and anger; the cohesiveness, loyalty, and compatibility of members; the nature of the members' shared identities on the one hand and their autonomous development and separateness on the other; the extent to which members treat one another respectfully or take one another for granted and use one another; the distribution of power and decision making among members; the maintenance of generational boundaries (e.g., age-appropriate performance of life roles); and the members' orientation, concurrence, and disagreement about important values involving moral, religious, intellectual, cultural, financial, occupational, and child-rearing issues, as well as aspirations, health practices, leisure activities, and other belief systems. Despite the lack of an accepted system for describing disturbances in family systems, some common patterns have been identified. Many imbalanced relationships in which one partner largely dominates the other, may remain stable for years ( skewed relationships). Some couples have chronically unstable relationships with constant overt conflict (schismatic relationships). A characteristic family environment, called high expressed emotion, has been identified that defines a relapse-prone family environment in which one individual has schizophrenia, bipolar I disorder, anorexia nervosa, or major depressive disorder. This interactional pattern includes demeaning, intense personal criticism (“You are rotten and lazy”) and emotional overinvolvement with the identified patient. Aspects of overinvolvement can be measured by quantifying the numbers of hours of face-to-face contact and by the extent to which relatives' categorically assert how the patients feel without ever bothering to ask the patients. Couple and family system difficulties are most likely to erupt during predictable stressful events in the normal family life cycle, such as during the newlywed period; pregnancy and childbearing; difficult or contentious child-rearing; difficulties with parents, in-laws, and other extended family; insurmountable and unanticipated financial or career problems; serious illness or death of a child or relative; the childrens' adolescence; departure of children from the home; infidelity; and separation. Interpersonal Disturbances in Illness Behavior Abnormal illness behavior (dysnosognosia) is a persistently pathological mode of experiencing, evaluating, and responding to one's own health status despite lucid and accurate appraisal and management options provided by a health professional. These behaviors can be considered as interpersonal disorders between patients and health care professionals. Central to all of these behaviors is the adoption of the sick role by the patient, who then engages in characteristic interactions with health care providers—which typically leave both the provider and the patient dissatisfied. Patients with abnormal illness behavior typically seek repeated medical evaluations from a multitude of physicians, often undergoing a series of expensive laboratory tests. At times, the level of complaints provokes unnecessary invasive laboratory examinations or surgeries which, in turn, place the patient at genuine medical risk. Abnormal illness behaviors may be unconscious or conscious. Unconscious abnormal illness behaviors are those in which the patient believes the symptoms reflect some genuine illness. These behaviors may occur in somatization disorder (in which multiple symptoms and organ systems are affected), conversion disorders, somatoform pain disorder (in which no cause can be found for the subjective level of pain), and hypochondriasis (in which the primary fear is of having a serious disorder). Abnormal illness behaviors in which patients act sick when they are fully aware that they are not include malingering (in which external incentives—usually financial—are the motivating factors) and factitious disorder with physical or psychological symptoms (Munchausen's syndrome). In Munchausen's syndrome (facticious disorder with predominantly physical signs and symptoms), patients repeatedly and compulsively present themselves for medical care with feigned or self-induced illness. These self-induced conditions may be so serious as to ultimately cause death: some patients inject themselves with feces to cause systemic infections that then warrant hospitalization and intensive care. When the self-induced nature of the illnesses is discovered, medical staff members often become outraged at these patients. The patients rarely accept or cooperate with psychiatric care, so few have been adequately studied. Most do not appear to be psychotic, but seem to have a disturbance in personality structure. In facticious disorder by proxy, a caregiver, usually a parent, induces illness in a child.

FUTURE DIRECTIONS Like psychiatric diagnostic classifications, fashions among psychiatric signs and symptoms change. Characteristics once given prominence, such as the bony protuberances of the skull studied by phrenologists a century ago, are no longer accorded much importance, whereas only in the past few decades have newly described clinical phenomena such as family-expressed emotion and alexithymia been appreciated. Because of the shifts in what is considered relevant and the current dominance of biological research, it would be easy to assume that the nuances of clinical, descriptive psychopathology are mostly of historical interest. As long as the ultimate goals of clinical psychiatry are to help patients feel better and function better, attending to patients' subjective complaints with a firm knowledge of clinical descriptors will continue to be vital aspects of the skills of psychiatry.

SUGGESTED CROSS-REFERENCES The psychiatric interview, history, and mental status examination are discussed in Section 7.2. Additional definitions of typical signs and symptoms of psychiatric illness are included in Section 7.3. Preception and cognition are discussed in Section 3.1, memory in Section 3.4, and classification of mental disorders in Section 9.1. CHAPTER REFERENCES Berrios GE, Gili M: Abulia and impulsiveness revisited: A conceptual history. Acta Psychiatr Scand 92:151, 1995. Cassad SL, Adami H, Moran M, et al: Spontaneous dyskinesia in subjects with schizophrenia spectrum personality. Am J Psychiatry 155:70, 1998. Cloninger RC, Svrakic DM, Przybeck TR: A psychobiological model of temperament and character. Arch Gen Psychiatry 50:975, 1993.

Coccaro EF, Kavoussi RJ: Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 54:1081, 1997. Committee on the Family—Group for the Advancement of Psychiatry: A model for the classification and diagnosis of relational disorders. Psychiatric Serv

46:926, 1995.

Costa PT Jr, McCrae RR: Stability and change in personality assessment: The revised NEO personality inventory in the year 2000. J Personality Assess 68:86, 1997. Crichton P: First-rank symptoms or rank-and-file symptoms? Br J Psychiatry 169:537, 1996. *Cummings JL: Clinical Neuropsychiatry. Grune & Stratton, New York, 1985. D'Esposito M, Grossman M: The physiological basis of executive function and working memory. The Neuroscientist 2:345, 1996. Flaum M, Arndt S, Andreasen NC: The reliability of “bizarre” delusions. Compr Psychiat 32:59, 1991. George MS, Parekh PI, Rosindky N, Ketter TA, Kimbrell TA, Heilman KM, Herscovitch P, Post RM: Understanding emotional prosody activates right hemisphere regions. Arch Neurol 53:665, 1996. Goodman M, Brown JA, Deitz PM: Managing Managed Care II: A Handbook for Mental Health Professionals. American Psychiatric Press, Washington, DC, 1996. Goodwin FK, Jamison KR: Manic-Depressive Illness. Oxford University Press, New York, 1990. Hays RD, Wells KB, Sherbourne CD, Rogers W, Spritze K: Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses. Arch Gen Psychiatry 52:11, 1995. Hilgard ER: Divided Consciousness: Multiple Controls in Human Thought and Action. John Wiley, New York, 1977. Ismail B, Cantor-Graae E, McNeil TF: Neurological abnormalities in schizophrenic patients and their siblings. Am J Psychiatry 155:84, 1998. Jaspers K: General Psychopathology. University of Chicago Press, Chicago, 1963. Kendler KS, Karkowski LM, Walsh D: The structure of psychosis: latent class analysis of probands from the Roscommon Family Study. Arch Gen Psychiatry 55:492, 1998. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, Kendler KS: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8, 1994. Koenigsberg HW, Handley R: Expressed emotion: From predictive index to clinical construct. Am J Psychiatry 143:1361, 1986. Lazare A, editor: Outpatient Psychiatry: Diagnosis and Treatment, ed 2. Williams & Wilkins, Baltimore, 1989. *Lyketsos CG, Steele C, Glaik E, Rosenblatt A, Steinberg M, Warren A, Sheppard JM: Physical aggression in dementia patients and its relationship to depression. Am J Psychiatry 156:66, 1999. *Nakaya M, Suwa H, Komahashi T, Ohmori K: Is schizophrenic symptomatology independent of the phase of the illness? Psychopathology 32:23, 1999. Nemiah J: Alexithymia: Present, past—and future? Psychosom Med 58:217, 1996. Oulis PG, Mavreas VG, Mamounas JM, Stefanis CN: Clinical characteristics of auditory hallucinations. Acta Psychiatr Scand 92:97, 1995. Pilowsky I: The concept of abnormal illness behavior. Psychosomatics 31:207, 1990. Purcell R, Maruff P, Kyrios M, Pantelis C: Neuropsychological deficits in obsessive-compulsive disorder. Arch Gen Psychiatry 55:415, 1998. *Rapaport D, editor: Organization and Pathology of Thought. Columbia University Press, New York, 1951. Ratakonda S, Gorman JM, Yale SA, Amador XF: Characterization of psychotic conditions. Use of the domains of psychopathology model. Arch Gen Psychiatry 55:75, 1998. Sachdev P, Loneragan C: The present status of akathisia. J Nerv Ment Dis 179:381, 1991. *Schneider K: Clinical Psychopathology. Grune & Stratton, New York, 1959. Shapiro D: Neurotic Styles. Basic Books, New York, 1965. Sims A: Symptoms in the Mind: An Introduction to Descriptive Psychopathology. Bailliere Tindall, London, 1988. *Simon GE, Gureje O: Stability of somatization disorder and somatization symptoms among primary care patients. Arch Gen Psychiatry 56:90, 1999. Snaith P: Anhedonia: A neglected symptom of psychopathology. Psychol Med 23:957, 1993. Sobin C, Sackeim HA: Psychomotor symptoms of depression. Am J Psychiatry 154:4, 1997. Stone MH: Abnormalities of personality: Within and beyond the realm of treatment. WW Norton, New York, 1993. Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Clinical description of the first 50 cases. Am J Psychiatry 155:264, 1998. Taylor CB, Arnow B: The Nature and Treatment of Anxiety Disorders. Free Press, New York, 1988. *Trabert W: Shared psychotic disorder in delusional parasitosis. Psychopathology 32:30, 1999. Yalom I: Existential Psychotherapy. Basic Books, New York, 1980. Yudofsky SC, Hale RE, editors: Textbook of Neuropsychiatry, ed 3. American Psychiatric Press, Washington, DC, 1997.

Textbook of Psychiatry

9.1 CLASSIFICATION OF MENTAL DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 9. CLASSIFICATION OF MENTAL DISORDERS

9.1 CLASSIFICATION OF MENTAL DISORDERS MICHAEL P. BOGENSCHUTZ, M.D., AND H. GEORGE NURNBERG, M.D. History Psychosis, Psychopathy, and Neurosis Features of Nosologic Systems Theory of Classification Development of DSM-IV Basic Features of DSM-IV Critique of DSM-IV Suggested Cross-References

Advances in scientific psychiatry are to a great extent shaped by its system of classification. Systems of classification are fundamental to all sciences, containing the concepts upon which theory is based, and influencing what can and can not be seen. The classification of illnesses (nosology) has always been an integral part of the theory and practice of medicine. Classification is necessary to provide a conceptual framework within which to place what is observed, to communicate efficiently about illness states, to allow decisions to be made regarding treatment, to predict outcomes to measure change, and to keep records. Medical diagnostic systems are predominantly open systems of hypothetical compound constructs that are subject to falsification and further scientific inquiry. These systems allow meaningful research questions to be posed, the answers to which in turn affect the diagnostic system. In medical nomenclature the primary categories of interest are diagnoses. A diagnosis may refer to a consistent syndrome whose cause is unknown or varied, a specified disorder of structure or function whose cause remains unknown, a deviation from a specified physiological norm, or the effects of a specified etiological agent or process. This underlying ambiguity has important implications. Psychiatry is not different from other branches of medicine in these respects; however, psychiatric classification has evolved independently of medicine. At present, the official psychiatric nosology is viewed as separate from the rest of medical nosology, with disorders conceptualized as psychiatric or nonpsychiatric although it is understood that medical illness can cause psychiatric symptoms and that psychiatric disorders can have biological bases. To the extent that mental disorders are generally typological in nature, with less emphasis on clear boundaries between disorders than on the central core of each disorder, the classification system and specialty of psychiatry are often held as less “medical” or scientific than other branches of medicine. Extensive efforts to correct this perception resulted in a paradigmatic shift from hermeneutic to empirically based approaches, and the development of a nosology intended to increase diagnostic reliability and facilitate research efforts. These changes are embodied in the third edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and its current successor, the fourth edition of DSM (DSM-IV).

HISTORY Psychiatric illnesses were widely recognized in the ancient world. Melancholia and hysteria were identified in Egypt and Sumeria as early as 2600 BC. In India a psychiatric nosology was contained within the medical classification system of the Ayur-Veda, written about 1400 BC. Both Hippocrates and Plato created systems to classify mental disorders in classical Greece. Although the Hippocratic system was based primarily on empirical observation, the Platonic system was philosophically rooted in rational idealism. However, this distinction between empiricism and rationalism is not absolute. Hippocrates' system included a humoral theory of temperament that could be considered idealist, and Plato's rational thought was partly aimed at explaining observed reality. Classification in classical Rome was based primarily on the system of Hippocrates. The Galenic, humoral system persisted into the Middle Ages in Europe. During the European Renaissance and Enlightenment, systems of classification came to reflect the belief in the ordered and uniform character of Nature. Classification was an important part of the largely descriptive science of the day. Thomas Sydenham was a leading proponent of the notion of discrete and uniform disease categories. Carolus Linneaus and Francois Boisser de Sauvages attempted to apply the taxonomic methods of biology to medical and psychiatric illnesses, with categories based on observed signs and symptoms. In contrast, a separate current of thought in late–eighteenth-century France urged the development of a theoretical framework for medical nosology. The tension between paradigms based on observation and theory continued in the nineteenth century. The establishment of asylums allowed more prolonged and intensive observation of patients than had previously been possible. Autopsies became increasingly common and were widely accepted, and attempts were made to find a neuropathological basis for psychiatric symptoms. Emil Kraepelin aimed to develop a “natural” classification in which cause, symptomatology, and course would converge; however, his categories were based largely on similarity of symptoms. At the beginning of the twentieth century, no universally accepted system of psychiatric diagnosis existed in Europe or the United States, creating confusion and credibility problems. In the United States the initial impetus for developing a classification of mental disorders was the need to collect statistical information for the census. By the 1880 census, seven categories of mental illness were distinguished: mania, melancholia, monomania, paresis, dementia, dipsomania, and epilepsy. The increasing role of government in health care created a greater push for diagnostic uniformity. The first standard psychiatric nosology was produced in this country in 1918 by the American Medico-Psychological Association (forerunner of the American Psychiatric Association [APA]) and the National Commission on Mental Hygiene. It consisted of 22 disorders to be used primarily for gathering uniform statistics in all mental institutions, and was meant to be revised every 5 years. In 1935 the APA collaborated with the New York Academy of Medicine to develop a nationally acceptable psychiatric nomenclature to be incorporated in the American Medical Association's (AMA's) Standard Classified Nomenclature of Disease. Because the AMA system focused on severe mental illness, the U.S. military produced a broader nomenclature to incorporate outpatient presentations of World War II veterans in the 1940s. The sixth revision of Manual of International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-6), developed in 1948 by the World Health Organization (WHO), was not entirely satisfactory to American psychiatrists, so the APA developed a variant that was published in 1952 as the first edition of DSM (DSM-I). Heavily influenced by Adolf Meyer's psychobiological view of reactions, this was the first official manual of mental disorders to focus on clinical utility for classification. DSM-II followed in 1968 without substantial change, other than the elimination of the term reaction from the diagnoses. As with DSM-I and II, the development of DSM-III was coordinated with the development of the ninth revision of International Statistical Classification of Diseases (ICD-9) and published in 1980 by the APA. It represented a return to a descriptive system of diagnosis, based on explicit operational diagnostic criteria, theoretically neutral, and multiaxial in format. The revised third edition of DSM (DSM-III-R) (1987) and DSM-IV (1994) refined the diagnostic categories based on available empirical data, and proceeded to make the current diagnostic system compatible with that of the current 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) system.

PSYCHOSIS, PSYCHOPATHY, AND NEUROSIS As eighteenth-century psychiatry widened the boundaries of insanity and encouraged the development of a descriptive psychopathology, the terms neurosis, psychosis, and psychopathic were conflated. Although these terms have essentially disappeared from the current names of individual diagnostic categories, they reflect the intellectual underpinnings of earlier psychiatric thinking, and influenced how disturbed thinking, moods, and behaviors came to be classified. Their usage persists, and more often than not is applied incorrectly in vernacular parlance. The word “psychopathic” in particular, conjures up a range of negative applications. Psychosis The term psychosis was introduced by Ernst Feuchtersleben in 1845 to describe mental illness as a complex interaction of the psychic and the physical, and to denote a subclass of the nervous diseases referred to at that time as the neuroses. Confusion soon arose when psychosis, psychoneurosis, and psychopathy all came to mean the same thing. Efforts to clarify the confusion in terminology continued over the remaining half of the nineteenth century. By the beginning of the twentieth century, under the strong influence of Kraepelin, the meanings of neurosis and psychosis had become reversed. Freud proposed a nonorganic etiology for psychoneuroses. Karl Jaspers and Kurt Schneider continued in Kraepelin's tradition in Germany, so that the psychoses came to represent severe constitutional or endogenous psychiatric illness. The neuroses and psychopathies (now called personality disorders) came to represent exogenous reactions or static deviations on a

continuum from normal. Perhaps more than any other psychodiagnostic construct, the term psychosis has been repeatedly misused for political ends. In the social-political context of Germany in the late 1930s, this classification served the ends of the Nazi regime by providing a pseudoscientific distinction or dividing line that could be used for the eugenics program that systematically killed institutionalized patients with mental retardation, schizophrenia, and manic-depressive illness (bipolar I disorder). Soviet psychiatry would later also be used to promote political agendas based on psychiatric nosological constructs. Although the traditional meaning of the term psychosis emphasized loss of reality testing and impairment of mental functioning—manifested by delusions, hallucinations, confusion, and impaired memory—two additional meanings have evolved over the past 100 years. One common use of the term psychosis denotes severe impairment of social and personal functioning characterized by social withdrawal and an inability to perform usual household and occupational roles. The second use of the term specifies the extent of ego regression as a criterion for psychosis. As a consequence of various and multiple meanings, the term has lost its precision in current clinical and research practice. It is possible that the term will fail to appear in future official nosological systems, following the trend set in DSM-III for the class of neuroses. According to the glossary of the American Psychiatric Association, psychotic means grossly impaired in reality testing. The term may be used to describe the behavior of a person at a given time or a mental disorder in which all persons with the disorder have grossly impaired reality testing at some time during its course. Gross impairment in reality testing is defined as existing when individuals incorrectly evaluate the accuracy of their perceptions and thoughts, and make incorrect inferences about external reality, even in the face of contrary evidence. Psychotic does not apply to minor distortions of reality that involve matters of relative judgment. For example, depressed persons who underestimate their achievements are not described as psychotic, whereas those who incorrectly believe that they have caused actual catastrophes are so described. Direct evidence of psychotic perceptions, thoughts, and behavior is the presence of delusions or hallucinations not accompanied by insight into their pathological nature. The term psychotic is also appropriate when behavior is so disorganized that it is reasonable to infer that reality testing is grossly disturbed. Examples include markedly incoherent speech without apparent awareness by the person that the speech is not understandable, and the agitated, inattentive, and disoriented behavior seen in a phencyclidine psychotic disorder. The psychotic disorders are those that are predominantly characterized by psychosis. In DSM-IV the psychotic disorders include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, and psychotic disorder not otherwise specified. In addition, some severe mood disorders can have psychotic features. A person with a nonpsychotic mental disorder may exhibit transient psychotic thoughts and behaviors. For example, a person with borderline personality disorder may, when under the influence of substantial stress, loss, or substance abuse, come to believe in the reality of hearing voices, of conspiracies, or of government persecution. Psychopathy As late as the end of nineteenth century, the adjective psychopathic meant psychopathological and applied to any form of mental disorder. However, Koch, Gross, Morel, and others were narrowing the concept to apply to less severe forms of pathology that would eventually evolve into the contemporary concepts of personality disorders. Kurt Schneider's publication of “Psychopathic” charted the course by moving the subject away from the realm of the nonspecific “moral” of James Cowles Prichard to abnormal personalities. He conceived of psychopathic personalities not as pathological in a medical sense, but as deviations from the mean or normal condition, although with a somatic basis that might modulate the form of psychoses. Thus, outside the disease model, they could be enduring, episodic, or reactive. Psychopathic personality became a subclass of the larger group of abnormal personalities. In the conceptualization of discordant adaptation, Eugen Kahn used the term psychopathic to designate these conditions as complex states that lay intermediately between mental health and illness. Although Sigmund Freud was less interested in the issue, other psychodynamic and psychoanalytic writers like Daniel Stern and Wilhelm Reich contributed significantly to the understanding of character pathology. Carl Gustav Jung reinvigorated views of personality by shifting the focus away from archaic views of stereotyped behavioral forms to the contemporary perspective of combinations of dimensions and typologies. Ernst Kretschmer proposed typology based on biological speculation that followed Kraepelin's approach to the psychoses. These perspectives led incrementally to the current concepts of personality disorder that, like the current nosological paradigm, are primarily descriptive and directed towards neurobiological explanatory hypotheses. Although psychopathy does not appear in the current official nosology, a residue of the concept is retained in DSM-IV's antisocial personality disorder and ICD-10's dissocial personality disorder. Neurosis William Cullen coined the term neurosis in 1784 to signify a broad category of disorders affecting the nervous system. The term is now defined as a chronic or recurrent nonpsychotic disorder, characterized mainly by anxiety, that is experienced or expressed directly, or is altered through defense mechanisms. It appears as a symptom, such as an obsession, a compulsion, a phobia, or a sexual dysfunction. Although not used in DSM-IV, the term is still found in ICD-10. DSM-III redefined neurotic disorder as a mental disorder in which the predominant disturbance is a symptom or group of symptoms that is distressing to the individual and is recognized by him or her as unacceptable and alien (ego-dystonic); reality testing is grossly intact. Behavior does not actively violate gross social norms although it may be quite disabling. The disturbance is relatively enduring or recurrent without treatment, and is not limited to a transitory reaction to stressors. Earlier psychoanalytic developmental explanatory theories have been stripped from the construct. Because of DSM-III's atheoretical stance, there is no defining etiologic factor. In ICD-10 a class called “neurotic, stress-related, and somatoform disorders” encompasses the following: phobic anxiety disorders, other anxiety disorders (including panic disorder, generalized anxiety disorder, and mixed anxiety and depressive disorder), obsessive-compulsive disorder, adjustment disorders, dissociative (conversion) disorders, and somatoform disorders. ICD-10 also includes neurasthenia as a neurotic disorder characterized by mental and physical fatigability, a sense of general instability, irritability, anhedonia, and sleep disturbances. Many cases diagnosed as neuroses outside the United States fit the descriptions of anxiety disorders as diagnosed by American psychiatrists. There are no diagnoses called “neuroses” in DSM-IV. For those who still adhere to the term, neurosis encompasses a broad range of disorders with various signs and symptoms. Beyond signifying that gross reality testing is intact, neurosis has lost the precision currently necessary for a diagnostic category. In terms of an individual's functioning, it can reflect an intermediate level of impairment in a number of areas.

FEATURES OF NOSOLOGIC SYSTEMS Nosology is the study and practice of classification in medicine. The basic purpose of classification is data reduction or condensation of information. The “natural” classification is that which predicts the maximum possible number of facts. Although seemingly straightforward, taxonomy raises a number of philosophical and methodological issues. Nosological systems generally consist of conjectured disorders (diagnostic categories) as well as rules for making the diagnosis of each category. Because they are not isomorphic concepts, the disorder should not be confused with the diagnosis. A disorder (disease, syndrome, or complex) is a hypothetical entity with ontological status. The process of diagnosis is the attribution of the disorder to particular cases. Once this attribution has been made, the individual can be said to “have” the diagnosis but not the disorder. Unless there is a known cause or an infallible definition or both, diagnosis requires the use of a fallible rule or algorithm. Thus, one can have a disorder without having the corresponding diagnosis, and one can have a diagnosis without the corresponding disorder. The fundamental question of the ontological status of the diagnostic categories is rarely addressed directly in psychiatry. The metatheoretical choice is between realism and nominalism. Realism assumes that the entity (e.g., the disorder) exists independently of its being named. Nominalism asserts that the entity has no reality independent of being named; diagnostic categories are cultural constructs, not independently existing entities. Every diagnostic system, including DSM-IV, also has an explicit or implicit epistemological position. The epistemological question is, “On what is valid knowledge based?” Depending on the paradigm chosen, (e.g., empirical-descriptive or etiologically based), different answers with different implications will be given to this question. Value judgments involved in choosing a nosological system concern the primary purposes for which the system is designed. Important considerations include the following: clinical utility; research utility; diagnostic reliability; diagnostic validity; other statistical features; administrative, political, forensic, and economic

consequences; theoretical relevance; and universal acceptability. The choice and evaluation of nosologic systems depends in large measure on the priority given these various factors. For example, a system designed solely for clinical use would emphasize convenience of use and coverage (i.e., what proportion of patients presenting clinically can be given a relevant diagnosis), whereas a system designed primarily for research purposes would place more emphasis on reliability, diagnostic validity, and theoretical relevance. Various systems of medical diagnosis refer to constructs (i.e., syndromes, disorders, diseases) of different epistemological status. A syndrome is a set of signs and symptoms that co-occur at a greater than chance frequency. Diagnoses based on groups of symptoms should at minimum represent syndromes. A disorder represents the conjunction of a syndrome with a clinical course. At this level, something is known about the mechanism of the illness as well as its symptoms, although the underlying causes remain obscure. A disease, the optimal medical category, is a conjunction of etiology and pathology. In the case of a true disease, the symptoms, pathology and pathophysiology, and underlying causes are all known, as are the relations between them. In medicine, criteria used in classification belong to all three levels: symptoms, mechanisms, and causes. Causes are considered definitional and are the ultimate basis for a natural nosology. Progress in medical understanding is the process of moving from the superficial symptoms to the underlying “real” disease. A precise understanding of syndrome and course furthers the discovery of mechanisms and causes. For example, the separation of Down syndrome from the more general category of mental deficiency facilitated LeJeune's discovery of the underlying etiology: trisomy 21. A similar relation is seen between the disorder dementia paralytica and the discovery of the causative agent of the disease syphilis: Treponema pallidum. The official diagnostic nomenclature in DSM-IV uses the term disorder because most of the entities lack the features necessary to warrant the term disease. Cause is not specified except for cases of posttraumatic stress disorder, mental disorders due to a general medical condition, and substance-induced mental disorders. Other than some of the dementias, even these disorders lack a specified mechanism; most psychiatric illnesses and many medical illnesses are not diseases in the strict sense of the word.

THEORY OF CLASSIFICATION Classification Versus Typology In a traditional system of classification, categories are defined by a small number of individually necessary and jointly sufficient criteria that can be applied unambiguously. Any case can be determined to belong or not to belong to a given category by applying the rules defining the category to the case. Thus, the boundaries are crisply defined. Individuals within such a category are homogeneous with respect to the defining characteristics of that category. For example, all vertebrates have a spinal column; no other creature has this characteristic. Hierarchies are composed of clearly nested sets. All the classes of vertebrates have a backbone, but are distinguished by other characteristics (e.g., the presence of hair and mammary glands for mammals). Every mammal and bird is a vertebrate. The periodic table of elements is another example of such a hierarchical, categorical system. This system works to the extent that the classes of interest have such a structure. Ludwig Wittgenstein showed that many common object categories (e.g., “game”) do not have clear defining features, which is true for many psychiatric illnesses as well. In the typological view, cases are assigned to categories if they sufficiently resemble a typical member (or prototype) of the category. Not all characteristics of the category are necessary for membership; some may be merely correlated with membership. This view permits the existence of borderline cases and heterogeneity within the category. Hierarchical sets need not be perfectly nested; members of a subset need not have all of the (correlated) characteristics of the more inclusive set. The typal category has a clearly defined center but the boundary is indistinct, dependent in borderline cases on judgment or the use of a chosen cut-off point. Typology has been called “the opposite of true classification” because it puts similar things together rather than taking different things apart. It is argued that the prototypal model more closely resembles clinical reality in psychiatry, where borderline cases are common and present the most diagnostic difficulty; studies have shown that this is the way that clinicians conceive diagnostic categories. DSM-IV is basically a prototypal system. Categorical and Dimensional Systems A fundamental distinction is made between categorical and dimensional systems. Modern psychiatry and medicine aspire to the categorical system of classification, that is, the disorder, and generally the diagnosis, is either present or not present. The patient has or does not have a discrete diagnosis that differs qualitatively from normal. In a pure categorical system all diagnostic criteria are necessary and sufficient to make the diagnosis. Patients with the diagnosis are a homogeneous group in respect to that entity. Categorical systems differ in the extent to which hierarchy is recognized, and the extent to which categories are allowed to overlap. Categories may overlap in two senses. Two different categories may share features (criteria) and they may share members (both diagnoses in the same individual). DSM-IV is a modified categorical system in that diagnosis is dichotomous (either present or absent), but individuals who have a given diagnosis may be quite heterogeneous with respect to the defining criteria. Both forms of category overlap occur in the current psychiatric nosology. In a dimensional classification system, there are no discrete categories. Individuals are described in quantitative terms along continuous factors that have a (usually normal) distribution throughout the whole population. Because the dimensions are continuous, various intermediate measures between the two extreme poles of the dimensions can be expressed quantitatively. Each individual can be represented on a point in N-dimensional hyperspace (N represents the number of factors or dimensions in the model) defined by the degree to which each factor is expressed. Pathology represents a statistical deviation from the quantitatively defined mean or norm. Multidimensional systems of personality classification have been used extensively in psychology, and found to be useful in predicting external validity variables. However, because of the long-held medical tradition of conceptualizing disease entities as discrete categories, dimensional approaches have met with less clinical acceptance in psychiatry. Dimensional approaches are found in portions of DSM-IV, such as Axis V and the three clusters of Axis II personality disorders ( odd, dramatic, and anxious). There are other systems, such as fuzzy set theory, that combine features of categorical and dimensional systems. Fuzzy set theory allows cases to belong to sets (e.g., diagnostic categories) to varying degrees. Diagnostic groupings are maintained, but membership varies in degree (from 0 to 1). Dimensional and categorical constructs can coexist within a system of classification. However, the structure of each needs to be recognized so that it can be used appropriately. For example, in cancer the diagnosis is either present or absent, but when present, the disease is graded along a severity dimension (staging) that has important implications for treatment and prognosis. Similarly, rating scales can be used to measure the severity or change in an illness that is conceived as categorical, for example, the Hamilton Rating Scale for Depression or Brief Psychiatric Rating Scale. Distinguishing categorical and dimensional structures is at present a major challenge for psychiatry, because categorical disease entities may be manifested dimensionally and dimensional entities may appear categorical. Diagnostic Hierarchy Another important structural consideration pertains to diagnostic hierarchy. Are categories mutually exclusive, or may an individual simultaneously belong to more than one category? In most cases DSM-IV has abandoned the hierarchical structure of the earlier edition, but exceptions still exist. A second issue in hierarchy is whether larger categories of a superordinate level of abstraction are recognized (e.g., “affective disorder”). Such categories are analogous to the genera, families, and so on of biological classification of animal and plant species. Various diagnostic systems differ in the emphasis placed on interrelationships of the categories. DSM-IV uses as many as three levels of grouping above the individual disorder. DSM-IV states that disorders are grouped into the larger sections “based on their shared phenomenological features in order to facilitate differential diagnosis.” In many cases there are also different codes for different types of a single disorder. Operational Methods of Diagnosis (Algorithms) In practice, illness categories are inseparable from the means of diagnosing them and the diagnostic process should reflect the true nature of the latent structure of the disorder as exactly as possible. For example, the diagnostic algorithm for a categorical construct should return a categorical diagnosis. Such a disorder is conceived as homogeneous, and the individuals assigned to the category should be homogeneous with respect to the diagnostic criteria. The simplest and optimal diagnostic algorithm is the use of a gold standard. The gold standard is an infallible criterion or test that is pathognomonic for a disorder. For example, Klinefelter's syndrome may be diagnosed unequivocally by histological demonstration of the XXY karyotype. However, there are few true gold standards in psychiatry. Biochemical or genetic etiological markers of psychiatric illness, if found, are possible gold standards of the future. Lacking a gold standard, categorical diagnoses are often made using a number of fallible diagnostic criteria, each one of which is thought to be correlated with the disorder. Diagnostic heterogeneity is introduced when not all, but a minimum number, of all criteria are necessary and sufficient to make the diagnosis. In a formal prototypal model of classification, the diagnosis is made if the individual represents the prototype closely enough. Although several forms of diagnostic algorithms are used in DSM-IV (Figure 9.1-1), it is predominantly a modified prototypal system. Thus, in DSM-IV's borderline personality disorder where 5 or more of 9 criteria are required to make the diagnosis, a total of 256 possible combinations of criteria can make the diagnosis. This diagnostic heterogeneity affects the validity of the diagnosis. Heterogeneity is inevitable and to be expected in research exploring heritability, biological test measures, treatment outcome, clinical course, and

comorbidity correlates of diagnoses made by such algorithms.

FIGURE 9.1-1 Differential diagnosis of psychotic disorders. (Reprinted with permission from American Psychiatric Association: Diagnostic and Statistic Manual of Mental Disorders, ed 4. ©American Psychiatric Association, Washington, DC, 1994.)

This procedure can be thought of as using a scale with a certain cutoff point to make the diagnosis. In the preceding example, the criteria for borderline personality disorder can be thought of as being scored 0 (absent) or 1 (present), and the diagnosis made if the individual scores 5 or higher on the scale. When such a scale is used, by making a number of assumptions it is also possible to use the score as a dimensional measure if the diagnosis is conceptualized in dimensional terms. The score contains more information (in the mathematical sense of the word) than the categorical diagnosis (e.g., knowing that a subject has exactly 7 of 9 criteria for borderline personality disorder is more informative than knowing that he or she meets the criteria for borderline personality disorder). However, if the latent structure is actually categorical, then the dimensional score might contain considerable “noise” that could obscure the true dimensional structure. Dimensional scoring procedures can be much more complicated than this, and individuals may be scored on a number (N) of dimensions of interest. Such dimensional categories can always be reduced to categorical diagnoses corresponding to particular regions of N-dimensional space. Psychometric Evaluation of Diagnostic Procedures Where there is a gold standard, it is possible directly to measure the relation of the results of the diagnostic test procedure to the actual presence or absence of the disorder. The sensitivity of the diagnosis is the probability that the diagnosis will be positive given the presence of the disorder. The specificity is the probability that the diagnosis will be negative given the absence of the disorder. The predictive value positive is the probability that the disorder is present given that the diagnosis is present. The predictive value negative is the probability that the disorder is absent given that the diagnosis is absent. It must be emphasized that these relationships are not inherent to the diagnostic procedure but must be measured in the context of particular populations, and can vary greatly between different populations. Reliability refers to the degree to which the results of a diagnostic procedure remain stable across different raters and at different times. Inter-rater reliability is high when two or more raters have a high probability of reaching the same diagnosis for the same individual tested at approximately the same time. Test-retest reliability refers to the situation in which rater bias is not an issue (e.g., self-report questionnaires or laboratory tests), but results still may differ when the same test is repeated in the same individual. Longitudinal reliability is a measure of the stability of the diagnosis over time. Pearson's r (correlation coefficient) and k are frequently used statistical measures of reliability. One reason that reliability is important is that it is a necessary although by no means sufficient condition for diagnostic validity. Diagnostic categories and algorithms are constructed in the hope that they will be meaningful and useful; this is true for dimensional as well as categorical measures. Diagnostic validity, a compound term derived from various realms of experience, is used to describe such meaningfulness. Face validity refers to the extent that a category appears to represent a real phenomenon, as judged by experts. Descriptive validity refers to the existence of reliably assessed criteria that can identify a category and distinguish it from other conditions, particularly those that are phenomenologically similar. Predictive validity is the ability of a conjectured entity to predict external variables. In the prevailing psychiatric epistemology, this is operationalized by the procedures described by John Feighner for establishing predictive validity. These include the study of familial transmission, course of illness, treatment response, and biologic markers for the construct in question. Construct validity is the ideal or hierarchically superordinate standard of diagnostic validity. It is defined as the experimental confirmation of hypotheses concerning the etiology and pathophysiology of an illness construct, demonstrating that the category represents a real and naturally occurring entity with a specific pathological mechanism. Construct validity has both convergent (sensitivity) and divergent (specificity) aspects. Mathematical Models The development of sets of operational criteria and assessment procedures has resulted in improved diagnostic reliability. Because most of the constructs in psychiatric nosology are latent (i.e., not directly observable) and without an infallible diagnostic criterion or definition (i.e., gold standard), refinements to establish diagnostic validity must rely on statistical methods. Consequently, as computers have become more powerful, statistical and other computational models have acquired increasing popularity and acceptance as methods to identify and confirm diagnostic categories and dimensions. Methods for isolating psychiatric disorders and assigning individuals to them are promoted under the concept of numerical taxonomy, the methodological sequel to typology. Exploratory analyses use the results to suggest divisions of patients into groups or taxa. Confirmatory analyses examine the syndromal homogeneity and underlying structure of existing diagnostic groups. If the classification system developed by numerical taxonomy conforms to the existing groups, the nosology can be considered to be mathematically valid. Numerical taxonomy involves the grouping of items according to their evaluated affinity. These procedures involve the mathematical analyses of a data matrix. Factor analysis used to be a common technique to identify component dimensions. It has been largely supplanted by cluster analysis, which is complementary and attempts to identify homogenous subgroups of individuals on the basis of some measure of similarity. Testing for multimodality or bimodality in the distribution of scores on a typological variable is another approach to distinguishing groups; for example, bimodality or a point of rarity in distribution between groups is proposed to indicate categorically distinct groups. To overcome some of the inherent limitations of these approaches, a variety of mixture models have come forward. They essentially posit that patients come from a mathematically describable mixture of probability distributions that can be characterized as true groups. The general mixture model assumes that each subject is described by a number of measurements that are normally distributed within groups. Categorical or qualitative group distinction is demonstrated by the presence of more than one normal component distribution in the distribution of canonical coefficient scores derived from discriminant function. The latent class model is another advanced type of mixture model that assumes that the observed data reflect a mixture of distributions in which indicants are not of normal distribution. For example, grade-of-membership typology utilizes the distribution of the presence and absence of probabilistic indicants in individual subjects to identify degrees of membership in pure types. All the numerical taxonomic methodologies produce groups or taxa on typological grounds. The critical test of their validity is their ability to predict important clinical variables in external domains of familial transmission, course of illness, treatment response, and biologic markers. Although these mathematical methods may produce taxa with strongly defined centers, further inquiry must proceed to determining clear boundaries to be ultimately compatible with the current idealized medical classification paradigm.

DEVELOPMENT OF DSM-IV In 1988 the APA announced its decision to revise DSM-III-R, which had been published the previous year. Scheduled for 1992, DSM-IV publication was delayed until 1994. Many believed its publication was premature because there would be insufficient time to accumulate a sufficient database on which to develop DSM-IV. Objections were raised in various sectors. Clinicians and recently graduated resident trainees were resistant to changes in the criteria in which they were trained. Patient advocacy groups were concerned that there would be confusion when diagnoses were changed because of a different diagnostic system. Researchers were concerned about the implications of a new nosological system on the relevance of findings obtained with a different system. The American Psychological Association and other organizations of nonpsychiatric mental health professionals, such as social workers and psychiatric nurses, were critical because they had little, if any, input into the final product that they were required by law to adhere to. Nevertheless, DSM-IV was published in 1994. The criticism of a lack of replicated research data on which to base DSM-IV was addressed in the introduction to the

manual. It states that the Task Force on DSM-IV conducted a three-stage empirical process prior to publication. The stages were: 1. Literature reviews, conducted to provide comprehensive and unbiased information on which to base DSM-IV diagnostic criteria. DSM-IV notes, however, that for some issues insufficient data were available, and in those cases existing data were reanalyzed. 2. Data reanalysis that consisted of “analyses of relevant unpublished data sets” of criteria included in DSM-III-R. According to the DSM-IV Task Force, this approach made it possible for work groups to “question several criteria sets that were then tested in the DSM-IV field trials.” 3. Field trials that compared DSM-III, DSM-III-R, and ICD-10, and proposed DSM-IV criteria sets. The field trials collected information on the reliability and performance characteristics of each criteria set as a whole and on specific items within each criteria set. Twelve field trials were conducted at more than 70 sites, evaluating more than 6,000 subjects. Whether that is a large enough database on which to base a revision is open to question. Many psychiatrists in various sectors (e.g., clinical, research) believe that insufficient time has elapsed between revisions of DSM to allow replicated research on which to base DSM-IV.

BASIC FEATURES OF DSM-IV DSM-IV is the current classification of mental disorders; it is used by mental health professionals of all disciplines and is cited in insurance reimbursement, disability deliberations, statistical determinations, and forensic matters. Although there has been substantial criticism of each consecutive version of the DSM, DSM-IV is the official nomenclature and is used throughout this textbook. Table 9.1-1 lists all the disorders as they appear in DSM-IV.

Table 9.1-1 DSM-IV Classification of Mental Disorders*

DSM-IV strives to be neutral or atheoretical with regard to causes. Thus, it attempts to describe what the manifestations of the mental disorders are; only rarely does it attempt to account for how the disturbances come about. The definitions of the disorders usually consist of descriptions of the clinical features. Specified diagnostic criteria are provided for each mental disorder. Those criteria include a list of features and, in most cases, how many must be present for the diagnosis to be made. The use of specific criteria tends to increase the reliability of the diagnostic process among clinicians. DSM-IV also systematically describes each disorder in terms of its associated features: specific age-, culture-, and gender-related features; prevalence, incidence, and predisposing factors; course; complications; familial pattern; and differential diagnosis. In cases where many of the specific disorders share common features, that information is included in the introduction to the entire section. Laboratory findings and associated physical examination signs and symptoms are described when relevant. DSM-IV explicitly states that it is not a textbook. No mention is made of causal theories, management, or treatment; nor are the controversial issues surrounding particular diagnostic categories discussed. DSM-IV provides explicit rules to be used when the information is insufficient (diagnosis to be deferred or provisional), or the patient's clinical presentation and history do not meet the required criteria of a prototypical category (atypical type, residual, or not otherwise specified). Multiaxial Evaluation DSM-IV is a multiaxial system that comprises five axes and evaluates the patient along each. Axis I and Axis II comprise the entire classification of mental disorders: 17 major groupings, more than 300 specific disorders, and almost 400 categories. In many instances the patient has one or more disorders on both Axis I and II. For example, a patient may have major depressive disorder noted on Axis I and borderline and narcissistic personality disorders on Axis II. In general, multiple diagnoses on each axis are encouraged ( Table 9.1-2 and Table 9.1-3).

Table 9.1-2 Multiaxial Evaluation Report Form

Table 9.1-3 Examples of How to Record the Results of a DSM-IV Multiaxial Evaluation

Axis I Axis I consists of all mental disorders except those listed under Axis II, and other conditions that may be a focus of clinical attention.

Axis II Axis II consists of personality disorders and mental retardation. The habitual use of a particular defense mechanism can be indicated on Axis II. Axis III Axis III lists any physical disorder or general medical condition that is present in addition to the mental disorder. The identified physical condition may be causative (e.g., hepatic failure causing delirium), interactive (e.g., gastritis secondary to alcohol dependence), an effect (e.g., dementia and human immunodeficiency virus [HIV]-related pneumonia), or unrelated to the mental disorder. When a medical condition is causally related to a mental disorder, a mental disorder due to a general condition is listed on Axis I and the general medical condition is listed on both Axis I and III. Axis IV Axis IV is used to code psychosocial and environmental problems that contribute significantly to the development or the exacerbation of the current disorder (Table 9.1-4). The evaluation of stressors is based on the clinician's assessment of the stress that an average person with similar sociocultural values and circumstances would experience from psychosocial stressors.

Table 9.1-4 Axis IV: Psychosocial and Environmental Problems

Axis V Axis V is the Global Assessment of Functioning (GAF) scale ( Table 9.1-5) with which the clinician judges the patient's overall level of functioning during a particular time period (e.g., the patient's level of functioning at the time of the evaluation or the patient's highest level of functioning for at least a few months during the past year). Functioning is conceptualized as a composite of three major areas: social functioning, occupational functioning, and psychological functioning. The GAF scale, based on a continuum of severity, is a 100-point scale with 100 representing the highest level of functioning in all areas.

Table 9.1-5 Global Assessment of Functioning (GAF) Scale*

Nonaxial Format DSM-IV also allows clinicians who do not wish to use the multiaxial evaluation format to list the diagnoses serially, with the principal diagnosis listed (Table 9.1-6).

Table 9.1-6 Nonaxial Format

DSM-IV's Relation to ICD-10 The DSM-IV was designed to correspond with ICD-10, developed in 1992. There was a strong consensus that diagnostic systems used in the United States must be compatible with the International Classifications of Diseases (ICD) to ensure uniform reporting of national and international health statistics. In addition, Medicare requires that billing codes for reimbursement follow ICD. ICD-10 is the official classification system used in Europe and many other parts of the world. All categories used in DSM-IV are found in ICD-10, but not all ICD-10 categories are in DSM-IV. In the United States, ICD-10 codes can be used on insurance forms and other documents requiring diagnoses. The codes in DSM-IV are fully compatible with ICD-10 and are listed in the appendix; however, some terms and diagnostic categories used in ICD-10 are not used in DSM-IV.

CRITIQUE OF DSM-IV In formulating a critique of the DSM-IV, it is important at the outset to establish what the DSM-IV is and is not intended to be. The introduction of the DSM-IV states: The utility and credibility of the DSM-IV require that it focus on its clinical, research, and educational purposes and be supported by an extensive empirical foundation. Our highest priority has been to provide a helpful guide to clinical practice. We hoped to make DSM-IV practical and useful for clinicians by striving for brevity of criteria sets, clarity of language, and explicit statements of the constructs embodied in the diagnostic criteria. An additional goal was to facilitate research and improve communication among clinicians. We were also mindful of the use of DSM-IV for improving the collection of clinical information and as an educational tool for teaching psychopathology. An official nomenclature must be applicable in a wide diversity of contexts. DSM-IV is used by clinicians and researchers of many different orientations (e.g.,

biological, dynamic, cognitive, behavioral, interpersonal, family, systems). It is used by psychiatrists, other physicians, psychologists, social workers, nurses, occupational and rehabilitation therapists, counselors, and other health and mental health professionals. DSM-IV must be usable across settings—inpatient, outpatient, partial hospital, consultation liaison, clinic, private practice, and primary care, and with community populations. It is also a necessary tool for collecting and communicating accurate public health statistics. Fortunately, all these many uses are compatible with one another. These goals are similar to those of DSM-III and DSM-III-R. A strong emphasis is placed on clinical utility across a variety of settings, consensus, and utility in education and research. Although laudable goals, they are not the only ones that could have been chosen as priorities, and they are not necessarily compatible in all cases. It is also important to note what the DSM-IV does not state as goals. It does not intend to be a definitive or permanent taxonomy. It does not claim that all the categories are necessarily valid, nor that they be clearly distinguished from each other in all cases. It uses the term disorder exclusively, rather than disease, indicating that it does not assume that the entities described are diseases. A common criticism of DSM-IV is that it seems to place consensus and universal acceptability above validity. This is essentially a value judgment supported by the goals quoted above. Although DSM-IV remains unpopular among some clinicians (especially those who are psychodynamically oriented), it appears to have been successful in this goal as evidenced by its position as the standard nomenclature in the United States and in much of the world. However, criticisms relating to validity remain. The rates of comorbidity, or more accurately co-occurrence, between many of the DSM-IV diagnostic categories are higher than those found in any other branch of medicine. This brings into question whether the categories actually represent discrete entities or rather different aspects of larger symptom complexes. It is also not clear whether many of the criteria sets actually represent syndromes in the statistical sense (i.e., criteria that occur together significantly more often than chance). Although the DSM-IV Task Force made a major effort to render the nosology consistent with existing empirical data, most categories lacked the adequate empirical database for that determination, even at the level of internal (face and descriptive) validity. In addition, the extensive heterogeneity allowed by the polythetic criteria sets and their algorithms limits the utility of many of the diagnoses. Another criticism of DSM-IV concerns its atheoretical stance. Beyond the inherent paradox of such a position, should a nosological system be atheoretical (i.e., purely empirical)? The goal was to create a document that would be acceptable to health professionals regardless of theoretical outlook; explicit etiological and pathological theories are for the most part eschewed. The structure of the DSM-IV implies that mental disturbances can be characterized as disorders and categorized in a meaningful way based on signs and symptoms, particularly related to cognition and behavior. This in itself constitutes a theoretical stance. Although it may be the best that can be done at this time, the failure to involve developments in theory and cause is a significant impediment to further advances. The categorical approach adopted by the DSM-IV is familiar and comfortable to those with medical training. However, other than an appeal to tradition, there is little evidence that such a system is more useful or valid than a dimensional or other taxometric system. There is an equally long tradition of evaluating personality traits in a dimensional fashion. Doubts have been raised regarding the categorical nature of personality disorders, psychotic disorders, and mood disorders. DSM-IV clearly acknowledges the potential contributions of the dimensional approach, and contains polythetic and dimensional as well as categorical constructs. Whether it is reasonable to apply a common form to all psychiatric disorders or whether different models, representing different structures, should be applied to different classes of illness remains an open question. The DSM-IV multiaxial system implies the existence of qualitative differences between Axis I psychiatric disorders, Axis II personality disorders, and Axis III medical disorders but there is little evidence to support this position. The distinction of Axis I and Axis II was originally made in DSM-III to encourage use of the latter diagnoses out of concern that they could be missed because of the established hierarchical rules of the nosology. Hierarchical diagnosis was essentially abandoned in DSM-III-R, and DSM-IV follows that revision. The categorical distinction between psychiatric and medical conditions makes less and less sense as knowledge accumulates concerning the biological bases of psychiatric disorders and the effects of psychosocial variables on medical illnesses. In the absence of supporting evidence, the distinction between Axes I, II, and III appears anachronistic and possibly counterproductive. In summary, DSM-IV is a practically-oriented, consensus system that incorporates much of current clinical belief and research data. Many of its limitations are direct consequences of its intentionally descriptive approach; others stem from an across-the-board adoption of a quasi-categorical system using polythetic criteria. To its credit, DSM-IV has achieved an acceptable level of validity, primarily in face validity and more modestly in descriptive validity, which has enabled advances to be made in external predictive realms. Most importantly, as an open system, it provides a medium of discourse for clinicians and researchers, and is intended to be replaced in the future by more definitive, research-based nosological systems that incorporate etiology and pathology.

SUGGESTED CROSS-REFERENCES The psychiatric report is discussed in Section 7.2, typical signs and symptoms in Section 7.3, neuropsychological assessment in Section 7.4, clinical manifestations of psychiatric disorders in Chapter 8, and international perspectives on psychiatric diagnosis in Section 9.2. SECTION REFERENCES American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. American Psychiatric Association, Washington, DC, 1994. *Andrews G, Slade T, Peters L: Classification in psychiatry: ICD-10 versus DSM-IV. Br J Psychiatry 174:3, 1999. Beer MD: Psychosis: A history of the concept. Comprehensive Psychiatry 37:273, 1996. Berrios GE: European views on personality disorders: a conceptual history. Compr Psychiatry 34:14, 1993. Bryant KJ, Rounsaville B, Spitzer RL, Williams JB: Reliability of dual diagnosis: Substance dependence and psychiatric disorders. J Nerv Ment Dis 180:251, 1992. Cloninger CR, Martin RL, Guze SB, Clayton PJ: Diagnosis and prognosis in schizophrenia. Arch Gen Psychiatry 42:15, 1985. *Frances A, Mack AH, First MB, Widiger TA, Ross R, Forman L, Davis WW: DSM-IV meets philosophy. J Med Philosophy 19:207, 1994. Grayson DA: Can categorical and dimensional views of psychiatric illness be distinguished? Br J Psychiatry 151:355, 1987. Grove WM, Andreasen NC: Multivariate statistical analysis in psychopathology. In Contemporary Directions in Psychopathology: Toward DSM-IV, T Millon, GL Klerman, editors. Guilford, New York, 1986. Kendall RE, Brockington IF: The identification of disease entities and the relationship between schizophrenic and affective psychoses. Br J Psychiatry 137:324, 1980. *Mack AH, Forman L, Brown R, Frances A: A brief history of psychiatric classification. Psychiatr Clin North Am 17:515, 1994. *Nathan PE, Langenbucher JW: Psychopathology: Description and classification. Annu Rev Psychol 50:79, 1999. *Pichot P: Nosological models in psychiatry. Br J Psychiatry 164:232, 1994. *Robbins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. Am J Psychiatry 126:983, 1970. Scadding JG: The semantic problems of psychiatry. Psychol Med 20:243, 1990. Widiger TA, Frances A: The DSM-III personality disorders: Perspectives from psychology. Arch Gen Psychiatry 42:615, 1985. Widiger TA: The categorical distinction between personality and affective disorders. J Pers Disord 3:77, 1989. Wilson M: DSM-III and the transformation of American psychiatry: A history. Am J Psychiatry 150:197, 1993. Woodbury M, Manton KG: A new procedure for analysis of medical classification. Meth Inform Med 21:210, 1982.

World Health Organization: The ICD-10 Classification of Mental and ehavioral Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization, Geneva, 1992. World Health Organization: International Statistical Classification of Diseases and Related Health Problems, rev 10. World Health Organization, Geneva, 1992.

Textbook of Psychiatry

9.2 INTERNATIONAL PSYCHIATRIC DIAGNOSIS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 9. CLASSIFICATION OF MENTAL DISORDERS

9.2 INTERNATIONAL PSYCHIATRIC DIAGNOSIS JUAN E. MEZZICH, M.D., PH.D., ANGEL A. OTERO-OJEDA, M.D. AND SING LEE, M.D. Conceptual and Methodological Developments ICD-10 Adaptations of ICD-10 Toward Comprehensive Diagnosis Models Future Directions Suggested Cross-References

The concept of “diagnosis” at any point in time, defines the field of medicine in general and psychiatry in particular. It does so by delineating the informational base necessary for clinical care. With various degrees of systematization and explicitness, diagnostic schemas, as consensual notions and formats for describing clinical conditions, have emerged since the dawn of mankind. In every case, these notions have been embedded within their time and culture. Building on conceptual contributions over the past two centuries in various parts of the world, and having the 100-year-old International Classification of Diseases (ICD) as general reference, the emphasis for advancing psychiatric diagnosis during the past several decades has been on more-systematic and clearer formulations of psychopathology and nosology. This has led to gains in interdiagnostician agreement (diagnostic reliability) and universal communicability of diagnostic statements. These developments have been widely regarded as propitious (although not guarantees) for diagnostic validity or usefulness and for the broader advancement of the field. Among recent efforts to update diagnostic validity, clinically and epidemiologically, are developments to enhance existing universalistic diagnostic systems by paying attention to both local realities and the uniqueness of the individual. The first type of these developments involves adaptations of the international classification system to regional or national clinical patterns and needs. The second corresponds to idiographic or personalized formulations.

CONCEPTUAL AND METHODOLOGICAL DEVELOPMENTS Through proposals arising in different parts of the world, the following have emerged in recent decades as key conceptual and methodological developments for psychiatric diagnosis. They refer to the following major themes: systematic psychopathological description and comprehensive diagnostic formulation. Systematic Description of Psychopathology Early roots of explicit and systematized psychopathological description can be found in nineteenth-century France when symptoms were first used as units of analysis of abnormal behavior. Current concepts of psychiatric nosology can be traced back to the end of the nineteenth century, highlighted by Valentin Magnan's notion of clinical evolution in France and Emil Kraepelin's dichotomy of the major psychoses in Germany. Other significant contributions to the nosology of severe mental disorders of recent impact on psychiatric classification are the German description of cycloid psychoses, the Scandinavian concept of psychogenic psychosis, and the French delineation of boufée délirant. More recently psychopathologists from Asia, Africa, and Latin America have offered informative reports on acute transient psychoses and somatically and psychologically textured characterizations of the neuroses. The manifestations of mental disorders constitute the focus of the so-called phenomenological description of psychopathology. That approach encouraged careful observation of clinical presentations, particularly symptom profiles, while minimizing etiological inferences. Many questions remain regarding the organization of standard nosologies, for example, the number of major classes of mental disorders, the arrangement of subclasses, and the hierarchical relationships among diagnostic categories. Furthermore, etiopathogenic perspectives—from genetics, to psychodynamics, to general systems—may in the future contribute enriched and more valid formulations of mental disorders. Explicit or operational diagnostic criteria, a mainstay of modern diagnostic methodology, were persuasively proposed by the British psychiatrist Edward Stengel as a step in dealing with the widespread confusion in classification documented in his international survey, commissioned by the World Health Organization (WHO). The actual development of operational criteria was pioneered, chronologically, by José Horwitz and Juan Marconi in Latin America, Peter Berner in Austria, and John Feighner and associates in the United States. Operationalized diagnostic criteria probably represent the most conspicuous response to the need for clarity in psychiatry and are considered essential for its progress as a scientific discipline. On the other hand, the limitations of using the criteria sets include the arbitrariness often involved in setting thresholds between cases and noncases, the cumbersomeness of their use in daily practice, and the burden they impose on meaning and usage across cultures. An approach that promises to enhance categorical definition by accommodating graded typicality and flexible boundaries involves the use of the prototypical categorization model. This is connected to mathematical fuzzy set theory, and its use is being explored on particularly problematic areas of psychopathology, such as personality disorders and even schizophrenia and obsessive-compulsive disorder. Multiaxial Diagnostic Formulation Attempts to represent more fully the complexity of a patient's condition have emerged predominantly under the generic term multiaxial approach. Multiaxial diagnosis intends to portray the intricacies of the clinical condition through the systematic and separate assessment and formulation of highly informative aspects or domains. Standardized measurements, either typologies or dimensional scales, have been proposed with which to appraise each domain. The first multiaxial schemata in both psychiatry and general medicine were aimed at articulating key components of an illness. Starting in 1949, the pioneers of the field who independently proposed a methodical and almost graphical assessment of syndromes and etiology were Erik Essen-Möller and Snorre Wohlfahrt in Sweden, Maurice Lecomte and associates in France, Tadeusz Bilikiewicz in Poland, and José Leme-Lopes in Brazil. The first multiaxial schema in general medicine was the Systematized Nomenclature of Pathology, which accommodated axes on topography, morphology, etiology, and symptoms. One of the latest is the International Classification of Diseases for Oncology (ICD-O), which focuses separately on neoplastic topography and morphology (the latter including tumor behavior and differentiation). A more recent and far-reaching purpose of the multiaxial model is to furnish a biopsychosocial description of the patient's entire clinical condition. This encompasses not only pathologies (mental and nonmental), but also psychosocial environmental factors and the consequences of illness on the individual's functioning and quality of life. The work of John Strauss, Michael Rutter, and associates in psychiatry and of Alvin Feinstein, J. S. House, and associates in general medicine are pertinent to this objective. Among the challenges for further development of the multiaxial model are the need for greater simplicity and ease of use as well as empirical appraisal of its reliability and validity across the world. The first national diagnostic system to incorporate a multiaxial approach was the Swedish classification of mental disorders, which was based on the previously referred proposals by Essen-Möller and Wohlfahrt. More recently, the methodological developments outlined previously (phenomenological description, explicit diagnostic criteria, and multiaxial formulation) have structured the third and fourth editions of the American Psychiatric Association's (APA's) Diagnostic and Statistical Manual of Mental Disorders (DSM-III and DSM-IV), as well as the WHOs 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10), which has a central role for diagnosis across the world.

ICD-10 Origins of the International Classification The origins of the ICD can be traced back to the taxonomic work of the Swedish biologist Carolus Linnaeus in the eighteenth century. In Genera Plantarum he stated: “All the real knowledge which we possess depends on methods by which we distinguish the similar from the dissimilar ... We ought therefore by attentive and diligent observation to determine the limits of the genera, since they cannot be determined a priori. This is the great work, the important labor, for should the general be confused, all would be confusion.” Linnaeus stimulated scholars from all walks of life. For example, Francois Boissier de Sauvages and William Cullen developed formidable nosologies encompassing thousands of species of disease, organized into classes, orders, and

genera. Bringing these leads to fruition, the first International Statistical Congress held in Brussels in 1853 commissioned the Englishman William Farr and the Italian Marc d'Espine to prepare a “uniform nomenclature of causes of death applicable to all countries” as a way to obtain comparable health status information across the world. The proposals that ensued were based primarily on either topographical or etiological principles. Accommodating both, Jacques Bertillón of Paris prepared the First International Classification of Causes of Death, adopted at the International Statistical Congress of 1893. Since then there have been revisions of the ICD approximately every 10 years. From its foundation the WHO, created in 1948, assumed the preparation of these revisions as a constitutional responsibility. The sixth revision contained a critical expansion of the scope of the international classification by covering morbidity in addition to mortality. Correspondingly, psychiatric illness appeared for the first time in the classification with one category: mental illness and deficiency. The ninth revision had as one of its innovations the presentation of a glossary for the capsular definition of mental disorders. While modest in informational detail, this glossary signified recognition by the WHO that the intricacy of mental problems required more than the labels used in all other chapters of the ICD. Outline of ICD-10 Work toward the preparation of ICD-10 started in 1979, the same year in which the ninth revision of International Statistical Classification of Diseases (ICD-9) was put into effect. Its developmental process involved the participation of the eight Collaborating Centers for the Classification of Diseases, specialty divisions (such as Mental Health) at both the headquarters and regional offices of WHO, nongovernmental organizations such as the World Psychiatric Association (WPA), and a miscellaneous panel of interested groups and individuals, all working under the coordination of the WHO Unit on the Development of Epidemiological and Health Statistical Services. First to be noted in ICD-10 is its expanded scope, as indicated by its title, International Statistical Classification of Diseases and Related Health Problems. This expression continues the trend that starting with an original set of causes of death, added morbidity in its fifth revision, and more recently added problems such as disabilities and factors that influence health status, recognizing that more information is needed to deal effectively with the evolving and complex issues of health care and health promotion. ICD-10 uses an alphanumeric code composed of a letter followed by several digits. That arrangement more than doubles the number of available categories. Splitting, rather than lumping, of categories has marked the progression of ICD revisions, which has increased the need for categorical slots. The first four characters of the code are internationally official. The fifth- and sixth-character fields are available for regional and special purpose adaptations. This arrangement maintains international communication while accommodating local diversity. Another powerful and innovative concept is ICD-10 as a family of disease and health-related classifications. At the core of the family are the 21 main chapters coded at the official three-character and four-character levels and the short tabulation lists of causes of death and morbidity. Peripherically located are the following classifications: (1) specialty-based adaptations (e.g., for oncology) where the chief difference from the core classification lies in the further extension of the ICD codes; (2) classifications for primary care and general medical practice, characterized by the condensation of categories and emphasis on less rigorous diagnostic terminology and more immediate therapeutic utility; and (3) classifications of information outside the core ICD, such as that corresponding to disabilities and medical procedures. Also part of the family is the International Nomenclature of Diseases, which encompasses a list of recommended names for all diseases as well as their definitions. In contrast to the concept of nomenclature, a classification, in the words of the ICD pioneer Farr, “groups diseases that have considerable affinity or that are lable to be confounded with each other, and therefore is likely to facilitate the deduction of general principles.” Main forms of human illness and related conditions constitute the 21 chapters as the core of ICD-10 ( Table 9.2-1). New chapters structure the enlarged lists of disorders of the nervous system (Chapter VI), eye and adnexa (Chapter VII), and ear and mastoid process ( Chapter VIII). The expanded chapter on neoplasms covers one full letter and shares another with blood disorders, which encompasses immunological conditions such as acquired immune deficiency syndrome (AIDS). Also the classification of neoplasms is multiaxial (one axis denotes topography and another morphology, i.e., histological type, and tumor invasiveness and differentiation).

Table 9.2-1 List of Core Chapters of ICD-10

ICD-10 Classification of Mental Disorders Mental and behavioral disorders are housed within Chapter V of ICD-10 and are coded with the letter F ( Table 9.2-2). The use of the sixth letter of the Gregorian alphabet to denote chapter V is explained by the assignment of two letters to a very lengthy list of conditions in chapters on infectious and parasitic diseases. After the letter F, the first digit of the Chapter V diagnostic codes denotes 10 major classes of mental and behavioral disorders: F0 through F9. The second and third digits (third and fourth characters) identify progressively finer categories. For example, the code F30.2 sequentially denotes the mental chapter, mood disorders class, manic episode, and the presence of psychotic symptoms. In this manner, 1000 four-character mental disorder categorical slots are available in ICD-10.

Table 9.2-2 ICD-10 Classification of Mental Disorders

F0-Organic, Including Symptomatic, Mental Disorders This class is etiologically based on physical disorders or conditions involving or leading to brain damage or dysfunction. The first clusters have disturbances of cognitive functions as prominent features and include the dementias (Alzheimer's, vascular, associated with other diseases, and unspecified), organic amnestic syndrome, and delirium not induced by psychoactive substances. The second cluster has as its most conspicuous manifestations alterations in perception (hallucinations), thought (delusions), mood (depressed or manic), various emotional domains (such as anxiety and dissociation), and personality. F1-Mental and Behavioral Disorders Due to Psychoactive Substance Use In contrast to earlier classifications, this class subsumes all mental disorders related to

psychoactive substance use, from patterns of dependence and harmful use to various organic brain syndromes induced by substances. The diagnostic process and coding starts with identification of the substance involved (i.e., alcohol, opioids, cannabinoids, sedatives, or hypnotics, cocaine, other stimulants, hallucinogens, tobacco, volatile solvents, and other substances and combinations of them). Identified next in the code is the involved clinical condition: acute intoxication, harmful use (previously known as abuse and characterized by a pattern of use causing damage to physical or mental health), dependence syndrome, withdrawal state (with or without delirium), psychotic disorder, amnesic syndrome, residual and late-onset psychotic disorder, and other and unspecified mental disorders. F2-Schizophrenia, Schizotypal, and Delusional Disorders This class has schizophrenia as its centerpiece, a disorder characterized by fundamental and distinctive distortions of thinking and perception and by inappropriate or blunted affect. The remaining categories of nonorganic, nonaffective psychoses are considered somewhat related, phenomenologically or genetically, to schizophrenia. Particularly interesting is the cluster of acute and transient psychotic disorders, which encompasses a heterogeneous set of acute-onset and relatively short-lived psychoses (polymorphic with or without schizophrenic symptoms, acute schizophrenia-like, and others) reportedly frequent in industrially developing countries (where most of the world population lives). F3-Mood (Affective) Disorders The fundamental disturbance in this class is a change in mood or affect, usually involving depression or elation, often accompanied by a change in level of activity. Included here are manic episode, bipolar affective disorder (characterized by recurrent episodes involving both depression and elation), depressive episode, recurrent depressive disorder, persistent mood disorder (cyclothymia, dysthymia), and other and unspecified mood disorders. F4-Neurotic, Stress-Related, and Somatoform Disorders This grouping is based on a historical concept of neurosis that presumes a substantial role played by psychological causation and that mixtures of symptoms are common, particularly in less severe forms often seen in primary care. Included in this book are phobic anxiety and other anxiety disorders, obsessive-compulsive disorder, reactions to severe stress and adjustment disorders, dissociative and conversion disorders, somatoform disorders, and other neurotic disorders (e.g., neurasthenia and depersonalization-derealization syndrome). F5-Behavioral Syndromes Associated With Physiological Disturbances and Physical Factors Included here are eating disorders, nonorganic sleep disorders, and sexual dysfunction, mental disorders associated with the puerperium and not elsewhere classified, psychological factors influencing physical disorders, and abuse of non-dependence-producing substances (e.g., antidepressants, hormones, analgesics, and many folk remedies). F6-Disorders of Adult Personality and Behavior This class includes clinical conditions and behavioral patterns that tend to persist and the expression of an individual's characteristic lifestyle and mode of relating to self and others. The main subclass involves personality disorders, which are deeply ingrained and enduring behavior patterns, manifesting as inflexible responses to a broad range of personal and social situations. An innovative category is that of enduring personality change, neither developmental nor attributable to brain damage or disease, and usually emerging after catastrophic experiences or another psychiatric illness. The broad class also includes impulse, gender identity, sexual preference, and sexual development and orientation disorders. F7-Mental Retardation Mental retardation, one of the oldest in the history of psychiatric classifications, involves arrested or incomplete mental development, characterized by impaired cognitive, language, motor, and social skills evidenced during the person's formative period and contributing to the overall level of intelligence. Its subcategories correspond to various levels of severity: mild, moderate, severe, and profound mental retardation. Extent of behavioral impairment is also coded. F8-Disorders of Psychological Development Disorders of psychological development are characterized, as a class, by the following attributes: onset during infancy or childhood, impairment or delay of functions connected to the maturation of the central nervous system, and a steady course unlike the remissions and relapses usual in many mental disorders. The functions affected most frequently include language, visuospatial skills, and motor coordination. A major subclass encompasses a variety of specific developmental disorders, classified by the abilities involved: speech and language, scholastic skills, and motor function. The other major subclass corresponds to pervasive developmental disorders, many of which are more saliently characterized by deviance rather than delay in development but always involving some degree of delay. Most conspicuous here are childhood and atypical autistic disorder and Rett's syndrome and other childhood disintegrative disorders. F9-Behavioral and Emotional Disorders With Onset Usually Occurring in Childhood and Adolescence This complex class complements F7 and F8. Child-onset disorders included first are hyperkinetic disorders characterized by early onset, overactive and poorly modulated behavior associated with marked inattention, lack of persistent task involvement, and pervasiveness over situations and time. Conduct disorders are defined by a repetitive and persistent pattern of dissocial, aggressive, or defiant behavior. Also included in this class are emotional, social-functioning, tic, and other disorders usually starting in childhood or adolescence. The full ICD-10 classification of mental disorders has three presentations corresponding to various degrees of definitional detail, aimed at serving different purposes and uses: 1. An abbreviated glossary containing the principal features of each disorder, for the use of statistical coders and medical librarians, published within the ICD-10 general volume 2. Clinical descriptions and diagnostic guidelines, containing widely accepted characterizations of an intermediate level of specificity, intended for regular patient care and broad clinical studies 3. Diagnostic criteria for research, characterized by more-precise and rigorous definitions Multiaxial Presentation of ICD-10 Over the past two decades, the WHO advanced some important initiatives on multiaxial diagnosis. One was the Multiaxial Classification of Child Psychiatric Disorders, first designed in 1969 and revised and expanded several times since then. Its 1975 pentaxial version encompassed the following axes: psychiatric disorders, physical disorders, developmental disorders, intellectual level, and abnormal psychosocial situations. Another was the Triaxial Classification of Health Problems for Primary Care, which contained axes on physical, psychopathological, and social problems. On these precedents and many others from the international literature, in the late 1980s the WHO Mental Health Division began preparing the Multiaxial Presentation of ICD-10. The conceptual bases of this development included a critical analysis of over 20 published multiaxial proposals originating in countries spanning three continents, which revealed important commonalties in the clinical domains covered. A second developmental principle was simplicity in the multiaxial schema, to enhance the prospects of its effective use across the world. The third principle was to base the instruments for axial assessment on components of the ICD-10 family of classifications, which had benefited from wide international consultations and field trials. The Multiaxial Presentation of ICD-10 is composed of three axes: I. Clinical Diagnoses; II. Disablement; and III. Contextual Factors. The number of axes is lower than the four or five usually included in published multiaxial schemata and constitutes a condensation of those axes most frequently included in multiaxial proposals published in the international literature, which affords a measure of content validity to the schema. The value of the simplicity of the schema is enhanced by its potential for generalization beyond psychiatric practice. Information on clinical pathology, disablement, and contextual factors appears to be relevant to all health care. Axis I—Clinical Diagnoses This axis accommodates both mental and nonmental (general medical) disorders, underlining a fundamental commonality among all illnesses. All significant disorders identifiable in a given individual are to be listed and coded according to Chapter I,Chapter II,Chapter III,Chapter IV,Chapter V,Chapter VI,Chapter VII,Chapter VIII,Chapter IX and Chapter X (the disease chapters) in the core classification of ICD-10 ( Table 9.2-2). Axis II—Disablements This axis appraises the consequences of illness in terms of impairment in the performance of basic social roles. The assessment instrument is a shortened version of the WHO Disability Assessment Scale, whose structure was condensed into four dimensions or areas: (1) personal care, (2) occupational functioning (as remunerated worker, student, or homemaker), (3) functioning with family (assessing both the regularity and quality of interactions with relatives and household members), and (4) broad social behaviors (interaction with other individuals and the community at large and leisure activities). Axis III—Contextual Factors This axis attempts to portray the context of illness in terms of several ecological domains. These include problems related to the family or primary support group, general social environment, education, employment, housing and economic circumstances, legal issues, family history of illness, and personal life management and lifestyle. Assessment involves identifying problematic broad categories and recording specific factors. This structure is based on ICD-10 Chapter XXI (factors influencing health status and contact with health services). Primary Health Version The ICD-10 Primary Health Version is a simple, brief classification arrangement compatible with and translatable into the ICD-10 standard classification of mental disorders ( Table 9.2-3). It is linked with management aids prepared for use by primary care practitioners. The short list of categories was selected principally on the basis of importance to public health and the availability of effective and acceptable management. The centerpiece of the package is a set

of pocket-sized flip-cards, one for each selected category. One side of the flipcard exhibits assessment information, such as presenting complaints, diagnostic features, and differential diagnosis. The other side displays management guidelines, such as essential information for patient and family, specific counseling for the patient and family, medication, and specialist consultation. Additional elements of the package include flow charts, symptom indexes, and a computerized version.

Table 9.2-3 ICD-10 Primary Health Care Categories

ADAPTATIONS OF ICD-10 The ICD-10 Classification of Mental and Behavioral Disorders is being accepted by most countries and by the WPA as the international standard in the field for both statistical reporting and for clinical care and research. Emerging now is the need to harmonize international communication with recognition of cultural diversity and specific local requirements. To express this perception, several national adaptations, versions, and annotations of ICD-10 are being developed and published. The rationale and arguments for the development of local glossaries include the following: 1. Local glossaries from across the world can serve as the fundamental bases for the preparation of bottom-up international diagnostic systems. 2. Local glossaries, through its attention to various aspects of clinical reality, can facilitate the implementation of a comprehensive biopsychosocial framework, away from reductionisms of different types. 3. Local glossaries can reflect the cultural integrity of different countries and human groups and promote the value of their health-related concepts and practices. 4. Local glossaries can embody and transmit the intellectual contributions of national and regional scientists and professional leaders for the benefit of the field around the world. 5. Local glossaries can facilitate the effective use of international diagnostic systems, by adapting the various components of these systems to national patterns and needs. The best known of these national versions is the APA's DSM-IV. In 1980 the APA published the innovative DSM-III characterized by a phenomenological emphasis on the conceptualization and organization of mental disorders, the use of explicit diagnostic criteria, and a multiaxial formulation. It acquired wide international visibility and significantly influenced the field of psychiatric classification. After preparations for ICD-10 were started by WHO, the APA initiated the development of DSM-IV, attempting this time to keep close to the international standard (which was already incorporating much of the methodological features advanced by DSM-III). Perhaps the principal attribute of DSM-IV is the scholarly emphasis in its development on the basis of critical literature reviews, reanalysis of existing databases, and focused field trials. Cuban Glossary of Psychiatry Development of the various editions of the Cuban Glossary of Psychiatry started in 1975. They have attempted to reflect the realities and needs of Cuba in particular, within the general framework of Latin American culture. Emphasis on this perspective was presented first as a responsibility to the local population and second as an effort to contribute to the bottom-up building of international classification. The latter implies that carefully prepared technical contributions are as worthy of consideration for constructing an international reference as those coming from Europe, North America, or any other part of the world. The Cuban glossaries have furthermore attempted to harmonize the general, represented by the existing ICD, with the local. Therefore, its authors consider the glossary to be the basic ICD-10 with only the changes and additions needed to ensure its applicability and usefulness for psychiatric care in Cuba. As a broader conceptual framework for the preparation of the Cuban glossaries, their authors considered a syncretism of local historical traditions, the existing social and clinical reality of the region, and international scientific contributions. Among the many specifically Latin American contributions they were attentive to the following. Honorio Delgado, a Peruvian psychiatrist, published the influential Curso de Psiquiatría in the middle of this century, with a masterful presentation of psychopathological phenomenology and nosology. In 1954 in Rio de Janeiro Leme Lopes published the innovative Dimensoes do Diagnóstico Psiquiátrico, with a pioneering multiaxial formulation of clinical conditions. The Cuban psychiatrist José Bustamante published in 1975 with anthropologist A. Santa Cruz, what can be arguably considered the first textbook of transcultural psychiatry in the world. Carlos Alberto Seguín from Peru, with his volume on folkloric psychiatry, is emblematic of the rich Latin American contributions to the description of popular or culture-bound syndromes in the region. Early Editions of Cuban Glossary of Psychiatry The Cuban glossaries of psychiatry have been the most complete and distinctive Latin American effort to annotate and adapt the existing ICD to local reality. The general principles guiding the preparation of the Cuban Glossaries of Psychiatry include the following: 1. 2. 3. 4.

Compatibility with ICD by incorporating modifications and additions through the fifth digits of the diagnostic code and the use of qualifying phrases Consideration of all suggestions offered at provincial and national seminaries on the classification of mental disorders Deliberate effort to harmonize different viewpoints Systematic participation of most psychiatrists in the country and many clinical psychologists and other professionals concerned with mental health (e.g., teachers, social workers, and forensic doctors).

Its first edition (GC-1), published in 1975, constitutes an adaptation of the eighth revision of the International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-8). Its architect was Carlos Acosta-Nodal, professor of psychiatry at Havana University, working under the auspices of Eduardo Ordaz, director of Havana Psychiatric Hospital. The GC-1 was composed of 69 adaptations of ICD-8. The second edition of GC (GC-2), published in 1983 ( Fig. 9.2-1), was an adaptation of ICD-9. Its development was again chaired by Acosta-Nodal. It contained 90 modifications of ICD-9 in addition to substantive chapters devoted to historical, theoretical, and clinical aspects of psychiatry.

FIGURE 9.2-1 Cover of the Third Cuban Glossary of Psychiatry, 1998 (Tercer Glosario Cubano de Psiquiatria [GC-3]).

Third Edition of Cuban Glossary of Psychiatry The current third edition Cuban Glossary of Psychiatry (GC-3) was developed under the chairmanship of Angel Otero-Ojeda, from Havana University and the Havana Psychiatric Hospital. It includes a number of contributions on the diagnosis of mental disorders as experienced and presented in Cuba. These encompass both general psychiatry and child psychiatry. A basic principle in the development of GC-3 was to be similar to ICD-10, with minimal differences. In line with this, the coding system of ICD-10 was faithfully followed. Contributions and changes were incorporated through the employment of fifth digits in the diagnostic code or through the utilization of codes not used in ICD-10. The ICD-10 diagnostic guidelines for the various psychiatric disorders were also respected to the largest extent possible. In some cases, supplemental text was added. References to DSM-IV and to the ICD-10 criteria for research were often made. Of note, the GC-3 encourages diagnostic formulations based on the judicious use of all information available and allows experienced clinicians to formulate diagnoses without strictly adhering to standard diagnostic criteria. GC-3 starts with an introductory chapter that outlines the principles of the diagnostic process and the positive aspects and problems of the current classifications. One such problem is the hospital-focus of most systems, which may limit their relevance to the emerging community-based psychiatry. Another interesting chapter of GC-3 is that on “Syndromes of Difficult Placement” (sometimes referred to as culture-based syndromes). This includes both widely known folk syndromes such as amok, brain fag, and rusto as well as some syndromes and idioms of distress reported by Cuban psychiatrists. Illustrative of the latter is abríu, which refers to certain children believed to have the power to exercise a malign supernatural influence on their relatives, particularly siblings, who as a consequence can experience various illnesses and even die. Additions made in the main body of GC-3 include (1) “neurotic behavior” as qualifier in broad categories such as mood disorders and neurotic, stress-related, and somatoform disorders, (2) diagnosis based on premorbid features for disorders of chronic or episodal source in broad categories such as schizophrenia and related disorders and mood disorders, (3) risky behaviors such as suicide or substance use, which are of particular relevance to community psychiatry. An illustrative deletion was dementia in children. Some of the most innovative contributions of GC-3 involve its multiaxial schemes, which build on the standard multiaxial presentation of ICD-10. The GC-3 multiaxial scheme follows: Axis I—Clinical Diagnosis. Both mental and nonmental disorders are included as in ICD-10's multiaxial system. Axis II—Disabilities. Disablements in personal care, occupational functioning, functioning with family, and broader social functioning are included following the guidelines of ICD-10's multiaxial presentation. Axis III—Psychoenvironmental Factors (Adverse). Included here are contextual problems listed under the third axis of WHO's multiaxial presentation of ICD-10. Axis IV—Psychoenvironmental Factors (Other). Illustrative of factors considered here are to live alone and to be particularly “practical” or “romantic.” Axis V—Maladaptive Behavior and Psychological Needs. Included here are conditions such as hypertrophic affective needs, indecisiveness, and difficulties managing hostility. Axis VI—Other Significant Factors. Included here is miscellaneous information such as that resulting from laboratory tests and responses to therapeutic interventions. Work on the GC-3 stimulated the Section on Diagnosis and Classification of the Latin American Psychiatric Association, under the leadership of Carlos Berganza (San Carlos University, Guatemala), Miguel Jorge (Escola Paulista de Medicina, Brazil), Otero-Ojeda (Havana University, Cuba) and Juan E. Mezzich (Mount Sinai School of Medicine in New York and Cayetano Heredia Peruvian University in Lima) to organize preparation of the first Latin American Glossary of Psychiatry as a Latin American annotation of ICD-10. Its components include the conceptual bases of psychiatric diagnosis, the hierarchical organization and diagnostic criteria of psychiatric nosology, culture-bound syndromes and idioms of distress, and multiaxial and comprehensive diagnostic formulations. Chinese Classification of Mental Disorders In China attempts to classify mental disorders began around 1958. The first classificatory scheme was published in 1979 and named the Chinese Classification of Mental Disorders, first edition (CCMD-1) in 1981. Under the influence of the DSM and ICD systems, a number of subsequent revisions culminated in the publication of the second edition (CCMD-2) in 1989 and the revised second edition (CCMD-2-R) ( Fig. 9.2-2) in 1995. For the first time in China operationalized criteria for a broad range of diagnostic categories have become available. Since China has over one fifth of the world's population, knowledge of the CCMD-2-R is central to the knowledge base of psychopathology in general. Chinese people also constitute one of the fastest growing ethnic minority groups in Western societies, so understanding the CCMD-2-R may attune clinicians to certain Chinese forms of distress in an intercultural treatment context.

FIGURE 9.2-2 Cover of the Chinese Classification of Mental Disorders, ed 2, Revised, (CCM-D-R), 1995.

In devising CCMD-2-R, Chinese psychiatrists sought to harmonize with the international classification on one hand and to sustain a nosology that is useful in a huge and heterogeneous country on the other. As a result, CCMD-2-R and the ICD-10 share a broadly comparable architecture. However, inasmuch as symptom recognition and taxonomic strategy in psychiatry reflect the cultural norms and values of the society in which they are embedded, this blending is legitimately incomplete. The CCMD-2-R is a concise handbook of 238 pages that contains the equivalent or closest ICD-9 and ICD-10 codes (crosswalks) alongside the diagnostic headings. It contains a number of cross-culturally salient features, including particular additions ( gigong-induced mental disorders, traveling psychosis), deletions (somatoform disorders, pathological gambling, a number of personality and sexual disorders), retentions (unipolar mania, neurosis), and variations (neurasthenia, depressive neurosis, anorexia nervosa) of diagnostic categories. A number of field trials have indicated adequate reliability and validity. Addition of Culture-Specific Diagnostic Categories Both ICD-10 and DSM-IV lack a coded classification of culture-bound syndromes, which are often cited in the argument against an international classification of mental disorders. By contrast, the CCMD-2-R includes qigong-induced mental disorder as a culture-related mental disorder. Qigong is a popular trance-based healing system that consists of meditational or diverse styles of movement exercise or both. It is induced by using a culture-syntonic set of suggestions based on the Chinese concept of qi (vital energy). Qigong-induced mental disorder is believed to arise from inappropriate or excessive application of qigong or inability to terminate the qigong. This causes the flow of qi to deviate from the jing luo conduits and become fire, and may result in a variety of symptoms that do not fit into one coherent syndrome recognized in ICD-10 or DSM-IV. These include qi-related somatic discomforts, uncontrolled motor activity, anxiety, fright, weepiness, irritability, delusions, identity disturbance, hallucinations, mania, depression, and suicidal, bizarre, and violent behavior. The condition is usually brief. Treatment consists of a short course of tranquilizers and education about the proper way of practicing qigong. Relapse is uncommon. In the Western psychiatric literature, psychosis related to traveling is uncommonly reported and is usually confined to air travel among subjects with a preexisting history of mental disorder. By contrast, the category of traveling psychosis arose from reports of acute psychosis developing among thousands of rural migrants who traveled in severely crammed trains over long distances in search of jobs in the richer regions of China. Its principal manifestations include an acute onset, perplexity,

disturbed consciousness, anxiety, persecutory delusions, horrifying illusions or hallucinations, motor excitement, impulsive and suicidal jumping off the train, and injuring others. In most cases, the termination of travel, rest, and renourishment lead to spontaneous recovery within a few hours to a few days. A personal or family history of mental disorder is rare. Even if traveling psychosis has an organic cause (e.g., hypercapnia, sleep deprivation, fatigue, and dehydration), its origin must be seen in the context of China's rapid market reforms, which result in marked economic regionalism and massive domestic migration. Granting traveling psychosis a special nosological status in CCMD-2-R is expected to promote research into its prevention (e.g., improved conditions for traveling and regulation of migration). It also serves judicial functions, since offenders with this diagnosis may be granted a verdict of diminished responsibility or acquittal. Deletion of Culturally Inappropriate Categories Despite the common belief that Chinese people are prone to somatization, almost the whole block of somatoform disorder in ICD-10 and DSM-IV is excluded in the CCMD-2-R. According to ICD-10, the main features of such conditions are the repeated presentation of physical symptoms and persistent requests for medical investigations despite negative findings and reassurances by doctors that the symptoms have no physical basis. The patient usually resists attempts to discuss the possibility of psychological causation even in the presence of precipitating psychosocial stressors. This definition embodies a radical mind-body epistemology that is exotic to traditional Chinese or Ayurvedic medicine. Several factors have made it difficult for Chinese psychiatrists to apply the category of somatoform disorders. Chinese patients, if given the opportunity, readily communicate dysphoria and relate somatic symptoms to psychosocial stressors. Rather than being mutually exclusive, their somatic and emotional symptoms are highly intercorrelated. Clinically, their somatization may be considered a context-dependent strategy of engaging the concern of physicians who often work at overcrowded clinics. Moreover, the hybrid (half Greek and half Latin) word “somatoform” is a terminological puzzlement to Chinese psychiatrists, who find that neuroses (including neurasthenia) are clinically more useful categories for engaging patients in treatment. N. S. was a 35-year-old lower social class housewife who presented to a psychiatric clinic with a mixture of symptoms associated with significant impairment. These included fullness in the head, weakness, worries, insomnia, cold intolerance, and difficulty in breathing for 2 years. She had previously worked as a clerk but quit to become a full-time housewife after marriage. Exploration revealed that she was burdened with caring for a teenage daughter and a 10-year-old son with childhood autistic disorder. She was also worried about the fidelity of her emotionally disengaged husband when he started to work in a nearby city for 1 to 2 days a week. Because of the absence of a persistently depressed or anxious mood, she did not meet the definitional thresholds for DSM-IV mood or anxiety disorders. Instead, she could be given the diagnosis of undifferentiated somatoform disorder according to DSM-IV or neurasthenia according to CCMD-2-R. During clinical interview, N. S. did not think she had major depression. She was particularly puzzled by the diagnosis of undifferentiated somatoform disorder (weifenhua quti zhangai), which was both unintelligible and experience-distancing to her. In her view, she merely had neurasthenia as a result of multiple stressors in the family. Although the Chinese psychiatrist wrote down the DSM-IV diagnosis in her case notes, he used the term neurasthenia to enhance clinical communication. N. S. declined pharmacotherapy but accepted counseling readily. From a cultural constructionist perspective, personality disorders are based on Anglo-American conceptions of personhood and codes of appropriate behavior and owe their existence to the medicalization of disvalued social behavior. Accordingly, transformations in the values of a society determine whether they are called disease, sin, or crime. Given the disparity between the Oriental and Occidental conceptions of personhood, queries over the contextual validity of personality disorders are to be expected. Personality disorders are neither common clinical diagnoses nor popular research topics in China. Published studies indicate that a high percentage of Chinese subjects fail to fall into the subtypes recognized in DSM-IV and ICD-10. Thus, anxious (avoidant) and dependent personality disorders are excluded in CCMD-2-R. This is because many of their defining features (e.g., excessive preoccupation with being criticized or rejected in social situations, and subordination of one's own needs to those of others on whom one is dependent) are normative in the Chinese culture, which defines personhood not by autonomy and assertiveness, but by intergenerational dependence and selfeffacement. Likewise, since people who gamble immoderately and ruin their lives are considered bad rather than mad in Chinese society, the category of pathological gambling is excluded in the CCMD-2-R. Retention of Diagnostic Categories Unipolar mania is no longer found in ICD-10 or DSM-IV, according to which a patient with two episodes of mania is assumed to have bipolar disorder. However, longitudinal studies indicate that recurrent mania continues to be seen in China and question the obligatory labeling of such Chinese patients as having bipolar disorder. The possibility that they may exhibit particular biological correlates, treatment response, and outcome supports a separate nosological status in CCMD-2-R. The words “neurosis” and “neurotic” have completely disappeared from the DSM-IV, while the ICD-10 no longer retains neurosis as a major organizing principle. Instead, neurosis is finely partitioned into a variety of anxiety and depressive disorders, resulting in a very high prevalence of comorbidity being found in recent Western epidemiological studies. Among Chinese psychiatrists, the neurosis (shenjing zheng) has been used as a popular descriptive and etiological concept since the 1950s. It is therefore preserved in CCMD-2-R, which emphasizes as its main characteristics chronicity (at least 3 months), the presence of predisposing personality and social factors, and the preservation of insight. Variation of Diagnostic Categories By tradition, Chinese psychiatrists have confined the diagnosis of mood disorder to bipolar disorder and psychotic depression. Chronic mild depression such as dysthymia is considered a form of neurosis and has been subsumed under neurasthenia and, more recently, depressive neurosis. Clinically, depressive neurosis encompasses a highly heterogeneous group of conditions that overlap with anxiety, mood, and personality disorders. Affected Chinese patients usually present with insomnia, headache, worries, and other indigenous forms of dysphoria rather than depression (yiyu), which is an uncommon term in the everyday life of Chinese people. Among Chinese psychiatrists, whether depressive neurosis should be classified as a mood or neurotic disorder remains a subject of debate that is unlikely to be solved by empirical research alone. Since CCMD-2-R has tightened the concept of neurasthenia according to Western epistemological assumptions (i.e., it should not be diagnosed if mood or other neurotic disorders are present), the use of the diagnosis is becoming less common among Chinese psychiatrists. But neurasthenia remains a common clinical diagnosis among doctors in China as a whole. According to CCMD-2-R, it is a type of neurosis composed of any three of five nonhierarchical groups of weakness, dysphoria, excitement, nervous pain, and sleep symptoms. This flexible symptom configuration is based on ample clinical experience in China and has been supported by culturally sensitive studies of the variegated illness experience of Chinese neurasthenic patients. By contrast, DSM-IV and ICD-10 representations of neurasthenia (as an undifferentiated somatoform disorder and a chronic fatigue disorder, respectively) lack contextual validity in Chinese society. Because anorexia nervosa is still a rare condition in China, CCMD-2-R criteria for anorexia nervosa closely follow ICD-10 and DSM-IV. However, recent studies indicate that the core diagnostic construct of intense fear of fatness even when underweight is overrestrictive in a cross-cultural context. Such a fear is often absent among Chinese anorectic patients, who use other rationales (e.g., abdominal bloating, loss of appetite, or no hunger) for voluntary noneating. More culture-flexible diagnostic criteria that take account of the local meanings of food refusal will be adopted in CCMD-3. N. F. aged 28, height 1.51 m (4 ft, 11 in), ideal body weight 47 kg (103 lb), was a single clerk who was referred to the psychiatric clinic from a gynecological unit for 6 years' history of unexplained secondary amenorrhea and weight loss from 43 kg (95 lb; body mass index, 18.9 kg/m 2) to 32 kg (70 lb; body mass index, 14.0 kg/m2). She came from a working-class family in which the father had sexually molested her when she was 12. She experienced chronically low self-esteem and a strong sense of loss of control over her life. Since graduation from high school, she had worked continuously in a Protestant church in the hope that it would provide security for her. N. F. had always been slim and had never thought of dieting to pursue beauty. She attributed her poor food intake to loss of appetite during family dinner, when her father scolded her ruthlessly. She no longer cared how much and what she ate but sought refuge by fleeing the dining table as quickly as possible. She regarded this as a form of silent protest against him. Physical examination revealed a pubescent look and the usual signs of emaciation. Extensive investigation revealed no physical cause for the weight loss. When interviewed with the Eating Disorders module of the Structured Clinical Interview for DSM-III-R (SCID), she failed to fulfill the criteria for anorexia nervosa, while her depressive symptoms fell short of those for a major depressive episode. N. F. received individual psychotherapy for 2 years, during which family conflicts, powerlessness, and the lack of meaning in life constituted the organizing theme of her illness experience. She never mentioned the fear of fatness and sometimes challenged why the therapist, instead of understanding her lack of meaning of life, was so preoccupied with her eating behavior and body weight. She fulfilled culture-flexible diagnostic criteria for anorexia nervosa. Regional Adaptations of ICD-10 in Other Asian Countries The ICD-10 has been tested and is increasingly used in other Asian countries such as India, Japan, and Korea. Available evidence indicates that it is a reasonably feasible scheme that promotes reliability and international comparisons across most diagnostic categories. Nonetheless, local modifications are required to enhance its contextual validity and make it user friendly. For example, the Japanese Society for International Diagnostic Criteria in Psychiatry (JSIDCP) has also decided to retain a unitary concept of neurosis, which should be connected with predisposing personality traits and life events. As in CCMD-2-R, mild depression is considered a form of neurosis rather than a mood disorder, and the term “somatoform disorder” is avoided. Further examination of the discrepancies between Asian and Western nosological systems will encourage reflective self-criticism in one hand and contribute to an internationally valid system of psychiatric classification on the other.

TOWARD COMPREHENSIVE DIAGNOSIS MODELS While the national adaptations of the ICD represent attempts at resolving the tension between universalistic and local perspectives and needs, another emerging cluster of efforts in the field is aimed at integrating different informational domains and the perspectives of different evaluators in the construction of comprehensive diagnostic formulations. Conceptual Framework The conceptual framework for these developments includes the articulation of previously divergent historical and philosophical traditions, new notions on health and health care being advanced by the WHO, and innovative developments in general and psychiatric epidemiology. From a historical and philosophical viewpoint, the longitudinal evolution of diagnostic systems can be seen as unfolding on three parallel lines. One is represented by a synthetic, bold, and abstract Platonic conceptualization of a disease entity as a sufficient descriptor of a patient's clinical condition. The second involves an analytical, textured, and experiential Aristotelian viewpoint. The third is an empathetic Hippocratic approach. The Platonic tradition has informed the long-standing international effort to classify illnesses as reflected in the various versions of the ICD and national versions such as DSM-IV. The Aristotelian perspective is reflected in the descriptions of the patient's contextualized clinical condition, using standardized typologies and scales, which has appeared under the term “multiaxial diagnostic evaluations” The Hippocratic tradition is related to recent efforts to focus on the individuality of the patient. The WHO, through recent meetings of its executive board, is expanding its 50-year definition of health, proposing that it is not merely an absence of illness but a dynamic (or interactive) state of complete physical, emotional, social, and spiritual wellbeing. Additionally, WHO's explorations on the description of health status is expanding its focus from disease to functioning and other positive aspects of health. One of these is quality of life, which is to be evaluated predominantly by the individual involved. Furthermore, in the formulation of its policy in Health for All for the 21st Century, WHO is incorporating ethics, equity, and human rights as new, important considerations. Epidemiology, as the basic science of public health, is undergoing a substantial conceptual revision. Newer formulations go beyond the infectious disease model and the chronic disease model, calling for approaches that incorporate multiple and interactive levels of analysis as suggested by Mervin Susser, editor of the American Journal of Public Health, under the term “ecological epidemiology.” Integrating Standardized and Idiographic Formulations Building on the traditions and developments outlined above, the WPA is designing a more comprehensive diagnostic model as part of a project on international guidelines for diagnostic assessment. The model has two key components: 1. A standardized multiaxial formulation that covers nosology, disabilities, and contextual factors. The multiaxial formulation is aimed at statistically reliable measurement of key aspects of the clinical condition to facilitate sharing of diagnostic and treatment information among clinicians and across the world. 2. An idiographic or personalized formulation that focuses on the individuality of a particular patient. The idiographic formulation is aimed at providing complementary descriptive information, engaging the patient more fully in the process of clinical care and fulfilling ethical aspirations of respect to the dignity of the patient and attending to his or her expectations in dealing with health problems and enhancing quality of life. Table 9.2-4 presents schematically the components of this diagnostic model. The standardized multiaxial formulation of this model is basically organized according to the multiaxial presentation of ICD-10.

Table 9.2-4 Comprehensive Diagnostic Model Incorporated Into the WPA International Guidelines for Diagnostic Assessment

A brief description of the components of the idiographic formulation follows: I. Clinician's perspectives. This involves an effort to synthesize the information available including a summary of the patient's problems and assets, biological explanations, psychological explanations, social explanations, and biopsychosocial integration, that is, a contextualized articulation of all explanatory models pertinent to the patient's clinical condition. II. Patient/family's perspectives. These may include a biographical history; an understanding of the nature, causes, and context of the illness experienced; self-appraisal of quality of life (e.g., physical and emotional health, functioning, social support and resources, personal and spiritual fulfillment); and attitudes and expectations toward clinical care (acute and rehabilitative treatment and preventive efforts). III. Integration of clinician and patient or family's perspectives. This integration is expected to be based on empathetic rapport, reflecting mutual respect, interest, and human feelings between clinician and patient. The clinician and patient attempt to reach the best possible joint understanding of the patient's clinical condition in a context that includes family factors. They negotiate a care plan, considering personal issues (e.g., patient's and clinician's preferences and disposition toward treatment, sense of autonomy, time available, travel requirements), social factors (e.g., social supports, particularly availability and interest of the family), and financial circumstances (e.g., insurance and managed care constraints). Finally, they jointly monitor the progress of care and its outcome.

FUTURE DIRECTIONS The developments on comprehensive diagnostic models and regional adaptation of ICD-10 reveal the ebullience of the diagnostic field, especially when appraised from a broad international perspective. It seems likely that the ongoing tension between universality and diversity in diagnostic systems will continue to yield innovative solutions. Emerging proposals are increasingly involving integrated assessments of health status and according pointed attention to the ethical requirements of psychiatric diagnosis. These proposals must be carefully formulated and thoughtfully and widely evaluated if they are to contribute effectively to the fulfillment of diagnosis as a conceptual and practical tool for clinical care, health promotion, and epidemiology.

SUGGESTED CROSS-REFERENCES Section 4.1 discusses anthropology and psychiatry, while Section 4.4 discusses cross-cultural psychiatry. Psychiatric diagnosis is covered in Chapter 7, and the DSM-IV classification is covered in Section 9.1. Neurasthenia is discussed in Chapter 16 on somatoform disorders. SECTION REFERENCES Acosta-Nodal C, editors: Glosario Cubano de la Clasificación Internacional de Enfermedades Psiquiátricas, (GC-1), ed 1. Hosp Psiquiátr Habana, Havana, Cuba, 1975. Acosta-Nodal C, editors: Glosario Gubano de la Clasificación Internacional de Enfermedades Psiquiátricas (GC-2), ed 2. Editorial Científico-Técnica, Havana, Cuba, 1983. *Andrews G, Slade T, Peters L: Classification in psychiatry: ICD-10 versus DSM-IV. Br J Psychiatry 174:3, 1999.

Badley EM: An introduction to the concepts and classifications of the International Classification of Impairments, Disabilities, and Handicaps. Disability Rehabil 15:161, 1993. Berner P: Der Lebensabend der Paranoiker. Wien Z Nervenheilkd 27:115, 1969. Berrios GE: The history of descriptive psychopathology. In Psychiatry Epidemiology: Assessment Concepts and Methods, JE Mezzich, MR Jorge, JIM Salloum, editors. Johns Hopkins University Press, Baltimore, 1994. Bramer GR: International Statistical Classification of Diseases and Related Health Problems—Tenth Revision. World Health Stat Q 41:32, 1988. Bustamante JA, Santa Cruz A: Psiquiatría Transcultural. Editorial Cientifico-Técnica, Havana, Cuba, 1975. Calles Bajo N, Valdés López G, Ceiro Valcarcel E: Estudio Comparativo en Cuba y Africa acerca de los Conceptos Populares sobre la Enfermedad Mental. La Habana Empresa Bibliográfica, MINSAP, Havana, Cuba, 1980. Chinese Medical Association: Chinese Classification of Mental Disorders, ed 2, (CCMD-II). Hunan Medical University Press, Hunan, China, 1989. Chinese Medical Association and Nanjing Medical University: Chinese Classification of Mental Disorders, ed 2, revised. Dong Nan University Press Nanjing, China, 1995. Cooper JE: The presentation of psychiatric classifications. In International Classification in Psychiatry. Unity and Diversity, JE Mezzich, M von Cranach, editors. Cambridge University Press, Cambridge, 1988. Delgado H: Curso de Psiquiatría. Editorial Centífico-Médica, Barcelona, 1963. Echazabal-Campos MA, Otero-Ojeda AA: Uso de sistemas taxonómicos por los psicólogos en Cuba. Rev Hosp Psiquiátr Habana 39:151, 1998. Essen-Möller E, Wohlfahrt S: Suggestions for the amendment of the official Swedish classification mental disorders. Acta Psychiatr Scand 47:551, 1947. *Fabrega H: International systems of diagnosis in psychiatry. J Nerv Ment Dis 182:256, 1994. Fujinawa A: Overview of Japanese experiences on diagnostic classification: Past and present of the classification of mental disorders in Japan. In Psychiatric Diagnosis. A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, New York, 1994. González Menéndez R: El Médico ante el Transtorno Psiquiátrico Menor, ed # 1. Editorial Oriente, Santiago de Cuba, Cuba 1989. Horwitz J, Marconi J: El problema de las definiciones en el campo de la salud mental. Definiciones aplicables en estudios epidemiológicos. Bol Oficinia Sanit Panam 60:300, 1966. House JS, Landis KR, Umberson D: Social relationships and health. Science 241:540, 1988. Huttenlocher J, Hedges LV: Combining graded categories: Membership and typicality. Psychol Rev 101:157, 1994. *James A, Kastrup M, Katsching A, Lopéz-Ibor JJ, Mezzich JE, Sartorius N: Multiaxial Presentation of ICD-10 for Use in Adult Psychiatry. Cambridge University Press, Cambridge, 1997. Kastrup MC: Psychosocial domains in comprehensive diagnostic models. In International Review of Psychiatry, A Costa e Silva, CC Nadelson, editors. American Psychiatric Press, Washington, DC, 1993. Kleinman A: Rethinking Psychiatry: From Cultural Category to Personal Experience. Free Press, New York, 1988. Kraepelin E: Psychiatrie, ed 5. Barth, Leipzig, 1896. Laín Entralgo P. El Diagnostico Medico: Historia y Teoria. Salvat, Barcelona, 1982. Lee S: The vicissitudes of neurasthenia in Chinese societies: Where will it go from the ICD-10? Trancult Psychiatry 31:153, 1994. Lee S: Self-starvation in contexts—towards the culturally sensitive understanding of anorexia nervosa. Soc Sci Med 41:25, 1995. *Lee S: Culture in psychiatric nosology: The CCMD-2-R and international classification of mental disorders. Cult Med Psychiatry 20:421, 1996. Leme Lopes J: As Dimensões do Diagnostico Psiquiátrico. Agir, Rio de Janeiro, 1954. Leonhard K: Afteilung der Endogenen Psychosen. Akademie, Berlin, 1957. Li XJ, Li RR, Ren HX, Ren BH, Gu HX, Wu TH, Shi CW: An investigation of inducing factors associated with sudden psychiatric disorders of train passengers. Chin J Psychiatry 29:47, 1996. Mezzich JE: Ethics and comprehensive diagnosis. Psychopathology, in press. Mezzich JE: The World Psychiatric Association and the development of ICD-10. In Psychiatry: A World Perspective, C Stefanis, AD Rabavilas, CR Soldatos, editors. Excerpta Medica, Amsterdam, 1990. Mezzich JE, Honda Y, Kastrup MC, editors: Psychiatric Diagnosis: A World Perspective. Springer-Verlag, New York, 1994. Mezzich JE, Kleinman A, Fabrega H, Parron D: Culture and Psychiatric Diagnosis. American Psychiatric Press, Washington, DC, 1996. Mezzich JE, Schmolke MM: Quality of life and comprehensive clinical diagnosis. In Quality of Life in Mental Disorders, H Katsching, H Freeman, N Sartorius, editors. John Wiley, New York, 1997. Orley J, Kuvken W: International Quality of Life Assessment. Springer-Verlag, Heidelberg, 1994. Otero-Ojeda AA: Adaptación Cultural del Sistema Multilaxial de la CIE-10 A Través De Ejes Complementarios. Hospital Psiquiatrico de la Habana, Editorial Científico-Técnica, Havana, Cuba, 1994. Otero-Ojeda AA, Acosta Nodal C: Características y Aportaciones Fundamentales del Tercer Glosario Cubano de Psiquiatría. Hospital Psiquiátrico de La Habana, Havana, Cuba, 1996. *Otero-Ojeda AA, editor: Tercer Glosario Cubano de Psiquiatría. Hospital Psiquiátrico de La Habana, Havana, Cuba, 1998. Percy C, van Holten V, Muir C: International Classification of Diseases for Oncology (ICD-0). World Health Organization, Geneva, 1990. Pull C, Chaillet G: The nosological views of French-speaking psychiatry. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, New York, 1994. Sartorius N, Kaelber CT, Cooper JE, Roper MT: Progress towards achieving a common language in psychiatry. Results of the field trials of the clinical guidelines accompanying the WHO Classification of Mental and Behavioral Disorders in ICD-10. Arch Gen Psychiatry 50:115, 1993. Seguin CA: The concept of disease. Psychosom Med 8:252, 1946. Strauss JS: The person—key to understanding mental illness: Towards a new dynamic psychiatry, III. Br J Psychiatry 161:19, 1992. Survey and Test Group for the CCMD-2-R: A report on the national field of the second revised edition of the Chinese classification and diagnostic criteria of mental disorders. Chin J Psychiatry 1996. Üstün TB, Goldberg DA, Sartorius N: ICD-10. Classifying primary care mental disorders. Proc 146th annual meeting of the American Psychiatric Association, May, 1993. World Health Organization: The ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization, Geneva, 1992. World Health Organization: The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. World Health Organization, Geneva, 1993. World Health Organization: International Statistical Classification of Diseases and Related Health Problems, rev 10, vol 1. World Health Organization, Geneva, 1992.

29:27,

Wu CY: A clinical analysis of seventy six cases of qigong induced psychotic disorders. J Clin Psychol Med 2:7 (in Chinese), 1992. Xu WY, Chen ZJ: An eight to ten year outcome study of unipolar mania. Arch Psychiatry 4:88 (in Chinese), 1992.

Textbook of Psychiatry

CHAPTER 10. DELIRIUM, DEMENTIA, AND AMNESTIC AND OTHER COGNITIVE DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 10. DELIRIUM, DEMENTIA, AND AMNESTIC AND OTHER COGNITIVE DISORDERS ERIC D. CAINE, M.D. AND JEFFREY M. LYNESS, M.D. Definition History Comparative Nosology Diagnosis Pathology and Laboratory Examination Etiology and Differential Diagnosis Cognitive Disorders Diagnosis and Clinical Features Diagnosis and Clinical Features Suggested Cross-References

Psychiatry is in the midst of a profound transformation, at once struggling to incorporate a dynamic understanding of neuroscience and molecular biology while maintaining a view of unique persons or individuals as the central focus of therapeutic intervention. To date it has been beyond the scope of knowledge to effectively integrate research data regarding individual differences with more abstract findings regarding fundamental aspects of brain development or aging-related neurodegeneration. Discovering the bases for the major neuropsychiatric diseases can be expected to provide powerful clues for defining the nature of how neurobiological processes are expressed as emotions, thoughts, or actions, or how life events and daily experiences alter and shape brain growth and development. Since the late 1980s, a major conceptual transition has occurred in the way clinicians and researchers view the relation between mental disorders and brain function. For much of the past century psychiatry was trapped in an either-or dilemma—either a condition was viewed as a symptomatic manifestation of structural cerebral or systemic pathology (organic), or it was considered psychological or emotional in nature (functional). However, clinicians recognized that there are no behaviors that do not involve the brain, and that the transmission of culturally derived processes from individual to individual is influenced by each person's central nervous system (CNS). Behaviors defined by some cultures as abnormal may be mediated by normal neurophysiology; in contrast, patients with damaged brains may develop compensatory strategies reflective of CNS plasticity to ameliorate the effects of disordered neural systems. The same behavior (e.g., suicide) may reflect normal or abnormal physiology. For many diseases the CNS develops normally but acquires its dysfunction later in life whereas other diseases may reflect aberrant wiring patterns or connections that function in a neurochemically or neurophysiologically normal fashion. Despite such complexity, clinicians often depended on a single criterion for defining organic disorders—either the detection of a structural lesion or, less often, the diagnosis of a known disease process; however, such an approach is no longer satisfactory. Diagnostic decisions have depended largely on available technology. For more than a century gross postmortem examination and microscopic histopathological examination were the primary tools. Working in a tradition of clinical-pathological correlation, psychiatrists, neurologists, and others used a dichotomous approach to both diagnosis and classification—that is, a lesion was either present or absent. This approach proved heuristically limiting and became increasingly unrewarding. Indeed, histopathology is now no longer the gold standard for defining brain-based diseases. It was only marginally useful for psychiatry, and in the near future molecular biological methods will replace it for neurology. The advent of new technologies already has undermined the pseudocertainty of earlier years. Many patients with functional syndromes are found to have CNS abnormalities when studied with magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT). Should these syndromes be reclassified as organic? Most would argue that such changes would be premature because the pathophysiological significance of newer findings remains obscure. Such arguments also are pertinent to the entire question of organic versus functional. The fourth edition of Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) establishes a new approach to those questions. The categories of organic and functional have been abandoned. When a psychopathological syndrome is known to be a symptomatic manifestation of a systemic medical or cerebral disorder, it is designated as “due to . . .” (secondary), with a designation of the specific disease process. When it is considered to be an idiopathic psychiatric disturbance, it is designated primary. A clinician should follow a careful process of case reasoning before settling on the primary or secondary status of a disorder. To appropriately diagnose a patient as having an idiopathic (i.e., primary) condition, the clinician must necessarily exclude all definable, potentially etiological disease processes. The clinician must exercise equal caution before diagnosing a disorder as secondary or symptomatic. To date there are no widely accepted guidelines for establishing probable causal relations between psychopathological conditions and detected cerebral abnormalities. Traditionally, such assignment of probable causality has been left to clinical judgment. DSM-IV outlines such guidelines; they have the effect of encouraging the clinician to undertake a thorough evaluation and to postulate causal connections conservatively.

DEFINITION The primary-secondary classification, like similar classifications, reflects the thinking of its time. The change in terminology in DSM-IV from organic to due to . . . is more than cosmetic in that it captures the conceptual shift away from structure and lesion and toward active disease process and etiology. The broad group of cognitive disorders includes dementia, delirium, amnestic disorder, and other syndromes in which disordered cognition caused by known (or presumed) disease entities is the central characteristic featuret ( Table 10-1). Specific secondary syndromes are scattered through the nosology, classified along with other phenomenologically similar clinical conditions (e.g., mood disorders due to general medical conditions are grouped among the mood disturbances). Such groupings are intended to foster differential diagnostic consideration; the changes in DSM-IV are intended to enhance rigorous clinical reasoning. Use of more specific designations (e.g., mood disorder due to thyroid deficiency, with major depressive-like episode) strengthens diagnostic specificity when contrasted to the previously used organic mood disorder and lays the foundation for more meaningful comparative research.

Table 10-1 DSM-IV Cognitive Disorders

Throughout this chapter the term “neuropsychiatry” is used in reference to the field of medicine that considers the brain bases of mental disorders. In the United Kingdom this field is sometimes called organic psychiatry. At one time nearly all of psychiatry was neuropsychiatry; at another time, few would have chosen that label. Considering the brain substrates of behavior necessarily forces clinicians and researchers also to recognize the experiential, psychological, social, and cultural aspects of the patients and the problems they encounter.

HISTORY The development of neuropsychiatry and the growth of general psychiatry coincided with competition and ultimately cooperation between public psychiatric asylums (now called hospitals or centers) and clinical practice in universities and private offices. Different ideologies or dogmas developed, depending on whether the clinician was seeing principally institutionalized psychotic patients, for whom there was little hope for improvement or recovery, or ambulatory patients, whose apparent psychological accessibility gave rise to therapeutic optimism. Additionally, psychiatrists in the asylums (often called alienists) had different needs than the nerve

doctors or neurointernists who saw the walking wounded in their offices. Table 10-2 presents a brief categorization of historical periods in neuropsychiatry. It is probably not presumptuous to state that Wilhelm Griesinger (1817–1868) created neuropsychiatry with the publication of his book in 1845, crafted after practicing 2 years in Winenthal, one of the leading German asylums. An advocate of physiological medicine, Griesinger attempted to steer German medical practice away from both the romantic and somatic schools of that time. He asserted that psychiatry was part of medicine and that “psychological diseases are diseases of the brain.” He also advocated knowing one's patients well, understanding their life course, and appreciating how their mental disease affected their overall functioning. He advanced a specific notion of the ego that attempted to explain all disease under a single conceptual view based on a gradual pathological erosion of ego integrity. He supported the idea of careful neuropathological observation, although he never pursued such work in the later fashion of Theodor H. Meynert, Karl Wernicke, or Alois Alzheimer.

Table 10-2 Historical Periods in Neuropsychiatry

Despite Griesinger's attempted integration, many of his notions now seem simplistic or misleading, especially the idea that all mental illnesses reflected one basic pathological process that could be divided into stages. The first of Griesinger's disease stages involved an assault on the ego by the basic disease, although no frank pathological disruption was apparent. In the second and third stages, ego disintegration was completed and permanent brain changes took place. Griesinger believed that therapeutic intervention would be successful only during the first stage. Griesinger and his contemporaries made no particular distinction between psychiatric and neurological problems, and patients with progressive neurological diseases were seen in asylums like Winenthal. He proposed joint psychiatry and neurology clinics, and founded one in Berlin in 1861. Most importantly he catalyzed the development of university neuropsychiatry in contrast to the asylum psychiatry that was prevalent in his day, and thus provided the means for developing academic, research-based approaches to questions that had largely been outside rigorous medical scrutiny. Meynert (1833–1893), the next major player on the neuropsychiatric scene, steered away from Griesinger's integrative center toward an extreme of neuropathological determinism. Meynert's 1874 book, titled Psychiatry: Diseases of the Forebrain, largely dealt with neuroanatomy. He is probably best remembered for his histopathological studies and has deservedly been called a pioneer of neuropsychiatric pathophysiology. Meynert also consolidated within universities what proved to be both a sterile theoretical position and a form of clinical psychiatry that had little benefit for either patients in the asylum or the walking wounded. Perhaps unwittingly, Meynert and his intellectual colleagues placed neuropsychiatry in a position where it would decline. It was presumptuous to believe that all clinically significant behavioral disturbances had a demonstrable cerebral substrate, especially given available laboratory techniques. Such work took place in a context of minimal understanding of the basic aspects of neuronal or regional cerebral functioning. It was ironic that the driving investigative force, a search for pathologically defined brain abnormalities, was to become a basis for undoing the field. Psychiatry in general and neuropsychiatry in particular have been plagued by a sense of intellectual exclusivity—the either-or dilemma—in their intellectual conceptions. This sense of exclusivity and the related tendency to decry integrative (multidetermined) theoretical approaches may have reflected the ultimate conceptual complexity of the research and clinical tasks that have confronted those who would understand the cerebral bases of behavior and mental disorders: “the brain we are studying is more complex than the brain that is studying it.” In the context of these limitations of neuropsychiatry, two fundamentally different paths emerged. The first was exemplified by the work of Emil Kraepelin (1856–1926). Although Kraepelin supported the neuropathological work of Alzheimer, he spent considerable effort developing a rigorous clinical classification of psychiatric disorders, particularly those observed in asylum settings. The classification was largely atheoretical, based as it was on form and course. Kraepelin hoped that clinical description and classification would ultimately lead to pathological correlation, a hope that has yet to be realized fully. The second path was developed by nerve doctors, neurointernists who saw their patients in offices or on the wards of neurological hospitals. Jean Martin Charcot (1825–1893) and Sigmund Freud (1856–1939) were notable among those practitioners. The idea of looking at an individual's development in the context of early life experience did not originate with Freud (Griesinger had also advocated it), but Freud pushed farthest the notion of defining the meaning of particular behaviors in terms of real and imagined life events. The different paths blazed by Freud, Kraepelin, and Meynert coexisted during the early decades of the twentieth century, with no one route of investigation clearly predominant. Clinical-pathological correlation had its greatest triumphs with the recognition of the causes of general paresis and pellagra. However, the large asylums remained full, and there were no specific therapies for clinicians to use. In the United States, by contrast, the period from 1930 to 1950 was a time of great ferment and change, with an examination of new ideas and therapies. Shortly before World War II clinicians experimented with a variety of somatic interventions and opined about the cerebral bases of the major psychiatric disorders. New treatments, including barbiturate coma, insulin shock, and the convulsive therapies, were developed. During this time of novel therapeutics, clinicians undertook what seemed a logical step to many—ablative neurosurgical intervention, ultimately dubbed psychosurgery. Although it was based on poorly substantiated notions of cerebral functions and how they went awry in the major psychiatric disorders, frontal lobotomy spread rapidly in the United States following World War II, fueled by a desire to empty large state mental hospitals and reduce public expenditures for patients with chronic mental disorders. Psychosurgery offered the prospect of instituting a definitive medical procedure that either cured or markedly improved previously intractable syndromes. However, psychosurgery and its practitioners failed to fulfill their promises and neuropsychiatry eventually became a term of opprobrium. By the mid-1950s brain-oriented views of behavior were widely considered to offer few clinically or theoretically fruitful insights, and brain-oriented psychiatrists were seen as useless or even clinically harmful to those they treated. Juxtaposed with the 1930s' plunge into organic psychiatry and its therapies was the growth of psychoanalysis, sparked by revolutionary theories brought from Europe by analysts fleeing Adolf Hitler. Young neuropsychiatrists, neurologists, and neuroscientists proved a receptive audience for these ideas, as they discovered far greater explanatory power in the notions of Freud than in those of Charles Sherrington and the doctrine of nerve transmission. Enthusiasts found analytic insights filling unmet needs: Freud's theories and techniques supplied both tools for data collection through the free-associative interview and a coherent system to organize these findings. More importantly, these techniques directed specific interventions and provided the physician with something to do beyond watching impaired patients remain unchanged or become progressively worse. Stanley Cobb (1887–1968) was among the leaders in the attempt to integrate psychiatry and neurology. Cobb trained in neuropathology and taught the basic neuropathology course at Harvard Medical School for several generations. A student of Adolf Meyer, he espoused a dynamic life course view. Although he maintained an appreciation for neuropathology, he moved away from a primary interest in cerebral circulation to a consideration of psychiatric disorders during the late 1920s and the 1930s. Cobb developed a conceptual pyramid as an integrative device to illustrate his views, deliberately leaving a gray, uncharted zone between pathology and clinical psychiatry. Despite subsequent advances in neuroscience, the uncharted zone seems no less opaque now than 60 years ago, when Cobb first published the conceptual pyramid in his textbooks. The years immediately after World War II were a time of rapid change, away from neuropathology-based psychiatry and toward psychodynamic and psychoanalytic psychiatry. The growth of psychiatry departments and medical schools was spurred by federal initiative, as was the deinstitutionalization of the seriously ill. Economic motives contributed to the latter, but more important was the sense that a therapeutic triumph might be at hand. This sense was associated with the optimism following World War II of psychiatrists and psychiatrists-to-be (often physicians from other disciplines who were assigned to wartime psychiatry services), coupled with the hope for the successful use of psychoanalysis in a wide variety of disorders and the development, during the 1950s, of a more specific psychopharmacology. Notably, psychopharmacology did not reflect a greater degree of neuroscientific understanding; rather, serendipity, clinical acumen, and innovative thinking served as guiding beacons. Later developments of new compounds did result from attempts at pharmacological modeling. Indeed, more recent understandings of CNS function were catalyzed by having specific agents that could reliably alter brain activity. Central to this activity were industry-sponsored initiatives to discover and develop novel pharmacotherapeutic medications.

Formal psychiatric classification and nomenclature evolved during the post-World War II era. Prior to the adoption of the first edition of DSM (DSM-I) in 1952, psychiatric hospitals used the Statistical Manual for the Use of Hospitals for Mental Disease, first published under a slightly different title in 1918. Nearly all the categories in the manual were used for classifying patients with brain-related mental disturbances. As noted in DSM, that approach proved suitable for only about 10 percent of the cases seen by the Armed Forces during World War II. In contrast to the Statistical Manual for the Use of Hospitals for Mental Disease, DSM outlined two broad categories, one for disorders caused by or associated with impairment of brain tissue function (divided into acute and chronic), and the second for those of psychogenic origin without clearly defined physical cause or structural change in the brain. The brain disorder section classified conditions by duration and defined etiology (e.g., infection, intoxication, and tumor) with no attention to clinical phenomena whereas the psychogenic section began the move toward a more clinically specific categorization. For the latter, difficulties adjusting to internal and external stresses were the key pathogenic factors. Thus, a psychological theory officially supplanted the dominant brain view of earlier classification manuals. Despite the change in dominant explanatory theory, DSM also maintained and further codified an either-or philosophy set forth by the earlier post-Griesinger neuropsychiatrists. A similar stance was taken in the second edition of DSM (DSM-II), with a separation of organic brain syndromes from psychoses not attributed to physical conditions listed previously. Brain syndromes were said to result from diffuse impairment of brain tissue and to be manifested by the following symptoms: impairment of orientation, memory, all intellectual functions (e.g., comprehension and calculation), and judgment, as well as lability and shallowness of affect. The organic brain syndromes were divided into psychotic and nonpsychotic conditions, the former also including senile and presenile dementia, depending solely on the severity of functional impairment. Beyond that crude separation, there were no specifying clinical features; further classification depended on defining a cause. Acute and chronic were indicated as diagnostic subcodes. Psychodynamic psychiatry was not successful in treating the more seriously impaired residents of the state hospitals, and often was found wanting among ambulatory populations. Competing approaches sprang up that claimed similar or greater effectiveness. Overall, it has been difficult to definitively demonstrate treatment success when using psychotherapeutic modalities, although recent efforts at treatment evaluation have proved both more enlightening and more promising. A neurochemically oriented biological psychiatry took hold and became pre-eminent in the research laboratory, if not always in the clinic setting. However, there has been no successful jump from synapse to behavior, integrating understanding anew. This dearth of explanation has made a fertile soil for the reemergence of neuropsychiatry.

COMPARATIVE NOSOLOGY DSM-III and DSM-III-R The third edition of DSM (DSM-III), published in 1980, and the 1987 revised third edition (DSM-III-R) moved to discard the theoretical underpinnings based on stress-related psychological reactions and emphasized phenomenology as part of an innovative multiaxial system of classification. Nonetheless, the organic versus nonorganic dichotomy was maintained. Organic mental disorders were clearer in their clinical typology, with a greater array of subtypes and causes, related either to Axis III physical disorders or conditions or to use of psychoactive substances. Importantly, categories for mood, personality, anxiety, and hallucinatory and delusional disorders were added. These changes were made in an effort to increase recognition of clinical variations, but they lacked sufficient descriptive detail to allow reliable comparisons with idiopathic Axis I syndromes. Unfortunately, like DSM-I and DSM-II, DSM-III provided no guidelines or discussion on the question of causal connection between systemic medical or cerebral diseases and secondary psychiatric manifestations. Thus, there has been no consideration of the clinical reliability of the organic designation or of its validity. Scientific Developments Since the 1970s a period of transition characterized by the absence of a dominant theoretical view within psychiatry has been under way. Scientific developments outside the field have profoundly shifted the direction of psychiatric thought and have come largely from behavioral neurology, clinical neuropsychology, and basic laboratory neuroscience. Challenged by the rehabilitative needs of many patients returning from World War II with focal cerebral lesions, a small number of neurologists and quantitative psychologists began to study the effects of those injuries just as psychiatrists were shifting their attention away from cerebral processes. This work quickly expanded to include patients with vascular lesions. By the late 1960s behavioral neurologists and clinical neuropsychologists were recognized specialists, although few in number, and a growing literature examined the intellectual and behavioral consequences of specific regional cerebral lesions. These writings stimulated a modern resurgence of the clinical-pathological correlative tradition first developed during the late 1800s. Since the late 1980s psychiatric researchers have drawn increasingly from the lessons of focal lesion models. Simultaneously, basic laboratory neuroscience burgeoned, with important findings reported at a fast pace in recent years. Researchers have moved from a focus on synapses and neurons to subneuronal molecular biological processes. Investigative techniques have changed extremely quickly, facilitating the detection of variations in complex neurobiological systems while outstripping the ability to define the terms normal and abnormal. Even as psychiatric researchers studied focal lesion syndromes with greater enthusiasm, the shortcomings of those models became more apparent. Most importantly, they involve cerebral substrates distinctly different from those of the major idiopathic psychiatric syndromes. Whereas strokes reflect vascular anatomy, major psychopathology is based on dysfunction in interacting and widespread neurochemical systems. Many clinical psychiatric disorders reflect long-term (perhaps developmental) abnormalities that affect psychological growth and interpersonal events across the life span. Focal cerebral lesions on the other hand are acquired later in life in the context of a developmentally intact CNS; thus, analogies must be drawn with caution. Psychiatric researchers face another, more daunting obstacle when considering the brain bases of mental disorders. Since the 1970s many have chosen to compare specific diagnoses with putative CNS alterations. The exclusive use of categorical diagnoses, while beneficial for enhancing clinical rigor, has yet to prove rewarding when applied to diagnosis-brain correlative research paradigms. Although empirically defined clinical syndromes form the bedrock of modern psychopharmacology, they may not be amenable to fundamental neurobiological characterization. The historic lessons of neuropsychiatry include the realization that a defined or unified etiology may be associated with a striking diversity of clinical presentation (e.g., general paresis and Huntington's disease); conversely, specific syndromes are often the manifestation of heterogeneous etiologies. Here again, maintenance of a rigid either-or view is likely to prove disappointing. Rather, future researchers will be required to understand how experiences in the midst of normal development permanently change the brain. Too often neuropsychiatry has viewed the universe along the trajectory of brain to behavior. It will be just as important to understand it from behavior to brain and back again. Psychiatry as a broad field, and neuropsychiatry in particular, must address an array of key questions regarding brain-behavior and behavior-brain relationships. 1. How do developmental abnormalities that occur in utero or in the early years of life lead to later emerging psychopathology? What are the genetic and environmental causes of these defects, and what are their molecular biological modes of expression? 2. How does environment and life experience change brain structure and function? In essence, what are the mechanisms of brain plasticity? How do normative and abnormally stressful life events lead to permanent changes in neural function? 3. How is brain and organism homeostasis maintained or lost? What are the neural underpinnings of cyclical or episodic changes in behavioral, emotional, and cognitive functioning? 4. What are the genetic, molecular, and environmental factors associated with brain aging and normative cognitive decline, and neurodegenerative diseases? The limits of neuroscientific inquiry need to be recognized. Neuroscience will not improve the interviewing skills of an individual psychiatrist; moreover, it will be many years or decades before there is a clear understanding of the neural bases for individual differences: When the field progresses to the point where clinicians and scientists can merge an appreciation of a person's life story with knowledge regarding laws of the nervous system, it will finally reach a level of true integration. DSM-IV The change in terminology in DSM-IV from organic to due to represents more than a simple semantic alteration—it emphasizes the need to define etiology, not site or structure. The term “ organic”, as used for many years pointed to defined pathological lesions and was contrasted with the term “ functional” or physiological abnormalities that could not be detected by existing laboratory procedures. In the absence of sensitive and specific diagnostic laboratory tests, descriptive laboratory technology was often misapplied, giving a false impression of diagnostic validity. Similarly, the presence of a definable abnormality was considered sufficient to establish an organic diagnosis even though no standards were available for setting a threshold of evidence or data needed to attribute the cause of a symptom to an observed lesion. DSM-IV takes a conservative approach to the problem. Establishing a secondary diagnosis should, whenever feasible, follow a chain of reasoning that etiologically connects a psychopathological syndrome with a systemic medical or primary cerebral disorder. The coexistence of Axis I and Axis III diagnoses in an individual case is not sufficient to infer a causal relationship, even when an apparent association or correlation is present. To more confidently determine whether an association is causal, the clinician should attempt to define the strength (relative risk), consistency of form, specificity, coherence of association, and temporal relation of clinical manifestations to the proposed disease process. Defining each attribute may not be feasible for all disorders or in every case, but it does provide stronger ground for

advancing an etiological link. When insufficient data are available to establish a causal relation, it is preferable to provide unlinked Axis I and Axis III diagnoses. It is notable that the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) maintained “organic” as a superordinate category. Although many specific examples of syndromic diagnostic criteria are similar to those in DSM-IV, ICD-10 retained the approach favored by earlier editions of the DSM. Where DSM-IV strives to highlight steps necessary for establishing a primary general medical diagnosis, ICD-10 states: “Rather, the clinical manifestations resemble, or are identical with, those of disorders not regarded as ‘organic' in the specific sense restricted to this block of the classification. Their inclusion here is based on the hypothesis that they are directly caused by cerebral disease or dysfunction rather than resulting from either a fortuitous association. . . or a psychological reaction to its symptoms. . .”

DIAGNOSIS Thorough clinical evaluation forms the basis for diagnosing secondary disorders. Beyond a detailed personal history and mental status examination, the clinician often must depend on supplementary laboratory evaluation, including such procedures as cerebral imaging, neuropsychological testing, and electroencephalography (EEG). Four steps form the basis for establishing a secondary (“due to . . .”) diagnosis with greater confidence: (1) definition of the specific psychopathological syndrome, (2) delineation of other manifestations of the primary disorder, (3) demonstration of active cerebral or systemic disease, and (4) demonstration of an elevated prevalence between the proposed etiological disorder and the described psychopathological picture. These steps may not always occur sequentially, as both syndrome and disease may be recognized. Definition of the Specific Psychopathological Syndrome It is essential to describe the clinical disorder as precisely as possible. Subtyping should be undertaken when feasible, particularly with the specification of target symptoms for treatment. Use of broader or not otherwise specified terminology is available for less phenomenologically specific cases. Ideally, the clinician seeks to establish etiological relationships between definable disease processes and specific clinical presentations. The multiple presentations of general paresis, however, underscore that one pathogenic agent may cause multiple syndromic forms. Patients with many secondary psychiatric disturbances present with symptoms that are atypical of primary (idiopathic) psychiatric disorders. Other clinical features, such as older age at onset, may serve to raise the index of suspicion. Syndrome definition involves severity as well as form. Severity implies a continuum, and the application of a diagnosis implies that the disorder has exceeded a threshold of severity. For example, although behavioral changes often arise following a cerebral lesion, a categorical diagnosis is not warranted when symptoms have not had a measurable impact on a person's functional integrity. Researchers may wish to study mildly symptomatic phenomena, but clinicians typically reserve diagnoses for conditions that cause substantially disordered behaviors, those interfering with the patient's daily life and personal well-being. Delineation of Other Manifestations of the Primary Disorder Secondary psychopathological syndromes rarely occur alone but typically keep company with other symptoms and signs of the primary systemic or cerebral disorder. Thus, it is essential to define those cognitive, neuropsychological, peripheral, or other clinically ascertained manifestations of the disease process. For example, human immunodeficiency virus (HIV)-induced manic symptoms typically are accompanied by signs of testable cognitive impairment whereas depression due to Huntington's disease can be diagnosed with confidence only in the setting of a defined movement disorder. Identifying co-occurring manifestation provides an overall clinical context for more confidently establishing a secondary diagnosis. Demonstration of Active Cerebral or Systemic Disease The clinician should seek nonbehavioral confirmation of the primary disease process. Such confirmation typically involves laboratory testing, including the full array of medical diagnostic procedures. One must be cautious, however, in the interpretation of many tests. An example is the use of cerebral imaging in psychiatric patients. Detection of a structural abnormality on computed tomography (CT) or MRI is not equivalent to demonstrating active cerebral disease because such imaging studies provide static (i.e., nonphysiological, nonfunctional) information in most applications. Much remains unknown regarding the link between MRI findings, definable cerebral pathology, and specific pathophysiologies or diseases. Elevated Prevalence Rate Between Proposed Etiological Disorder and Described Pathological Picture This guideline cannot always be fulfilled, but argues for utilizing data-based conclusions that can be applied to clinical practice. Simply recording that a change in behavior occurs after the emergence of a particular cerebral disorder, for example, is insufficient proof. A specific syndrome should occur with a prevalence in association with an etiological disorder that is above the base rate in the general population. Many clinicians recommend as the principal criterion for establishing causality the demonstration of a close temporal association of onset and course of the primary disorder and the secondary psychiatric syndrome. Although frequently useful, this criterion is not always applicable. For example, symptomatic psychosis due to epilepsy may gradually emerge 10 to 15 years after the onset of seizures. Conversely, psychiatric symptoms and signs may be the first clues to a systemic or cerebral disease, and detection of the primary pathological process may follow the emergence of psychiatric symptoms by months or longer. Many secondary psychiatric conditions also may persist after the primary disease process has resolved; examples are the secondary conditions consequent on thyroid deficiency, long-term alcohol use, or long-term exposure to neurotoxic compounds. Secondary syndromes may remit quickly, slowly, or incompletely, depending on the specific disease and whether lasting cerebral changes are present. Also, secondary syndromes may be amenable to symptomatic treatment even while the primary disorder remains without a cure. ICD-10 recommends four criteria for classifying a syndrome as organic: (1) evidence of cerebral disease, damage, or dysfunction, or of systemic physical disease, known to be associated with one of the listed syndromes; (2) a temporal relationship (weeks or a few months) between the development of the underlying disease and the onset of the mental syndrome; (3) recovery from the mental disorder following removal or improvement of the underlying presumed cause; and (4) absence of evidence to suggest an alternative cause of the mental syndrome (such as a strong family history or precipitating stress). ICD-10 also lists conditions known to increase the relative risk for the syndromes classified here, including epilepsy; limbic encephalitis; Huntington's disease; head trauma; brain neoplasms; extracranial neoplasms with remote CNS effects (especially carcinoma of the pancreas); vascular cerebral disease, lesions, or malformations; lupus erythematosus and other collagen diseases; endocrine disease (especially hypothyroidism and hyperthyroidism, Cushing's disease); metabolic disorders (e.g., hypoglycemia, porphyria, hypoxia); tropical infectious and parasitic diseases (e.g., trypanosomiasis); toxic effects of nonpsychotropic drugs (propranolol [Inderal], levodopa [Dopar], methyldopa [Aldomet], steroids, and antihypertensive and antimalarial agents). Ultimately the clinician must make an informed judgment as to whether the psychiatric condition is primary or secondary. Prevalence data, for example, reflect group trends whereas the clinician has to make a decision regarding an individual. Two approaches are available. The clinical decision is relatively uncomplicated if a previously demonstrated elevated prevalence links a specific syndrome with a specific etiology, in the presence of additional supporting clinical features and consistent laboratory tests. Probabilistic reasoning in such cases leads to the conclusion that there is a cause-and-effect relation. A temporal association, when meaningfully present, further confirms the connection. When a clinical research data base is less well established, however, it becomes even more critical to document rigorous clinical reasoning, in effect demonstrating how the detected historical, clinical, and laboratory features are not consistent with what is known about idiopathic psychiatric conditions. Again, establishing the causal connection should reflect the clinician's effort to undertake conscientious probabilistic case reasoning. Attribution of a secondary designation implies a link that is more probable than not: a standard that exceeds 50 percent is recommended, although absolute certainty may be possible. Such a standard does not require that the systemic medical or primary cerebral disease be the sole factor contributing to symptom expression; rather, due to . . . connotes a predominant pathogenic role. When causal probability is considered less certain (i.e., possible but not probable), the clinician should not define a syndrome as secondary in nature. Diagnostic decisions based on incomplete data will be inevitable, and thoughtful clinical judgment remains the abiding rule. Due to . . . should be used conservatively; attribution of cause invites a careful consideration of the factors that contribute to disease formation. When doubt remains, the provision of a primary (idiopathic) psychiatric diagnosis will best serve the interests of the patient and avoid the premature closure of clinical evaluation. Neuropsychiatric Assessment Neuropsychiatric assessment follows the principles of all comprehensive clinical evaluations: it is based on thorough acquisition of the current and past medical history, family history, developmental and social history, and a review of personal habits. The neuropsychiatric clinician seeks to integrate the data on unique individual development, the signs and symptoms of disease, and an understanding of behavior-brain relationships into a meaningful appraisal of functional integrity. Clinical reasoning should entail a time-oriented view, with the clinician noting how the patient has progressed or failed to develop across his or her life course. The temporal perspective is buttressed by an understanding of normative development as well as by an appreciation of the natural history of disease processes. In

particular, the clinician should be mindful of the unique characteristics of primary cerebral disorders, whether inborn, acquired early in life, or of later onset. Fundamental to neuropsychiatric evaluation, diagnosis, and prognosis is an understanding of disease evolution at psychological and neurobiological levels of analysis. Frequently the clinician must tolerate the uncertainty of not knowing (in an absolute sense) the mechanisms by which brain diseases cause behavioral problems; the clinician then has the task of developing practical and effective solutions to problems that may not have specific scientific answers. Despite having a recognized pathological basis, most neuropsychiatric disorders do not have specific cures and continue to require empirical, symptomatic treatment approaches. Clinicians repeatedly face a dual dilemma: etiological specificity often is related to variable clinical expression (e.g., general paresis and Huntington's disease). There is no biological law such as “one pathogen, one clinical presentation.” Clinical variability is the rule rather than the exception. Conversely, there are relatively few final common pathways for the expression of a wide variety of disease processes. These pathways include (1) alterations in arousal, attention, and concentration; (2) alterations in affective state, including both the expression of emotion and the feeling of mood; (3) alterations in perception, including ideational or physical and internal or external; (4) alterations in intellectual function (such as memory, language, or the organization of thought processes); (5) alterations in personality; and (6) alterations in motor function. Thus, behavioral abnormalities tend to be nonspecific, and despite substantial evidence from behavioral neurology that focal lesions may lead to distinctive patterns of intellectual deficit, there are insufficient data to confidently support such assertions for major psychopathological syndromes. Moreover, idiopathic or primary psychiatric disorders may mimic symptomatic psychopathological conditions that are secondary to specific systemic medical or cerebral disease processes and vice versa. What confounds the situation is that there has been insufficient research to establish how often cerebral lesions lead to discrete psychopathological syndromes or specifically how any defined psychopathological disorder is related to a particular localized cerebral abnormality. Thus, the clinician must use an empirical method, based on careful clinical reasoning, that allows the development of a preliminary diagnosis and an initial treatment plan. The clinician should specify in advance what possible therapeutic benefits might be derived and should understand how the natural history of the disorder will unfold if proposed treatment options prove ineffective. The clinician should also be ready to undertake further evaluation if an unanticipated outcome arises. By establishing a future-oriented or outcome-oriented clinical perspective, the clinician can reduce the degree of uncertainty and establish a structural approach for systematically and self-critically scrutinizing treatment interventions. Neuropsychiatric Case Reasoning The approach to neuropsychiatric case reasoning required for such formulation and planning entails blending the disparate traditions that developed in psychiatry in the past century. It draws from Meynert and John Hughlings Jackson (1835-1911), as well as from the behavioral neurologists of recent decades, an appreciation of brain-behavior and behavior-brain relations, with an attempt to understand the laws that govern the CNS. Such a pathobiological method, through lesion location and an appreciation of probabilistic generalities about brain function and neuropathology, in effect argues that all nervous systems are created equal. It benefits from a thoroughly documented array of case studies that seek to define the specific behavioral expression of focal cerebral lesions. It suffers from the fact that nervous systems are not identical and that personal circumstances powerfully influence the expression of disease. Nonetheless, it has taught clinicians much about what to assess and expect when dealing with disordered brain function. The second approach to case reasoning is derived from the Kraepelinian tradition that continues to be expressed in DSM-IV. This method argues for the precise elaboration of symptoms and signs, the definition of specific syndromes, the identification of target symptoms amenable to therapeutic intervention, and the use of diagnoses for prognostic purposes. The strengths of such an approach lie in the rigorous case definition based on thorough observation and data collection, with the derived ability to generalize from one case to another. Shortcomings, akin to the problems with lesion localization, include the substantial degree of variability that exists within the boundaries of stereotypic diagnostic descriptions and the difficult-to-quantify influences of personal life circumstances. The third method of case reasoning evolved from dynamic psychiatry and recognizes the individual as having unique personal and developmental attributes that are expressed throughout the course of life. The clinician using this method of case reasoning seeks to understand meaning as well as event and to appreciate disease process in the patient's broader social and cultural context. The neuropsychiatric clinician must view illness in all its complexity. The different modes of case reasoning are brought together for clinical purposes through understanding how psychological meaning, symptoms, and disease process and socially defined aspects of illness each affects the patient's ability to function autonomously. Although function is not a direct measure of pathology or disease process, assessing how each person has undertaken specific developmentally important tasks is useful for appraising the interaction of those factors. Depending on the individual case, it may be possible to more clearly state which method of case reasoning is most effective for developing a treatment plan and understanding aspects of prognosis. Ultimately, the clinician is as much interested in the patient's return to prior functional integrity as in symptom remission. Treatment success cannot be proclaimed, for example, in the resolution of psychotic symptoms associated with epilepsy if the patient continues to be socially withdrawn or isolated and no longer capable of independent living. Aging Age and its relation to the expression of illness must be recognized as a changing backdrop for all neuropsychiatric disorders. Age may be used as a convenient indicator for locating the patient in an evolving biological, psychological, and social matrix; a consideration of aging effects cannot await the last stages of the assessment, at which point aging is viewed solely as a factor modifying disease expression. Rather, thoughtful understanding of the aging-related context of a patient's illness is essential to obtaining the fullest view of the relevant life factors contributing to disordered behavior. Data Acquisition The patient's history is an essential feature of neuropsychiatric evaluation because it provides the clinician the opportunity to develop the equivalent of a serial mental status examination across the patient's life course and to identify target symptoms that may respond to treatment. The clinician seeks to discern when, if ever, the patient functioned autonomously and effectively and to define the personal, social, psychological, symptomatic, and medical factors related to primary disease that contributed to a decline in function or to a failure of normal development. The history provides the opportunity to view the unfolding or evolution of signs and symptoms. The clinician strives to develop a variety of corollary information sources when assessing the patient's history so that the most complete view of the illness may be obtained. Corollary information sources may be particularly important for evaluating the history of patients who lack the cognitive capacity to relate their own life stories effectively and they are especially important for understanding the social and cultural context of specific symptoms. During the history taking, the clinician seeks to elicit the functional anatomy of an illness. Subtle cognitive disorders, fluctuating symptom pictures, and progressing disease processes may be effectively tracked in a detailed rendition of changes in the patient's daily routine involving such factors as self-care, job responsibilities, and work habits; meal preparation; shopping and personal support; interactions with friends; hobbies and sports; reading interests; religious, social, and recreational activities; and ability to maintain personal finances. Understanding the fabric of life for each patient provides an invaluable source of data regarding many of the final common behavioral pathways cited previously, including attention and concentration, intellectual abilities, personality, and motor skills, and more typical symptomatic psychiatric features such as mood state and perception. The examiner seeks to find the particular pursuits that the patient has identified as most important or central to his or her lifestyle and attempts to discern how those pursuits have been affected by the emerging clinical condition. Such a method provides the opportunity to appraise both the impact of the illness and the patient-specific settings for monitoring the effects of future therapies. Mental Status Examination Following a thorough history acquisition, the neuropsychiatrist's primary tool is the assessment of mental state. Formal mental status examination fell into disrepute when descriptive psychiatry was seen as irrelevant to the effective implementation of dynamically oriented psychotherapies. Its value is now undisputed. Like the physical examination, the mental status examination is a means of surveying predetermined functions and abilities to allow a definition of personal strengths and weaknesses. It is a repeatable, structured view of symptoms and signs; uniformity of approach assists in the reliable definition of findings and promotes effective communication between clinicians. It also establishes the basis for future comparison, essential for documenting therapeutic effectiveness, and it allows comparisons between different patients, with a generalization of findings from one to another. Table 10-3 lists the components of a comprehensive neuropsychiatric mental status examination.

Table 10-3 Neuropsychiatric Mental Status Examination

General Description Often, teachers and texts place the so-called sensorium as one of the last items for reporting when describing the mental status examination; the term is too broad, but consideration of arousal and responsiveness to the environment should be one of the first domains of assessment. If the patient has a significant disorder of attention or arousal, other aspects of the examination may be invalid. Together, attention and comprehension are the pillars of the mental status examination. Problems of arousal and inability to comprehend the fundamental aspects of the examination tend either to invalidate many findings or to warrant caution in their interpretation. Language and Speech The clinician may use language function, particularly when assessing output, to estimate the patient's level of education and intelligence. It is essential, whenever possible, to estimate the patient's premorbid intellectual abilities. Definition of educational attainment during acquisition of the history aids in this process, but further appraisal during mental status assessment is valuable. However, this method must be used carefully because low educational attainment, a different language or cultural background, or acquired brain damage may confound any estimation. Thought Assessment of thought processes involves appraising form and content. Thought form relates closely to language; for example, the clinician must distinguish between fluent aphasia or other disorders of word output and formal thought disorders related to psychosis (such as tangential responses or derailment). There are no ideational or perceptual manifestations that exclusively reflect neuropsychiatric disorders. Although some investigators have emphasized that olfactory hallucinations, for example, indicate brain disease specifically, such assertions have not been supported by well-designed epidemiological studies. Moreover, whereas the major primary psychiatric disorders have no known etiologies, there is no doubt that they involve abnormalities of brain functioning that result in the widest array of symptoms. Mood and Affect When assessing affective and mood state, the examiner should appraise the congruence between expressed mood and demonstrated emotion. Patients with cerebral lesions occasionally demonstrate pseudobulbar affect or affective incontinence. The signs of pseudobulbar affect often include affective overshoot or disconnected affect, in which the patient responds to an appropriate stimulus but the expression is exaggerated or the emotional expression is unrelated to any defined mood. Although such behaviors can be observed in patients with idiopathic or primary psychiatric disorders, careful observation over an extended period often demonstrates that they are distinguishable from behaviors encountered in patients with mood disorders. Insight and Judgment Insight denotes looking in while judgment reflects looking out. Both entail processes of appraisal or assessment, of one's own state of mind, one's motivations and actions, or one's relationships to others. Discussing the events leading to a clinical evaluation and comparing the patient's version with data gleaned from key informants (family, friends, other clinicians) provide an opportunity to define the congruity of the patient's understanding with that of others. Comparing examination-derived findings with the patient's insight (self-appraisal of mental state) serves as a direct or first-hand assessment. Cognition When testing cognitive functions the clinician should evaluate memory; visuospatial and constructional abilities; and reading, writing, and mathematical abilities. Abstraction ability is also valuable to assess, although a patient's performance on tasks, such as proverb interpretation, may be difficult to evaluate when abnormal. Proverb interpretation may be a useful bedside projective test in some patients, but the specific interpretation may result from a variety of factors, such as poor education, low intelligence, and failure to understand the concept of proverbs, as well as a broad array of primary and secondary psychopathological disturbances. Although testing similarities are also education-sensitive, similarities may be more easily understood by patients. A variety of standardized assessments have been developed in recent decades to assist with mental status evaluation. These include psychopathological rating scales that depend on self-report as well as examiner administration and brief evaluations of cognitive function that have proved helpful in examining individuals with developing cerebral diseases. Clinicians who use brief evaluations, however, must be cautious when interpreting their findings, which are subject to both false-negative and false-positive errors. For example, many tests use single cutoff points as thresholds for establishing abnormality. However, patients with focal lesions who experience discrete intellectual impairments may remain within the normal range of performance. Patients with idiopathic psychiatric disorders, such as major depressive disorder, may perform at abnormal levels on standardized cognitive protocols, inviting unwary clinicians to diagnose them as having dementia. Such assessments may also be susceptible to systematic differences among the elderly and are sensitive to lower educational level. Because they are tools for screening a large number of persons, bedside cognitive tests tend to be least helpful at the extremes, either when appraising highly intelligent individuals who are suffering intellectual declines but remain above the top rung of the test or when testing those who show substantial cognitive decline. The latter may continue to have residual intellectual abilities, some of which may prove helpful for maintenance care, but tests may prove insensitive to assessing those abilities.

PATHOLOGY AND LABORATORY EXAMINATION Like all medical tests, psychiatric evaluations such as the mental status examination must be interpreted in the overall context of thorough clinical and laboratory assessment. Psychiatric and neuropsychiatric patients require careful physical examination, especially when there are issues involving etiologically related or comorbid medical conditions. When consulting internists and other medical specialists, the clinician must ask specific questions in order to focus the differential diagnostic process and use the consultation most effectively. In particular, most systemic medical or primary cerebral diseases that lead to psychopathological disturbances also manifest with a variety of peripheral or central abnormalities. Assignment of a patient's behavioral disturbance to a symptomatic or secondary status reflects, in part, the definition of other nonbehavioral manifestations of the primary disease. An important element in the description of secondary psychiatric disorders is the use of laboratory assessment procedures to further define the characteristics of the systemic medical or cerebral process that is etiologically related to the psychiatric symptoms in question. This requires that psychiatrists understand the range of disorders that can lead to behavioral abnormalities. A screening laboratory evaluation is sought initially and may be followed by a variety of ancillary tests to increase the diagnostic specificity. Table 10-4 lists such procedures.

Table 10-4 Screening Laboratory Tests

A clinician requesting specific laboratory tests should be led by informed clinical suspicion as well as by an appreciation of the relative costs and benefits of each test. With the exception of low-cost screening procedures, few tests should be requested without a clearly defined rationale. Different approaches are taken for inpatients versus outpatients and for those with regular medical care versus those who have none. Repetition of recently performed tests is often without value. Electroencephalography EEG is an easily accessible, noninvasive test of brain dysfunction that has a high sensitivity in many disorders but relatively low specificity. Beyond its recognized uses in epilepsy, EEG's greatest utility is in detecting altered electrical rhythms associated with mild delirium, space-occupying lesions, and continuing complex partial

seizures where the patient remains conscious although behaviorally impaired. EEG is also sensitive to metabolic and toxic states, often showing a diffuse slowing of brain activity. Focal slowing, when present, may be indicative of a variety of causes such as space-occupying lesions (tumors, cerebral abscesses) or subdural hematomas. However, a superficial EEG (one that is recorded through the skull) is often insufficient for source localization and may prove insensitive to a variety of abnormal processes, necessitating nasopharyngeal recording to better define abnormalities generated by the temporal lobes or direct cortical (surface) recording to localize seizure foci. The EEG findings change with aging, with a general reduction in alpha wave activity, and with increases in the relative amounts of theta and delta wave activity. Early in the course of disorders such as Alzheimer's disease the standard EEG finding usually remains normal and therefore is often unrevealing. As part of sleep polysomnography, recent studies have suggested that the EEG may aid in the future in the distinction between elderly subjects with major depressive disorder associated with cognitive impairment and those with a primary neurodegenerative process underlying their dementia. Computed Tomography and Magnetic Resonance Imaging CT scanning and MRI have proved to be powerful neuropsychiatric research tools. Recent developments in MRI allow the direct measurement of structures such as the thalamus, basal ganglia, hippocampus, and amygdala, as well as temporal and apical areas of the brain and the structures of the posterior fossa. MRI has largely replaced CT as the most utilitarian and cost-effective method of imaging in neuropsychiatry. Patients with acute cerebral hemorrhages or hematomas must continue to be assessed using CT, but these patients present infrequently in psychiatric settings. MRI better discriminates the interface between gray and white matter and is useful in detecting a variety of white matter lesions in the periventricular and subcortical regions. The pathophysiological significance of such findings, designated by such terms as rims, caps, unidentified bright objects, and leukoaraiosis, remains to be defined. Such abnormalities are detected in younger patients with multiple sclerosis or HIV infection and in older patients with hypertension, vascular dementia, or dementia of the Alzheimer's type. However, their prevalence is also increased in healthy, aging individuals who have no defined disease processes. At present, those types of findings should be viewed in the same light as one would consider atrophic changes; namely, they are detected in a highly sensitive fashion but are usually nonspecific or nondiagnostic in meaning. White matter hyperintensities are more extensive and more frequent in individuals with disease, particularly those with disorders involving cognitive dysfunction, but they are too variable to contribute to the diagnosis or prognosis in an individual case. Like CT, the greatest utility of MRI when used in the evaluation of patients with dementia arises from what it may exclude (tumors, vascular disease) rather than what it can demonstrate specifically. Because of MRI's ability to delineate brain anatomy and its sensitivity to white matter changes, these guidelines remain utilitarian when modified appropriately. Indications for ordering MRI in psychiatric patients include (1) delirium or dementia of unknown etiology; (2) a first episode of psychosis of unknown etiology; (3) a movement disorder of unknown etiology; (4) the initial evaluation of anorexia nervosa; (5) prolonged catatonia; (6) the initial onset of a major mood disorder or personality change after age 50 years; (7) the presence of unanticipated behavioral, intellectual, or functional decline in an already diagnosed psychiatric patient in whom the clinician would normally expect long-term stability or, at worst, a relapsing-remitting course with a return to baseline between episodes; and (8) the presence of any new behavioral or intellectual disorder in a patient infected with HIV. Imaging studies have been overused in the periodic monitoring or reassessment of patients with suspected dementia of the Alzheimer's type in whom earlier examinations showed characteristic cerebral changes. Unless one suspects a missed diagnosis of normal pressure hydrocephalus, or perhaps failure to detect microinfarctions on CT when such a finding on MRI might have ruled out Alzheimer's type, repeated scans are not warranted. Occasional patients may become agitated in the MRI tube; premedication with a benzodiazepine can minimize the problem. The magnetic field prohibits use of MRI in patients with pacemakers or metal implants, including metallic surgical clips, although many patients now receive MRI-compatible clips at surgery. Positron Emission Tomography, Single Photon Emission Computed Tomography, and Functional Magnetic Resonance Imaging Physiologically based techniques for imaging the brain, such as PET and SPECT, involve the injection of radioactively labeled, naturally occurring compounds or a radiopharmaceutical, with subsequent demonstration of cerebral blood flow or the incorporation of the labeled compounds into specific metabolic pathways. Such imaging methods have shown promise in studying the neurochemical and physiological bases of a variety of neuropsychiatric disorders. However, the cost of PET currently precludes its use as a routine diagnostic procedure, and there are insufficient data to project its ultimate utility for routine clinical evaluation. SPECT can be performed more readily and more cheaply, but whether it will have specific diagnostic utility in general psychiatry remains to be determined. Functional MRI (fMRI) holds great promise as a research tool to explore the physiological bases of complex behavioral processes. However, its potential utility as a clinical diagnostic tool remains to be defined. Neuropsychological Testing Neuropsychological testing provides a standardized, quantitative, reproducible evaluation of a patient's cognitive abilities. Such procedures may be useful for initial evaluation and periodic assessment. Tests are available that assess abilities across the broad array of cognitive domains, and many offer comparative normative groups or adjusted scores based on normative samples. The clinician seeking neuropsychological consultation should understand enough about the strengths and weaknesses of selected procedures to benefit fully from the results obtained. For example, many tests do not have appropriate aging-related norms (because they have been used primarily in young and middle-aged adults who are better educated) and therefore are less useful when used in children or the elderly. In general, clinicians should understand that a variety of distinct, competing neuropsychological schools of thought have developed different views regarding methods of individual evaluation, use of the tests, and interpretation of the data. Because neuropsychological evaluation is evolving rapidly and provides a remarkable array of tools for assaying disordered behavior, sophistication in the use and interpretation of those tests will benefit the clinician.

ETIOLOGY AND DIFFERENTIAL DIAGNOSIS Factors Affecting Disease Presentation Neuropsychiatric evaluation and diagnosis are based on a fundamental understanding of the mechanisms by which pathobiological processes, both systemic and cerebral, express themselves through altered CNS function. The factors that influence symptom expression can be approached from several perspectives. The first perspective relates to what might be called mode of action. Systemic disorders typically express themselves indirectly, through as yet undefined centrally active substances, defined endocrine disruptions, or fundamental metabolic alterations. Their effects tend to be generalized but often include delirium, dementia, or mood disturbance. In contrast, selective destruction of specific brain regions is more frequently associated with decrements in discrete cognitive tasks or behaviors. One must be cautious with such generalizations, however, as focal lesions in key brain regions (such as those involving brainstem structures) may cause delirious states. Moreover, the clinician may encounter substantial variability in the range of behavioral abnormalities caused by specific focal damage. A second perspective relies on knowing the natural history of particular pathological processes. Diseases tend to progress or unfold in characteristic fashions, thus allowing for continuing differential diagnostic consideration over time. Also, meaningful prognosis depends on a thorough appreciation of natural history. A third perspective derives from recognizing the timing of an insult within a neurodevelopmental framework, where the long-term impact of any process or event will depend in part on the compensatory or recovery capacities of the brain. Such capacities change as part of the aging process (they may be fundamental to aging), but much remains unknown. A final perspective has to do with the types of cells and regions damaged by specific diseases. Degenerative disorders (Huntington's disease, Parkinson's disease) often lead to destruction of neurochemical systems. Hypoperfusion or pulmonary insufficiency both cause hypoxia, which in turn affects regions with especially vulnerable cell populations (such as the hippocampus) or regions near the ends of vascular trees (the so-called watershed zones, including many brain association areas). Lesions due to ischemic and hemorrhagic cerebrovascular disease reflect vascular anatomy rather than the pathoanatomy associated with degeneration of functionally significant neurochemical systems. Brain toxins may act by binding to specific neurochemical receptors, causing differential damage in direct proportion to regional variations in receptor concentration. Knowledge of the cell populations and anatomical regions affected, when integrated with the other perspectives, assists in understanding or anticipating the full effects of the primary disorder. A variety of disorders can lead to behavioral abnormalities. They can be subsumed under the following broad categories: trauma, tumor, infection, immune and autoimmune disorders, cardiovascular disease, congenital and hereditary conditions, physiological disorders, primary psychiatric disorders, metabolic disorders, demyelinating disorders, degenerative diseases, substance-induced disorders and disorders due to toxins, and malingering. Trauma Head trauma leading to brain injury is a possible cause for delirium, dementia, and amnestic disorder, as well as all of the secondary psychiatric syndromes.

Traumatic brain injury is largely a disease of modernity, with the majority of injuries resulting from motor vehicle accidents, gunshot wounds, or occupational mishaps. Estimates point to an annual incidence of 400 to 600 cases per 100,000 population, but such figures must be viewed with caution in light of variable definitions at the less severe (mild) end of the injury spectrum. Pathophysiology Head trauma can cause brain injury through multiple mechanisms, both direct and indirect. Table 10-5 lists the factors that contribute to brain injury after head trauma. The clinician must recognize that brain injury from head trauma often results in pathology in areas beyond the site of direct impact. In addition, certain areas of the brain are more susceptible to injury regardless of the site of impact ( Fig. 10-1). Those areas include the orbitofrontal and frontal pole convexities as well as the anterior temporal lobes, which lie close to bony skull prominences. Rotational and horizontal movements can produce shearing in areas of the brain that are relatively immobile, such as central white matter fiber pathways. Shearing forces can produce diffuse and extensive damage, also unrelated to the actual site of impact. Thus, frontal, subcortical, and limbic structures are especially vulnerable to traumatic head injury. This may explain the diversity of neuropsychiatric sequelae and the occasional occurrence of disproportionate disruptions in personality, behavior, and affect when cognitive and motor functions are largely spared. Penetrating head injuries or injuries in which the head has not been able to rotate or move may spare patients from the extensive injuries associated with indirect effects, despite significant direct damage. Bullet or penetrating missile injuries, however, may disrupt neuronal function beyond the site of impact through the effects of high-frequency vibratory waves.

Table 10-5 Pathophysiological Mechanisms of Brain Injury After Head Trauma

FIGURE 10-1 Severe contusion of the frontal poles has resulted in their atrophy and distortion. (Courtesy of H. M. Zimmerman, M.D.)

Psychiatric Symptoms Delirium is the acute manifestation of all head injuries that are likely to produce long-lasting sequelae. In severe head injury there is an initial loss of consciousness (coma), followed by gradual recovery, with the delirium taking the form of progressive stages of semiwakefulness, distractibility, and confusion, and finally a stable level of consciousness. The entire process may be brief or may take hours to weeks. In milder injuries there may be a brief absence of consciousness, such as momentary dazing, passing out, or transient confusion. A brief lapse or alteration of consciousness occurring after head trauma is defined as concussion. Table 10-6 includes frequently observed features of concussion and Table 10-7 lists common symptoms. Table 10-8 divides concussion cases into three grades of severity. Grades 2 and 3 cases require neurological evaluation; Grade 3 cases warrant immediate transport to an emergency department for assessment.

Table 10-6 Frequently Observed Features of Concussion

Table 10-7 Symptoms of Concussion

Table 10-8 Gradations of Concussion

Cognitive disorders are frequent after traumatic brain injuries. Global impairment may be seen after extensive head injury or prolonged coma, although those deficits may improve dramatically in the months following injury. Dementia or a persistence of global cognitive impairment is less common, reflecting the high mortality associated with more severe injuries. When dementia is seen, it is usually associated with hemiparesis, aphasia, or other indicators of severe and extensive injury. Persisting dementia with gradually progressive deficits may be associated with multiple recurrent head traumas. The condition has been termed chronic traumatic encephalopathy and has been noted to occur after even minor multiple head traumas. Dementia pugilistica, or boxer's dementia, is an example. Onset usually occurs at the end of a boxer's career but chronologically earlier than the onset of the degenerative dementias. A subcortical pattern of dementia (discussed later under degenerative diseases) is typically present, with prominent parkinsonian features as well as dense memory impairment. Neuropathological studies have demonstrated global atrophy with specific involvement of the midbrain and mesial temporal lobe, presumably reflecting the direct and indirect effects of multiple injuries. Plaques and tangles are often noted, but the pathophysiological mechanism remains unknown. Memory disturbance is nearly always present with any trauma severe enough to cause a concussion. Posttraumatic amnesia occurs invariably after concussive brain injury and refers to the inability to register new memory. The duration of posttraumatic amnesia, which may be very brief, is a significant indicator of severity but can be assessed only after the patient has regained a stable level of consciousness. Retrograde amnesia is the inability to recall events prior to the injury. It can be assessed by asking patients about their last memories before the injury. Retrograde amnesia generally shrinks with recovery whereas a postinjury memory deficit tends to remain constant; patients do not recover memories from the period of posttraumatic amnesia. Additionally, patients may suffer persisting impairment of new learning and recall (an amnestic disorder) as a result of permanent pathological changes incurred because of the traumatic event. Persisting specific deficits in the context of overall robust recovery can be disabling and frustrating for the patient, who appears normal to others although still impaired cognitively and functionally. Depending on the specific nature of any deficits, these patients would be diagnosed according to DSM-IV as having cognitive disorder not otherwise specified or amnestic disorder due to traumatic brain injury. Postconcussional disorder is a disabling cluster of symptoms of uncertain pathophysiology. It emerges within hours to days (or a few weeks) of a mild head injury and is characterized by headache, dizziness, fatigue, poor concentration and mild memory impairment, problems sleeping, irritability, anxiety, and often significant problems with mood regulation or frank clinical depression. Diminished spontaneity, apparent apathy, and other personality changes are noted also. The cluster of symptoms is remarkably consistent from patient to patient. Table 10-9 presents the proposed research diagnostic criteria for postconcussional disorder that are included in DSM-IV.

Table 10-9 DSM-IV Research Criteria for Postconcussional Disorder

ICD-10 defines postconcussional syndrome as follows: The syndrome occurs following head trauma (usually sufficiently severe to result in loss of consciousness) and includes a number of disparate symptoms such as headache, dizziness (usually lacking the features of true vertigo), fatigue, irritability, difficulty in concentrating and performing mental tasks, impairment of memory, insomnia, and reduced tolerance to stress, emotional excitement, or alcohol. These symptoms may be accompanied by feelings of depression or anxiety, resulting from some loss of self-esteem and fear of permanent brain damage. Such feelings enhance the original symptoms and a vicious circle results. Some patients become hypochondriacal, embark on a search for diagnosis and cure, and may adopt a permanent sick role. The etiology of these symptoms is not always clear, and both organic and psychological factors have been proposed to account for them. The nosological status of this condition is thus somewhat uncertain. There is little doubt, however, that this syndrome is common and distressing to the patient. At least three features of the syndrome are necessary for diagnosis, according to ICD-10 ( Table 10-10). Laboratory tests may be helpful for corroboration. Some observers have argued that the requirement in DSM-IV to wait 3 months before a definitive postconcussional diagnosis may lead to a delay in establishing a proper diagnosis and initiating therapy for some patients. Indeed, postconcussional conditions transiently or spontaneously resolve for most affected individuals, with symptom remission during the first 3 to 6 months following injury. Although occasional individuals develop posttraumatic migraine, patients with postconcussional disorder more commonly describe symptoms reminiscent of muscle tension headaches arising frontally or posteriorally and occasionally involving temporal regions as well. Some report tenderness persisting at the site of impact, but that is less frequent and its pathophysiological basis is unknown. Major depression in the context of postconcussional disorder may not remit unless specific antidepressant treatment is initiated. Postconcussional symptoms that persist beyond 12 weeks should raise suspicions of additional brain pathology, such as an undetected subdural hematoma or a chronic cognitive impairment syndrome. A thorough evaluation is warranted. Postconcussional headaches can persist and prove disabling, and patients may benefit from the judicious use of analgesic as well as antidepressant agents. However, clinicians also must be vigilant regarding the development of headaches caused by analgesic rebound, a paradoxical but common cause of apparent chronic posttraumatic headaches. Secondary mood disorders are commonly seen with severe injury, although they may be more common after minor injury as part of the postconcussional syndrome. All forms of psychotic symptoms that are seen in idiopathic schizophrenia can be seen after traumatic injury. They are most common in the immediate delirious period but can persist once a stable level of consciousness has been obtained.

Table 10-10 ICD-10 Diagnostic Criteria for Personality and Behavioral Disorders Due to Brain Disease, Damage and Dysfunction

Personality Change Due to a General Medical Condition This disorder is a frequent concomitant of traumatic brain injury, owing to the vulnerability of the frontal lobes and the important role those structures play in the expression of personality. Two personality syndromes have been described with frontal lobe injury: the orbitofrontal syndrome, characterized by disinhibition, explosiveness, and jocularity; and the frontopolar syndrome, characterized by apathy, behavioral inertia, and indifference. Patients may appear indifferent to their incapacities or may confabulate regarding their injury and hospitalization. Less marked personality changes, such as irritability and a so-called short fuse, are common, especially as part of the postconcussional syndrome. Adjustment disorders can occur at any point once a stable level of consciousness has been attained. Patient and family must adjust to loss of capacity, increased irritability and fatigue, a possible change in family roles, absence from work, financial constraints, and legal entanglements. As in all adverse circumstances, premorbid personality heavily influences the patient's adaptive capacities. Unfortunately, clinicians have at times seen the presence of an adjustment disorder or a prior history of maladaptive personality functioning as a reason to conclude that patients are not suffering from behavioral or cognitive impairments arising from brain injury. The evaluation and treatment of head trauma require clinical flexibility to address the broadest range of symptoms and syndromes. Course and Prognosis The course of recovery from posttraumatic syndromes depends on the severity of the initial injury and the location of damage. The duration of coma and of posttraumatic amnesia may be useful prognostic indicators. Dramatic improvements can occur within days and continue for up to 6 months. Overall recovery may continue up to 24 months, with motor and physical improvement often preceding behavioral and cognitive restoration; less frequently, recovery continues beyond 2 years after injury. The neurobiological mechanisms leading to recovery are unknown. Treatment There are no specific treatments for the cognitive abnormalities associated with head trauma. Life-sustaining and life-supportive short-term therapies may be needed initially, and the psychopathological conditions resulting from head trauma may warrant symptomatic therapies. Despite a boom in institutions and companies offering cognitive rehabilitation, it remains unproved scientifically whether those methods significantly augment natural recovery processes. Litigation The high frequency of closed head injuries and posttraumatic complaints, together with the ready availability of psychiatrists, neurologists, and psychologists willing to testify as “experts,” have combined with lawyers in today's litigation-prone culture to bring postconcussional disorder center stage in American courtrooms. While there are numerous instances of claims related to bona fide cognitive, emotional, and behavioral deficits resulting from brain injury, it also is clear that many are unsubstantiated. There appear to be four often interacting factors that contribute to the latter situation: (1) Absence of concussion—Suits frequently request damages for postconcussion syndrome (or a related term) when a careful review of medical records reveals no evidence of pertinent symptoms or signs, such as altered consciousness, posttraumatic amnesia, nausea and vomiting, photophobia, or headache: (2) Nonspecific symptoms—Postconcussional disorder is diagnosed due to fatigue, headache, and dysphoria in the absence of symptoms or signs of concussion; complaints may have developed weeks or even months after an accident or injury. (3) Diagnostic mythology—Once a clinician labels a condition postconcussional without substantiation, this label is then promulgated and other clinicians accept it at face value without an independent review of all necessary data. The diagnosis soon assumes mythic proportions. (4) Lack of common sense—[A patient is diagnosed as having specific posttraumatic psychopathology or cognitive decline without the earlier medical, psychiatric, educational, and vocational records having been reviewed, which reveals the presence of the claimed symptoms or signs before the purported brain injury.] In all litigation-related evaluations, the possibility of malingering needs to be considered. Relevant hints or clues include: a substantial discrepancy between mild clinical findings and severe or dramatic subjective complaints; relatively intact personal and vocational functioning and markedly abnormal neuropsychological test scores; vague complaints without objective test or functional correlates; disparity between complaints of vocational limitations and continued vigorous recreational activities (e.g., hunting, weight training, volleyball, or tennis); a history of legal difficulties or multiple accident claims; evidence of a clinically significant personality disorder. An evaluator must also be vigilant to assess whether there is evidence of an undiagnosed mood disorder. Frequently an individual with severe physical injuries gradually develops complaints of dysphoria, headaches, poor concentration, and memory dysfunction. Diagnosed as suffering a postconcussional disorder, the plaintiff or patient believes he has permanent brain damage rather than an eminently treatable mood disorder. Tumor Intracranial tumors, whether of primary CNS or metastatic origin, can cause behavioral disturbances by directly affecting brain function. They may do so by destroying or compressing brain parenchyma (from mass effect or edema), through obstructive hydrocephalus, or by disrupting brain vasculature ( Fig. 10-2). The nature of the ensuing behavioral disturbance depends on factors already discussed, such as time course and injury location.

FIGURE 10-2 Glioblastoma multiforme. The massive tumor crosses the midline in the corpus callosum. (Reprinted with permission from Hirano A: A Guide Neuropathology. Igaku-Shoin, New York, 1981.)

Extracranial nonbrain neoplasms may indirectly alter brain function and cause psychiatric symptoms by any of several pathways. The cancer may disturb one or more organ systems known to affect brain function. For example, lung cancer may cause hypoxemia and metastatic prostate carcinoma may lead to obstructive uropathy with consequent renal failure. Paraneoplastic syndromes may lead to metabolic abnormalities (e.g., hypercalcemia) commonly associated with behavioral changes. Intriguingly, cancer may cause psychiatric symptoms without any known metabolic or other organ system disturbance; a commonly cited example is the onset of a major depressive disorder as the first clinical manifestation of occult pancreatic carcinoma. The mechanisms of such phenomena are unknown, although it has been speculated that blood-borne humoral factors secreted by the tumor are centrally active. Infection Infections can produce any of the range of cognitive impairments or secondary syndromes that are sudden or insidious in onset. Acute infectious processes involving the CNS often produce delirium as a component of fulminant deterioration. Chronic psychopathology can result either from a chronic infectious process, such as neurosyphilis or Creutzfeldt-Jakob disease, or from persisting structural brain damage incurred as a result of an acute infection, as in the long-term sequelae

of herpes simplex encephalitis. Syphilis Syphilis is a chronic infection resulting from inoculation with the spirochete Treponema pallidum. It is transmitted through sexual contact. Primary syphilis is a local disease manifested by a lesion at the site of inoculation, usually the penis, vagina, or mouth, within 2 to 3 weeks after inoculation. Secondary syphilis, manifested by a recurrent rash occurring anywhere on the body but especially on the palms and soles, has its onset 6 weeks to 6 months after initial exposure. After the rash resolves, syphilis may enter a latent stage that lasts 2 to 10 years after inoculation; serology remains positive throughout the latent stage. Tertiary syphilis may involve skin, bone, and the aorta, as well as the CNS. Neurosyphilis can occur 5 to 35 years after the initial inoculation. Neurosyphilis is divided into four stages: (1) an asymptomatic stage, without symptoms but with abnormal cerebrospinal fluid (CSF); (2) meningovascular syphilis, characterized by headache, nuchal rigidity, irritability, and delirium; (3) tabes dorsalis, with signs of posterior column degeneration, such as ataxia (due to loss of proprioception resulting in a slapping or high-stepping gait and trophic joint changes—Charcot's joints), areflexia, paraesthesias (described as lightning pains and typically involving the extremities), incontinence, impotence, and abnormal pupillary findings (the classic Argyll Robertson pupil, which accommodates but does not respond to direct light response); and (4) general paresis, also known as general paralysis of the insane, dementia paralytica, or paretic neurosyphilis, the classic neuropsychiatric disorder of tertiary syphilis (Fig. 10-3).

FIGURE 10-3 Paretic neurosyphilis. Thickening of the meninges and atrophy of the cerebral convolutions. (Reprinted with permission from Merritt HH, Adams RD, Solomon HC: Neurosyphilis. Oxford University Press, New York, 1946.)

General paresis has great significance for the history of psychiatry because it was one of the first instances in which severe behavioral and cognitive disturbances could be attributed directly to an etiologically definable brain disease. General paresis can present as almost any form of psychiatric disturbance or dementia syndrome. The classically described grandiose presentation has become rare whereas depressive presentations have become more common. Often a general change in personality is the initial presentation, with apathy, lability, and coarsening of behavior. Dementia is of a mixed pattern, with prominent impairment of memory, language, and judgment, as well as loss of initiative and psychomotor slowing. Neuropathologically the brain demonstrates diffuse degeneration with marked lymphocytic infiltration throughout. Creutzfeldt-Jakob Disease Creutzfeldt-Jakob disease is an infection that causes a rapidly progressive cortical-pattern dementia. The infectious agent, a prion, is a subviral replicative protein that is now known to cause a variety of so-called spongiform diseases in animals and humans. The 1998 Nobel Prize for Medicine was awarded to Stanley Prusiner for his work describing this novel biological entity. The age at onset of Creutzfeldt-Jakob disease is usually in the sixth or seventh decade, although onset can occur at any age. The incidence is 1 in 1,000,000. The clinical symptoms vary with progression of the illness and depend on the regions of the brain that become involved. Patients may present initially with nonspecific symptoms, including lethargy, depression, and fatigue. Within weeks, however, more fulminant symptoms develop, including progressive cortical pattern dementia, myoclonus, and pyramidal and extrapyramidal signs. Although blood, CSF, and imaging studies are unremarkable, the EEG can demonstrate a characteristic pattern of diffuse symmetric rhythmic slow waves. A presentation with rapid deterioration, myoclonus, and the characteristic EEG pattern should raise suspicion of Creutzfeldt-Jakob disease. The definitive diagnosis is made by postmortem microscopic examination, which demonstrates spongiform neural degeneration and gliosis throughout the cortical and subcortical gray matter; white matter tracts are usually spared. Prion disease can incubate for decades before the emergence of clinical symptoms and subsequent rapid progression. Reported routes of transmission include invasive body contacts, such as direct tissue transplantation (e.g., corneal transplants) or hormonal extracts (e.g., human growth hormone, before synthetic supplies were developed). Familial patterns have also been reported, which suggests that there may be genetic susceptibility to infection or vertical transmission of the disease agent. No antiviral agents have been shown to be effective in retarding or slowing disease progress, although amantadine (Symmetrel) has been reported occasionally to have had some success. Death usually ensues within 6 months to 2 years of onset. During the past several years, a pathologically similar condition, bovine spongiform encephalopathy, has been described. Diagnosed primarily in the United Kingdom, this disease underscores the effects of modern animal husbandry methods on the amplification of rare diseases and the continuing threat of zenobiotic transmission of these to humans. Viral Encephalitis Viral encephalitis varies in severity, depending on the specific etiological agents. Mild disease is more common with mumps, and enteroviral infections can be limited to headache and malaise. Severe disease is characteristic of infections such as rabies and herpes simplex. Herpes simplex encephalitis is the most common of the severe nonepidemic encephalitides. It is of interest to neuropsychiatry because of the preferential involvement of the orbitofrontal and medial-temporal regions of the brain. A typical presentation consists of severe encephalitis of rapid onset, high fever, headache, nuchal rigidity, focal neurological signs, and delirium. Rarely, a sudden, transient psychosis may herald the onset. Occasionally the onset is more insidious, with the clinical picture at presentation limited to personality change or memory impairment. Necrosis of the frontal and temporal lobes can occur rapidly. Mortality is high: approximately 70 percent. Whenever herpetic encephalitis is suspected, a definitive diagnosis should be made as rapidly as possible by brain biopsy, with the subsequent urgent initiation of antiviral therapy. Survivors may sustain deficits related to temporal and frontal lobe damage, including a dense amnesia disproportionate to the degree of other intellectual impairment; hallucinations in all spheres, including olfactory and gustatory; components of a Kluver-Bucy syndrome; partial complex seizures; aphasia; and anosmia. Human Immunodeficiency Virus HIV-1 has created a late–twentieth-century epidemic parallel in severity and pervasiveness to the scourges of bygone eras. Acquired immune deficiency syndrome (AIDS), the later stages of HIV infection, has been recognized since the 1980s. In recent years its neuropsychiatric manifestations have become a focal point for diagnosis and therapy, as patients live longer through the use of partially effective antiviral therapies and a variety of second-line medications employed for treating opportunistic infections. The following discussion focuses on neuropsychiatric phenomena that appear to result from HIV-1 action in the brain.

Mr. Zeigler is a 55-year-old, married, Latin American businessman who is hospitalized with an 8-month history of diarrhea, fatigue, and weight loss. He has sought help from several institutions both in the United States and Europe, but his illness remains undiagnosed. A psychiatric consultation is requested because both the patient and his physician think he is depressed and wonder what role this might play in his weight loss and overall condition. Mr. Zeigler gives a detailed history of his family's emigration from Europe when he was a child, his personal success in business, and the progressive difficulty he has been experiencing because of his weight loss and fatigue. He has lost 85 pounds over the 8 months and now has to force himself to eat. In the past, eating had been a great pleasure for him and he considered himself a gourmet cook. Although he complains of some difficulty with his memory and concentration, he continues to manage a multinational business and to conduct complex financial deals. He says he feels sad but is hopeful that the diagnosis can be made quickly. He conducts himself in the same autocratic manner in the hospital that he is accustomed to displaying in business and with his family. He has many interests, including an active sex life, which he wishes to resume once he regains his strength. Mrs. Zeigler confirms her husband's history and speaks of his complete control of his business and of the family's financial affairs. She describes how this has created conflicts with her sons, who resent their father's unyielding control, even though they work in the family company. It is her opinion that her husband is depressed and that this is the cause of most of his symptoms. In response to questions about his activities, she agrees that his fatigue seems the only obstacle to pursuing his interests. She cannot answer any questions about his sex drive because she stopped having sex with him 10 years before this illness. He accepted this, and she presumed he frequented prostitutes. Over the next few days Mr. Zeigler's condition deteriorates markedly, and he is thought to have had a stroke because of some slurred speech and a slight weakness of the right side of his body. He then becomes short of breath and is admitted to the intensive care unit. A chest X-ray suggests Pneumocystis carinii pneumonia, which is confirmed by bronchoscopy. He does not respond to co-trimoxazole (Bactrim) and is started on pentamidine (NebuPent). While in the intensive care unit Mr. Zeigler is delirious, frequently hallucinating, and often incoherent in both Spanish and English. His children fly to the United States because he is not expected to survive. This prediction proves to be incorrect, and his pneumonia resolves after several weeks of treatment. A CT scan of the brain suggests a CNS infection with toxoplasmosis, and examination of the stomach by endoscopy leads to the diagnosis of gastrointestinal Isospora. Surprisingly, all these infections respond to treatment. It is now clear that Mr. Zeigler has AIDS, and his physician presents this diagnosis to him along with an inquiry about his sexual experiences. Mr. Zeigler is enraged by his doctor's implication of homosexuality and adamantly denies any homosexual activity. He discusses his adaptation to his wife's decision to cease sexual activity with him. He has frequented prostitutes in the Far East, where he traveled regularly on business. It seems impossible to him that he might have AIDS, although he admits to having contracted syphilis 4 years before his current illness. On discharge, Mr. Zeigler is given the diagnosis of AIDS, with the only clear risk factor his sexual contact with prostitutes. Six months later Mr. Zeigler and his wife return to the United States for further evaluation of his mental status. His wife is concerned that he has become depressed because he is no longer able to handle his financial affairs. She feels his personality has undergone a radical change in that he no longer seems to care about anything, in spite of the fact that his appetite has returned to normal and he has regained much of his lost weight. Much of his time is now spent sitting idly in their garden. When examined, Mr. Zeigler appears to be in good physical health. However, his mental condition has obviously deteriorated; it is not possible to conduct an interview in English although previously he had spoken several languages fluently. He smiles pleasantly, but is both disoriented and confused, even when speaking in Spanish. This surprises even his wife, since she had not been aware of this change in his cognitive functioning. He has poor short-term memory and cannot perform simple calculations. His remote memory is intact, although his wife feels that he has confused some historical events. Mr. Zeigler seems unaware that there are any deficits in his intellectual functioning. Medical evaluation does not reveal any active infections. (Reprinted with permission from DSM-IV Casebook.) Clinicians began to recognize the variety of neuropsychiatric manifestations of HIV in the mid-1980s. Most prominent were major mood disturbances (major depressive, dysthymic, and less commonly, bipolar disorders) and a characteristic progressive cognitive impairment that was labeled AIDS dementia complex. Rarely, patients developed psychoses, at times with a schizophrenic presentation, as well as alterations of personality. Later, carefully conducted epidemiological studies revealed that persons at highest risk for HIV infection suffered elevated rates of mood and substance use disorders before contracting the disease. Intertwined with syndromes that were thought to be direct results of primary HIV infection of the CNS or secondary complications from other infections or tumors were a variety of adjustment and mood disturbances, reflecting responses to a progressive, inevitably terminal disease. The psychopathological manifestations of HIV cover the major symptom clusters, as well as AIDS dementia complex and delirium. Clinicians have used empirical treatments, many with substantial symptomatic response. Intervention with antiviral therapies also has shown beneficial behavioral effects, especially when CSF indices of CNS infective activity have suggested that the primary disease has increased in its activity. However, there have been few carefully conducted therapeutic trials to establish the overall efficacy of any symptomatic psychopharmacotherapy. AIDS dementia complex is characterized predominantly by a subcortical presentation, with prominent psychomotor slowing and difficulties with concentration and memory. Early associated motor deficits include ataxia, leg weakness, tremor, and loss of fine motor coordination. Patients commonly become apathetic or withdrawn. The course is steadily progressive, at times punctuated by abrupt acceleration. Like other dementing disorders, AIDS dementia complex progresses to a late stage characterized by severe dementia, mutism, incontinence, paraplegia, and in some cases, myoclonus. During the latter part of the 1980s, controversy developed regarding the temporal sequence of the emergence of cognitive abnormalities versus other symptoms reflecting the advance of HIV infection to full-blown AIDS. There is no dispute that AIDS dementia complex may be the predominant feature of AIDS for some patients, but there is uncertainty regarding the presence of cognitive abnormalities in patients who are both clinically asymptomatic and without laboratory evidence of encroaching immune suppression. Many patients with HIV develop a mild (minor) cognitive disorder that has many of the same features of AIDS dementia complex but that is as not cognitively severe or as impairing functionally. Recently, an American Academy of Neurology AIDS Task Force developed a set of standard nomenclature for neurological manifestations of HIV-1 infection, including both cognitive and peripheral neurological findings. In autopsy series, 75 to 90 percent of brains of patients dying from HIV infection show neuropathological alterations. In addition to changes due to secondary or opportunistic infections, there is widespread subcortical white matter pathology with relative sparing of cortical structures. Those diffuse, noninflammatory changes are now subsumed under HIV leukoencephalopathy. Microscopic examination also reveals foamy macrophages and multinucleated giant cells invading both white matter and subcortical nuclei, particularly basal ganglia structures. Such focal inflammatory findings are characterized as HIV encephalitis. Also, there may be pathology in the spinal cord associated with paraparesis, particularly vacuolar myelopathy. Insofar as many other patients have significant cognitive deficits in the context of relatively little pathological alterations, it is clear why investigators have encountered difficulty when attempting strict clinical-pathological correlation. The mechanism by which HIV causes its functional effects remains unknown. Current data point to (1) neurons and supporting cellular structures, through the actions of the virus itself or from its coat proteins; (2) the undesirable effects of activated immune components (such as activated macrophages); and (3) possible excitatory neurotoxic effects of endogenous neurotransmitters that have been dumped into surrounding interstitial fluids (e.g., quinolinic acid affecting glutamate receptor subtypes, leading to the toxic accumulation of intracellular calcium). The diagnosis of HIV-related neuropsychiatric syndromes requires a high index of suspicion and a sensitivity to possible demographic risk factors, including homosexual behavior, sexual promiscuity, intravenous substance abuse, and sexual relations with high-risk partners. In addition, there is a gradual movement of the HIV virus into the broader heterosexual population. Psychopathological changes may precede frankly defined cognitive abnormalities. The clinician also must be alert to early, subtle intellectual decline: the patient may remain within the normal range on standard neuropsychological tests but may perform at a level lower than was attained previously. In addition to neuropsychological assessment, neuroimaging may demonstrate abnormalities in subcortical periventricular and deep white matter. AIDS dementia complex has become a major target in pharmacotherapeutic trials to cure or ameliorate the effects of HIV infection. Preventing its emergence or prolonging the time it takes to appear have become possible end points for some studies. Others are considering AIDS dementia complex as a direct target for intervention. Future antiviral pharmacotherapies may be targeted specifically to the brain to eradicate any possible reservoirs of HIV, in a fashion similar to the use of irradiation or antitumor agents in children with leukemia. Immune and Autoimmune Disorders Three broadly defined pathophysiological mechanisms involving the immune system can be associated with neuropsychiatric

disorders: (1) hypofunction of the immune system may contribute to infectious diseases and possibly to neoplastic illnesses; (2) definite or putative autoimmune diseases may cause behavioral disturbances by affecting the function of organ systems in a way that compromises brain activity (e.g., the hyperthyroidism of Graves' disease or hepatic failure from primary biliary cirrhosis); (3) autoimmune illnesses may also affect brain function more directly by causing cerebral ischemia due to vasculitis or by direct CNS parenchymal inflammation. Some primary neurological diseases (e.g., multiple sclerosis) may involve autoimmune pathophysiology ( Fig. 10-4). A major example of an autoimmune disorder involving the CNS is systemic lupus erythematosus.

FIGURE 10-4 Multiple sclerosis. Coronal section of cerebral hemispheres showing large, sharply demarcated plaques adjacent to the bodies of the lateral ventricles (arrows). Other plaques are found adjacent to the temporal horns and smaller plaques are present in the subcortical white matter and centra semiovales. (Reprinted with permission from Golden A, Powell DE, Jennings CD: Pathology: Understanding Human Disease, ed 2. Williams & Wilkins, Baltimore, 1985.)

Cathy Jarvis, a 25-year-old mother with a 3-year history of systemic lupus erythematosus was admitted to a university hospital in an acute confusional state with inability to maintain attention or to carry on a coherent conversation and with marked disorientation to time and place. Before her hospitalization she had become progressively more confused over a number of days, and had started to believe that the neighbors were watching her. On the day of admission she had run out of her house and into the street in a state of uncontrollable agitation. On admission to the hospital emergency room, Cathy was given intramuscular haloperidol (Haldol), but by the next morning her clinical picture had worsened dramatically. She was now rigid, mute, uncommunicative, and unresponsive to all questions and she exhibited facial grimacing. Her course fluctuated so that at times she became excited, screamed continuously, and seemed to be responding to auditory and visual hallucinations; at other times she was mute and rigid. She required total nursing care, with intravenous feeding, catheterization, and four-point restraint. She received frequent sedation with lorazepam (Ativan), a short-acting benzodiazepine. Because she was thought to have lupus cerebritis, intravenous methylprednisolone (Depo-Medrol), a steroid, was begun, but there was no improvement in her clinical condition. During the next 3 weeks Cathy's condition deteriorated. She lost considerable weight, was unable to stand, and continued to require total nursing care. On day 28 she was referred for electroconvulsive therapy (ECT). After seven treatments she gradually responded, sought to feed herself and to stand, was more alert, and recognized her family. Rigidity was now only occasionally present. A lumbar puncture demonstrated the presence of immunoglobulin-G (IgG) antineuronal antibodies in high titer, consistent with a diagnosis of CNS involvement with lupus. Over the next few weeks periods of lucidity alternated with rigidity, mutism, negativism, and staring. By day 90 of Cathy's hospitalization, a second course of ECT was begun. After 10 treatments, she was verbal, euthymic, and cooperative. (Reprinted with permission from DSM-IV Casebook.) Often lupus is considered in the differential diagnosis of new-onset psychopathological syndromes. Although the etiology of lupus is not known, evidence implicates immunological mechanisms in its pathogenesis. Numerous organ systems may be involved. The disease may affect brain function (thereby producing psychiatric symptoms) indirectly, through such mechanisms as fever, renal failure, or pulmonary disease. In a minority of patients it may cause pathology directly, most likely from vasculitis affecting cerebral vessels. Patients with CNS disease may experience seizures, transverse myelopathies, or behavioral abnormalities, including delirium, psychotic syndromes, and affective lability. Clinicians evaluating patients with psychiatric symptoms of recent onset (particularly women in the second through fifth decades of life) should carefully consider the medical history, review of systems, physical examination findings, and routine laboratory screens, to look for evidence of systemic organ system involvement. The erythrocyte sedimentation rate (ESR), while nonspecific, is substantially elevated during acute CNS lupus and provides a useful screen. More specific laboratory tests (e.g., antinuclear antibody assay and antibodies to double-stranded deoxyribonucleic acid [DNA]) may be pursued when indicated. Neuroimaging scans may show cerebral infarctions but are often normal early in the disease. Glucocorticoids are the mainstay of treatment for acute CNS systemic lupus erythematosus. Psychotropic medications may be needed to treat specific behavioral symptoms (e.g., antipsychotic agents for severe agitation during delirium). Cardiovascular Disease Because the extremely high metabolic activity of the brain is obligatorily aerobic, the brain is exquisitely sensitive to relatively minor perturbations in blood flow. Thus, alterations in cardiac function ranging from grossly obvious (cardiogenic shock) to relatively subtle (compensated congestive heart failure, chronic low-output states) often manifest with CNS dysfunction. The consequent psychiatric phenomenology may vary due to largely unknown factors, but delirium, dementia, and depressive episodes are especially common. Perfusion failure, depending on its cause, may lead to insidious, gradual changes or dramatic decrements in function. Transient profound drops in blood pressure, typically associated with major cardiac events (including surgery), may lead to mental status alterations that are difficult to pinpoint initially. Clinicians are faced with distinguishing soon-to-remit symptoms, such as postoperative delirium arising from metabolic imbalances, from subtle persisting intellectual and behavioral alterations caused by hypofusion leading to cell death. Intrinsic cardiac illness, such as mural thrombus or valvular disease, may also be a source of embolic cerebral infarction ( Fig. 10-5). Cardiovascular disease may also lead to brain dysfunction by serving as a risk factor for cerebrovascular disease. Identified risk factors for stroke include hypertension, diabetes mellitus, cigarette smoking, atrial fibrillation, left ventricular hypertrophy, and coronary artery disease.

FIGURE 10-5 Acute cortical infarction. A and B, Proton-density and T2-weighted axial MRI scans show increased signal intensity within the medial cortex of left frontal and parietal lobes. Note swelling of gray matter and prominence of blood vessels within this lesion. C and D T1-weighted axial MRI scans before and after gadolinium administration demonstrate several linear foci of contrast enhancement within the area of infarction in the left frontal and parietal lobes, most consistent with enhancing arterial branches. Contrast enhancement of arterial branches is consistent with static blood flow within the infarct, and generally is seen only within the first few hours to 5 days after the onset of acute infarction. (Reprinted with permission from Rowland LP, editor: Merritt's Textbook of Neurology, ed 9. Williams & Wilkins, Baltimore, 1995.)

Cerebrovascular disease of any cause and pathophysiology—thrombotic, embolic, or hemorrhagic—will affect brain function. Psychiatric symptoms may develop

either suddenly (presumably in relation to abrupt neuronal losses and dysregulation) or gradually (perhaps in relation to cumulative infarcted brain tissue and to longer-term adaptations of neurochemical systems). Table 10-11 presents an overview of the variety of cerebrovascular events.

Table 10-11 Types of Cerebrovascular Events

Recent data have undercut the long-held notion that vascular disease due to a vascular etiology always progresses in stair-step fashion, as has been described for the course of vascular dementia. Rather, progression appears to vary in rate and form, depending both on the type of vasculature affected (large versus small vessels) and on basic pathobiology (perfusion insufficiency versus occlusive disease). It is important to recognize that psychiatric phenomena may manifest without other clinical evidence of a neurological event. For example, patients with right parietal infarction have presented with delirium but no other neurological symptoms or signs. Alternatively, an infarction in the distribution of the left middle cerebral artery may cause Wernicke's aphasia, characterized by fluent paraphasic or jargon-filled speech, poor comprehension and repetition, and suspicious or aggressive behavioral responses. No other signs of cerebral disease may be evident, and such patients have been misdiagnosed as having paranoid schizophrenia. It is also important to understand that pathology does not specify phenomenology. For example, patients with multiple infarcts on MRI are often labeled as having vascular dementia; however, multiple infarctions may manifest with dementia, with other behavioral syndromes (mood disorder, psychosis, anxiety, personality change), or with no definable neuropsychiatric syndrome. Congenital and Hereditary Conditions Patients with congenital and hereditary conditions often present for psychiatric evaluation because of the frequency of associated behavioral disturbances. A 15-year-old boy was brought to the emergency room by his mother, who, clutching the on-call resident's arm, pleaded, “You've got to admit him; I just can't take it anymore.” The patient had been brought home from a special school by his mother 6 months previously. The mother showed the resident papers from the school that indicated that the patient's IQ was 45. He had had several placements, beginning at age 8. On visiting days, the boy always pleaded with his mother, “Mommy, take me home.” After a year or so away, the patient would be brought home by his mother, who had always been wracked by guilt because of his retardation and her inability to manage him in the home. The patient was an only child whose parents had been divorced for the past 4 years. The father had moved to another city. During the last 6 months at home, the patient had increasingly become a behavior problem. He was about 5'9" tall and weighed almost 200 pounds. He had become destructive of property at home—breaking dishes and a chair during angry tantrums—and, more recently, physically aggressive. He had hit his mother on the arm and shoulder during a recent scuffle that began when she tried to get him to stop banging a broom on the apartment floor. The mother showed her bruises to the resident and threatened to call the mayor's office if the hospital refused to admit her son. On examination, the boy was observed to have the typical signs of Down syndrome, including thick facial features, slightly protruding tongue, epicanthic fold of the eyelids, and simian crease of the palms of the hands. With indistinct and slurred speech, the boy insisted that he “didn't mean to hurt anybody.” (Reprinted with permission from DSM-IV Casebook.) Congenital and hereditary conditions are of great significance in the understanding of brain-behavior relationships because they are often seen in biologically homogeneous populations with relatively specific behavioral and neuropsychiatric syndromes. Congenital conditions are caused either by genetic abnormalities affecting autosomes, sex chromosomes, or single genes or by fetal insults during the prenatal, perinatal, or immediate postnatal periods. Table 10-12 lists several developmental and hereditary disorders with significant neuropsychiatric manifestations. In DSM-IV these conditions are classified according to the age at which symptoms manifest, what symptoms are present, and whether the symptoms are progressive or static.

Table 10-12 Examples of Developmental and Hereditary Disorders With Neuropsychiatric Manifestations

Down Syndrome Down syndrome results in static phenotypic abnormalities, including characteristic facies and mental retardation, and has been associated with a progressive decline in functioning beginning in the third or fourth decade of life. Alzheimerlike pathological changes are frequently detected at autopsy, even in patients who did not exhibit functional decline before death. Fragile X Syndrome Fragile X syndrome is the second most common cause of mental retardation in men and one of the few known causes of the autism syndrome. Female heterozygotes also manifest significant psychiatric pathology, including mood disorders, difficulties with behavioral control, and a neuropsychological profile of dyscalculia, right-left disorientation, and constructional dyspraxia similar to the Gerstmann syndrome, described in patients with acquired lesions in the dominant parietal lobe. Learning disorders usually become obvious when the child begins school. Huntington's Disease Huntington's disease, also known as Huntington's chorea, has been the focus of intensive neuropsychiatric, genetic, and pharmacological research since the 1970s. First described by George Huntington on Long Island in 1872, the disorder has received intense scrutiny, and its site on chromosome 4 has been determined. The disorder is related to an unstable trinucleotide repeat (CAG), associated with more than 36 copies of the specific sequence. Onset typically occurs in middle life, usually between ages 25 and 50 years. The juvenile form, with onset occurring during adolescence, is somewhat different phenomenologically, with a greater degree of dystonia early in the disease process and a faster rate of disease progression. A greater number of CAG trinucleotide repeats is associated with an earlier age of onset of clinical disease. Lower cognitive performance is detectable in those clinically asymptomatic at-risk individuals who have greater numbers of repeats. A greater number of repeats is associated with more severe neuronal loss in both caudate and putamen at postmortem examination, and perhaps a faster rate of pathological deterioration. Although the exact neurobiological role of the abnormal protein ( huntingtin) encoded in Huntington's disease remains

unknown, other findings point to defects in mitochondrial energetics as a possible contributing mechanism. Huntington's disease is not diagnosed formally until the typical movements appear, although both psychiatric and neuropsychological manifestations may precede the emergence of motor abnormalities. The psychopathology associated with Huntington's disease has a wide range of manifestations, commonly including affective presentations (typically depression, but mania as well); psychoses, often with a schizophrenic appearance; personality changes, and anxiety disorders. Some individuals, however, may proceed through the entire course of the illness with no evident psychopathology. Often the psychopathology is most florid during the early and middle stages of the disease, but as the characteristic subcortical dementia proceeds patients begin to exhibit less characteristic behavior and thus appear less symptomatic. The suicide rate is higher in patients with Huntington's disease than in the general population but suicidal ideation may be difficult to detect because patients tend to be less spontaneous and forthcoming as a result of the cognitive difficulties associated with the disorder. Interviewers must take an active or probing approach; patients who quickly pass off inquiries when presented with open-ended questions may provide more information when queried with specifically structured interview methods. The cognitive disorder of Huntington's disease is more consistent in its presentation than the psychopathological picture, although it too evolves over the course of the disorder. Patients usually experience mild memory difficulties, and the first symptoms may be subtle problems with organizing, planning, and sequencing. Spontaneity and verbal elaboration may be diminished relatively early, although that appears to be somewhat more variable in its time of onset. As the disease progresses, psychomotor slowing progresses relatively rapidly, with concomitant difficulty with complex tasks, while recall of old knowledge and factual information remains less affected. Unlike patients with dementia of the Alzheimer's type, many patients with Huntington's disease remain insightful long into the course of their disease. Thus, their mood disturbances and potential suicidality may be tied in part to a clear realization of their situation. Indeed, even as patients respond to standard antidepressant therapy with enhanced sleep, energy, appetite, and improved overall mood state, they may remain realistically pessimistic about their long-term situation. Patients with Huntington's disease begin to develop an apathetic appearance as the disease progresses. Early in the course, they continue to show interest and responsiveness when presented with structured situations in which they can take part; frank apathy and disinterest develop later and persist even in the context of prompted or structured assistance. Although some degree of verbal learning impairment is an early feature of the dementia, it is more prominent later in the disease course. Similarly, subtle visuospatial processing problems may occur early but do not become prominent clinically until later. Just as the cognitive disturbance of Huntington's disease evolves slowly, so too there is a gradual change in the associated movement disorder. In most affected adults the movement disorder is typically choreiform at the outset but becomes more dystonic and bradykinetic as the disease progresses. Toward the end of the disease course, patients are bedridden, mute, and overcome by a severe dystonic state. The pathology and neurobiology of Huntington's disease have been studied intensively in recent years ( Fig. 10-6). The striatum bears the brunt of the pathology, with interruption of crucial corticostriatothalamocortical relays. Although there are no immediate, reciprocal corticostriatal connections, that multineuronal pathway similarly modulates motor function, cognition, and perhaps mood. Recent theories suggest abnormal function of excitatory neurotransmitters, most apparently acting on glutamate receptors, that serve as endogenous neurotoxins. Although efforts have been made to use symptomatic pharmacological treatments for both the psychiatric and motor symptoms, more recent pharmacotherapeutic trials have aimed at preventing progression of the disease by employing potential glutamate receptor blockers. Such efforts have provided models for similar therapeutic approaches to Parkinson's disease and Alzheimer's disease.

FIGURE 10-6 Huntington's chorea. There is marked atrophy of the caudate nuclei (arrows) and mild dilatation of the lateral ventricles. (Reprinted with permission from Golden A, Powell DE, Jennings CD: Pathology: Understanding Human Disease, ed 2. Williams & Wilkins, Baltimore, 1985.)

The mood disorders associated with Huntington's disease have proved amenable to symptomatic treatments. Standard doses of antidepressant medications may be needed, although patients often respond sensitively to rapid changes in medication and experience unwanted adverse effects. ECT has been beneficial for severe major depressive symptoms, especially in high-risk suicidal patients. The schizophrenia-like presentations of Huntington's disease appear less responsive to antipsychotic therapy than phenomenologically similar idiopathic disturbances. Patients with Huntington's–disease–related anxiety disorders have shown sufficient benefit from available medication regimens to warrant empirical trials. Psychotherapy, usually with the patient and family treated together, may lead to substantial therapeutic gains. Clinician commitment to the long haul may prove especially reassuring and stabilizing. Like other hereditary neuropsychiatric disorders, Huntington's disease illustrates the need for all psychiatric evaluations to include a careful documentation of family history. Patients with Huntington's disease may present with mood or psychotic disturbances and no apparent abnormal involuntary movements and may be treated symptomatically with pharmacotherapeutic agents, only to evince the characteristic motor disorder later. Ignorance of the family history has led some to misinterpret that progression as evidence of tardive dyskinesia. The patient may remain incorrectly diagnosed until cognitive impairment becomes unmistakable. In the meantime, patients and families have lost the opportunity to clarify their life plans and develop support for future needs. Psychiatrists must remain vigilant in taking the family history whenever evaluating a new patient. Other Conditions Learning disorders involving left hemisphere functions such as reading, writing, or mathematics are well known clinically. A learning disorder of the right hemisphere has been described that is characterized by intact linguistic and academic skills; left-sided soft (nonlocalizing) neurological signs; and profound impairments in functions dependent on the right hemisphere, including visuospatial skills, modulation of affect, and the paralinguistic aspects of communication. The etiology of the learning disorder is unknown, although a retrospective history of prenatal or perinatal insults is common, as is a family history of similar impairments. Acute intermittent porphyria is a hereditary disorder that is intermittent. In between episodic attacks, most patients maintain normal development. The leukodystrophies and degenerative hereditary disorders listed in Table 10-12 can produce symptoms during childhood or not until adulthood. Development until the appearance of symptoms is normal. However, in each of these disorders psychiatric symptomatology can precede other evidence of the disease process and lead to an erroneous diagnosis of an idiopathic psychiatric disorder. Physiological Disorders—Epilepsy Epilepsy is the prototype of a physiological disease process that manifests psychiatric symptoms. It has long held the interest of neuropsychiatry and has been studied intensively, if not always fruitfully. The complexities of defining brain-behavior relationships in epilepsy merit extended discussion. Definition Epilepsy is defined as a condition of recurrent seizures due to CNS disease or dysfunction. Seizures are behavioral alterations of abrupt onset and termination that are associated with sudden electrical discharges of the brain. Although the essential paroxysmal form remains constant and in fact defines a seizure, the content of the behavioral disturbance can vary widely. Seizures can be generally classified into two broad categories, generalized and focal. In generalized seizures the electrical abnormality usually originates from subcortical structures (primarily the brainstem) and then spreads simultaneously to all areas of the cortex. Loss of consciousness is invariable, and the seizure phenomenology is symmetrical and bilateral. Focal seizures originate from a specific brain locality, usually the temporal lobe. The abnormal electrical discharge may remain at the site of origin, proceed gradually to adjacent areas, or spread to include the entire cortex (secondary generalization). The clinical phenomenology of a focal seizure depends on the site from which that seizure originates and may be unilateral and restricted to a particular muscle group, sensation, affect, and so on. The epilepsies are classified based on the type of seizure and the inferred anatomical substrate ( Table 10-13). Seizure type and phenomenology are usually constant within the course of a particular patient's disorder. The stereotyped presentation is a major feature of

evaluation, diagnosis, and assessment of treatment efficacy.

Table 10-13 Classification of the Epilepsies

Clinical Features Seizures can proceed in stages and may include a prodrome, aura, ictus, and a postictal period. Psychopathology may manifest during any of these stages as well as during the interictal (between-seizure) period ( Fig. 10-7). A prodrome can be seen in generalized epilepsy, although it is more common in focal epilepsy, particularly temporal lobe epilepsy. A prodrome may consist of irritability, apprehension, sullenness, or a sense of discomfort or disease that builds up gradually over hours to days before a seizure. The prodromal state remits abruptly with the onset of the seizure. The pathophysiological basis for the prodromal state is unknown.

FIGURE 10-7 Progression of phases in epileptic seizure disorders.

Auras are focal seizures or the initial focal onset of a seizure and are associated with definable abnormal electrical discharges. Auras are abrupt in onset, last for seconds to minutes, may progress to a generalized seizure, or may terminate as the seizure ends. The type of clinical phenomenon depends on the site of origin and can include motor, sensory, autonomic, perceptual, cognitive, and affective abnormalities. Table 10-14 lists a number of common clinical manifestations of auras or focal seizures based on the anatomical site of origin. The auras accompanying seizures originating in the temporal lobe are the most varied. In general, auras may comprise a variety of symptoms and may have unique, individual-specific features, such as the crying out of a particular phrase in a particular language. Despite the great variety of auras, in any individual auras tend to be stereotyped and consistent from seizure to seizure.

Table 10-14 Neuropsychiatric Manifestations (in the Aura and Ictus) of Focal Epilepsy

The ictus, the epileptic attack, may be generalized or focal. Primary generalized tonic-clonic epilepsy (grand mal epilepsy) is characterized by a behavioral arrest or sudden loss of consciousness. This is followed by tonic extension of the upper and lower extremities, then clonic, rhythmic jerking of the extremities. The jerking gradually decreases in frequency, leading to muscle flaccidity. The total duration of the ictus is usually 2 to 5 minutes. Associated features may include urinary and bowel incontinence, sweating, and tachycardia. Generalized absence or petit mal epilepsy is characterized by brief lapses of consciousness lasting 3 to 30 seconds. There are no associated tonic-clonic movements, nor is there loss of postural tone. There may be a slight rhythmical twitching of the mouth. Seizures can occur numerous times during the day. Absence seizures are common and occur primarily in children ages 4 to 12 years. In both types of generalized epilepsies there is amnesia for the epileptic event. Myoclonic epilepsy is characterized by nonrhythmic, brief jerks of the limbs, trunk, and head. Myoclonic jerks are asynchronous, with body parts jerking at different times and in different sequences, and there is no loss of consciousness. Myoclonic epilepsy is frequently of familial etiology, although it may be associated with brain injury or systemic disease that affects brain function, such as chronic renal disease or hepatic insufficiency. Partial or focal seizures are distinguished by their localized site of origin. The symptomatology can be simple (elementary) or complex, with the latter characterized by some degree of impairment of consciousness. Partial seizures with elementary symptomatology include focal motor symptoms, focal sensory symptoms, autonomic symptoms, or mixed symptomatology; consciousness is retained throughout the episode, although the seizure discharges can spread to other areas of the brain (jacksonian march) and can also develop into a generalized seizure (secondary generalization). The postictal period may be characterized by a residual focal deficit, such as motor weakness (Todd's paralysis) or dysphasia. Secondary generalization may occur rapidly, giving the false impression of an immediate generalized seizure; videotaped monitoring with simultaneous EEG may be necessary for differentiation. Partial complex seizures, also known as psychomotor seizures, temporal lobe seizures, or temporal-limbic seizures, are perhaps of greatest interest to psychiatry. The great majority of partial complex seizures originate in the temporal lobes, but the frontal lobes and other sites have also been recorded as seizure foci. The range of presenting symptomatology varies from patient to patient and may include a broad spectrum of disturbances in behavior, cognition, and affect. Auras are frequent in partial complex seizures, representing the focal onset, and it may be difficult to distinguish the aura from the ictus. They are generally associated with clouding of consciousness but retention of posture and muscle tone. The patient may exhibit simple or complex movements, such as pulling on clothing, buttoning or unbuttoning clothing, purposeless hand movements, and fumbling with objects, or may continue with the behavior initiated prior to the seizure, such as closing a window. There may be staring, lip smacking, and wandering. The actual ictus cannot be distinguished from the aura.

Psychiatrists should be familiar with the range of symptomatology associated with partial complex or temporal lobe epilepsy because that disorder is an important diagnostic consideration in adult patients presenting with the new onset of behavioral disturbances. In light of the protean possible manifestations of partial complex epilepsy, the physician must keep in mind that there is a general consistency to the form of partial complex seizures: They have a definite and observable onset and termination; they are always associated with impairment in consciousness, such as confusion or inability to perform cognitive tasks; and they are relatively stereotyped for an individual from episode to episode. The postictal period may also be characterized by severe disturbances of behavior. Primary generalized tonic-clonic seizures are usually followed by a period of sleep, sometimes headache, and nausea. Focal or partial seizures may have residual focal deficits of varying duration. In partial complex seizures, recovery of consciousness may lag behind recovery of motor function. Frequently automatic behavior, such as repetitive mouth movements, arm movements, and pacing, can be observed. As the postictal period is essentially a delirious state, confusion and cognitive impairment remain. Any disturbance of mood is possible, including anger, lovingness, and the epileptic furor (random, typically nondirected displays of violence and property destruction). The postictal period usually lasts only minutes, although it may last hours to days. A very rare but disturbing psychiatric postictal complication has been termed subacute postictal aggression. This is associated with directed violence that occurs in well-documented cases of epilepsy, where a patient stereotypically becomes increasingly psychotic, paranoid, and combative following a bout of uncontrolled seizures. Treatment requires both anticonvulsant and antipsychotic medications, although reported cases have occurred in patients who have poorly controlled epilepsy. Course Epilepsy has an annual incidence of approximately 20 to 50 new cases per 100,000 population. The prevalence is 0.2 to 1.0 percent. The majority of cases of epilepsy in patients older than 15 years are of the partial or focal type. Only approximately 25 percent of adolescents or adults over the age of 15 years with seizures have generalized epilepsy. Seizures with onset in childhood are more commonly generalized, particularly absence seizures. Primary generalized tonic-clonic seizures usually occur for the first time before the age of 35 years, although they can occur at any age; absence seizures usually first manifest between the ages of 4 and 12 years. Focal seizures also have their onset commonly before the age of 20 years. The natural history of seizure disorders has not been defined clearly. Up to one third of all seizures may remit spontaneously without treatment. Absence seizures are generally outgrown by the age of 20 years, although many patients do develop another form of generalized epilepsy as adults. The etiological considerations for seizures vary with the age at onset. Early-onset epilepsy is usually a concomitant of genetic factors or an insult to the developing neural system in utero or in childhood; the latter can include trauma, infections, or toxic exposures. For seizures starting in adulthood, the etiological considerations include alcohol or drug withdrawal, trauma, infection, and tumors. The tumors are the primary causes of seizure disorders during the middle adult years; cerebrovascular disease is the most common etiology among the elderly. Treatment Anticonvulsant pharmacotherapy first developed empirically, without specific knowledge of either the pathophysiology of seizures or the neurochemical mechanisms of therapeutic agents. Although the primary prescribed anticonvulsants (carbamazepine [Tegretol], phenytoin [Dilantin], valproic acid [Depakene], and phenobarbital) have remained consistent since the 1980s, recent years have seen the rapid emergence of new compounds ( Table 10-15). Most medications work through one of three mechanisms of action: potentiation of g-aminobutyric acid (GABA)-mediated neuronal inhibition, inhibition of glutamate-mediated excitatory postsynaptic receptors, or control of sodium and calcium voltage-gated ion channels; Table 10-16 summarizes these actions. It is particularly important to note that anticonvulsant medications have proven to be a fruitful source of novel psychiatric compounds.

Table 10-15 Chronology* of Antiepileptic Drugs

Table 10-16 Antiepileptic Drugs

Psychopathology Psychopathology, namely disturbances in behavior, cognition, perception, or mood, can occur at any point in the seizure process. The prodrome may be characterized by a sense of irritability or apprehension. Families often report that they know when a relative is going to have a seizure on the basis of a change in temperament or disposition. Auras may include a variety of psychopathology, including dissociative experiences, hallucinations in all spheres, derealization, depersonalization, and disturbances of mood or affect. The disturbances of mood, such as a subjective sense of fear, anxiety, or depression, can be distinguished from normal expressions of the same emotion in that generally they are more crude, stereotyped, and brief emotional states. Joy, elation, or euphoria is less common. Ictal states can manifest striking changes in behavior that are likely to be coarse and disorganized. The list of ictal manifestations in Table 10-14 includes a variety of hallucinations and dissociative experiences, as well as sudden and unpredictable shifts in mood. Other sensory or psychic experiences can occur out of their usual context (a classic case is that of a woman who had spontaneous orgasms in church). The postictal state is a delirium that can display the full range of disturbances in level of arousal, ranging from stupor to hypervigilance. Partial seizures may be followed by a milder delirium that is detectable only from disorganization in behavior or difficulty with simple cognitive tasks such as registration and repetition. The issue of interictal psychopathology has been much studied and debated, in general, the psychiatric symptomatology associated with the prodrome, aura, ictus, and postictal state is remarkably broad—virtually any thought, feeling, movement, or perception that the brain can produce may be seen. The clinician must be attentive to the form and course of these symptoms whenever considering epilepsy as a possible etiological explanation for abnormal behavior. Violence and Aggression The issue of violence or aggression as a neuropsychiatric manifestation of an ictus has provoked much controversy. In the legal arena epilepsy is occasionally invoked as a defense to mitigate culpability for a violent or even murderous act. Irritability or agitation can be a component of the prodrome, the aura and ictus can encompass angry affect and striking out, and the postictal state can manifest with fear and confusion with intact motor function. Although this might suggest the possibility of violent acts as a component of seizures, there is limited potential for such actions. Automatic acts of violence during epileptic seizures are short-lived, fragmentary, undirected, and most often occur in response to actions (such as attempts at restraint) that provoke or irritate the seizing individual. Examples include spitting, swearing, and striking out in a flailing fashion. For violence to be considered a manifestation of epilepsy, it must conform to the known

temporal sequence and symptomatology of a seizure; namely, there must be a clear onset and termination, together with other clinical signs (e.g., confusion, incontinence, and impairment of consciousness) and stereotypy. A special 1981 epilepsy task force of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS), after studying videotapes of selected violent patients with epilepsy, recommended criteria to determine if a particular act of violence is ictal: (1) a clear diagnosis of epilepsy; (2) documented automatisms, preferably on videotape; (3) documented aggression during the automatisms that corresponds to an EEG-proved ictus; (4) demonstration that the aggressive act is characteristic of the patient's usual seizure form; and (5) clinical consensus that the act was related to the actual seizure. People with epilepsy have long been thought to display psychopathology during the interictal period as well. Epilepsy was thought to be a subtype or complication of insanity, and so was included in most psychiatric nosologies of the past two centuries. Epilepsy patients typically were housed in asylums for the insane. In 1791 Philippe Pinel included among his recommendations for asylums the suggestion that other patients be shielded from epilepsy patients because of their “almost always incurable” status and his sense that “few objects are found to inspire so much horror and repugnance . . . than the sight of epileptic fits.” Griesinger stated that “a very great number of epileptics are in a state of chronic mental disease even during the intervals between the attacks.” Interictal psychopathology can be grouped into psychotic disorders, mood disorders, personality abnormalities, cognitive disorders, and secondary repercussions. Psychotic Disorders Jean Etienne Esquirol, in his 1845 description of female institutionalized epilepsy patients, reported frequent psychotic symptoms, including hallucinations in all spheres: They have hallucinations most varied . . . they think they see luminous bodies by which they fear they might be embraced . . . they smell odors the most fetid . . . they hear sounds like the bursting of a thunderbolt, the roll of drums, the clash of arms in the din of combat. Karl Jaspers, in General Psychopathology, classified epilepsy as one of the three major psychoses, along with schizophrenia and manic-depressive illness. He defined genuine epilepsy as “convulsive disorders which are not due to any known somatic process.” Numerous studies have evaluated psychosis among epilepsy patients; unfortunately, most have been hampered by the lack of clear or standardized definitions for the symptoms being investigated. In addition, many studies have not distinguished between psychosis occurring in the context of the ictus, the prodrome, or the postictal state, and many have not indicated whether such symptoms were detected specifically during periods of interictal electrical stability. Few studies have discriminated between symptoms occurring in clear consciousness versus those occurring coincident with impaired consciousness. Nonetheless, clinicians generally encounter a higher incidence of psychosis among epilepsy patients, particularly those with temporal lobe foci, than in the general population. Some studies have specifically referred to paranoid ideation, delusions, ideas of reference, visual hallucinations, and first-rank auditory hallucinations as being common. In 1963 Eliot Slater and A.W. Beard identified an atypical schizophrenia, characterized by visual and auditory hallucinations, ideas of reference, and persecutory delusions, occurring in the context of preservation of affect and a level of social adaptation better than that of comparably psychotic schizophrenia patients. They further noted that the psychotic symptoms did not occur until many years after the onset of seizures (a mean of 14 years) and then occurred with an apparent periodicity. The occurrence of the psychotic episodes was unrelated both to the frequency of seizures and to measured anticonvulsant efficacy. Although the true incidence or prevalence of psychotic disorders in epilepsy patients is unknown, there is general consensus that the psychotic disorder seen in epilepsy is distinct in form from idiopathic psychiatric diseases and is characterized by the features described by Slater and Beard. Other associated findings may include an association between psychosis and left hemispheric seizure focus (especially in the temporal lobe), female sex, sinistrality, or tissue abnormality (alien tissue, such as hamartomas or focal dysplasia, is more commonly found at autopsy or after surgical excision in the psychotic patients). These psychotic disturbances have been referred to as the schizophrenia-like psychosis of epilepsy and the interictal psychosis of epilepsy. Standard antipsychotic medications are beneficial symptomatically but not as efficacious as in idiopathic psychotic disorders. Some studies have noted marked improvement in the psychotic symptoms with improved seizure control following either pharmacotherapy or surgical excision of the seizure focus. A smaller number of studies have reported an increase in psychotic symptoms occurring with improved seizure control, prompting a theory of antagonism between symptoms of psychosis and seizure control. The observation of a consistent psychotic disorder of increased prevalence in epilepsy patients has led to an intense search for the underlying mechanism in the hope of describing a more general explanation for psychotic processes. Three hypothetical mechanisms for interictal psychoses have been advanced. The first hypothesis suggests that the schizophrenia-like illness in epilepsy is epileptic in origin or related to abnormal electrical brain discharges. Kindling, an experimental animal model for the spread of epileptic foci, has been suggested as a paradigm for the development of psychosis in epilepsy. Chronic stimulation of the brain in animals can lower the electrical threshold for the development of electrical or clinical seizures. Over time, abnormal discharges develop at previously subthreshold levels of stimulation or even spontaneously. Abnormal behaviors associated with these experimentally induced brain discharges can also persist, even after stimulation has ceased and there are no motoric convulsions. It has been suggested that human kindling occurs at various brain foci, particularly the temporolimbic structures, resulting in psychotic and behavioral disturbances that may manifest only after years of seizure activity. A second hypothesis for the development of interictal psychosis focuses on a proposed antagonistic relationship between seizure frequency (or, more accurately, EEG abnormality) and psychotic symptoms: forced normalization is the putative process by which a psychosis of sudden onset can manifest with the achievement of seizure control and associated with a normal cortical EEG. Studies of forced normalization have primarily involved case reports, and findings have been difficult to replicate. Clinical treatment regimens based on the antagonism theory, such as allowing episodic seizures or performing ECT on psychotic epilepsy patients, have proved ineffective, further weakening that proposal. A third hypothesis to explain interictal psychosis suggests that it may not be related specifically to abnormal electrical activity but may instead reflect a common brain dysfunction that causes both epilepsy and psychosis. This hypothesis stresses the dysfunctional or broken brain inferred in epilepsy and regards the psychotic disorder as yet another symptomatic manifestation. Recent quantitative brain-imaging studies in epilepsy patients with psychotic disorders have not revealed consistent structural abnormalities within that patient group. However, specific symptom correlations have been reported, among them an increased frequency of temporal lobe structural abnormalities in epilepsy patients with auditory hallucinations. Similar findings associating specific psychotic symptoms with defined cerebral abnormalities have also been reported in other psychiatric conditions (e.g., schizophrenia). Further symptom-based research utilizing imaging and physiologically sensitive techniques may better delineate the brain regions where dysfunction can lead to particular psychotic symptoms. Mood Disorders Affective changes can occur as part of the seizure prodrome, aura, ictus, or postictal state. Irritability is a common prodromal manifestation. Temporal lobe auras may be accompanied by mood abnormalities, most commonly fear and anxiety, although a depressive affect is possible and, more rarely, elation or euphoria. Descriptions of postictal sadness are common. All of those affective changes are generally brief, lasting minutes to hours. They differ from normally experienced vacillations in mood, in that they occur independent of any particular context, and from the pervasive and enduring affective changes found in primary mood disorders. Mood disorders in the interictal period have not been studied as comprehensively as psychotic or personality disorders. Many authors have noted that epilepsy patients have a strong tendency to endorse items of sadness and anxiety on self-report inventories. Few studies have used clinical examinations or standardized interviews to determine the presence of mood disorders such as major depressive disorder or bipolar I disorder. One study of epilepsy patients diagnosed with major depressive disorder found that at least half of the patients had family histories of mood disorder and that no clear relation existed between severity of depression and seizure type, seizure frequency, seizure focus, or age at seizure onset. Although definitive studies of the incidence and prevalence of clinically defined mood disorders in epilepsy are needed, there is less support overall (compared with psychosis) for an elevated prevalence of mood disorders in epilepsy patient populations. Many patients do express persisting dysphoria, perhaps reflecting the dissatisfaction and maladjustment associated with a chronic disease. Regardless of the cause of the dysphoria or dissatisfaction in epilepsy patients, there is an increased prevalence of suicide attempts and completed suicides. The incidence of suicide in patients with epilepsy is fivefold greater than in the general population. In patients with temporal lobe epilepsy the incidence of suicide increases to 25 times that of the general population, but the underlying psychopathology remains to be defined. Personality Change There has been a long-standing misperception that an epileptic personality is distinguishable and common. Esquirol noted in his studies of 385 female epilepsy patients that “only one fifth were free from intellectual derangement, but nearly all of these were irritable, peculiar, and easily enraged.” Griesinger commented on the “dominant, suspicious, discontented, misanthropic perversion of sentiment . . . observed in many epileptics.” Eugen Bleuler spoke of the “epileptic excess of emotion . . . easily aroused, remarkably persistent . . . difficulty in abandoning any particular thought . . . fixation to a single theme . . . precise attention to detail.” Karl Jaspers described “viscosity, slowing down, explosiveness and dementia” as characteristic of epilepsy patients. These characterizations were frequently based on chronically institutionalized patient populations representing a selection of the most severely impaired patients, in whom the effects of brain injury (especially related to repeated seizures, status epilepticus, and recurrent hypoxia), the deprivations of institutionalization, and toxic treatments undoubtedly confounded clinical observation. More recent attempts at detecting a recognizable, diagnosable personality disorder in community samples of epilepsy patients resulted neither in the description of a discrete personality syndrome nor in a higher prevalence of known personality disorders.

Because standard personality inventories have not uncovered specific abnormalities in epilepsy patients some researchers have focused on particular traits or behaviors. An interictal behavior syndrome of temporal lobe epilepsy has been described that encompasses four traits or behaviors: (1) altered sexuality, usually a decreased interest in sexual matters but at times involving hypersexuality or deviant sexual interests; (2) hyperreligiosity, described as an unusually deepened interest in moral affairs and matters of global importance, with vivid case descriptions of multiple religious conversions and intrusive polemicizing; (3) hypergraphia, with patients maintaining voluminous writings, including journals, essays, and novels; and (4) viscosity or stickiness, a characteristic described for more than a century, including a preoccupation with detail, digressive or overly inclusive speech, and resulting impairments in social discourse. Although the literature supporting such a personality syndrome is rich with clinical case histories, systematic study to define such a syndrome has been difficult to replicate. Investigators using an 18-point inventory of those behaviors found they could not distinguish patients with epilepsy from other psychiatric populations or patients with temporal lobe epilepsy from those with generalized epilepsy. Thus, the bulk of data suggests that the clinical complex of overinclusiveness in speech, interpersonal action, and writing; alteration of sexuality; and intensified emotion and cognition (hypercosmiscity) is rare and not specific for temporal lobe epilepsy. However, isolated features of this cluster may be more common among patients with temporal lobe epilepsy. When the entire picture is encountered clinically in the absence of a readily apparent seizure disorder, the clinician may wish to pursue a more intensive evaluation if the patient fails to respond to standard psychiatric therapies. Cognitive Disorders An early view of epilepsy considered it a degenerative disorder with a progressive deterioration in cognition, similar to that seen in the degenerative dementias. Modern prospective studies, however, have disproved this belief and have demonstrated no progressive decline in cognitive skills in a general population of epilepsy patients. A subpopulation of patients with epilepsy does demonstrate a lower intelligence quotient (I.Q.) spread than the normal distribution. This probably results from a combination of factors, including the original brain damage or dysfunction responsible for the epilepsy, occasional disruption attributable to the seizure disorder, and drug effects. Numerous anticonvulsants, including ethosuximide (Zarontin), phenytoin, phenobarbital (Solfoton), and carbamazepine, have been demonstrated to lower performance on tasks of concentration, memory, and motor speed; motor speed is least impaired.) Epileptic dementia, while certainly uncommon, has been described in patients with defined CNS lesions or uncontrolled seizures. It probably reflects the cumulative effect of frequent seizure-induced hypoxic episodes and perhaps toxicity from long-standing treatment with high dosages of anticonvulsants. Phenytoin, in particular, has been demonstrated to cause cerebellar degeneration with long-term use. Behavioral and Secondary Repercussions Despite a less glamorous research appeal, the more compelling and clinically demanding aspects of interictal function may be the behavioral, interpersonal, and social problems arising from irritability, agitation, or aggression. There are no well-defined, systematic, or tested approaches to treating those behavioral difficulties when they arise. It was long believed that maladaptive behavior, particularly aggressive behavior, as characterized by physical assaultiveness, destructiveness, and self-injury, was more common in patients with epilepsy. Recent methodologically rigorous studies, however, demonstrated that maladaptive behavior does not correlate with the presence of epilepsy when epilepsy populations are compared with appropriately matched controls. Maladaptive behavior is, however, related to the overall extent of brain damage in both types of populations. This important point cannot be overemphasized: Epilepsy is a florid manifestation of a physiologically abnormal brain, and in most instances, the fundamental CNS dysfunction that causes seizures also causes associated neuropsychiatric abnormalities. Especially among severely afflicted epilepsy patients, obstacles to effective social functioning and personal autonomy pose the greatest therapeutic challenges for clinicians and families. Patients may not receive adequate education because seizures may interfere with daily school attendance. Patients may be restricted from many occupations owing to employers' fears of patients sustaining injury in the workplace. Limitations on driving can markedly diminish the independent functioning of these individuals and many patients are compelled to remain dependent on family, even into adulthood. Pseudoseizures Pseudoseizures simulate the motor behavior of true seizures but do not involve abnormal electrical discharges. Pseudoseizures can be distinguished from true seizures by the form of the seizure and by the lack of the usual associated features. The form does not fit the known patterns for epileptic attacks and can consist of random flailing about. Furthermore, the form can be variable from seizure to seizure, lacking the stereotypy typical of true seizures. Incontinence and tongue biting are rare. There is minimal confusion at the conclusion of the episode, and no abnormalities are detected on neurological examination. EEG can be helpful in distinguishing pseudoseizures, especially if one can be obtained during an event and then studied for evidence of electrical discharges that would correspond with the motor behavior. An EEG obtained after a true seizure should demonstrate areas of slowing that would not be seen after a pseudoseizure. Serum prolactin levels increase markedly immediately after a seizure and can be helpful in distinguishing true seizures from pseudoseizures. Video EEG telemetry is the definitive means of determining whether an observed seizure is epileptic in origin or a pseudoseizure. Pseudoseizures are more likely in patients who suppress emotion or express emotion through somatic means. Pseudoseizures most often are conversion disorders in which the patient does not have conscious volitional control of the behavior; rarely are pseudoseizures the result of faking or malingering. Pseudoseizures frequently occur in patients who have true epileptic disorders, confounding the diagnosis. W. Alwyn Lishman has aptly noted that the diagnostic error of interpreting epilepsy as pseudoseizures is probably much more common than the reverse and is far more detrimental to the patient's well-being. The diagnosis of pseudoseizures rests not on the presence of any particular personality traits or identifiable psychosocial stressors, but rather on the form of the seizure, associated features, and EEG confirmation. Primary Psychiatric Disorders The presence of intellectual deficits, whether identified with bedside procedures or on standardized neuropsychological tests, does not automatically warrant the diagnosis of a cognitive impairment disorder. Neuropsychological abnormalities occur frequently in many patient populations. Once neglected or considered epiphenomena of more central emotional disturbances, cognitive processing deficits are now known to be key components of clinical disorders such as major depressive disorder (especially in the elderly), acute and chronic schizophrenia, chronic alcohol dependence, and perhaps obsessive-compulsive disorder. Cognitive impairment disorders, such as dementia or delirium, or secondary psychiatric syndromes are all caused by specific disease processes; vigilant diagnostic evaluation usually leads to detection of a primary systemic or cerebral disturbance. Difficulties may arise when the cause is presumed but cannot be proved, as in the case of dementia of the Alzheimer's type, where the definite diagnosis must await postmortem brain examination. When a patient has both a major depressive syndrome and clinical findings consistent with incipient dementia of the Alzheimer's type, it may not be possible to determine immediately the fundamental disturbance being evaluated. Such confusing situations typically arise with the near-simultaneous onset of both symptom clusters or in patients who have experienced major depressive disorder previously. Such patients require careful definition of symptoms, initiation of therapy for all potentially treatable conditions, and serial monitoring of the patient's responses. Documentation of the longer-term course also assists in disentangling and recognizing separately contributing disease processes. Despite careful observation and follow-up evaluation, the clinician may remain uncertain whether a syndrome is idiopathic or secondary to other detected diseases. In such instances, it is preferable to diagnose a primary psychiatric condition on Axis I, define all systemic or cerebral conditions on Axis III, and thereafter maintain a high order of vigilance while monitoring the course of the disorder longitudinally. It is important to note questions or uncertainties in the medical record for later scrutiny, for that practice avoids premature diagnostic closure. Clinicians must also guard against willingness to provide a psychiatric diagnosis when specialists from other medical disciplines have ruled out specific disease processes after laboratory tests have been unrevealing. The failure to define an organic disease does not warrant a functional diagnosis by default. As emphasized in DSM-IV, specific clinical signs, symptoms, and course are needed to establish the presence of a primary psychiatric disorder. Metabolic Disorders Because most systemic medical conditions can directly or indirectly affect brain function, any list of illnesses that may cause a secondary psychiatric syndrome or cognitive disorder must be incomplete. Table 10-17 lists some frequently described potential causes. The precise pathophysiological mechanisms by which the disease process alters brain function are poorly understood in most cases. More than one process may be involved. For example, a patient with acute myelogenous leukemia may have altered brain function resulting from the neoplastic process itself, anemia (with decreased oxygen delivery to the brain), brain hemorrhages (caused by thrombocytopenia), and infections.

Table 10-17 Metabolic and Other Systemic Disturbances

Secondary psychiatric syndromes may be the first, most prominent, or only clinical phenomena to call attention to the underlying condition (e.g., depression due to occult pancreatic carcinoma and cognitive deficits due to vitamin B 12 deficiency even in the absence of other neurological or hematological signs). Secondary behavioral changes may also result from multiple etiologies, of which any one alone might or might not be sufficient to produce the psychiatric disturbance (e.g., delirium due to mild anemia, mild hyponatremia, and marginal hypoxemia). The rate of change may also be important with certain etiologies. For example, a sudden drop in serum sodium to 125 mEq/L is more likely to produce behavioral changes than a chronic hyponatremia of 125 mEq/L. Etiologies particularly identified with specific psychiatric syndromes are discussed under each syndrome. However, most etiologies can produce more than one syndrome (e.g., hypothyroidism is most often associated with a depressive state but may also cause mania, delirium, or dementia). How a specific etiological factor causes varied behavioral changes presumably results from both trait-dependent and state-dependent brain diatheses that largely are not understood. Demyelinating Disorders With regard to secondary psychiatric syndromes, multiple sclerosis is the most important demyelinating disorder. Although it may cause delirium, dementia, and nonaffective psychoses, mood disturbances have been described frequently. Isolated, persistent euphoria has long been noted and is thought to be physiologically related to demyelinated lesions in the limbic system, frontal lobes, and basal ganglia ( Fig. 10-8). Emotional incontinence, also termed pathological laughing or weeping, is a state of labile affective expression that is apparently disconnected from underlying mood. Although pathophysiological mechanisms remain uncertain, it is speculated that interruption of pathways between the telencephalon and lower regions is responsible.

FIGURE 10-8 MRI study of the head. Extensive confluent periventricular lesions are seen in a patient with multiple sclerosis. The corresponding CT scan was normal. (Reprinted with permission from Lukes SA, Crooks LE, Aminoff MJ, Kaufman L, Panitch HS, Mills C, Norman D: Nuclear magnetic resonance imaging in multiple sclerosis. Ann Neurol 13:596, 1983.)

Depressive syndromes are especially prevalent in patients with multiple sclerosis. Most studies have focused on major depressive disorder or have not used specific diagnostic criteria; therefore, little is known about minor or other subsyndromal depressions. Some data suggest that depressive syndromes can be caused directly by the demyelinating process in specific CNS regions; for example, patients with cerebral disease have higher rates of depression than patients with spinal multiple sclerosis. However, there is also evidence implicating psychological and social factors in the pathogenesis of depression in these patients, and it is likely that many of their depressive syndromes are not secondary to or specifically symptomatic of cerebral disease. Bipolar disorders are less well studied, although they appear to be more prevalent in multiple sclerosis populations than in the general population. Whether bipolar disorders in multiple sclerosis patients represent true secondary bipolar disorders, mania induced by treatments with corticosteroids, or manifestations of a shared genetic diathesis is not known. Other demyelinating disorders include variants of acute encephalomyelitis (including postinfectious encephalomyelitis and acute posttraumatic demyelinization). These disorders generally manifest initially with coma or delirium, and survivors may have lasting cognitive and behavioral disturbances. The treatment of psychiatric syndromes in demyelinating disorders, as for most secondary syndromes, is empirical and based on target symptoms (e.g., antipsychotic agents for psychosis). Studies suggest that antidepressant medications, when used in conjunction with supportive psychotherapy, are helpful in patients with multiple sclerosis. Tricyclic drugs, and possibly other classes of antidepressant drugs, reduce emotional incontinence associated with multiple sclerosis even in the absence of a full depressive syndrome. Degenerative Diseases Degenerative disease processes involve deterioration of brain function resulting in the loss of previously attained capacities. Some degree of CNS degeneration occurs as part of the aging process and is reflected in alterations in gross brain structure; neuronal cell number, morphology, and function; and neurotransmitter synthesis, metabolism, and function. The degeneration manifests clinically with psychometrically definable cognitive declines, particularly in secondary or long-term memory, speed of mental processing, visuospatial processing, divided attention, and cognitive flexibility. A range of decrements is associated with normal aging, and clinicians and investigators are developing neuropsychological procedures that distinguish such normative processes from those associated with degenerative diseases. Indeed, DSM-IV includes age-related cognitive decline as a clinical condition that may be a focus for clinical attention although it is not a mental disorder. It allows physicians to explain to concerned healthy patients that their aging-associated decrements in cognitive processing are distinctive from incipient dementia. Other similar conditions include problems such as borderline mental functioning or bereavement. However, the border between normative cognitive changes and incipient dementia is ill defined. Patients who present with acquired deficits below the normal range are at higher risk statistically of developing progressive problems. However, cross-sectional cognitive tests cannot reveal time of onset, and in some individuals test results are always below normal. Conversely, people with above-average intellectual abilities may experience cognitive decline without exhibiting objective deficits because their performance remains within normal limits despite obvious functional impairments. Degenerative CNS diseases can produce disturbances in cognition, mood, behavior, personality, and motor and perceptual function. In recent years investigators have more clearly defined that the major degenerative diseases (whether hereditary or idiopathic) reflect deterioration in specific or discrete neurochemical systems where there is as well a regional specificity that reflects the location of cell bodies and their ultimate terminal zones. Such diseases are best considered neurochemical system diseases and their general pattern is one of insidious onset with a gradual progression of deficits. Dementia is the most common syndromic presentation and worsens as a reflection of the long-term progressive process; it ultimately reflects widespread CNS disease. Secondary mood, psychotic, and personality syndromes are also seen but are more likely to manifest earlier in the course, when the degeneration may be more localized. Cortical and Subcortical Dementia Degenerative CNS diseases can be distinguished clinically from one another by the relative impairment and sparing of various cognitive and behavioral functions. Two basic clinical patterns of dementia have been characterized clinically: cortical and subcortical. The cortical pattern of

dementia is characterized by impairments in memory (primarily a storage and recall deficit) and gnostic-practic abilities (primarily involving language, visuospatial abilities, calculation, and motor praxis). Executive or managerial functions such as organization, judgment, abstraction, emotional control or modulation, and insight and social judgment are similarly affected. Fine and gross motor movements are generally preserved until later in the disease course. Personality often remains intact or displays subtle variations, with patients becoming more passive or less spontaneous, or becoming coarse and crude in their interactions. With disease progression the changes in personality become more common and pronounced. Affective expression is generally preserved, although again a coarsening may be noted in the form of emotional lability. Early in the disease, patients frequently discern and express dismay about their intellectual decline. The subcortical pattern is characterized by a generalized slowing of mental processing. Specific cognitive skills, such as calculation, naming, or copying are less affected initially, in contrast to their early decline in the cortical degenerative processes. Verbal and visual memory impairment may be present early in the course, although such impairment more often takes the form of forgetfulness or a failure of retrieval that is initially amenable to prompting, in contrast to the more severe recall deficits of cortical dementia. Patients also show deficits in learning new motor movements or complex psychomotor procedures. Planning and organizational skills are disrupted. Abnormal movements are common and manifest as a slowing and awkwardness in normal movement or as the intrusion of such extraneous movements as chorea or tremor. In contrast to the early impairment of language function in cortical disease, language is relatively spared, although the motor production of speech may be abnormal. The personality change is often marked, with striking patterns of apathy, inertia, and diminished spontaneity. Mood disorders, including major depression and mania, occur frequently. The presenting symptoms in subcortical degenerative processes may be those of a personality change or a mood disorder at a time when cognitive impairment or motor dysfunction is not yet obvious. In the cortical processes, by contrast, the presenting symptoms more often reflect cognitive impairment, particularly memory and language dysfunction. As the dementia and the degenerative process progress, the clinical presentations of cortical and subcortical diseases become nearly indistinguishable from one another. The term “subcortical dementia” was first used to describe the cognitive and behavioral deficits seen in patients with Huntington's disease. A similar clinical pattern was soon described for other subcortical diseases, such as progressive supranuclear palsy and Parkinson's disease. Although the term was initially used in reference to a clinical picture that could be localized to the subcortex, subcortical dementia is now considered a pseudoanatomical designation. It is clear from imaging and neuropathological studies that cortical dementia (e.g., dementia of the Alzheimer's type) is not restricted pathologically to the cortex; major affected cholinergic fiber pathways are subcortical in origin. Subcortical diseases similarly affect regions outside the subcortex, especially the frontal lobes, because of the brain's robust frontal-subcortical connections. Moreover, failure of subcortical nuclei that directly receive cortical efferent pathways can lead to clinical symptoms whose cerebral level of origin cannot be differentiated. Nonetheless, the cortical-subcortical distinction has been of clinical utility in defining patterns of cognitive, behavioral, mood, personality, and motor impairment, especially in the early stages of the degenerative disease process. Alzheimer's Disease Alzheimer's disease is the prototype of a cortical degenerative disease. Alzheimer's original description in 1906 detailed most of the familiar clinical and neuropathological features. Of note, his patient suffered from paranoia in addition to cognitive decline. Currently, the diagnosis of Alzheimer's disease requires neuropathological confirmation, and the diagnosis is used clinically for cases identified antemortem. Age at onset s earlier in patients with a family history of the disease. Despite some data to suggest distinctive age-related clinical patterns, no phenomenological separation between early-onset and late-onset cases has been found consistently enough for age to substitute for detailed clinical description; however, early-onset dementia of the Alzheimer's type may have a more rapidly progressive course. A major component of the presenting symptoms is usually subjective complaints of memory difficulty, language impairment (“I can't find the word”), and dyspraxia (e.g., difficulty driving). Diagnosis at this juncture is primarily based on exclusion of other possible etiologies for dementia. No features of the physical examination or laboratory evaluation are pathognomonic for dementia of the Alzheimer's type. Some studies have apparently discriminated patients with dementia of the Alzheimer's type from patients with dementia of other etiologies and from normal controls by using techniques such as EEG, MRI, and SPECT. These studies have been difficult to replicate consistently, and at present, brain-imaging studies are best used to exclude other identifiable causes. Indeed, available technological diagnostic methods have not proved more sensitive and specific than astute clinical evaluation in comparisons of patients with dementia of the Alzheimer's type and healthy control subjects. PET holds promise but currently is too expensive for clinical diagnostic use. A variety of diagnostic criteria sets have been developed for dementia of the Alzheimer's type. Clinical criteria have been verified prospectively in autopsy studies and have been found to be highly specific although only moderately sensitive. Implementation of the criteria requires extensive evaluation, including an informant-based history, neurological examination, neuropsychological testing, and laboratory and neuroimaging data. Studies using clinical samples collected in research centers tend to show the highest correlation between premorbid diagnosis and postmortem histopathology. In part this reflects the sophisticatmon of the evaluators; also, research cohorts can exclude subjects who show signs of other confounding conditions during the evolving disease course. Recent studies have shown substantial inter-center diagnostic variation, as well as variation when using different diagnostic criteria. Variability is greatest in population studies, in contrast to clinical samples. Factors found to be protective in epidemiological studies include higher education, larger head circumference, and cigarette smoking. The latter factor likely reflects some type of neuroprotective effect of nicotine; the former two point to a “brain reserve” hypothesis, where the unknown deleterious effects of the basic Alzheimer's disease pathobiology are mitigated by initially having either more brain substance or greater associative connections because of the stimulator effects of education. Alzheimer's disease is characterized pathologically by generalized atrophy of the cerebral cortex ( Fig. 10-9) and by neurofibrillary tangles, neuritic (amyloid) plaques, and granulovacuolar degeneration ( Fig. 10-10). Although plaques and tangles may be detected in the brains of the nondemented elderly, they are more numerous in patients with dementia. In recent years investigators have attempted to circumvent the qualitative overlap in symptoms by developing stricter quantitative, age-adjusted pathological criteria for Alzheimer's disease. Controversy remains whether brains with plaques from individuals without dementia were “normal variations” or early pathological signs of incipient disease. A definitive diagnosis ultimately requires both the characteristic dementia in life and the characteristic pathology after death.

FIGURE 10-9 Alzheimer's disease. View of exposed left cortex showing severe atrophy. (Reprinted with permission from Golden A, Powell DE, Jennings CD: Pathology: Understanding Human Disease, ed 2. Williams & Wilkins, Baltimore, 1985.)

FIGURE 10-10 Light micrograph of the cerebral cortex showing neurofibrillary tangles (arrows) and senile plaque (curved arrow) in Alzheimer's disease. (Reprinted with permission from Golden A, Powell DE, Jennings CD: Pathology: Understanding Human Disease, ed 2. Williams & Wilkins, Baltimore, 1985.)

During recent years substantial effort has been devoted to the study of the molecular pathobiology of Alzheimer's disease, with the identification of at least four chromosomal loci associated with familial cases; the degeneration of central neurochemical systems, especially basal forebrain structures related to acetylcholine-mediated neurotransmission; factors associated with the formation of plaques and tangles; and exogenous (e.g., infectious and toxic) processes that may contribute to the development of sporadic cases. Molecular biologists have sought to understand the formation of the abnormal amounts of amyloid that constitute the cerebral plaques characteristic of the disease. Although amyloid itself is a normal brain product, it has been suggested that excessive amounts may be neurotoxic. Others continue to see amyloid accumulations solely as a disease byproduct. Attention has recently turned to amyloid precursor protein and the intriguing possibility of regulating amyloid production pharmacologically. The discovery of an association between apolipoprotein E4, controlled by a gene located on chromosome 19, suggests further avenues for investigating risk factors and pathogenetic mechanisms. Taken together, these recent findings point to a heterogeneous array of pathobiological processes contributing to the final clinical and histological picture known as Alzheimer's disease. The postmortem and antemortem presentations appear to be relatively generalized (i.e., nonspecific) outcomes of widely divergent etiologies. The natural course of dementia of the Alzheimer's type, as of all the degenerative disorders, is exacerbation and progression of clinical symptomatology. Brain degeneration as measured by in vivo imaging techniques such as MRI has not been found to correlate closely with the state of clinical disease. The final common clinical picture is of a bedridden patient, wholly dependent on others for all basic functions, even for turning in bed. Nutrition can often be provided only by nasogastric or gastrointestinal tubes. Death usually results from aspiration or from infectious processes associated with prolonged recumbency. Parkinson's Disease Described by James Parkinson in 1817, Parkinson's disease is a prototype of a subcortical degenerative disease. It is idiopathic and must be distinguished from parkinsonian syndromes that arise from a variety of causes. Parkinson's disease is the result of the degeneration of subcortical structures, primarily the substantia nigra but also the globus pallidus, putamen, and caudate ( Fig. 10-11). Cells containing dopamine are predominantly affected, although serotonergic and other systems are disrupted as well. Just as the appellation “cortical pattern” is pseudoanatomical, so in subcortical Parkinson's disease there can be significant degeneration of cortical structures. The parkinsonian syndrome manifests with structural damage that reflects the underlying process or insult. Medication-induced parkinsonism presumably involves only a dysfunction of the basal ganglia structures, without any obvious pathoanatomical abnormality. The typical age at onset of Parkinson's disease is between 50 and 60 years but may vary widely, with onset sometimes occurring one to two decades earlier. The clinical course is chronic and progressive, with severe disability attained after approximately 10 years. A smaller proportion of patients have a more rapidly progressive disease, and a yet smaller group has a slowly progressive disorder in which deterioration plateaus or remains minimal for two to three decades.

FIGURE 10-11 Parkinson's disease. Section of midbrain and pons showing depigmentation of substantia nigra and locus ceruleus in Parkinson's disease on left (arrows) and normal substantia nigra and locus ceruleus on right. (Reprinted with permission from Golden A, Powell DE, Jennings CD: Pathology: Understanding Human Disease, ed 2. Williams & Wilkins, Baltimore, 1985.)

In general, subcortical diseases are thought to impinge on the three Ms—movement, mentation, and mood. In Parkinson's disease all three of these areas are affected, although not always uniformly. The movement abnormalities are characterized by the triad of tremor, rigidity, and bradykinesia. The tremor and rigidity can be unilateral or bilateral. Bradykinesia is manifested by slowness in the initiation and execution of movement. The typical presentation, with a masklike facies, minimal blink, and monotonic speech, is a concomitant of the rigidity and slowness of movement. Other prominent characteristics include postural changes such as chin-to-chest flexion and gait abnormalities. The gait is characteristically slow and shuffling, and the patient has difficulty turning (en bloc turning) and trouble initiating and stopping walking. Seborrhea, sialorrhea, excessive fatigue, and constipation are also common. Maurice Rosen was 69 when he made an appointment for a neurological evaluation. He had recently noticed that his memory was slipping and he had problems with concentration that were beginning to interfere with his work as a self-employed tax accountant. He complained of slowness and losing his train of thought. Recent changes in the tax laws were hard for him to learn, and his wife said he was becoming more withdrawn and reluctant to initiate activities. However, he was still able to take care of his personal finances and accompany his wife on visits to friends. Although mildly depressed about his disabilities, he denied other symptoms of depression, such as disturbed sleep or appetite, feelings of guilt, or suicidal ideation. Mr. Rosen has a long history of treatment for episodes of depression, beginning in his 20s. He has taken a number of different antidepressants, and once had a course of electroconvulsive therapy. As recently as 6 months before this evaluation, he had been taking an antidepressant. Two years ago he developed an intermittent resting tremor in his left hand and a shuffling gait. Although the diagnosis of Parkinson's disease was considered by his psychiatrist, it was not confirmed by a neurologist, and therefore no additional treatment was given. The neurologist who was now evaluating him found that his spontaneous speech was hesitant and unclear (dysarthric). Cranial nerve examination was normal. Motor tone was increased slightly in the neck and all limbs. Alternating movements of his hands were performed slowly. He had a slight intermittent tremor of the left arm at rest. Reflexes were symmetrical. A diagnosis of idiopathic Parkinson's disease was made, and he was placed on a low dose of carbidopa (Atamet), a medication that alleviates the symptoms of Parkinson's disease. A neuropsychological examination performed 3 weeks later revealed average performance on the Wechsler Adult Intelligence Scale-Revised (full scale I.Q. = 104), but a verbal I.Q. of 118 and a performance I.Q. of 84. Memory as assessed by a 12-item, 10-trial, selective reminding task was poor, with no more than 7 items recalled on any trial, and only 3 words recalled after a 15-minute delay, although the patient could recognize the remaining words. He showed marked difficulty in drawings of overlapping figures and parallel lines. He was unable to draw three-dimensional figures. In language testing he demonstrated impaired naming. In summary, Mr. Rosen displayed evidence of impairment in memory, naming, and constructional abilities. These may have been secondary to slowness, poor planning, and perseveration. The deficits were believed to result from Parkinson's disease. Additional evaluation included an MRI, which revealed only generalized atrophy, and an EEG, which was significant for background generalized slowing. (Reprinted with permission from DSM-IV Casebook.) Mentation or cognition in Parkinson's disease is an area of controversy. Most patients complain of slowed thinking, sometimes called bradyphrenia. In general, approximately 20 to 30 percent of patients with Parkinson's disease are found to have dementia, with the likelihood greater in those with late-onset disease (after age 70 years). Approximately 40 percent of nondemented patients with Parkinson's disease, however, demonstrate some neuropsychological impairment in most studies. The impairments are primarily in visuospatial capacities, as measured by copying, tracing, and tracking tasks, and in the shifting of cognitive sets, as measured by the Wisconsin Card Sorting Test or the Stroop Test. Such deficits have been noted in the absence of cognitive-based functional decline or other evidence of cognitive impairment. Controversy has emerged over whether these two patterns represent a single continuum of dementia integral to the process of Parkinson's disease or are two separate processes indicative of two distinct diseases. Neuropathologically, cases intermediate between Parkinson's disease and Alzheimer's disease exist, with the characteristic microscopic features of the latter and Lewy bodies in the substantia nigra suggesting the former. There is no clear line of division as yet between a process resembling dementia of the Alzheimer's type on which abnormal parkinsonian movements are superimposed and a clinical presentation of Parkinson's

disease in which the patient slowly develops a global progressive dementia. Mood disorders have been frequently reported in association with Parkinson's disease. Depression is the most common; mania is virtually unreported. The mean frequency of depression is approximately 40 percent, with a reported range of 4 to 70 percent. No relation has been demonstrated between the frequency and severity of depression and the patient's current age, the age at onset of symptoms of Parkinson's disease, the duration of those symptoms, the severity of motor signs, or the response to medication. No relation has been demonstrated among mood, rigidity, bradykinesia, or tremor. Although depression has been found more commonly in patients with Parkinson's disease who display prominent gait and postural changes, the relation between mood and the severity of the disability is limited. There may be some association between depression and laterality of disease, for patients with left brain disease appear to have a higher frequency of depression than patients with right brain disease. This pattern suggests that the mood disturbance is a primary manifestation of brain deterioration and not a reactive psychological response to chronic illness and disability. Although the evidence relating lateralization to a higher frequency of depression is preliminary, it does recall data regarding poststroke depression and its putative relationship to left hemisphere localization but not to the extent of disability. The phenomenology of depression in Parkinson's disease is similar to that of idiopathic major depressive disorder, for it includes subjective dysphoria, pessimism, irritability, and suicidality, but perhaps less self-disparagement and self-blame. Some patients present with anxiety or panic attacks. Anergia, psychomotor retardation, and early-morning awakening are three symptoms that have been found to be nonspecific for depressive disorder in those patients, as they overlap considerably with the manifestations found in nondepressed patients with Parkinson's disease. Some data support the view that the depression of Parkinson's disease is associated specifically with decreased CNS serotonin concentrations. The on-off syndrome, in which patients experience severe fluctuations in mobility ranging from normal movement to a frozen state, has also been associated with changes in mood. On-off phenomena usually occur after years of chronic treatment with levodopa and can manifest as a between-dosage effect or randomly throughout the day. Many studies have reported changes in mood coincident with changes in motoric function, namely, subjective and objective dysphoria in the off period and, less frequently, abnormal elation and euphoria during the on period. Psychosis as a concomitant of Parkinson's disease has been reported in the context of mood disorders (e.g., psychotic depression) or as a consequence of treatment. There are no reports of a specific personality change characteristic of Parkinson's disease except for the apparent apathy and lack of initiative that are often subsumed under bradykinesia and bradyphrenia. The pharmacological treatment of Parkinson's disease addresses mood and movement because there is no known regimen for the improvement of cognition. For movement dysfunction dopamine precursors, such as levodopa or levodopa-carbidopa, (Sinemet), are a mainstay of treatment. Gait, posture, rigidity, and akinesia are generally more responsive to levodopa than is tremor. Anticholinergic agents and the dopamine agonists (bromocriptine [Parlodel] and pergolide [Permax]) are second-line agents. The monoamine oxidase (MAO) type B inhibitor selegiline (Eldepryl) has been demonstrated to apparently slow the progression of motor dysfunction, although in the low doses used it did not have significant antidepressant efficacy. Its effects on the development of cognitive impairment are unknown. Currently a new generation of dopamine receptor agonists is emerging; their long-term utility will become clear in the coming years. All symptomatic antiparkinsonian agents can cause delirium, a common iatrogenic concomitant of the disease. Levodopa has also been reported to cause visual hallucinations in some patients, even in the absence of delirium. Surgical treatments—stereotactic lesioning of the thalamus or globus pallidus—were used in the past to alleviate the motor dysfunction of Parkinson's disease. Although that approach had largely been replaced by pharmacological treatment, newer and more precise operative procedures have been developed in the past few years. Transplantation of fetal neural tissue into the caudate of the adrenal medulla also has been attempted, but no data from well-controlled studies are available regarding the effects of the procedure on mood and mentation. Recent findings suggest that fetal tissue transplantation may dramatically alleviate severe motor symptoms. Many differences exist in surgical protocols and transplantation methods, underscoring the highly experimental nature of these procedures. Treatment of the mood disorder associated with Parkinson's disease involves the same agents that have proved valuable in treating idiopathic major depressive order. Antidepressant medication from all categories have proved efficacious. ECT is of value for treating both the mood component and the motor dysfunction; dramatic improvement in all aspects of movement has been demonstrated on standardized neurological examinations. Several studies have reported sustained improvement in motor function for as long as 6 months after treatment; however, most detected a short-lived improvement of days to weeks. ECT is recommended for patients with Parkinson's disease and the on-off syndrome, particularly when significant mood changes are present. In summary, Parkinson's disease is a prototypical subcortical pattern degenerative disease. The overlap of clinical phenomena between a basal ganglia disease, such as Parkinson's disease, and major depressive disorder can be striking. Both are characterized by qualitatively similar impairments in the realms of movement, mentation, and mood. Differing terminologies have arisen to describe similar signs and symptoms in each. Psychomotor slowing (psychomotor retardation) a term used to encompass both the motoric and cognitive slowing seen in depression, is quite similar to the bradykinesia and bradyphrenia described early in the course of Parkinson's disease. A recent study that used a nonmotor measure of bradyphrenia demonstrated close correlations between cognitive slowing and severity of the mood disorder both in depressed patients with Parkinson's disease and patients with idiopathic major depressive disorder, suggesting a close phenomenological relation between the bradyphrenia of Parkinson's disease and so-called psychomotor slowing. It underscored the idea that basal ganglia disorders are fertile ground for research and insight into the neurobiological bases of idiopathic mood disorders. Dementia With Lewy Bodies Since the late 1980s research has revealed that, beyond dementia of the Alzheimer's type and vascular dementia, a common cause of progressive dementia may be related to the presence of Lewy bodies in the brainstem and cerebral cortex. Lewy bodies—intracytoplasmic, spherical, eosinophilic neuronal inclusion bodies—are scattered through the brainstem, subcortical nuclei, limbic cortex (cingulate, entorhinal, amygdala), and neocortex (temporal > frontal = parietal). Parkinson's disease, in contrast, manifests Lewy bodies in subcortical nuclei, in addition to degeneration of dopamine cell bodies in substantia nigra. Table 10-18 lists the pathological features of dementia with Lewy bodies; Table 10-19 includes recently developed consensus guidelines for clinical diagnosis. Neuropsychiatric features, including visual hallucinations, delusions, fluctuating attention, and executive or managerial cognitive deficits, are prominent; although not specific, mood disturbances are common.

Table 10-18 Pathological Features Associated With Dementia With Lewy Bodies

Table 10-19 Consensus Criteria for the Clinical Diagnosis of Probable and Possible Dementia With Lewy Bodies

Substance-Induced Disorders Pharmacological compounds are potent and frequent causes of psychopathology. This effect, especially when caused by environmental and occupational neurotoxins, has been little studied; more attention has been paid to peripheral or motor effects than to the less easily quantified behavioral alterations. Although alcohol-induced neuropsychiatric syndromes have long been known of, the CNS consequences of abuse of recreational drugs received attention only in recent decades, in part because of societal disapproval of recreational drug use, disinterest among investigators, and the inherent difficulty of separating drug effects from confounding person effects. Broadly speaking, there are four classes of chemically induced psychopathology: (1) that due to environmental contamination, both natural (e.g., venoms and poisonous foods) and human-made (e.g., gasoline contamination of well water); (2) that due to occupational exposure; (3) that due to recreational use, abuse, or dependence on substances causing transient or lasting CNS toxic effects; and (4) the iatrogenic complications of prescribed or over-the-counter medications. Compounds must be considered from the perspectives of (1) acute or immediate effects (e.g., behavioral symptoms of acute intoxication), (2) longer-term responses to persistent exposure, and (3) lasting consequences that persist after the cessation of any direct pharmacological action. The last may be especially complex because of the extremely prolonged retention (months to years) of some compounds within the body. When considering the possibility of drug- or toxin-induced psychopathology, the clinician must undertake a careful chain of reasoning, akin to deciding on any secondary diagnosis but differing in several respects. Initially, the clinician must ascertain whether an exposure occurred and at what level; for example, an industrial hygienist may have been exposed in a possible occupational incident. Next, it is critical to understand the toxicity of a substance (especially as it might relate to different chemical forms), its mode of action (when known), its effects in various animal species, and its clinical manifestations. Typically, these issues are within the realm of toxicologists. Subsequently, the clinician seeks to define the systemic clinical manifestations of the exposure in the particular patient. Although behavioral changes may be the only exposure-related findings, more often there is a variety of consistent symptoms, signs, and laboratory findings that together make a coherent clinical picture. It is within that larger context that the clinician views any presumptively related psychopathology. When attempting to establish a neurotoxic diagnosis, physicians also must recognize other cardinal features of toxic exposures that influence clinical reasoning: (1) neurotoxic chemicals often cause nonfocal/nonspecific syndromes; (2) standard laboratory tests may have limited diagnostic utility; (3) there usually are strong dose-response relationships; (4) a single toxin may produce multiple syndromes; (5) with a few specific exceptions (e.g., asbestos, therapeutic cerebral radiation exposure), toxin-induced illnesses occur concurrently with exposure or following a short latency period; (6) the chemical formula may not predict toxicity; (7) a compound without known neurotoxic activity can interact or potentiate the effects of known neurotoxins; and (8) neurotoxic disease often may be asymptomatic. Ideally, one would like to know the neuropsychiatric effects of all CNS toxic compounds. In the absence of such information, the clinician must describe symptoms and signs in detail and compare them with available data. The clinician defines the temporal course of exposure and assesses how the emergence of specific psychiatric manifestations relates to known actions of the compounds in question. Simultaneously, the clinician must consider the form of the disorder and establish whether it suggests a pathological CNS process or is more consistent with primary (idiopathic) psychopathology. The clinician must decide whether the syndrome in question might reflect other unrelated disease processes as well. Any measurable clinical and laboratory manifestations of CNS disease should be identified. Although no single measurement can be considered proof, taken together such measurements offer the possibility of establishing a diagnosis with a high degree of clinical certainty. The array of environmental and occupational compounds to which people may be exposed is large. Except for patients exposed to recreational and iatrogenic agents, until recently most psychiatrists did not treat patients with toxic exposures. This is changing rapidly as a result of late twentieth-century technology and increasing societal awareness. The clinician should remember that toxic exposures are used by some patients to explain a pantheon of personal ills, many of a psychiatric nature. It is neither appropriate to treat those complaints lightly nor clinically sound to accept such pathogenic explanations without firm clinical support. Recreational drugs may be used or abused intentionally to cause dose-dependent behavioral changes, including anxiolysis with nicotine, intoxication with alcohol or marijuana, or psychosis with mescaline. There may be additional unwanted psychiatric phenomena with drug intoxication. Unwanted secondary syndromes commonly described include anxiety and insomnia due to caffeine; paranoid psychosis with cocaine; mood alterations (dysphoria, anxiety, euphoria) accompanying the perceptual disturbances induced by hallucinogenic substances; agitated (often violent) psychotic states with phencyclidine (PCP); and depressive symptoms and seemingly paradoxical disinhibition of aggressive impulses with sedative-hypnotic agents. However, there may be considerable variability and therefore lack of specificity in syndromic association with particular substances. Also, many substances in sufficient doses can cause delirium, which may itself have associated psychiatric symptoms ranging from mood disturbance to psychosis. Withdrawal syndromes are also commonly encountered with drugs of abuse and tend to be characteristic of the class of drug. Withdrawal from nicotine may produce anxiety or irritability; withdrawal from stimulants produces a hypersomnic dysphoric crash; and withdrawal from opiates produces a well-described state that includes malaise, anxiety and irritability, drug craving, insomnia, psychomotor agitation, anorexia, and a variety of physical symptoms (e.g., diarrhea, piloerection, mydriasis, hypertension, and tachycardia). Delirium often follows withdrawal from alcohol and sedative-hypnotic medications but is not a component of other drug withdrawal syndromes (e.g., opioid-related). Numerous medications have been implicated in causing psychiatric phenomena. Prescription drugs and over-the-counter preparations may cause physiologically induced behavioral changes, either through intoxication (which may involve use at therapeutic or supratherapeutic levels) or withdrawal. As with other causes of secondary psychiatric disorders, combinations of medications and medical illnesses may cause behavioral changes even when each medication or illness alone does not. Among prescribed medications, psychotropic drugs are designed to effect behavioral changes. Unwanted psychiatric syndromes, such as antipsychotic-induced depressive syndromes or the delirium of lithium toxicity, occur often. Countless medications have been implicated in secondary psychiatric syndromes; it is rare indeed for a medication to be listed in the Physicians' Desk Reference without an accompanying description of some potential neuropsychiatric adverse effect. However, this information must be interpreted with caution. Behavioral adverse effects are also noted with placebos; therefore, distinguishing physiological from psychological symptoms may be difficult. Psychiatric symptoms may also reflect the clinical manifestations of the primary illness being treated (e.g., delirium in a patient receiving a new parenteral antibiotic may be due to the antibiotic or the targeted infection). Finally, numerous other factors may complicate the process of establishing the etiological significance of a particular medication. For example, b-adrenergic-receptor antagonists have been postulated for many years to cause depressive syndromes, yet a recent large study, carefully controlled for patient demographics, medical illness, medications, and other factors, was unable to find a significant independent association between b-adrenergic receptor antagonists and depression. Despite these caveats, many medications clearly can cause secondary psychiatric syndromes.

COGNITIVE DISORDERS Delirium Delirium, a transient disorder of brain function manifested by global cognitive impairment and other behavioral phenomena, is a common disease state that has been described for centuries. Nevertheless, it is frequently missed or misdiagnosed, with the potential for substantial attendant morbidity and mortality. Recognition and appropriate evaluation and treatment of delirium should be an imperative, not just for psychiatrists but for all physicians. Definition DSM-IV includes delirium under cognitive disorders. Delirium is a syndrome, with core features of impairment of consciousness with attentional deficit, other cognitive alterations, and a relatively rapid onset of the disorder with a characteristically fluctuating course. Frequently there are other associated clinical phenomena, which may appear more prominent to the uneducated observer than the core features. History Physicians have long recognized states of altered behavior, including changes in level of consciousness, of acute onset that were associated with fever, poisons, or other medical or neurological diseases. There are references to such presentations in the writings of Hippocrates and in much subsequent Greco-Roman literature. Descriptions of the syndrome similar to modern definitions appear from the late Middle Ages through the eighteenth century. The history, however, is obscured by an etymological web that to this day impedes communication and education about the disorder. Numerous terms have been used to describe the syndrome of delirium, including phrenitis, frenzy, and febrile insanity; conversely, the term “delirium” has also been applied to other psychiatric states that led to insanity. By the nineteenth century emphasis was placed on disordered consciousness as the hallmark of delirium. The phrase “clouding of consciousness” dates to that time

and is still used in many quarters today despite lack of clarity as to what it means. Similarly, the term “confusion” was used frequently, despite the lack of a specific relation to delirium. The work of George Engel and John Romano in the 1940s, summarized by them in publications from the 1950s, indicated that attentional and other cognitive disturbances were best viewed as the core features of the syndrome and that the state was associated with acute brain failure, as demonstrated by slowing on the EEG. Subsequent work on the pathophysiology of delirium has been relatively scant. Zbigniew Jerzy Lipowski, beginning in the 1960s and continuing to the present, has been instrumental in raising clinical and research awareness of delirium, defining the syndrome according to strict criteria and popularizing (especially in the psychiatric community) the use of the term “delirium.” Recent years have seen alterations in diagnostic criteria, as evidenced by the removal of associated clinical features such as psychomotor changes from the required criteria. There has also been increasing study of epidemiology, clinical course, and risk factors for onset or poor outcome. Unfortunately, etymological confusion remains. Numerous synonyms remain in common use, especially in nonpsychiatric medical fields; some of them are encephalopathy, acute confusional state, and acute organic brain syndrome. Some neurologists maintain a distinction between delirium, which they reserve to describe extremely agitated delirious states with frank thought process disorganization, perceptual disturbances, and autonomic hyperactivity, and acute confusional states, which they use to describe all other, often less severe delirious states. Most psychiatrists, and many other workers in the field, believe that such distinctions are premature at best (because of a lack of evidence of differing causes or pathophysiologies between the two) and misleading at worst, obscuring the commonality of core clinical features, potential etiologies, and management approaches. Epidemiology There have been relatively few studies of the incidence and prevalence of delirium. Little is known about the epidemiology of delirium in community or other nonpatient, noninstitutionalized populations. An estimated 10 to 15 percent of general medical inpatients are delirious at any given time, and studies indicate that as many as 30 to 50 percent of acutely ill geriatric patients become delirious at some point during their hospital stay. Rates of delirium in psychiatric and nursing home populations are not well established but are clearly substantial. Risk factors for the development of delirium include increased severity of physical illness, older age, and baseline cognitive impairment (e.g., due to dementia). Delirium is frequently unrecognized by treating physicians. Because of its wide array of associated symptoms, it may be detected but misdiagnosed as depression, schizophrenia, or other psychiatric disorder. Delirium is a frequent cause for psychiatric consultation in the general hospital but often is not recognized as such by the referring physician. Etiology The syndrome of delirium reflects brain dysfunction that is almost always due to identifiable systemic or cerebral disease or to drug intoxication or withdrawal. A partial list of frequently encountered causes is given in Table 10-20. Often delirium is due to multiple simultaneous causes, each one of which may or may not be enough to cause delirium by itself. On rare occasions a syndrome nearly indistinguishable from delirium may manifest as part of the course of another Axis I disorder such as bipolar I disorder.

Table 10-20 Causes of Delirium

Diagnosis and Clinical Features The syndrome of delirium is almost always caused by one or more systemic or cerebral derangements that affect brain function. A 74-year-old African-American woman, Ms. Richardson, was brought to a city hospital emergency room by the police. She is unkempt, dirty, and foul smelling. She does not look at the interviewer and is apparently confused and unresponsive to most of his questions. She knows her name and address, but not the day or the month. She is unable to describe the events that led to her admission. The police reported that they were called by neighbors because Ms. Richardson had been wandering around the neighborhood and not taking care of herself. The medical center mobile crisis unit went to her house twice, but could not get in and presumed she was not home. Finally, the police came and broke into the apartment, where they were met by a snarling German shepherd. They shot the dog with a tranquilizing gun, and then found Ms. Richardson hiding in the corner, wearing nothing but a bra. The apartment was filthy, the floor was littered with dog feces. The police found a gun, which they took into custody. The following day, while Ms. Richardson was awaiting transfer to a medical unit for treatment of her out-of-control diabetes, the supervising psychiatrist attempted to interview her. Her facial expression was still mostly unresponsive, and she still didn't know the month and couldn't say what hospital she was in. She reported that the neighbors had called the police because she was “sick,” and indeed she had felt sick and weak, with pains in her shoulder; in addition, she had not eaten for 3 days. She remembered that the police had shot her dog with a tranquilizer, and said the dog was not in “the shop” and would be returned to her when she got home. She refused to give the name of a neighbor who was a friend, saying, “he's got enough troubles of his own.” She denied ever being in a psychiatric hospital or hearing voices, but acknowledged that she had at one point seen a psychiatrist “near Lincoln Center” because she couldn't sleep. He had prescribed medication that was too strong, so she didn't take it. She didn't remember the name, so the interviewer asked if it was Thorazine. She said no, it was “allal.” “Haldol?” asked the interviewer. She nodded. The interviewer was convinced that was the drug, but other observers thought she might have said yes to anything that sounded remotely like it, such as “Elavil.” When asked about the gun, she denied, with some annoyance, that it was real and said it was a toy gun that had been brought to the house by her brother, who had died 8 years ago. She was still feeling weak and sick, complained of pains in her shoulder, and apparently had trouble swallowing. She did manage to smile as the team left her bedside. (Reprinted with permission from DSM-IV Casebook.) DSM-IV gives separate diagnostic criteria for delirium due to a general medical condition ( Table 10-21), for delirium related to systemic medical conditions or primary cerebral conditions, substance intoxication delirium ( Table 10-22), substance withdrawal delirium (Table 10-23), delirium due to multiple etiologies ( Table 10-24), and delirium not otherwise specified ( Table 10-25) for a delirium of unknown cause or due to causes not listed, such as sensory deprivation. However, the core syndrome is the same, regardless of cause.

Table 10-21 DSM-IV Diagnostic Criteria for Delirium Due to a General Medical Condition

Table 10-22 DSM-IV Diagnostic Criteria for Substance Intoxication Delirium

Table 10-23 DSM-IV Diagnostic Criteria for Substance Withdrawal Delirium

Table 10-24 DSM-IV Diagnostic Criteria for Delirium Due to Multiple Etiologies

Table 10-25 DSM-IV Diagnostic Criteria for Delirium Not Otherwise Specified

The core features of delirium include altered consciousness, such as decreased level of consciousness; altered attention, which may include diminished ability to focus, sustain, or shift attention; impairment in other realms of cognitive function, which may manifest as disorientation (especially to time and space) and decreased memory; relatively rapid onset (usually hours to days); brief duration (usually days to weeks); and often marked, unpredictable fluctuations in severity and other clinical manifestations during the course of the day, sometimes worse at night (sundowning), which may range from periods of lucidity to quite severe cognitive impairment and disorganization. Associated clinical features are often present and may be prominent. They may include disorganization of thought processes (ranging from mild tangentiality to frank incoherence), perceptual disturbances such as illusions and hallucinations, psychomotor hyperactivity and hypoactivity, disruption of the sleep-wake cycle (often manifested as fragmented sleep at night, with or without daytime drowsiness), mood alterations (from subtle irritability to obvious dysphoria, anxiety, or even euphoria), and other manifestations of altered neurological function (e.g., autonomic hyperactivity or instability, myoclonic jerking, and dysarthria). The EEG usually shows diffuse slowing of background activity, although patients with delirium due to alcohol or sedative-hypnotic withdrawal have low-voltage fast activity. ICD-10 takes a somewhat different approach to establishing the diagnosis of delirium ( Table 10-26). It requires the concurrent presence of disturbances in consciousness and attention, perception, thinking, psychomotor behavior, emotion, and the sleep-wake cycle. All features must be present to some degree for a definite diagnosis, thus making for a more restrictive classification than DSM-IV. The key to diagnosing delirium is to maintain a heightened suspicion for the syndrome whenever a patient experiences a relatively rapid change in or the new onset of any psychiatric symptom or sign. Once the diagnosis is suspected, the history (usually obtained from informants such as family, nursing staff, and prior treaters) and mental status examination can elucidate the cognitive disturbances at the core of the syndrome and uncover associated clinical phenomena that may affect management or suggest the etiology.

Table 10-26 ICD-10 Diagnostic Criteria for Delirium, Not Induced by Alcohol and Other Psychoactive Substances

The presence of delirium should prompt careful investigation for contributing causes. Delirium may be the first, most prominent, or only clinical manifestation of the new onset of a medical condition or the worsening of a previously diagnosed illness. A careful medical history (including medication and drug history), physical examination, and neurological examination must be undertaken, and various laboratory tests, neuroimaging procedures, lumbar puncture, and EEG may be useful. In searching for cause, physicians should remember that relatively minor abnormalities (e.g., a mild anemia plus slight hyponatremia plus slight hypercalcemia) may additively produce delirium even if each abnormality alone would not normally do so. Sometimes the search for an etiology does not yield a clear cause of the delirium; the patient still has the syndrome of delirium, however, and vigilance for clinical contributing factors must be maintained. Physicians should avoid the common mistake of believing delirium to be ruled out by the lack of obvious etiology, thereby proving that the behavioral disturbance is functional in origin. EEG may be helpful in such cases by demonstrating diffuse brain dysfunction, although that in itself does not demonstrate etiology. Current understanding of the pathophysiology of delirium is limited. Dysfunction of the reticular activating system has been speculated, given its role in arousal. There is evidence for hypofunction of cholinergic systems, particularly in the basal forebrain and pons. There is some evidence for dysfunction of several other neurochemical systems, including noradrenergic, GABAergic, and serotonergic; more undoubtedly await investigation. Earlier speculation about globally decreased cerebral metabolism has not been confirmed, but also has not been carefully studied in delirium despite the availability of techniques such as PET and SPECT. Even more obscure is the pathophysiological link between specific systemic conditions and delirium. The classic model of such a link is anticholinergic drug toxicity, which has been presumed to cause delirium as a direct consequence of hypoactivity of cholinergic systems. Some recent work has demonstrated increased GABAergic transmission, putatively because of increased concentrations of endogenous benzodiazepine-like substances, in patients with delirium and fulminant liver failure. Differential Diagnosis Much attention has been given to differentiating delirium from dementia. Usually that distinction can be easily made by noting temporal factors (course of onset and progression of the disturbance) and by recognizing that level of consciousness and attention are affected prominently and early in delirium. Dementia by definition does not involve an alteration of consciousness, although attentional dysfunction develops as the syndrome progresses in severity. However, delirium is often superimposed on a pre-existing dementia. If the history is unknown and mental status examination results are lacking in a patient with severe dementia, it can be difficult to tell if there is a new delirium, or if the delirium has resolved and the patient is back to baseline (which may be a new baseline reflecting deterioration from a previous level of function). In such cases it is prudent to assume that the patient has delirium and to proceed with a careful clinical evaluation. Although thought process disorganization, perceptual disturbances, or mood symptoms may lead the uninitiated to diagnose idiopathic psychiatric illness, the constellation of altered level of consciousness, prominent attentional and other cognitive deficits, and temporal course usually makes the differentiation of delirium from mood, psychotic, and anxiety disorders straightforward. The previous psychiatric history can be helpful, but the clinician must use care in interpreting it because patients with chronic psychiatric illness are also at risk for developing delirium due to medications, drug abuse, or other conditions. Rarely, patients with other Axis I illnesses (particularly the schizophrenias and bipolar disorders) may develop flagrantly disorganized, incoherent states with obvious attentional impairment and the examiner may be unable to test their other cognitive functions. (When found in the course of bipolar disorder, this state has been incorrectly called manic delirium.) Such states cannot be reliably distinguished phenomenologically from delirium due to the more usual medical causes, and they warrant the same thorough search for contributing etiologies accorded other deliria. Course and Prognosis By most definitions, although not by DSM-IV criteria, delirium is a transient condition. For most patients the syndrome resolves within days to a few weeks. However, in sicker populations the mortality associated with delirium is high in the short term (acute hospitalization) and increases with several months of follow-up. It is not clear if increased mortality is independently associated with delirium or if it can be accounted for by known medical pathology. In some patients an apparently new dementia becomes evident on resolution of the delirium; the dementia may not have been present or may have been present but unrecognized prior to the delirium. Treatment The primary treatment of delirium is to identify and ameliorate any causal or contributing medical conditions. As part of that effort, the dosages of all sedatives and other CNS-active medications should be minimized as much as possible. (The exception is sedative-hypnotic or alcohol withdrawal delirium, in which treatment of the underlying problem requires the administration of a cross-tolerant agent such as a benzodiazepine.) Delirious patients may need extra supportive physical care; maintenance of basic functions such as food and fluid intake is crucial to rapid recovery. Keeping the patient in an environment that is quiet and free of unnecessary stimulation may help reduce agitation. Frequent cues to orientation may also be helpful. Supportive contacts with the patient, family, and sometimes staff members are necessary to reassure the patient that the new, often frightening behavioral state reflects physical illness and that the patient is not going crazy. Attention may need to be paid to the patient's legal capacity to participate in informed clinical care decisions. The patient with a quiet, hypoactive delirium needs no specific pharmacotherapy. However, many delirious patients show persistent or intermittent psychomotor agitation that may interfere with nursing care or necessary tests and procedures. Control of the agitation is essential to prevent inadvertent self-damage and allow appropriate evaluation and treatment. Physical restraints may be used transiently when necessary. If sedation is desired, the drug of choice is a high-potency antipsychotic agent in relatively low dosages (e.g., haloperidol 0.5 to 1 mg orally or parenterally, up to several mg a day). Low-potency agents, benzodiazepines, and other sedatives (antihistamines, barbiturates) should generally be avoided because they are likely to worsen the delirious state. At times of severe, life-threatening agitation (e.g., if a patient in the intensive care unit is removing the endotracheal tube, arterial lines, and so forth), sedation at nearly any cost becomes necessary, and combinations of antipsychotic agents, benzodiazepines, and opioids have been used, as have neuromuscular-blocking agents, such as pancuronium (Pavulon), use of which depends on the availability of adequate ventilatory support). There have been case reports of improvement in or remission of delirious states due to intractable medical illnesses with ECT. Although ECT may rarely be advised by a consultant with expertise in the procedure, routine consideration of ECT for delirium is not advised. Dementia Interest in the study and care of patients with dementia has increased, coincident with the proportional increase of the elderly in the population. Although dementing disorders are defined by their multiple cognitive deficits, patients can present with the full array of psychiatric symptoms. And although dementia is most often associated with progressive processes, it does not by itself denote a deteriorating course. Thus, the clinician must seek any curable or treatable causes of dementia whenever it is recognized clinically, before irreversible CNS changes supervene. Definition Dementia is a diminution in cognition in the setting of a stable level of consciousness. Dementia denotes a decrement of two or more intellectual functions, in contrast to focal or specific impairments such as amnestic disorder or aphasia. The persistent and stable nature of the impairment distinguishes dementia from the altered consciousness and fluctuating deficits of delirium. Dementia must also be distinguished from long-standing mental subnormality, as the former represents an acquired loss of or decline in prior intellectual and functional capacities. History Dementia has long been understood as describing an acquired cognitive and behavioral decline associated with brain disease. Jean Étienne Dominique Esquirol, in his classic, early nineteenth-century nosological work, Mental Maladies: A Treatise on Insanity, provided perhaps the first modern definition of dementia: “A cerebral affection usually chronic . . . and characterized by a weakening of the sensibility, understanding, and will.” In his study of over 300 patients, Esquirol described the noncognitive symptoms of dementia, reporting hallucinations, delusions, aggressive behavior, and motor abnormalities in many of the patients. Interestingly, however,

he included among the causes of dementia not only aging, head trauma, syphilis, and alcohol abuse, but also conditions such as “menstrual disorders, . . . onanism, . . . disappointed affections, . . . and political shocks.” Later investigators described neuropathological correlations for the dementia syndromes, firmly establishing the relation between brain disease and dementia. Contemporary interest has focused again on an etiological basis for the observed pathological and pathophysiological abnormalities and on risk factors, preventive measures, and specific treatments for dementia. Comparative Nosology In DSM-III and DSM-III-R, dementia was listed as both a syndrome and a disorder. The development of specific criteria for the symptom constellation was a major departure from all previous nosologies. It proved to be a major conceptual advance for clinical practice and research. The dementia syndrome was one of the possible presentations of psychoactive substance-induced organic mental conditions and of organic mental conditions associated with Axis III physical disorders. Dementia was also listed as a group of specific disorders, including primary degenerative dementia of the Alzheimer's type, multi-infarct dementia, dementia associated with alcoholism, and dementia not otherwise specified. A severity scale of mild, moderate, or severe was provided. DSM-IV eliminates the distinction between dementia as a syndrome and dementia as a disorder. Instead, it delineates those dementing disorders that are related to specific systemic medical or cerebral conditions (e.g., dementia of the Alzheimer's type and vascular dementia). DSM-IV criteria emphasize the defining features of dementia, namely the multiple deficits that represent a decline from a previously attained level of functioning, and incorporate specific information for distinguishing the etiological subcategories from each other, relying on course of the disease, the presence or absence of focal neurological signs and symptoms, laboratory evidence of neurological damage, a history of significant substance abuse, or other evidence of a contributing medical condition. Dementia of the Alzheimer's type is a diagnosis of exclusion, requiring that other potentially etiological CNS or systemic medical conditions be ruled out. Beyond DSM-IV, there are alternative, conceptually overlapping systems for diagnosing dementia. ICD-10, in contrast to DSM-IV, maintains the approach adopted in DSM-III and DSM-III-R, with a general syndromic definition, which is then applied to specific disorders; for example, dementia in Alzheimer's disease or dementia in Huntington's disease. ICD-10 defines dementia as a syndrome in which: there is a disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement. Consciousness is not clouded. Impairments of cognitive function are commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behaviour, or motivation . . . In assessing the presence or absence of a dementia, special care should be taken to avoid false-positive identification: motivational or emotional factors, particularly depression, in addition to motor slowness and general physical frailty, rather than loss of intellectual capacity, may account for failure to perform. ICD-10 also states: Dementia produces an appreciable decline in intellectual functioning, and usually some interference with personal activities of daily living, such as washing, dressing, eating, personal hygiene, excretory and toilet activities. How such a decline manifests itself will depend largely on the social and cultural setting in which the patient lives. Changes in role performance, such as lowered ability to keep or find a job, should not be used as criteria of dementia because of the large cross-cultural differences that exist in what is appropriate, and because there may be frequent, externally imposed changes in the availability of work within a particular culture. This latter statement differs fundamentally from DSM-IV. It underscores an unresolved controversy in the clinical and scientific literature where, in the absence of diagnostic tests for specific disease entities, clinicians and researchers look for sensitive indicators of onset and disease impact. Although ICD-10 explicitly eschews a functional performance criterion, its diagnostic guidelines for dementia then state: “The primary requirement for diagnosis is evidence of a decline in both memory and thinking which is sufficient to impair personal activities of daily living. The impairment of memory typically affects the registration, storage, and retrieval of new information, but previously learned and familiar material may also be lost, particularly in the later stages. Dementia is more than dysmnesia: there is also impairment of thinking and of reasoning capacity, and a reduction in the flow of ideas. The processing of incoming information is impaired, in that the individual finds it increasingly difficult to attend to more than one stimulus at a time, such as taking part in a conversation with several persons, and to shift the focus of attention from one topic to another. If dementia is the sole diagnosis, evidence of clear consciousness is required.” Thus the central component outlined in ICD-10 is “a decline . . . sufficient to impair personal activities of daily living.” Many investigators view this level of decrement as overly severe or too far progressed, potentially precluding use of newly available therapeutic agents until the degenerative process has advanced unnecessarily. Also, these distinctive approaches to diagnostic criteria underscore the potential for substantial variation between the results of studies employing one set versus the other. In the absence of a ‘gold standard' test to externally validate one approach or the other, clinicians and investigators comparing research results must maintain a high degree of caution. ICD-10 includes four dementia categories: (1) dementia in Alzheimer's disease; (2) vascular dementia; (3) dementia in diseases classified elsewhere in the ICD (e.g., dementia in Pick's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease); and (4) unspecified dementia. Another set of research criteria for the diagnosis of dementia of the Alzheimer's type, established by the National Institute of Neurological Communicative Diseases and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA), now the Alzheimer's Association, has become known as the NINCDS-ADRDA criteria. Several studies have shown that a diagnosis of probable dementia of the Alzheimer's type according to NINCDS-ADRDA criteria selects patients similar to those diagnosed using DSM-III criteria. Depending on the case series, both criteria sets have been capable of identifying cases of Alzheimer's disease confirmed postmortem with a 70 to 90 percent specificity. The DSM-IV criteria share many features for the diagnosis of probable dementia of the Alzheimer's type but go beyond them to more clearly define important behavioral subtypes, akin to ICD-10, that may help guide symptomatic treatment interventions. Recent critics regard the DSM-IV specifying phrase “with behavioral disturbance” as inadequate. Some advocate the enumeration of discrete subtypes of noncognitive neuropsychiatric syndromes to further classify the behavioral and psychological signs and symptoms found in patients with neurodegenerative dementing disorders. Whether such an approach will prove useful will depend upon defining more completely: (1) the presentation (i.e., form) of the clinical signs and symptoms that require treatment; (2) whether specific noncognitive neuropsychiatric syndromes exist as a central feature (although neither necessary nor sufficient diagnostically) of Alzheimer's disease or other diseases that cause dementia; (3) the prognostic significance of such symptoms, signs, or syndromes; (4) their pathobiological and causal substrates; (5) psychological, social, and environmental factors that affect their expression; and (6) their response(s) to specific therapeutic interventions. Epidemiology The prevalence of dementia rises exponentially with age. The estimated prevalence of moderate to severe dementia in a population aged 65 years or older is consistently reported at approximately 5 percent. Within that age group the exponential curve is pronounced so that the prevalence in the subgroup aged 65 to 69 years is 1.5 to 2 percent; in the subgroup aged 75 to 79 years it is 5.5 to 6.5 percent; and in the subgroup aged 85 to 89 years it is 20 to 22 percent. Dementia of the Alzheimer's type is the most common dementing disorder in clinical and neuropathological prevalence studies reported from North America, Scandinavia, and Europe. Prevalence studies from Russia and Japan show vascular dementia to be more common in those countries. It remains unclear whether those apparent clinical differences reflect true etiological distinctions or inconsistent uses of diagnostic criteria. Dementia of the Alzheimer's type becomes more common with increasing age; among persons older than 75 years, the risk is six times greater than the risk for vascular dementia. There is a suggestion of higher rates of dementia of the Alzheimer's type in females and higher rates of vascular dementia in males. In geriatric psychiatric patient samples, dementia of the Alzheimer's type is a much more common etiology (50 to 70 percent) than vascular dementia (15 to 25 percent). Studies of the incidence of dementia have been plagued by widely differing methodology and results. Again, there is an exponential increase in incidence with age, although some reports have noted a leveling off starting around age 75 years. Etiology Table 10-27 lists common causes of dementia. Alzheimer's disease, the most common type of degenerative dementia, was discussed in an earlier section. Huntington's disease and Parkinson's disease were also discussed earlier in the chapter as paradigmatic examples of subcortical degenerative processes, with clinical and neuropathological descriptions separating them from cortical dementias. There may be clinical and neuropathological overlap between Alzheimer's disease and Parkinson's disease, especially among older patients. The significance of this finding remains unknown.

Table 10-27 Causes of Dementia

Frontal Lobe Degeneration In recent years several authors have sought to distinguish dementias of the frontal lobe from other disorders. The uncertain status of dementias of the frontal lobe as distinct clinical and neuropathological entities has not yet warranted their formal inclusion in DSM-IV or ICD-10. They are described as cortical dementias that are found in as many as 10 to 20 percent of cases in some neuropathological series. Age at onset is apparently between 50 and 60 years for the majority, but the reported range is broad—20 to 80 years. The early clinical features of frontal lobe dementias are typified by damage to the frontal lobes and include prominent changes in personality and behavior. The personality changes include disinhibition, social misconduct, and lack of insight; these changes progress to apathy, mutism, and repetitive behaviors. A variant of the Kluver-Bucy syndrome, a condition originally described in monkeys that had undergone surgical ablation of the temporal lobes, is also described in the early stages of frontal lobe dementias and is characterized by combinations of disrupted eating behavior, hyperorality, mood disturbances, and sensory agnosias. Language, praxis, and gnosis are relatively spared early in the disease course, in contrast to dementia of the Alzheimer's type. However, dementias of the frontal lobe are described as progressive conditions that may in some cases involve memory as well as other cognitive functions. To date no studies have attempted to prospectively discriminate dementia of frontal lobe origin from dementia of the Alzheimer's type, with subsequent neuropathological confirmation to determine clinical diagnostic accuracy. Neuropsychological testing in patients suspected of having dementia of frontal lobe origin may demonstrate disproportionate impairment in tasks related to frontal lobe function, such as deficiency in abstract thinking, attentional shifting, or set formation. Structural neuroimaging, such as CT or MRI, may reveal prominent atrophy of the frontal lobe, especially early in the disease process. Functional neuroimaging may prove more reliable for distinguishing dementia of frontal lobe origin from dementia of the Alzheimer's type. Regional cerebral blood flow studies using radioactively labeled xenon and SPECT studies have demonstrated disproportionate decreases in blood flow, radio tracer uptake, and glucose metabolism in the frontal lobes in patients with suspected or autopsy-confirmed frontal lobe dementia. At present, the definitive diagnosis of any degenerative dementia rests on postmortem neuropathological examination. Only one type of frontal lobe dementia, Pick's disease, is associated with distinctive histopathological abnormalities that allow for certain diagnosis. Swollen neurons known as Pick cells and intraneuronal inclusions known as Pick bodies define the disorder neuropathologically ( Fig. 10-12). Demyelination and gliosis of the frontal lobe white matter may also be found. Other frontal lobe dementias have been referred to as dementia of the frontal lobe type or frontal lobe degeneration of non-Alzheimer's type. They have been distinguished from Alzheimer's disease by their marked gross morphological involvement of frontal and anterior temporal lobes, with relative sparing of the postcentral and temporoparietal areas mostly affected in Alzheimer's disease, and by the absence of amyloid plaques and neurofibrillary tangles microscopically. The lack of positive neuropathological inclusion criteria leaves many of these clinical conditions as disease entities of uncertain status, defined histopathologically by the absence of specific features. Whenever the hallmark findings of Alzheimer's disease are present, that diagnosis has been applied, irrespective of prior clinical findings. Thus, there are no data available to determine how many clinically diagnosed cases of frontal lobe dementia have been recast as Alzheimer's disease after death.

FIGURE 10-12 Intraneuronal inclusions in Pick's disease. Silver stain. (Reprinted with permission from Rowland LP, editor: Merritt's Textbook of Neurology, ed 9. Williams & Wilkins, Baltimore, 1995.)

Of the potentially multiple forms of dementia associated with progressive frontal lobe dysfunction, only one type can be distinguished from Alzheimer's disease neuropathologically; the others show no defining postmortem signs. They may also be difficult to distinguish clinically in life. In the early stages of disease, the predominance of behavioral and personality disturbance, the presence of primitive reflexes, and neuropsychological and neuroimaging evidence of disproportionate frontal lobe involvement can help with a more confident premortem diagnosis of frontal lobe dementia. Some authors have assumed that there are many variants of dementia of frontal lobe origin that cannot be distinguished from each other clinically; at present, only Pick's disease has definitive neuropathological features. Subcortical Degeneration Huntington's disease and Parkinson's disease were discussed earlier as examples of degenerative disorders with a subcortical pattern of deficits. Progressive supranuclear palsy, first described in 1964, is a degenerative disease involving the brainstem, cerebellum, and basal ganglia. The presenting history is usually notable for a gait disturbance, particularly spontaneous toppling. The clinical examination is notable for supranuclear paralysis of extraocular movements, particularly in the vertical plane. Dysarthria and dystonic rigidity of the neck and trunk are also common. Onset is usually after age 50 years, with progressive muscular rigidity. Neuropathology is notable for cell loss and gliosis of various nuclei in the brainstem, basal ganglia, and cerebellum, with striking preservation of the cortex. Progressive supranuclear palsy and Huntington's disease were the two disorders to which the label “subcortical dementia” was originally applied. In progressive supranuclear palsy a marked slowing of cognitive processes, apathy, and lack of initiative have been described, associated with relative sparing of language, memory, and praxis. Fahr's disease involves idiopathic calcification of the basal ganglia. A subcortical dementia with a parkinsonian syndrome has been described. (Mild basal ganglia calcification is frequently observed incidentally on neuroimaging studies. The clinical significance of that finding is unknown.) Basal ganglia calcification can also be seen in patients with disorders of calcium metabolism, with the expected patterns of subcortical dementia and movement disorder. Vascular Etiologies Cerebrovascular diseases together comprise the second most common cause of dementia. This category of dementia was referred to in the past as arteriosclerotic dementia, reflecting the belief that vascular insufficiency was responsible for the cognitive degeneration. That has now been supplanted by the belief that tissue damage or infarction underlies the vascular dementias. Cerebral infarction can be the result of a number of processes, of which thromboembolism from a large vessel plaque or cardiothrombus is the most common ( Fig. 10-13). Anoxia due to cardiac arrest, hypotension, anemia, or sleep apnea can also produce ischemia and infarction. Cerebral hemorrhage related to hypertension or an arteriovenous malformation accounts for approximately 15 percent of cerebrovascular disease (Fig. 10-14).

FIGURE 10-13 Hemorrhagic infarct in the territory of the middle cerebral artery. (Reprinted with permission from Hirano A: A Guide to Neuropathology. Igaku-Shoin, New York, 1981.)

FIGURE 10-14 Giant aneurysm. A, T2-weighted axial MRI scan shows a large, hyperintense mass in the left suprasellar region with medial displacement of the distal left internal carotid artery. B, T1-weighted coronal MRI scan demonstrates the heterogeneous parasellar mass; the areas of increased signal intensity indicate thrombus. A small curvilinear focus of flow void is seen medially most consistent with small residual patent vascular lumen. These findings are suggestive of partially thrombosed giant aneurysm. C, Anteroposterior view of arterial phase of left common carotid arteriogram illustrates a giant aneurysm of the left internal carotid artery. (Reprinted with permission from Rowland LP, editor: Merritt's Textbook of Neurology, ed 9. Williams & Wilkins, Baltimore, 1995.)

The clinical characteristics of a vascular dementia depend on the area of infarction. As such, there is a wide variability in the possible presenting features of a vascular dementia. Single infarctions may result in the discrete loss of one particular function (e.g., language) without dementia per se. However, some strategically located infarctions can affect more than one domain of cognitive function and mimic the clinical picture of a global dementia. An example is the angular gyrus syndrome that can occur with large posterior lesions in the dominant hemisphere. It has been characterized as manifesting with alexia with agraphia, aphasia, constructional disturbances, and Gerstmann syndrome (acalculia, agraphia, right-left disorientation, and finger agnosia). Although the findings are similar to those of dementia of the Alzheimer's type, angular gyrus syndrome can be distinguished by its abrupt onset, the presence of focal neurological, EEG, and imaging abnormalities, and preservation of memory and ideomotor praxis. Vascular dementia is more commonly associated with multiple infarctions. The infarctions may take the form of numerous large infarctions accompanied by widespread cognitive and motor deficits. Tiny, deep infarctions, lacunes, result from disease of the small arteries that usually involves subcortical structures, such as the basal ganglia, thalamus, and internal capsule. The neurological and cognitive deficits may resolve quickly after each of the small strokes; however, the deficits may accumulate, leading to a persisting functional and intellectual decline. In the past a stepwise pattern of deterioration was described for that type of vascular dementia, but it was dropped from the DSM-IV criteria, as no specific pattern of deterioration has been reliably demonstrated for vascular dementias. Similarly, the description of patchy deficits has been deleted, in light of the marked variability in presentation of vascular dementia, depending on the type of vasculature and the site and extent of infarction. Binswanger's Disease Also called subcortical arteriosclerotic encephalopathy, this is characterized by microinfarctions of the white matter with sparing of the cortex. It was originally believed to be a rare form of dementia that could be diagnosed only at autopsy. With the advent of sophisticated neuroimaging techniques such as CT and MRI and the common observation of white matter hyperintensities, there is renewed interest in the disease. Binswanger's disease produces a subcortical pattern of dementia, as the neuropathology is restricted to white matter. However, the mere presence of white matter hyperintensities on MRI is not adequate for diagnosis, as those areas may represent small infarctions, focal demyelination, or simply dilated perivascular spaces. Some studies have found no postmortem pathological correlate to white matter hyperintensities detected on MRI in vivo. Recently, criteria have been proposed for the diagnosis of Binswanger's disease that include clinical and neuropsychological confirmation of dementia, the presence of vascular risk factors, evidence of focal cerebrovascular disease, evidence of subcortical dysfunction, and bilateral white matter abnormalities greater than 2 mm in size on CT or T2-weighted MRI scans. Vascular dementia of the hemodynamic type is a classification that has been used to refer to cognitive impairments that arise secondary to hypotensive episodes, such as those due to cardiac dysrhythmias or hypotension. They may overlap phenomenologically with other conditions that result from chronic hypoxia. Wilson's disease (hepatolenticular degeneration) is an inherited disorder involving abnormal metabolism of copper. Copper accumulates in both the liver and the CNS, particularly in the striatum, caudate, and putamen. Onset usually occurs during childhood or adolescence, although it may be delayed until middle age. Personality change and behavioral disturbance are the most common neuropsychiatric manifestations (and frequently the presenting symptoms of the disease), but cognitive impairment may also be present. The latter takes the form of a subcortical dementia, with psychomotor slowing and loss of initiative, in the presence of relatively spared language functions, memory, and praxis. Motor symptoms are prominent in a parkinsonian pattern and include rigidity, tremor, and, at times, athetosis. The diagnosis is confirmed by assay of serum copper levels and urinary copper excretion. Treatment with chelating agents—dimercaprol (BAL); in the past and penicillamine (Cuprimine) more recently—can retard the progression of the disease and in some instances can result in improvement in clinical features. Neuropsychiatric symptoms are treated symptomatically. Other Causes Primary psychiatric disorders can present with cognitive impairment. The term “pseudodementia” has been used to describe cognitive deficits that can be seen in the presence of idiopathic psychiatric illness, especially major depressive disorder. The deficits are usually subcortical in nature, involving attention, speed of mental processing, memory retrieval, and verbal fluency and elaboration. Patients may register new material but have difficulty with spontaneous recall that typically improves when they are presented with recognition cues. Pseudodementia was originally thought to be simply another expression of the depressed patient's lack of energy and unwillingness to attend to tasks. More recently, it has become clear that the deficits of pseudodementia represent fundamental cognitive deficits related to the same brain dysfunction that is responsible for the depressive symptoms. Pseudodementia syndrome of depression is one current term that is synonymous with pseudodementia and may more accurately reflect the nature of the pathobiological process. Recent studies have indicated that it may have a poorer prognosis, especially in the elderly, and several investigators have described a persistent mild anomia in the same patient population. Schizophrenia was viewed at first as a disorder in which cognitive impairment was a prominent feature (dementia precox). Negative symptoms such as paucity of speech, poverty of ideas, blunting of affect, and functional deterioration contributed to that perception. Contemporary studies have demonstrated consistent cognitive deficits in certain subgroups of schizophrenia patients, primarily involving neuropsychological tasks thought to be sensitive to frontal lobe function. However, it is unclear whether those deficits are acquired over the course of the illness or represent cognitive skills that have never developed, consistent with the neurodevelopmental hypothesis of schizophrenia. Normal pressure hydrocephalus is an idiopathic disorder caused by partial obstruction to the flow of CSF into the subarachnoid space. Onset typically occurs after age 60 years. The pathophysiology is thought to be related to disruption of neural function, either through stretching of periventricular fibers or through disruption of the pressure differential between the ventricular and subdural spaces, compromising neuronal function by altering cerebral blood flow. The classic clinical triad of dementia, incontinence, and gait disturbance is not present uniformly in all patients with normal pressure hydrocephalus, especially early in the course, although it

nearly always emerges if the condition goes unrecognized or untreated. The diagnosis is based on clinical findings, neuroimaging evidence of ventricular dilation in the absence of sulcal widening ( Fig. 10-15), and normal CSF pressure measurements on lumbar puncture. The dementia can be of a subcortical or cortical pattern and may at times be reversed with CSF shunt surgery. Specific indicators of a positive outcome remain to be established, although identification of the etiology and a short disease course favor improvement in the dementia. Rarely, case reports have documented marked improvements up to 4 years after the onset of progressive dementia.

FIGURE 10-15 Brain CT scans. Marked ventricular dilatation ( A) and widening of cortical sulci ( B) indicative of hydrocephalus ex vacuo in a 64-year-old woman with dementia. (Reprinted with permission from Rowland LP, editor: Merritt's Textbook of Neurology, ed 9. Williams & Wilkins, 1995.)

Irradiation-induced dementia is an iatrogenic concomitant of cranial radiation treatment that has been reported with greater frequency as the posttreatment survival time for patients with intracranial tumors has lengthened. Although transient cognitive deficits can be observed coincident with treatment or soon after treatment, a progressive irreversible dementia can begin 6 to 24 months after the termination of treatment. White matter is particularly sensitive to the deleterious effects of irradiation, and the dementia is predominantly subcortical in nature, reflecting the preferential white matter degeneration. The pathophysiology has been hypothesized to involve arteriolar leakage and localized edema.

DIAGNOSIS AND CLINICAL FEATURES DSM-IV has eliminated the general syndrome of dementia that was included in DSM-III-R. The dementia diagnoses in DSM-IV are dementia of the Alzheimer's type (Table 10-28), vascular dementia (Table 10-29), dementia due to other general medical conditions ( Table 10-30), substance-induced persisting dementia ( Table 10-31), dementia due to multiple etiologies ( Table 10-32), and dementia not otherwise specified (Table 10-33). The ICD-10 diagnostic criteria for dementia are presented in Table 10-34, Table 10-35, Table 10-36, and Table 10-37.

Table 10-28 DSM-IV Diagnostic Criteria for Dementia of the Alzheimer's Type

Table 10-29 DSM-IV Diagnostic Criteria for Vascular Dementia

Table 10-30 DSM-IV Diagnostic Criteria for Dementia Due to Other General Medical Conditions

Table 10-31 DSM-IV Diagnostic Criteria for Substance-Induced Persisting Dementia

Table 10-32 DSM-IV Diagnostic Criteria for Dementia Due to Multiple Etiologies

Table 10-33 DSM-IV Diagnostic Criteria for Dementia Not Otherwise Specified

Table 10-34 ICD-10 Diagnostic Criteria for Dementia

Table 10-35 ICD-10 Diagnostic Criteria for Dementia in Alzheimer's Disease

Table 10-36 ICD-10 Diagnostic Criteria for Vascular Dementia

Table 10-37 ICD-10 Diagnostic Criteria for Dementia in Other Diseases Classified Elsewhere

Dementia of the Alzheimer's Type The DSM-IV diagnostic criteria for dementia of the Alzheimer's type emphasize the presence of memory impairment and the associated presence of at least one other symptom of cognitive decline (aphasia, apraxia, agnosia, or abnormal executive functioning). The diagnostic criteria also require a continuing and gradual decline in functioning, impairment in social or occupational functioning, and the exclusion of other causes of dementia. DSM-IV suggests that the age of onset be characterized as early (at age 65 or below) or late (after age 65) and that a predominant behavioral symptom be coded with the diagnosis, if appropriate. Vascular Dementia The general symptoms of vascular dementia are the same as those for dementia of the Alzheimer's type, but the diagnosis of vascular dementia requires the presence of either clinical or laboratory evidence supportive of a vascular cause of the dementia. Dementia Due to Other General Medical Conditions DSM-IV lists six specific causes of dementia that can be coded directly: HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, and Creutzfeldt-Jakob disease. A seventh category allows the clinician to specify other nonpsychiatric medical conditions associated with dementia. Substance-Induced Persisting Dementia The primary reason that this DSM-IV category is listed both with the dementias and with the substance-related disorders is to facilitate the clinician's thinking regarding differential diagnosis. The specific substances that DSM-IV cross-references are alcohol; inhalant; sedative, hypnotic, or anxiolytic; and other or unknown substances. Clinical Diagnosis and Evaluation The first step in the diagnosis of dementia is to establish that the cognitive deficits have occurred in a patient with a stable level of consciousness, without fluctuation or waxing and waning. It must also be demonstrated that the patient has multiple deficits rather than a focal disturbance such as that seen in amnestic disorder or primary progressive aphasia (the insidious onset of a slowly progressive language disturbance with relatively preserved memory, reasoning, judgment, and comportment). Once the basic criteria for the diagnosis of dementia have been met, the task is to determine which etiology is responsible by using the standard means of history, clinical examination, and laboratory evaluation. A 61-year-old high-school science department head, who was an experienced and enthusiastic camper and hiker, became extremely fearful while on a trek in the mountains. Gradually, over the next few months he lost interest in his usual hobbies. Formerly a voracious reader, he stopped reading. He had difficulty doing computations and made gross errors in home financial management. On several occasions he became lost while driving in areas that were formerly familiar to him. He began to write notes to himself so that he would not forget to do errands. Very abruptly, and in uncharacteristic fashion, he decided to retire from work, without discussing his plans with his wife. Intellectual deterioration gradually progressed. He spent most of the day piling miscellaneous objects in one place and then transporting them to another spot in the house. He became stubborn and querulous. Eventually he required assistance to shave and dress. When examined 6 years after the first symptoms had developed, the patient was alert and cooperative. He was disoriented with respect to place and time. He could not recall the names of four or five objects after a 5-minute interval of distraction. He could not remember the names of his college and graduate school or the subject in which he had majored. He could describe his job by title only. In 1978 he thought that John Kennedy was president of the United States. He did not know Joseph Stalin's nationality. His speech was fluent and well articulated, but he had considerable difficulty finding words and used many long and essentially meaningless phrases. He called a cup a vase, and identified the rims of glasses as “the holders.” He did simple calculations poorly. He could not copy a cube or draw a house. His interpretation of proverbs was concrete, and he had no insight into the nature of his disturbance. An elementary neurological examination revealed nothing abnormal, and routine laboratory tests were also negative. A CT scan, however, showed marked cortical atrophy. (Reprinted with permission from DSM-IV Casebook.) For dementia of the Alzheimer's type, a family history of the dementia is probably the most important risk factor after advanced age. A family history of Down syndrome or of hematological malignancies, such as leukemia, myelolymphoma, or Hodgkin's disease, is also associated with an increased risk for Alzheimer's disease. There is some evidence for a familial predisposition to vascular dementia, but it has not been demonstrated as clearly as for dementia of the Alzheimer's type. The family history is of greatest significance in the heredity dementias, such as Huntington's disease, which is transmitted via a single autosomal dominant gene with nearly 100 percent penetrance. A history of a parent or grandparent with a movement disorder and dementia should alert the clinician to that diagnostic possibility. Huntington's disease does not skip generations, although family members may have died from other causes prior to the emergence of definable symptoms. A familial pattern has been established for Wilson's disease, with a presumptive autosomal recessive gene responsible for abnormal copper metabolism. Metachromatic leukodystrophy similarly is inherited in a recessive pattern with incomplete penetrance. Degenerative dementias as a group do not have well-established risk factors other than old age and familial patterns. For dementia of the Alzheimer's type, other risk factors identified tentatively in recent years include female sex, a past history of head trauma, and lower education. Vascular dementias are highly associated with the risk factors for cerebrovascular disease. Those factors include hypertension (especially with systolic pressures greater than 160 mmHg), cardiac disease, transient ischemic attacks, diabetes mellitus, carotid bruits, and sickle cell disease. Obesity, a sedentary lifestyle, tobacco use, alcohol consumption, and elevated serum cholesterol and lipid levels are less well established as risk factors for cerebrovascular disease. A history of severe head trauma or multiple traumas over a period of time (such as in boxers) should raise the suspicion of dementia related to brain trauma. Although severe head trauma earlier in life increases the risk of dementia of the Alzheimer's type, its mechanism of action is unknown. A history of an untreated or partially treated sexually transmitted disease should raise the suspicion for neurosyphilis. The presence of risk factors for HIV infection, namely homosexuality, multiple sexual partners, and intravenous drug use, similarly increase the risk for dementia due to HIV disease. Patients with chronic medical illnesses, especially if poorly controlled, such as epilepsy, renal failure, or hepatic cirrhosis, are also at greater risk for developing dementias. A history of occupational exposure to heavy metals or other toxins should be obtained as part of any evaluation for dementia. Pathology and Laboratory Examination A general physical examination is a routine component of the workup for dementia. It may reveal evidence of systemic disease causing brain dysfunction, such as an enlarged liver and hepatic encephalopathy, or it may demonstrate systemic disease related to particular CNS processes. The detection of Kaposi's sarcoma, for example, should alert the clinician to the probable presence of AIDS and the associated possibility of AIDS dementia complex. Focal neurological findings, such as asymmetrical hyperreflexia or weakness, are seen more often in vascular than in degenerative diseases. Frontal release signs and primitive reflexes, while suggesting pathology in the frontal lobe, are present in many disorders and often point to a greater extent of

progression. Laboratory evaluation can assist in definitive identification of the etiological agent. The range of possible etiologies of dementia mandates selective use of laboratory tests. The evaluation should follow informed clinical suspicion, based on the history and physical and mental status examination results. Table 10-4 lists a number of laboratory tests useful in evaluating specific diseases presenting as dementia. Differential Diagnosis The first step in the diagnosis of dementia is to exclude delirium. Delirium can mimic every possible psychiatric disorder and symptom. It is most common in the same populations in which dementia is most common, namely the elderly and the brain-injured. It can be distinguished from dementia by its cardinal feature, disturbance of consciousness. Level of consciousness or arousal must be determined to be stable before a diagnosis of dementia can be made with confidence. Dementia must also be distinguished from focal or specific cognitive impairments, such as those seen in aphasic or amnestic patients. Mood disorders can present with cognitive symptoms, particularly in the dementia of depression or pseudodementia. A history of a mood disorder or a current disturbance in neurovegetative function should alert the clinician to the possibility of a major depressive disorder. Course and Prognosis The course and prognosis of a dementia syndrome vary with its cause. Dementia does not in itself imply a progressive deterioration, although many of the pathobiological processes underlying dementia are degenerative, and there is no known means of altering the progressive clinical deterioration. The rate of progression may vary within families or from individual to individual. Occasionally, progression can be halted or slowed in the vascular dementias if contributing risk factors for further vascular events can be reduced. Some dementias, such as those related to endocrine or metabolic processes or drug intoxications, may resolve entirely with the treatment or with removal of the basic disorder. However, a long-standing cerebral insult often leads to chronic clinical deficits that persist even when the insult has been removed. Dementias related to tumor and infection usually follow a similar pattern. Age at onset is an important feature of any illness. Alzheimer's disease is the most common cause of dementia in the United States. Onset usually occurs after age 60 years and the prevalence increases exponentially with each successive decade, although cases have been reported in patients as young as 30 years. Familial forms of dementia of the Alzheimer's type appear to have an earlier age at onset. Cerebrovascular disease, the second most common cause of dementia, is associated with an earlier age at onset overall. Dementia secondary to other medical conditions usually arises only after the disease has progressed for some time. This observation is true of the dementias associated with infectious, physiological, metabolic, and toxic processes. The age at onset of Huntington's disease is usually between 30 and 50 years, but onset may occur earlier or later. The dementias can be distinguished to some extent by their course, especially earlier in the disease process. Degenerative dementias are insidious in onset and gradually progressive. Despite the clinical rule of a steadily progressive course in dementia of the Alzheimer's type, some individuals may reach a plateau for several years in the overall functional impairment before progression resumes and continues on to death. Vascular dementias may follow a stepwise pattern, in which new deficits appear abruptly and associated with new vascular events, but the vascular dementias also often have an insidious onset and a slow but steadily progressive course. Dementias related to infection are usually acute, although syphilis and cryptococcal meningitis can have an indolent course. Metabolic dementias may begin rapidly or slowly, depending on the underlying systemic disease; correction of the basic deficiency or disturbance may result in improvement, although the cognitive deficits often persist. Drug- or toxin-related dementias may improve once the insult has been discontinued, although radiation-induced dementia is an exception: It first manifests many months after radiation exposure has ceased, and a progressive course ensues. Treatment The first step in the treatment of dementia is verification of the diagnosis. Accurate diagnosis is imperative, for the progression may be halted or even reversed if appropriate therapy is provided. Preventive measures are important, particularly in vascular dementia. Such measures might include changes in diet, exercise, and control of diabetes and hypertension. Pharmacological agents might include antihypertensive, anticoagulant, or antiplatelet agents. Blood pressure control should aim for the higher end of the normal range, as that has been demonstrated to improve cognitive function in patients with vascular dementia. Blood pressure below the normal range has been demonstrated to result in further impairment of cognitive function in the patient with dementia. The choice of antihypertensive agent can be significant in that beta-blocking agents have been associated with exaggeration of cognitive impairment. Angiotensin-converting enzyme (ACE) inhibitors and diuretics have not been linked to the exaggeration of cognitive impairment and are thought to lower blood pressure without affecting cerebral blood flow (cerebral blood flow is presumed to correlate with cognitive function). Surgical removal of carotid plaques may prevent subsequent vascular events in carefully selected patients. For the degenerative dementias, no direct therapies have been demonstrated conclusively to reverse or retard the fundamental pathophysiological processes. The search for such an agent has been exhaustive and fraught with frustration. Such studies are constructed on a growing foundation of knowledge regarding brain neurochemistry and the derangements found in dementia. Numerous neurotransmitters, including acetylcholine, dopamine, norepinephrine, GABA, and serotonin, and several neuropeptides, including somatostatin and substance P, are decreased in dementia. Alzheimer's disease has been studied the most extensively, but similar decreases in neurotransmitters have been found in Huntington's disease, alcohol–induced persisting dementia, vascular dementia, Parkinson's disease, and (rarely) in normal aging. Multiple neuropharmacological strategies have been devised in the hope of replenishing the deficient neurotransmitters. Replacement therapy for acetylcholine has been the most common and widely publicized strategy. Efforts at replenishment have included the use of acetylcholine precursors (e.g., example, choline [Anthropan] and lecithin [Phoschol]), cholinergic agonists (e.g., pilocarpine [Salagen] and arecoline), and cholinesterase inhibitors. Treatment with physostigmine (Antilirium, Eserine), a short-acting cholinesterase inhibitor, has consistently resulted in small but statistically significant improvements in memory in patients with dementia of the Alzheimer's type and in healthy control subjects during brief-duration infusion studies. New, longer-acting forms now are being investigated. Tacrine (Cognex), became the focus of public debate after a 1986 study reported alleged marked improvements in 16 patients with dementia of the Alzheimer's type. That study, however, was criticized for substantial methodological limitations and was not replicated in several subsequent attempts. Two multicenter studies of varying design were published in late 1992. One study, with an enriched population, aimed to maximize detection of beneficial effect, but found only marginal improvement and no overall evidence of clinically meaningful change. The second reported statistically significant but still modest improvements in cognition. The Food and Drug Administration (FDA) eventually approved the use of tacrine as a therapeutic agent for dementia of the Alzheimer's type. Clinicians must be aware of both its limited demonstrated benefit and its hepatotoxic potential. Recently the FDA approved the cholinesterase inhibitor, donepezil (Aricept), for symptomatic treatment of mild to moderate cognitive deficits in patients with presumed Alzheimer's disease. Therapeutic effects have been modest. Dosages of 5 to 10 mg daily were given in experimental trials; common adverse effects have included nausea, diarrhea, and vomiting. Insomnia, muscle cramps, and anorexia have occurred occasionally, but unlike tacrine, so far there has been no reported hepatotoxicity. In summary, it has become clear that there are therapies available that may improve the function of patients with dementia of the Alzheimer's type without incurring severe toxicity. Thus it now seems reasonable to declare “When in doubt, treat!” This reflects a fundamental shift in the care of these individuals, moving beyond long-held nihilism to a more optimistic view of clinical intervention. It is the first step in a treatment revolution that will reach full force during the next 10 to 15 years. Other experimental approaches to treating cognitive impairment or disease progression include a plant extract of Ginkgo biloba, estrogens, vitamin E, and prednisone (Deltasone, Orasone). Many researchers have concluded that the notion of a single or selective neurotransmitter defect for any specific dementing illness is simplistic and that future research efforts should be directed toward neuronal protection and regeneration. Selegiline (Eldepryl), a monoamine oxidase (MAO) type B (MAOB) inhibitor, has apparently slowed the progression of Parkinson's disease, presumably by limiting endogenous generation of destructive oxidative products. Similar antioxidant treatments are being used experimentally with other dementias, including Huntington's disease and vascular dementia. Naloxone (Narcan), an opiate antagonist, is thought to have possible application in vascular dementia based on animal studies in which it was demonstrated to decrease the sequelae of cerebral ischemia. Nerve growth factor is being studied as a means of promoting neural regeneration or sprouting. The absence of curative therapies does not preclude efforts to ameliorate disturbing clinical problems. Symptomatic measures are the rule for behavioral management of most dementia syndromes. Programs that emphasize a high degree of regularity and consistency in daily schedule and environment can mitigate the risk of development of catastrophic reactions or explosive outbursts. All pharmacological agents that are used for the idiopathic psychiatric disorders can be used in patients with dementia, although usually at dosages one half to two thirds lower. Antidepressant medications and ECT are safe and effective for significant depressive symptoms. The use of antipsychotic should be restricted to patients with defined psychotic symptoms because patients with dementia are more susceptible to the parkinsonian adverse effects inherent in these agents. Clinicians and researchers are now cautiously using newer atypical antipsychotic drugs, seeking to avoid these adverse effects. Benzodiazepines may be used briefly and judiciously for emergency sedation but otherwise should be avoided because they can produce delirium and tend to further compromise residual cognitive capacities. Lithium (Eskalith), centrally active b-adrenergic blockers, carbamazepine (Tegretol), and valproate (Depakene) have been used empirically in the treatment of affective lability and aggressive outbursts. Empirical management therapies should be used in conjunction with environmental modifications. Individual psychotherapy may have benefit for patients in the early stages of dementia, especially to assist them in coping with their losses. The positive effects of a therapeutic relationship can still be felt at later stages when patients have more severe cognitive deficits. Family education and support are vital components of any treatment approach, as all members benefit from extensive knowledge about course and prognosis, as well as needing

assistance when assuming new roles in their relationships with the patient. Amnestic Disorders The inclusion of amnestic disorders in the psychiatric nosology reflects the classification's roots as a manual for state hospital or asylum patients. The number of individuals given amnestic diagnoses due to nutritional deficiency, often related to chronic alcohol dependence, has declined. In contrast, traumatic causes have increased dramatically during recent decades. Definition The essential feature of amnestic disorders is the acquired impaired ability to learn and recall new information, coupled variably with the inability to recall previously learned knowledge or past events. The impairment must be sufficiently severe to compromise personal, social, or occupational functioning. The diagnosis is not made if the memory impairment exists in the context of reduced ability to maintain and shift attention, as encountered in delirium, or in association with significant functional problems due to the compromise of multiple intellectual abilities, as seen in dementia. Amnestic disorders are secondary syndromes caused by systemic medical or primary cerebral diseases, substance use disorders, or medication adverse effects, as evidenced by findings from clinical history, physical examination, or laboratory examination. History and Comparative Nosology Although amnestic disorder has been long described, its specific recognition has been relatively recent. It was most clearly elaborated by Sergei Korsakoff and was included among the alcoholic psychoses in DSM-I and DSM-II, as well as in earlier editions. In DSM-I it was classified under chronic brain syndrome associated with intoxication. Understanding that psychosis was the term used to denote more severe disturbances of mental status, the authors of DSM-I stated: “The latter [severe alcohol-related brain damage] may manifest itself by the type of chronic delirium formerly diagnosed as Korsakoff's psychosis.” Specific discussion of the amnestic syndromes was absent. Like DSM-I, DSM-II provided little clinical description of amnestic disorders, although a slightly longer definition was presented in the text. DSM-III and DSM-III-R, in contrast, provided an in-depth discussion and more specific diagnostic criteria. However, both volumes failed to underscore the essential quality of amnestic disorder as characterized by a specific cognitive deficit in the realm of memory, while dementia syndromes were reflective of multiple failures, including memory and other impaired intellectual abilities. DSM-III and DSM-III-R required “demonstrable evidence of impairment in both short- and long-term memory,” whereas the key feature of the disorder is an inability to learn and later recall new information. In addition, neither DSM-III nor DSM-III-R provided for the separation of transient from persistent amnesia. ICD-10 maintains the approach of DSM-III. Epidemiology Data are not available for estimating the point or lifetime prevalence, incidence, or lifetime risk of persistent amnestic disorder. One recent study indicated that transient global amnesia may have an incidence of 5.2 cases per 100,000 population per year. There are no specific data available on age at onset or culture- or sex-related aspects beyond those relating to the genesis of primary etiological disease processes. For example, transient global amnesia typically occurs after age 50 years. Etiology Amnestic disorder often occurs as the result of pathological processes that cause damage to specific diencephalic and middle temporal lobe structures (e.g., mammillary bodies, the hippocampus). The pathology is commonly bilateral, but deficits may arise from unilateral lesions. Pathogenic processes include closed-head trauma and penetrating missile wounds, focal tumors, surgical intervention, encephalitis due to infection from herpes simplex virus, infarction of the territory of the posterior cerebral artery, and hypoxia. A common cause of amnestic disorder is the chronic use of alcohol and associated thiamine deficiency. Transient amnestic disorder, when encountered as a transient global amnesia, is typically associated with cerebrovascular disease and pathology in the vertebrobasilar system. Transient amnesia may also arise from episodic physiological or metabolic disorders, such as acute intoxications or seizures.

DIAGNOSIS AND CLINICAL FEATURES Diagnosis The differentiation between amnestic syndrome and amnestic disorder made in DSM-III-R has been eliminated in DSM-IV. For the diagnosis of amnestic disorder, DSM-IV requires the “development of memory impairment as manifested by impairment in the ability to learn new information or the inability to recall previously learned information,” and the “memory disturbance causes significant impairment in social or occupational functioning.” A diagnosis of amnestic disorder due to a general medical condition ( Table 10-38) is made when there is evidence of a causatively relevant specific medical condition (including physical trauma). DSM-IV further categorizes the diagnosis as being transient or chronic. A diagnosis of substance-induced persisting amnestic disorder is made when there is evidence that the symptoms are causatively related to the use of a substance ( Table 10-39). DSM-IV refers the clinician to specific diagnoses within substance-related disorders: alcohol-induced persisting amnestic disorder; sedative, hypnotic, or anxiolytic-induced persisting amnestic disorder; and other (or unknown) substance-induced persisting amnestic disorder. DSM-IV also provides for the diagnosis of amnestic disorder not otherwise specified ( Table 10-40 ). The ICD-10 diagnostic criteria for organic amnesia syndrome not induced by alcohol and other psychoactive substances are listed in Table 10-41.

Table 10-38 DSM-IV Diagnostic Criteria for Amnestic Disorder Due to a General Medical Condition

Table 10-39 DSM-IV Diagnostic Criteria for Substance-Induced Persisting Amnestic Disorder

Table 10-40 DSM-IV Amnestic Disorder Not Otherwise Specified

Table 10-41 ICD-10 Diagnostic Criteria for Organic Amnesic Syndrome, Not Induced by Alcohol and Other Psychoactive Substances

Clinical Features The inability to learn and recall new information, the cardinal feature of the disorder, is most apparent on spontaneous, unstructured recall tasks but is also evident on tasks that provide recall cues or recognition paradigms where the stimulus is presented again, often among mnemonically equivalent distractor items. Depending on lesion localization, deficits may be predominantly related to verbal or visual stimuli. (Studies have demonstrated repeatedly that individuals with amnestic disorder may learn how to perform novel procedures that are not mediated verbally, such as motor tasks, even though they later fail to recall having had those learning experiences.) Problems remembering previously learned materials are present variably among amnestic patients. For example, a patient who suffered traumatic brain damage and who continues to exhibit deficits in new learning may remember events up to a time shortly before the injury. In some cases the interval of preinjury recall impairment may diminish as the patient recovers (shrinking retrograde amnesia), where inaccessible memories from several years before the injury are gradually produced and the extent of the amnesia diminishes in the context of clinical improvement. Recall deficits due to other causes may involve memory for knowledge and events gained over many years' duration. For some forms of amnestic disorder, events from the remote past may be better remembered than more recent events. However, such a gradient of recall is not present uniformly among individuals with amnestic disorders. Typically, the ability to immediately repeat a sequential string of information (e.g., a digit span) is not impaired in amnestic disorder; when such impairment is evident, it suggests the presence of attentional dysfunction that may be indicative of delirium. Amnestic disorders may be transient, lasting for several hours to a few days, as in transient global amnesia, or persistent, lasting at least 1 month. In the context of a newly developed but unresolved memory impairment, the term provisional should be added to a diagnosis of transient amnesia. Transient global amnesia is a form of transient amnestic disorder associated with episodes that are characterized by a dense, transitory inability to learn new information (i.e., to form sustained memories), with a variable (ultimately shrinking on recovery) inability to recall events that occurred during the duration of the disturbance. The episode is followed by restoration to a completely intact cognitive state. There are no data to suggest that the memory impairment is associated with disturbed or abnormal behavior beyond the mild confusion or perplexity that may be manifest during the episode. Depending on the cause of the disorder, the onset of amnesia may be sudden or gradual. Head trauma, vascular events, or specific types of neurotoxic exposure (e.g., carbon monoxide poisoning) may lead to acute mental status changes. Prolonged substance abuse, chronic neurotoxic exposure, or sustained nutritional deficiency exemplify conditions that may lead to an insidious memory decline, eventually causing a clinically definable cognitive impairment. Amnestic disorder may develop as a result of alcohol dependence, associated with dietary and vitamin deficiency. Alternatively, it may be the primary clinical deficit arising from traumatic head injury and may present as the major feature of a postconcussional state. When memory dysfunction exceeds other features of a postconcussional syndrome, it is preferable to diagnose the condition as amnestic disorder due to head trauma. Although persons with amnestic disorders may manifest other features of the primary systemic or cerebral disease that cause the development of the memory impairment, disordered mental status may be the sole presenting feature. Thus, a clinician may misconstrue the history of a blandly confabulating person unless other corroborating persons are available. When amnestic disorder is the result of alcohol dependence and vitamin deficiency, other neurological complications of alcohol ingestion and malnutrition such as peripheral neuropathy and cerebellar ataxia, may be observed. A 46-year-old house painter is admitted to the hospital with a history of 30 years of heavy drinking. He has had two previous admissions for detoxification, but his family states that he has not had a drink in several weeks, and he shows no signs of alcohol withdrawal. He looks malnourished, however, and on examination is found to be ataxic and to have a bilateral sixth cranial nerve palsy. He appears confused and mistakes one of his physicians for a dead uncle. Within a week the patient walks normally, and there is no longer any sign of a palsy. He seems less confused and can now find his way to the bathroom without direction. He remembers the names and birthdays of his siblings, but has difficulty naming the past five United States presidents. More strikingly, he has great difficulty in retaining information for longer than a few minutes. He can repeat a list of numbers immediately after he has heard them, but a few minutes later does not recall being asked to perform the task. Shown three objects (keys, comb, ring), he cannot recall them 3 minutes later. He does not seem worried about this. Asked if he can recall the name of his doctor, he replies, “Certainly,” and proceeds to call the doctor “Dr. Masters” (not his name), whom, he claims, he first met during the Korean War. He tells a long untrue story about how he and “Dr. Masters” served as fellow soldiers. The patient is calm, alert, and friendly. Because of his intact immediate memory and spotty but sometimes adequate remote memory, one can be with him for a short period and not realize he has a severe memory impairment. Although treated with high doses of thiamine, the short-term memory deficit persists and appears to be irreversible. (Reprinted with permission from DSM-IV Casebook.) Pathology and Laboratory Examination Laboratory findings diagnostic of the disorder may be obtained using quantitative neuropsychological testing. Standardized tests also are available to assess recall of well-known historical events or public figures, to characterize the nature of an individual's inability to remember previously learned information. Performance on such tests varies among individuals with amnestic disorder. Subtle deficits in other cognitive functions may be noted in individuals with amnestic disorder. However, memory deficits constitute the predominant feature of the mental status examination and account largely for any functional deficits. No specific or diagnostic features are detectable on imaging studies such as MRI or CT. However, damage of middle-temporal lobe structures is common and may be reflected in enlargement of third ventricle or temporal horns or in structural atrophy detected on MRI. Differential Diagnosis The central feature of amnestic disorder is the inability to learn and recall new information, in the context of variable difficulties recalling

previously learned factual knowledge. Less efficient memory is a component of normatively defined age-related cognitive decline but is neither functionally impairing nor below the statistically normal range when assessed with quantitative procedures. Patients with amnesia uniformly show significant abnormalities on cognitive or neuropsychological tests. Disordered memory is also a feature of delirium and dementia. When memory dysfunction occurs in the context of impaired consciousness, with reduced ability to focus, sustain, or shift attention, delirium predominates. The coexistence of memory impairment and multiple cognitive deficits (e.g., aphasia, apraxis, agnosis, and disturbance in executive functioning) warrants the diagnosis of dementia. Confabulation is a mental status finding encountered in patients with dementia as well as amnesia. Amnestic disorder may emerge from an evolving clinical picture that includes confusion and disorientation, occasionally with attentional problems that suggest delirium. For example, classically described Korsakoff's syndrome has been associated most often with the delirium of Wernicke's encephalopathy. The latter typically clears quickly with appropriate treatment. Confabulation may be noted during the early stages of the disease process and is often indicated by the recitation of imaginary events to fill gaps in memory, but that sign tends to disappear with time. Profound amnesia typically is associated with disorientation to place and time but rarely to person. Disorientation to self may be encountered in patients with severe dementing disturbances characterized by multiple cognitive deficits but is atypical of pure amnestic disorder. Many patients with severe amnestic disorder lack insight into their deficits, and they explicitly deny its presence despite evidence to the contrary. The lack of insight may contribute to accusations or agitation in rare instances. More commonly, apathy, lack of initiative, emotional blandness, or other changes suggestive of altered personality function may be encountered. Individuals may be superficially friendly or agreeable, but they frequently have a shallow or diminished range of affective expression. Patients with transient global amnesia most often appear bewildered or befuddled. Although they have been described participating in complex activity or conversations in the course of an episode, that is a much less common presentation. Occasionally, patients may demonstrate intact abilities to learn new information associated with profound memory loss for a circumscribed period of time. That pattern occurs in the setting of a discrete (time-limited) process that temporarily interferes with the patient's ability to establish new memories. Such processes include acute intoxication, transient delirium or encephalopathy (e.g., a seizure), or some other transient disruption of cerebral functioning (e.g., a transient ischemic attack). Such transient amnestic episodes must be defined clinically in the context of the primary disease processes; failure to establish a primary systemic or cerebral etiology suggests a psychogenic origin when that symptom pattern is encountered. Dissociative amnesia typically does not involve deficits in learning and recalling new information; rather, patients present with a circumscribed inability to recall previously learned information while they continue to function normally in the present. Psychiatric consultation is requested by an emergency room physician on an 18-year-old male who has been brought into the hospital by the police. The youth appears exhausted and shows evidence of prolonged exposure to the sun. He identifies the current date incorrectly, giving it as September 27 instead of October 1. It is difficult to get him to focus on specific questions, but with encouragement he supplies a number of facts. He recalls sailing with friends, apparently about September 25, on a weekend cruise off the Florida coast, when bad weather was encountered. He is unable to recall any subsequent events and does not know what became of his companions. He has to be reminded several times that he is in a hospital, as he expresses uncertainty as to his whereabouts. Each time he is told, he seems surprised. There is no evidence of head injury or dehydration. Electrolytes and cranial nerve examination are unremarkable. Because of the patient's apparent exhaustion, he is permitted to sleep for 6 hours. Upon awakening, he is much more attentive, but is still unable to recall events after September 25, including how he came to the hospital. There is no longer any doubt in his mind that he is in the hospital, however, and he is able to recall the contents of the previous interview and the fact that he had fallen asleep. He is able to remember that he was a student at a southern college, maintained a B average, had a small group of close friends, and has a good relationship with his family. He denies any previous psychiatric history and says he has never abused drugs or alcohol. Because of the patient's apparently sound physical condition, a sodium amytal interview is performed. During this interview he relates that neither he nor his companions were particularly experienced sailors capable of coping with the ferocity of the storm they encountered. Although he had taken the precaution of securing himself to the boat with a life jacket and tie line, his companions had failed to do this and had been washed overboard in the heavy seas. He completely lost control of the boat and felt he was saved only by virtue of good luck and his lifeline. He had been able to consume a small supply of food that was stowed away in the cabin over a 3-day period. He never saw either of his sailing companions again. He was picked up on October 1 by a Coast Guard cutter and brought to shore, and subsequently the police had brought him to the hospital. (Reprinted with permission from DSM-V Casebook.) Patients with resolved transient amnesia (e.g., transient global amnesia) may have a superficially similar history retrospectively. They manifest failure of recall for matters or events that occurred during the discrete episode in question. Thorough clinical investigations of patients with amnestic disorder typically reveal a primary cerebral or systemic medical condition that is etiologically related to the genesis of the mental status abnormality. During an episode, patients with transient amnesia generally have a confused or bewildered demeanor and exhibit marked difficulty with new learning tasks. Episodes of psychogenic amnesia end abruptly, typically associated with an expressed awareness of having no memories for the time period of the amnestic or fugue state. In contrast, the retrograde memory defect of transient global amnesia gradually shortens as the patient recovers; when recovery is complete, the memory gap spans only the period of the episode. Course Although the mode of onset is typically abrupt, data suggest that individuals with alcohol-induced amnestic disorder may develop deficits insidiously over many years as a result of repeated toxic and nutritional insults before the emergence of a final, dramatically impairing episode of illness apparently related to thiamine deficiency. Transient amnesia due to a cerebrovascular etiology may be recurrent, with episodes lasting from several hours to several days. Amnestic disorders due to head trauma, for example, may last variable amounts of time, with the greatest deficit apparent immediately after injury and improvement occurring during the ensuing 2 years (further improvement beyond 24 months has been noted, but less commonly). Full recovery may occur, although severe injuries are typically characterized by residual deficits. Disorders due to destruction of middle-temporal lobe structures, such as infarction, encephalitis, surgical ablation, or malnutrition in the context of alcohol dependence, may cause densely persisting impairments. Treatment Whenever a primary systemic or cerebral disorder is causally tied to the amnestic syndrome, initial treatment (with thiamine, antiviral medication, aspirin) must be directed toward the underlying pathological process. Presently there are no known, definitively effective treatments for amnestic disorder that are specifically aimed at reversing apparent memory deficits. A variety of pharmacotherapeutic trials have been to no avail. Recently, centers for cognitive rehabilitation have been established whose rehabilitation-oriented therapeutic milieu is intended to promote recovery from brain injury, especially from traumatic causes. Despite the high cost of extended care at these sites, which provide both long-term institutional and daytime services, no data have been developed to define therapeutic effectiveness for the heterogeneous groups of patients who participate in such tasks as memory retraining. Persons with amnestic disturbances worthy of diagnosis experience major impediments in their social and vocational functioning. They may require supervised living situations to ensure appropriate feeding and care. Other Cognitive Disorders Disorders such as dementia and amnesia are specific categorical designations that are intended to define disease states. However, intellectual functioning can also be viewed from a dimensional perspective, ranging from optimal to grossly deficient. Dementia represents an abnormal decline from a previous level of attainment; mental retardation reflects the failure to develop adequate intellectual function. Within this broad framework multiple domains of intellect are recognized that involve a wide variety of brain-related cognitive processes. The determination of normal and abnormal usually is made by comparing a person's performance on a variety of neuropsychological tests with predetermined normative standards. Ideally, the clinician would like lifelong (i.e., premorbid) serial cognitive testing to aid with diagnosis; occasionally, school, military, or vocational records provide an acceptable alternative. Usually one must compare a patient's results against published norms. Those norms may vary in quality, and the clinician should be aware whenever possible of factors such as the education, sex distribution, socioeconomic status, and age distribution of normative samples. Cognitive Disorder Not Otherwise Specified DSM-IV includes a new diagnostic category, cognitive disorder not otherwise specified, to deal with patients whose clinical presentation does not conform to a diagnosis of delirium, dementia, or amnesia. The designation is useful for patients with mild deficits in cognitive functioning that result from conditions such as head trauma, chronic alcohol dependence, or HIV infection. In the recovering alcoholic, for example, or the patient with a significant but resolving posttraumatic amnesia, intellectual abnormalities may be detectable objectively and noted subjectively, although they may be only minimally impairing functionally. Those deficits may disappear over time or remain as subtle residua. HIV infection may cause a mild decline in cognition; current research has demonstrated such decrements repeatedly. Of note, the performance of many patients has remained within the normal range even as the test scores have decreased significantly. The diagnostic criteria for cognitive disorder not otherwise specified appear in Table 10-42.

Table 10-42 DSM-IV Diagnostic Criteria for Cognitive Disorder Not Otherwise Specified

Mild Neurocognitive Disorder To define those conditions with greater specificity, the World Health Organization developed the ICD-10 diagnostic category of mild cognitive disorder ( Table 10-43). A similar DSM-IV construct (mild neurocognitive disorder) is included in an appendix as an example of cognitive disorder not otherwise specified. Table 10-44 lists the DSM-IV research criteria for mild neurocognitive disorder. To date, the interface between amnestic disorders or dementing disorders and mild neurocognitive disorder has not been defined reliably or validly.

Table 10-43 ICD-10 Diagnostic Criteria for Other Mental Disorders Due to Brain Damage and Dysfunction and Due to Physical Disease

Table 10-44 DSM-IV Research Criteria for Mild Neurocognitive Disorder

In addition to conditions such as HIV infection, head trauma, or alcohol dependence, mild cognitive decline with neuropsychological performance below the level of age-matched peers may be encountered as an early sign of a progressive degenerative disease. The use of cognitive disorder not otherwise specified as a diagnosis can serve to describe provisionally a patient who the physician suspects will develop a more malignant dementia of the Alzheimer's type and in whom a definitive diagnosis is premature owing to the relative mildness of the symptoms and an associated lack of clarity regarding clinical course. The label of not otherwise specified demands maximum clinical scrutiny and vigilance when employed in this fashion. Other Cognitive Conditions Clinical investigators and geriatric psychiatrists have recently joined cognitive psychologists in studying aging-related cognitive decline involving such functions as spontaneous verbal memory, cognitive flexibility and abstracting ability, visuospatial processing, divided attention, speed of mental processing, and naming. Aging-related decrements in those functions do not relate to any specific or defined neuropathology, although they may reflect underlying neurobiological deterioration. Of note, objective documentation of individual decline in test performance may be impossible. Although experimental comparisons of groups of healthy older subjects with comparably educated younger groups show consistent changes with aging, there are no data to suggest that the overall decline is a harbinger of disease. Many persons with normal (i.e., normatively defined) aging-related intellectual decrements seek clinical evaluation for forgetfulness, especially out of fear that they may be developing Alzheimer's disease. Their complaints often include inability to recall names or words spontaneously, absent-mindedness, the need to use reminder lists, or subtle problems with concentration. Careful interviewing typically reveals mild anxiety about minor intellectual problems, the use of effective compensatory mental strategies, and intact personal and social functioning, with little evidence of definable interference from perceived cognitive inadequacies in their daily lives. The absence of significant functional decline, together with performance within the normative (i.e., based on similarly aged samples) range on neuropsychological testing, in the context of an unrevealing general medical evaluation points to aging-associated cognitive alterations. Because of ample data on the phenomenon and clinicians' need to provide concerned patients with an understandable terminology to define their perceived difficulties, DSM-IV groups age-related cognitive decline among those conditions not attributable to a mental disorder that are a focus of attention or treatment. A variety of other common problems are included in that class, among them borderline intellectual functioning, academic problems, adult antisocial behavior, and marital problems. Figure 10-16 presents schematically in a dimensional perspective the relations between increasing age and cognitive performance, depicting changes in the normative range, mild cognitive impairment, and dementia. The aging-related decline in normative performance underscores the difficulty of establishing an absolute standard of cognitive deficit that is indicative of impairment due to a categorical disease process. The figure also suggests that there will always be patients detected in the range of mild impairment. As long as there are few (or no) pathobiologically exact laboratory tests to determine with certainty specific cognitive impairment disorders, thoughtful clinical judgment will remain a central part of the diagnostic process.

FIGURE 10-16 Aging-associated changes in ranges of cognitive performance.

Mental Disorders Due to a General Medical Condition DSM-IV has taken a different approach to categorizing the mental disorders due to a general medical condition than did DSM-III-R. In DSM-III-R the disorders were classified under the broader category of organic mental disorders. In DSM-IV each mental disorder due to a general medical condition is classified within the category that most resembles its symptoms ( Table 10-45). For example, the diagnosis psychotic disorder due to a general medical condition is found in the DSM-IV section on schizophrenia and other psychotic disorders. The symptom-based organization of DSM-IV is meant to facilitate clinical decision making regarding the differential diagnosis of symptoms. For example, the clinician who is evaluating a patient with depression can refer to the DSM-IV section on mood disorders and find mood disorder due to a general medical condition as one of the diagnoses. That diagnosis should help to clarify the importance of considering the possibility of a mental disorder due to a general medical condition for almost all psychiatric presentations.

Table 10-45 Mental Disorders Due to a General Medical Condition

Mood Disorder Due to a General Medical Condition Secondary mood syndromes are characterized by a prominent mood alteration that is thought to be the direct physiological effect of a specific medical illness or agent. These disorders are often difficult to define and have not been extensively researched; therefore, only limited information can be provided. Definition The key feature is prominent, persistent, distressing, or functionally impairing depressed mood (anhedonia) or elevated, expansive, or irritable mood, judged to be caused by either an Axis III condition or by substance intoxication or withdrawal. Cognitive impairment is not the predominant clinical feature; otherwise, the mood disturbance would be viewed as part of delirium, dementia, or other cognitive deficit disorder. The diagnostician is asked to specify if the mood syndrome is manic, depressed, or mixed, and if criteria for a fully symptomatic major depressive or manic syndromic are fulfilled. History and Comparative Nosology Mood disturbances secondary to medical conditions have long been described, but attention was rarely paid to the presence or absence of coexisting intellectual deficits. DSM-III introduced the term and the formal concept of organic affective syndrome, which required both mood alteration and two associated symptoms (as found in primary affective illnesses) to be present and thought due to specific medical etiologies. DSM-III-R eliminated the requirement for associated symptoms. DSM-IV marks the first explicit diagnostic criteria to denote whether or not the disturbance meets full major depressive or manic syndromic criteria. There has been much disagreement in the literature about primary depressive disorders and whether minor depressive disorders exist and how best to define them. Similar arguments might apply to lesser depressive syndromes of secondary origin. Terminology aside, there has been little research in the area of secondary mood disorders; what data exist are hampered by differing (or absent) operationalization of what constitutes sufficient evidence for defining causality. Epidemiology There are no clear data on which to base statements of incidence or prevalence of secondary mood disorders in any clinical or community population. It is clear that depressive symptoms and a wide array of systemic and primary cerebral conditions coexist to a far higher degree than can be explained by chance. Unfortunately, establishing a causal relation between depressive symptoms and a specific medical entity is difficult; therefore, the percentage of those coexisting symptoms that can be called secondary remains unknown. Further, many reported studies did not assess a range of syndromic criteria (i.e., major versus minor depression), and many simply quantified depressive symptoms by using rating scales without determining if the symptoms attained a threshold level of clinical significance. One noteworthy point is that depression in the medically ill appears to be equally prevalent by sex, or possibly slightly higher in men than in women. This disparity, when compared with the preponderance of females with primary depressive disorders, is often cited as an indicator of the importance of viewing secondary mood disturbances separately. Rates of mood disorder in the medically ill have been carefully described in several neurological diseases. For example, at least one research group has documented high rates of criteria-defined major and minor depressive syndromes in patients shortly after cerebrovascular accidents. Correlation of stroke lesion location and size with presence (and possibly with type) of depressive syndrome suggests the role of direct disruption of brain physiology as a causal mechanism. Also, the presence or severity of depression does not correlate highly with physical impairment due to hemiparesis, for example, and may be higher than rates found in patients with similar levels of overall disability due to nonneurological conditions, suggesting that depression in neurological patients is not simply a psychological reaction to illness and disability. Similarly, less extensive descriptions of increased rates of depressive symptoms and syndromes have been reported for populations with Parkinson's disease, Huntington's disease, HIV infection (with presumed direct CNS involvement), and multiple sclerosis. Determination of the secondary or symptomatic nature of these mood syndromes is problematic and is further complicated by the fact that at least some of the patients with these neurological illnesses had substantial cognitive impairment. Although DSM-IV attempts to address these issues directly, uncertainties remain. For example, if a patient with Huntington's disease has dementia and a depressive syndrome, the clinician might choose the diagnosis of dementia due to Huntington's disease with depressed mood. However, early in the disease process a syndromically depressed Huntington's patient with few cognitive impairments would warrant a diagnosis of mood disorder due to Huntington's disease with major depressive episode. As the intellectual impairment progresses, does the clinician abandon one diagnosis for another or add a second Axis I diagnosis of dementia? Such borderline situations are expected to generate uncertainty, which can be ameliorated by careful documentation of one's clinical reasoning. Secondary mania appears to be much less prevalent in most neurological illnesses, with the exceptions of multiple sclerosis and possibly Huntington's disease. Case reports abound of putative secondary mania due to a variety of other causes, but the prevalence is not known. Finally, patients with secondary mood syndromes may have increased rates of prior mood disorders and higher rates of family history of mood disorder. Therefore, secondary syndromes may reflect an interaction between a precipitating agent or illness and the patient's diathesis toward mood pathology. Etiology The list of potential causes for both depressive and manic syndromes is long. Table 10-46 lists some of the causes most commonly considered.

Table 10-46 Causes of Secondary Mood Disorders

Diagnosis and Clinical Features The depressive or manic symptoms found in secondary mood disorders are phenomenologically similar to those found in primary (idiopathic) mood disorders (see Table 14.6-17). It is not known if certain symptoms occur more commonly in the secondary disorders; presumably the prevalence may vary depending on the specific etiology of the secondary disorder. For example, anxiety has been described as prominent in major depressive syndromes seen in patients with Parkinson's disease; however, no studies have compared depressed patients with Parkinson's disease with similarly aged patients experiencing idiopathic major depressive disorder. Associated clinical phenomena may include other manifestations of the cause of the secondary mood disorder, such as soft neurological signs or contributing cognitive impairment; indeed, those findings are used to support the assessment of the mood symptoms as secondary in origin. There are no specific tests to confirm the diagnosis of a secondary mood disorder. In addition, little is known about how neurobiological abnormalities seen in idiopathic mood disorders differ from secondary syndromes. Moreover, despite recent interest in secondary mood disorders, there is still little definitive understanding of the neuroanatomical substrate of those disorders. Physical (including neurological) examination and specific laboratory tests or procedures may be crucial to establishing the presence of the primary disease state. Differential Diagnosis There are two broad domains of differential diagnosis to consider when establishing the presence of a secondary mood disorder. The first is phenomenological: Does the patient have clinically significant manic or depressive symptoms in the absence of evidence of a predominant cognitive deficit? That assessment requires attention to symptoms and function in the history and mental status examination. As part of the process, the clinician is also establishing whether there is a clearly defined mood syndrome sufficient to warrant an empirical treatment trial with antidepressant medications. The second domain is etiological: Does the patient have an Axis III condition or a state of substance intoxication or withdrawal that is causing the mood disturbance? Establishing the presence of the relevant condition depends on standard psychiatric and medical-neurological assessments; establishing the causal relation to the mood disorder may be difficult. Course and Prognosis Although the literature on the course of clearly defined secondary mood disorders is scant, substantial work has demonstrated that all depressive conditions that are comorbid with general medical illnesses or substance-related disorders have poorer prognoses than those that have no demonstrated associations, whether measured by means of symptomatic expression, functional disability, or mortality. It is therefore likely that secondary depressive illness is most often a chronic disease that is sometimes characterized by periods of remission followed by recurrences and sometimes by continuous illness. The prognosis varies, depending on the etiological disease state; depression secondary to a readily treatable disease (e.g., hypothyroidism) has a better outcome than depression associated with a terminal, essentially untreatable condition (e.g., metastatic pancreatic carcinoma). Little is known about the relation of specific depressive syndromes to outcome even within a specific etiological group. For example, there have been attempts to distinguish outcome in poststroke patients based on the presence of minor or major depressive syndromes; this work has had little replication by other investigator groups and the results may not generalize to depression secondary to other conditions. There is even less information available on the course of secondary mania, although many case reports suggest it is chronic and refractory to treatment. Treatment Treatment response has received limited study. Standard antidepressant medications (e.g., tricyclic antidepressants, MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), and ECT are effective in many depressed patients with medical and neurological illnesses or substance use disorders. However, the utility of studies of antidepressant drugs has been limited by the scant clinical definition of study patients in many publications; a designation of secondary mood disorder, with depressive features, provides little information on specific target symptoms and their response. The efficacy of newer somatic agents (e.g., SSRIs, bupropion [Wellbutrin]) and of newer psychotherapeutic approaches has received little systematic study. A comparison of response to specific treatment modalities in syndromically similar primary and secondary mood disorders has not been done. However, the comorbid pathology found in secondary syndromes may limit treatment trials, either because of contraindications or because of increased susceptibility to adverse effects. Given the severely limited data, the clinician treating a patient with a secondary mood disorder must rely on the following general guidelines. The underlying causes should be treated as effectively as possible. Persisting manic or major depressive syndromes are likely to require somatic therapies; standard treatment approaches as used for the corresponding primary mood disorder should be employed, although the risk of toxic effects may require more gradual dosage increases. At a minimum, psychotherapy should focus on psychoeducational issues (in particular, the concept of a secondary behavioral disturbance may be new or difficult for many patients and families) and support. More specific intrapsychic, interpersonal, and family issues are addressed as indicated. Approaches to subsyndromal secondary mood disorders are even less well established, but clinically significant disturbances warrant empirical trials of the same treatments used in fully syndromic patients. Psychotic Disorder Due to a General Medical Condition Psychosis has been a term of inconsistent definition, used in recent years to refer exclusively to symptoms of a striking nature, such as hallucinations and delusions, but in the past to severe affective syndrome (e.g., psychotic versus neurotic depression); to cognitive symptoms, such as confusion, disorientation, or altered memory (such as Korsakoff's psychosis); or as a means of describing the severity of any psychiatric symptom (“of psychotic proportions”). DSM-III-R in its appended glossary defined psychosis as “gross impairment in reality testing and the creation of a new reality.” Hallucinations, delusions, bizarre behavior, and incoherent speech were considered direct evidence of psychosis. Psychotic symptoms have been recognized as nonspecific, as they can be seen in any of the major psychiatric illnesses, such as dementia, schizophrenia, or bipolar I disorder, as well as in many systemic medical or cerebral disorders. Definition In order to establish the diagnosis of psychotic disorder due to a general medical condition the clinician first must exclude syndromes in which psychotic symptoms may be present in association with cognitive impairment (e.g., delirium and dementia of the Alzheimer's type) but not the defining feature, and the clinician must determine with confidence the causal link. In turn, secondary psychotic disorders must be excluded before a diagnosis of a primary (idiopathic) psychotic disorder is entertained. History Psychotic symptoms, including delusions, hallucinations, incoherent speech or formal thought disorder, and bizarre behavior, have been recognized for centuries. In medical prehistory they were perceived in a theological light as evidence of demonic possession or punishment for a moral failing. In the eighteenth century, at the threshold of the modern brain disease model, psychosis was sometimes attributed to a bodily dysfunction, either systemic or related specifically to the CNS. However, tension has persisted among clinicians since the 1800s as to whether psychotic symptoms are the manifestations of a dysfunctional brain or are volitional or psychological reactions to life circumstances. Reports of secondary psychosis have abounded for centuries and have contributed to an understanding of those behaviors as specific symptoms of brain disease. Many descriptions, however, have had limited use because of vagaries in the definition of psychosis and the lack of any uniform means for establishing a correlation between psychotic symptoms and the associated systemic or cerebral medical condition under study. Recently, three types of investigations have emerged for the study of secondary syndromes, including secondary psychosis. One type of study compares psychopathological symptoms in patient groups with and without known primary medical conditions. This comparison has been done strictly on a retrospective basis for secondary psychosis, with only one available prospective study of secondary delusional disorders. Another type of investigation has examined patient groups with known CNS disease, such as cerebrovascular disorder or Huntington's disease, with a careful description of any associated psychopathology. The third investigative track has selected patients with known psychopathology, such as hallucinations in schizophrenia, and sought evidence to correlate symptoms with CNS dysfunction using a variety of measures (e.g., neuroimaging of the temporal lobe). The secondary psychotic disorders are a window through which insights into the

neurobiological basis for psychotic processes may be obtained. Comparative Nosology Secondary psychotic syndromes were categorized in DSM-II as psychoses associated with organic brain syndromes. The syndromes included in that category were the dementias, deliria, and psychoses associated with other cerebral and systemic conditions. Entry into the category depended on cognitive symptoms, such as disturbances of orientation, memory, judgment, and lability of affect. The term “psychosis” continued to be used for the sake of historic continuity, with the acknowledgment that “many patients for whom these diagnoses are clinically justified are not in fact psychotic.” DSM-III improved on the nosology by establishing the general rubric of organic brain syndromes, with six specific syndromes, including organic hallucinosis and organic delusional syndrome. In DSM-IV, psychotic disorder due to a general medical condition (with its available subtypes) has been moved out of the organic group to the phenomenological cluster to which it is related. This shift underscores the need for differential diagnosis, the clinical importance of defining etiology whenever possible, and the idea that primary psychopathology is idiopathic—that is, without known cause. Epidemiology The incidence and prevalence of secondary psychotic disorders in the general population are unknown. The prevalence of psychotic symptoms is increased in selected clinical populations, such as nursing home residents with dementia of the Alzheimer's type, but it is unclear how to extrapolate these findings to other patient groups. Etiology Virtually any cerebral or systemic disease that affects brain function can produce psychotic symptoms. Table 10-27 lists examples within each of the broad categories of diseases that can produce dementia; each of those diseases is also capable of producing psychotic symptoms, both in the presence and in the absence of cognitive impairment. Degenerative disorders, such as Alzheimer's disease or Huntington's disease, may present initially with new-onset psychosis, with minimal evidence of cognitive impairment at the earliest stages. Diagnosis and Clinical Features To establish the diagnosis of a secondary psychotic syndrome (see Table 13.3-13). The clinician first determines that the patient is not delirious, as evidenced by a stable level of consciousness. A careful mental status assessment is conducted to exclude significant cognitive impairments, such as those encountered in dementia or amnestic disorder. The next step is to search for systemic or cerebral diseases that might be causally related to the psychosis. Psychotic symptomatology per se is not helpful in distinguishing a secondary from a primary (idiopathic) cause. Comparative studies have not demonstrated any distinguishing phenomenological features in secondary psychosis or any difference in frequency or severity of the psychosis when compared to idiopathic psychosis. Olfactory and auditory hallucinations, although claimed anecdotally to suggest a secondary or symptomatic etiology, have proved unreliable. Some studies have suggested that exclusively positive psychotic symptoms, in the absence of negative symptoms and personality change, reflect a secondary cause; this suggestion has not been tested prospectively. Age at onset is a factor that should alert clinicians to the possible emergence of a secondary psychotic disorder, reflecting both the age-related increased prevalence of diseases affecting brain function and the natural history of primary psychotic syndromes, with their markedly diminished incidence after ages 40 to 45 years. All patients who present with the new onset of psychotic symptoms should undergo a thorough clinical evaluation emphasizing personal medical history, family medical history, and medical review of systems. A systematic physical and neurological examination should be performed. (The examiner should bear in mind, however, that nonlocalizing, soft neurological signs and a variety of dyskinesias can be present in idiopathic schizophrenia, even in the drug-naïve patient.) A neuroimaging evaluation with MRI for any new-onset psychosis, irrespective of patient age, is recommended. The detection of a systemic or cerebral abnormality does not automatically lead to the determination of secondary psychosis; establishing a secondary status requires thoughtful clinical reasoning. Differential Diagnosis The differential diagnosis involves first establishing that the symptoms and signs encountered are in fact psychotic, according to the more specific modern definition. Confabulation may be mistaken for delusions. Confabulation is the spontaneous or prompted production of inconsistent and fabricated statements, often in response to questions or environmental stimuli. Although memory impairment is present in those who confabulate, the more salient cognitive deficit involves an inability to suppress or self-analyze the automatic fabrications and responses. Confabulation differs from delusions in that the fabricated beliefs are quite transient and varying. A behavioral response to the confabulated belief is usually absent. The presence of confabulation is also suggestive of brain disease, often involving the anterior temporal lobe (memory impairment) and the frontal lobes (loss of self-analysis). Perceptual disturbances that result in illusions or other misinterpretations of environmental stimuli must be distinguished from hallucinations, which are experienced as true perceptual experiences but without an actual stimulus. Agnosias, or deficit syndromes, such as prosopagnosia, topographic agnosia, or phonagnosia (inability to recognize familiar faces, places, or sounds, respectively), can occur in the context of intact peripheral perception and can be mistaken for delusional beliefs as well as hallucinations. It is important to distinguish these deficit syndromes and to recognize that they point to parietal lobe dysfunctions that are not associated with other psychotic symptoms. The phenomenology or type of psychotic symptom does not help distinguish idiopathic from secondary etiologies. However, once the suspicion of a secondary etiology has arisen, the specific psychotic presentation may suggest a particular brain region or direction for further investigation. Table 10-47 lists a number of specific psychotic symptoms that have been consistently associated with disease in particular brain regions. First-rank symptoms, originally described by Kurt Schneider as pathognomonic symptoms of schizophrenia, are now accepted as nonspecific psychotic symptoms occurring in all psychotic disorders. Although nonspecific for diagnosis, they have been associated with abnormalities in the left temporal lobe. Complex delusions have been associated with lesions in subcortical regions. Simple persecutory ideas are more common than complex or systematized delusions in patients with significant cognitive deficits. Patients apparently require a variety of intact intellectual abilities (and presumably underlying brain substrate) in order to produce psychotic symptoms of greater complexity. Anton's syndrome refers to denial of blindness, classically described in patients with acquired cortical blindness arising from bilateral occipital cortex damage. More recently, it has been described in patients with peripheral optic neuropathy, suggesting that the syndrome may be a variant of the other denial-of-deficit syndromes, such as anosognosia. Misidentification syndromes have been described primarily in idiopathic psychotic disorders, although recent studies have pointed to nondominant parietal and frontal lesions as the basis for many. One recent neuropsychological theory proposes that the right hemisphere plays a role in the appreciation of the individuality or uniqueness of people, places, and objects and that lesions in the right hemisphere can result in delusions of misidentification.

Table 10-47 Psychotic Symptoms Associated With Abnormality of Specific Brain Regions

Course and Prognosis The course and prognosis of secondary psychotic syndromes depend on their etiology. Vivid psychotic symptoms arising from head trauma may improve dramatically during recovery. Delusions associated with degenerative diseases may diminish as the disease worsens, for the capacity to generate those more complex cognitions is gradually lost. Some secondary psychotic disorders improve with treatment of the underlying disorder, such as the interictal psychosis of epilepsy, which often improves with the pharmacological or surgical control of seizures. Psychotic disorders secondary to infectious disease may not improve, despite eradication of the infectious organism, because of irreversible tissue damage sustained during the acute infection. Treatment The principles of treatment for a secondary psychotic disorder are similar to those for any secondary neuropsychiatric disorder, namely, rapid identification of the etiological agent and treatment of the underlying cause. Antipsychotics medications afford empirical symptomatic treatment for the psychotic symptoms, although secondary psychotic disorders often prove more refractory than idiopathic disorders to such treatment. Patients with primary systemic or cerebral diseases frequently are more vulnerable to the untoward adverse effects of antipsychotic drugs. To date, there has been insufficient use of serotonin-dopamine antagonists,

such as clozapine (Clozaril), to judge their utility with these conditions. Anxiety Disorder Due to a General Medical Condition Secondary anxiety syndromes are characterized by prominent anxiety symptoms that are thought to be the direct physiological effect of a specific physical illness or agent. Those disorders have received even less careful scrutiny than secondary mood disorders; therefore, the qualifications made in the section above apply equally or more so to the following discussion. Definition The key feature of anxiety disorder due to a general medical condition is the presence of prominent anxiety symptoms, which may include generalized anxiety, panic attacks, obsessions, compulsions, or phobias and which are judged to be caused by either an Axis III condition or by substance intoxication or withdrawal. In addition, the anxiety symptoms are not thought to be better explained by another mental disorder (e.g., the anxiety that can be seen in delirium or adjustment disorder with anxious mood). The diagnostician is asked to specify if the anxiety syndrome includes generalized anxiety, panic attacks, obsessive-compulsive symptoms, or phobias. History and Comparative Nosology For centuries clinicians have described anxiety symptoms as prominent features in a variety of conditions; for most of the twentieth century many of those descriptions focused on patients with endocrinopathies, neurological illnesses, mitral valve prolapse, and substance-related states. The formal concept of any organic mental disorder other than cognitive disorders was introduced by DSM-III; however, organic anxiety disorder was not presented as a distinct entity until DSM-III-R. DSM-III-R limited the diagnosis to either generalized anxiety or panic attacks; DSM-IV broadens the possible related phenomena to include obsessions and compulsions. Secondary anxiety syndromes have received little study. There are numerous descriptions of anxiety symptoms associated with medical illness or substance-related states, but the operationalization of “secondariness” is generally absent. Further, most studies have included patients with generalized anxiety or panic symptoms; reports of secondary obsessive-compulsive phenomena are few. Epidemiology The prevalence of anxiety symptoms is high in general medical patients and in patients with many of the specific medical illnesses that are putative potential causes for secondary anxiety syndromes. However, the incidence and prevalence of secondary anxiety disorders, obtained from well-operationalized criteria for syndromic and etiological diagnosis, are not known. Similarly, rates of prior anxiety disturbances or of a family history for anxiety disorders are not known. Etiology The list of potential causes for anxiety syndromes is long, with nearly complete overlap with the potential causes for mood syndromes. Causes most commonly described in anxiety syndromes include substance-related states (intoxication with caffeine, cocaine, amphetamines, and other sympathomimetic agents; withdrawal from nicotine, sedative-hypnotics, and alcohol), endocrinopathies (especially pheochromocytoma, hyperthyroidism, hypercortisolemic states, and hyperparathyroidism), metabolic derangements (e.g., hypoxemia, hypercalcemia, and hypoglycemia), and neurological disorders (including vascular, trauma, and degenerative). Many of these conditions are either inherently transient or easily remediable. Whether that reflects the pathophysiology of secondary anxiety or is an artifact of reporting (e.g., anxiety with subacute onset and complete resolution after removal of a pheochromocytoma is more likely to be reported as an example of anxiety due to a medical illness than is chronic anxiety in the context of chronic obstructive pulmonary disease) is not known. Much attention has been paid to the association of panic attacks and mitral valve prolapse. The nature of that association is unknown, and therefore the diagnosis of panic attacks secondary to mitral valve prolapse currently is premature. Interestingly, several recent reports have sought to tie obsessive-compulsive symptoms to the development of pathology in the basal ganglia. Diagnosis and Clinical Features The symptoms of secondary anxiety disorders are by definition phenomenologically similar to those found in the corresponding primary anxiety disorder (e.g., panic attacks and obsessions) (see Table 15.6-17). It is not known if certain symptoms are seen more commonly in the secondary variety; presumably the rate of co-occurrence may vary, depending on the specific etiology of the secondary disorder. As with all secondary syndromes, associated clinical phenomena may include other manifestations of the cause of the secondary anxiety disorder, such as soft neurological signs or subtle cognitive impairment (which may have been used to support the assessment of the anxiety symptoms as being secondary in origin). There are no specific tests to confirm the diagnosis of secondary anxiety disorder, and little is known about how neurobiological abnormalities seen in primary anxiety disorders differ in secondary syndromes. Physical (including neurological) examination and specific laboratory tests or procedures may be necessary to establish the presence of the etiological disease state. Differential Diagnosis As for other secondary disorders, two broad domains of differential diagnosis must be considered to establish the presence of a secondary anxiety disorder. The first is phenomenological: does the patient have clinically significant anxiety, panic attacks, obsessions, or compulsions, along with an absence of evidence for another primary or secondary psychiatric syndrome? The second is etiological: does the patient have an Axis III condition, or a state of substance intoxication or withdrawal, that is causing the phenomenology? As always, establishing the causal relationship may be difficult. Course and Prognosis Little information is available on the course of secondary anxiety disorders. The outcome presumably depends on the specific etiology; thus, anxiety due to hyperthyroidism may well remit with treatment of the hyperthyroid state whereas anxiety due to cardiomyopathy with a low-output state may run a more chronic course. Treatment Well-designed treatment studies of carefully described patients with secondary anxiety disorders are lacking. Aside from treating the underlying causes, clinicians have found benzodiazepines to be helpful in decreasing anxiety symptoms; supportive psychotherapy (including psychoeducational issues focusing on the diagnosis and prognosis) may also be useful. The efficacy of other, more specific therapies in secondary syndromes (e.g., antidepressant medications for panic attacks, SSRIs for obsessive-compulsive symptoms, behavior therapy for simple phobias) is unknown. Sleep Disorder Due to a General Medical Condition Sleep disorders can result from a diversity of causes, among them stressful life circumstances, crossing time zones, pulmonary or laryngeal structural abnormalities, systemic diseases (e.g., renal failure), or primary cerebral pathology. However, many sleep disorders, such as narcolepsy, sleep terrors, and enuresis, are idiopathic and occur without known systemic or central abnormalities. The epidemiology of secondary sleep disorders has not been studied systematically. Definition and Diagnosis Sleep disorders can manifest in four ways: by an excess of sleep ( hypersomnia), by a deficiency of sleep (insomnia), by abnormal behavior or activity during sleep ( parasomnia), and by a disturbance in the timing of sleep ( circadian rhythm sleep disorders). Primary sleep disorders occur unrelated to any other medical or psychiatric illness. The DSM-IV nosology is deliberately simple and nondetailed. The patient is assigned to broad categories based on presenting symptoms and the etiological consideration of primary versus secondary disorder (see Table 21-17). The International Classification of Sleep Disorder is a more comprehensive and detailed nosology that requires the usage of polysomnography for many of the diagnoses (see Table 21-3). Etiology and Differential Diagnosis Table 10-48 lists a number of conditions in which a disturbance of sleep has been frequently and characteristically described, allowing conditions to be designated as causes of secondary sleep disorder. Parkinsonism, related to either idiopathic Parkinson's disease, medications, or head trauma, frequently results in a secondary sleep disorder. As many as 75 percent of patients with Parkinson's disease complain of sleep disturbance, usually frequent awakenings during sleep. The difficulty maintaining sleep can have a number of causes. Sleep is fragmented owing to the brain degeneration that disrupts the neurophysiological and neurochemical pathways of sleep. In addition, the symptoms of Parkinson's disease can disrupt sleep. Although tremor is diminished during sleep, muscular rigidity is increased and can prevent the patient from turning or finding a comfortable position, resulting in arousal and awakening. Medications used to treat Parkinson's disease can disrupt sleep. Levodopa preparations frequently cause disruptive dreams and nightmares and may also increase nocturnal myoclonus, repetitive, brief leg jerks that awaken the patient and fragment sleep. Levodopa can be stimulating and may prevent the initiation of sleep if taken close to bedtime. Dementia due to degenerative disease can impinge on sleep in a manner similar to parkinsonism, with the degeneration of pathways vital for normal sleep. Sundowning, the emergence of severely disruptive behavior, such as agitation and paranoia, at night, associated with the inability to maintain sleep, is a major management issue in the home care of patients with dementia. The pathophysiology is unknown at present, although some have speculated that sundowning is a nocturnal delirium secondary to degeneration of the suprachiasmatic nucleus. Alternatively, sundowning is viewed as a disruption of circadian rhythms, rapid eye movement (REM) parasomnias, or simply postawakening confusion during which the patient with dementia is unable to distinguish between dreams and current reality. Dementia of the Alzheimer's type is accompanied by an exaggeration of the sleep changes associated with normal aging, with a decrease in total sleep time as well as in slow wave and REM sleep. The sleep disturbances worsen as the disease progresses.

Table 10-48 Medical Conditions Commonly Associated With a Secondary Sleep Disorder

Epilepsy can be a true sleep disorder. Most seizure disorders are activated by sleep or arousal from sleep. Both local and generalized epilepsy can occur during sleep, resulting in difficulties maintaining sleep. Seizures may manifest as parasomnias, such as night terrors, sleepwalking, or head banging, although most parasomnias are not related to epilepsy. Cerebrovascular disorders can impinge on the initiation and maintenance of sleep. No specific lesions have been consistently correlated with a particular sleep disturbance, although brainstem lesions in general are apt to disrupt sleep architecture. In Huntington's disease patients experience frequent awakenings and decreased total sleep time, a pattern common to many subcortical dementia syndromes. With the progression of the disease the movement disorder may manifest during sleep, further disrupting sleep. Chronic renal failure, anemia, and diabetes mellitus can cause nocturnal myoclonus and the restless legs syndrome. The latter is characterized by the experience of deep pains in the lower calf, prompting the patient to keep the legs in constant motion and impinging severely on the ability to initiate sleep. Kleine-Levin syndrome is a rare disorder characterized by hypersomnia, compulsive eating, sexual disinhibition, personality change, and psychosis. There is a 3 to 1 male-to-female predominance, with onset of symptoms typically occurring in adolescence. Hypersomnia is marked and is the most consistent feature. Compulsive eating and sexual disinhibition, such as public masturbation or propositioning of strangers, complete the syndrome. Incomplete or atypical variants are more common than the full syndrome. Irritability is frequent, and hallucinations or affective symptoms may be present. Symptoms last hours to weeks and are cyclical, with a full return to baseline on many occasions. Symptoms recur in a varying frequency of 1 to several months. The syndrome can be preceded by flulike symptoms or head trauma, although the precise etiology and pathophysiology are unknown. Presumably, there is hypothalamic system dysfunction with the manifest disturbances in sleep, eating, and sexual behavior. In most patients the episodes decrease in frequency and eventually disappear entirely. Treatment The diagnosis of a secondary sleep disorder hinges on the identification of an active disease process known to exert the observed effect on sleep. Treatment first addresses the underlying neurological or medical disease. Symptomatic treatments focus on behavior modifications, such as improvement of sleep hygiene. Pharmacological options may also be used, such as benzodiazepines for restless legs syndrome or nocturnal myoclonus, stimulants for hypersomnia, and tricyclic antidepressant medications for manipulation of REM sleep. Sexual Dysfunction Due to a General Medical Condition Specific syndromes characterized by sexual dysfunction thought to be physiologically caused by a general medical condition are female or male hypoactive sexual desire disorder, male erectile disorder, dyspareunia, and other male or female sexual dysfunction. History and Comparative Nosology Numerous medical conditions, medications, and drugs of abuse can affect sexual desire and performance. However, despite the attention psychiatry has paid to presumed psychologically mediated sexual dysfunction, the role of physiological diseases was downplayed in earlier psychiatric diagnostic systems. DSM-III listed only functional sexual dysfunctions. DSM-III-R allowed sexual dysfunctions to be classified as psychogenic only or as due to both biogenic and psychogenic causes, but required purely biogenic syndromes to be coded on Axis III. The inclusion of secondary sexual disorders as Axis I diagnoses in DSM-IV is consistent with that edition's inclusive approach to behavioral syndromes. Epidemiology Although surveys have repeatedly demonstrated a high prevalence of sexual dysfunctions in the general population, valid data on secondary dysfunctions are lacking. Similarly, certain medications may be associated with specific rates of sexual symptoms, but the percentage of patients with truly secondary syndromes is not known. Etiology Potential causes of sexual dysfunctions are listed in Table 10-49. The type of sexual dysfunction is affected by the etiology, but specificity is rare; that is, a given etiology may manifest as one (or more than one) of several syndromes. General categories include medications and drugs of abuse, local disease processes that affect the primary or secondary sexual organs, and systemic illnesses that affect sexual organs via neurological, vascular, or endocrinological routes.

Table 10-49 Causes of Secondary Sexual Dysfunctions

Diagnosis and Clinical Features The clinical features of the sexual dysfunction resemble those of the various primary dysfunctions (see Table 19.1a-17. There may be additional findings due to the underlying disease process. For example, in male erectile disorder due to diabetic autonomic neuropathy, the patient may have symptoms of bowel and bladder autonomic dysfunction as well as evidence of diabetes mellitus itself. Differential Diagnosis Phenomenology determines the syndromic diagnosis (e.g., erectile dysfunction versus orgasmic disorder). Medical history, physical examination, and relevant laboratory testing are required to demonstrate the presence of physical conditions that are potentially etiological for the sexual dysfunction. However, presence alone does not establish an etiological link. Clinical judgment is necessary and is based on temporal association, assessment of potentially contributory psychosocial factors (or more gross psychopathology), and other factors; the determination of secondary status is often difficult. One exception to that difficulty is male erectile dysfunction. Patients with secondary erectile dysfunction are unable to sustain erections under any circumstances whereas those with primary (i.e., psychogenic) disorders may give a history of variable erectile ability, depending on environment, partner, or other circumstances. If in doubt, a nocturnal penile tumescence study may be helpful because only males with secondary erectile dysfunction will fail to demonstrate tumescence during sleep. Course and Prognosis The course and prognosis of secondary sexual dysfunctions vary widely, depending on the etiology. Drug-induced syndromes generally remit with discontinuation (or dosage reduction) of the offending agent. Endocrine-based dysfunctions also generally improve with restoration of normal physiology. By

contrast, dysfunctions due to neurological disease may run protracted, even progressive, courses. Treatment The treatment approach varies widely, depending on the etiology. When reversal of the underlying cause is not possible, supportive and behaviorally oriented psychotherapy with the patient (and perhaps the partner) may minimize distress and increase sexual satisfaction (e.g., example, by developing sexual interactions that are not limited by the specific dysfunction). Support groups for people with specific types of dysfunction are available. Other symptom-based treatments may be used in certain conditions; for example, sildenfanil (Viagra) administration or surgical implantation of a penile prosthesis may be used in the treatment of male erectile dysfunction. Mental Disorders Due to a General Medical Condition Not Elsewhere Classified DSM-IV has three additional diagnostic categories for clinical presentations of mental disorders due to a general medical condition that do not meet the diagnostic criteria for specific diagnoses. The first of the diagnoses is catatonic disorder due to a general medical condition ( Table 10-50). The second diagnosis is personality change due to a general medical condition. The third diagnosis is mental disorder not otherwise specified due to a general medical condition ( Table 10-51).

Table 10-50 DSM-IV Diagnostic Criteria for Catatonic Disorder Due to a General Medical Condition

Table 10-51 DSM-IV Mental Disorder Not Otherwise Specified Due to a General Medical Condition

Personality Change Due to a General Medical Condition Personality refers to the constellation of enduring traits and behavioral style that essentially defines the person. Personality develops through adolescence and achieves a degree of stability in early adulthood. Both biological disposition as well as environmental factors influence the development of personality. In adults, behavioral style can be described in terms of interests, activities, pleasures, social relations, predominant mood and temperament, standards, usual outlook on life, range of coping mechanisms, and so forth. There is a robust theoretical and clinical literature delineating specific traits, such as self-consciousness, impulsivity, gregariousness, excitement-seeking, openness, and so forth, along dimensions or continua. Standardized measures are available to determine where along the spectrum for each trait a particular patient lies. This provides a personality profile that can be considered relative to standardized norms. The process is quite similar to the dimensional perspective used to assess intelligence and the determination of an I.Q. The past concept of organic personality syndrome focused on identifying a generic category of particular traits and behaviors associated with brain injury or dysfunction. This conceptual approach has been maintained in DSM-IV, although it sought to base its classification of personality changes solely upon consistently reported behavioral alterations. Suggestions to classify disorders upon anatomical localization (such as frontal lobe syndrome) were rejected. To date there has been little theoretical work attempting to integrate the dimensional perspectives used in the description of normal personality with the categorical approach used in the study of CNS disease and related personality disturbances. Definition Personality change means that the person's fundamental means of interacting and behaving have been altered; that is, traits that had been regular and consistent over a lifetime have changed. Personality change must be distinguished from the transient disturbances of behavior that frequently occur in reaction to environmental circumstances. When a true personality change occurs in adulthood, the clinician should always suspect brain injury or insult. History The impact of brain insults on personality has long been recognized. John M. Harlow's description of personality change in Phineas Gage, who sustained a penetrating head injury, remains the classic description: He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passions of a strong man. . . . In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was “no longer Gage.” The frequency of association between brain injury and personality change prompted a search for a generic personality disorder applicable to all brain injury, as well as brain–locale-specific or disease-specific personality disorders. An example of the former is the organic personality disorder found in the earlier versions of DSM. Organic personality disorder was defined as a persistent disturbance of personality due to a specific organic factor involving affective instability, recurrent aggression or rage, impaired social judgment, apathy and indifference, or suspiciousness or paranoid ideation. The interictal personality disorder of temporal lobe epilepsy, characterized by hyperreligiosity, overinclusive speech and behavior, and sexual deviance, was originally presented as a disease-specific personality disorder that was thought to be of high validity. Subsequent studies did not find these traits specific for temporal lobe epilepsy or any other epilepsy. Attempts at defining locale-specific personality disorder have been hampered by difficulties in finding naturalistic human lesions that are indeed localized: Strokes, head trauma, and degenerative diseases, for example, rarely are confined to neat anatomical lobar boundaries. Nonetheless, the most fruitful approach to delineating personality change disorders has come from the study of frontal lobe injury, where consistent and well-defined traits and behaviors have been associated with particular areas of brain injury. At least two distinct but overlapping secondary personality changes have been identified after injury to the orbitofrontal and frontal convexity areas. Frontal lobe dysfunction may play a key role in all personality and behavioral disturbances because there are vast networks of neural connections between specific areas of the frontal lobe and various limbic and subcortical structures. A similarly complex neuropsychological system suggests that the frontal lobe (more specifically, the prefrontal cortex) modulates many of the basic cognitive, linguistic, attentional, and perceptual processes that originate in other brain areas. Injury to the frontal lobes results in dysfunction in how basic cognitive functions, such as language or memory, are expressed. Comparative Nosology DSM-I included a category of acute and chronic brain syndromes, defined as disorders due to a diffuse impairment of brain tissue function

from any cause. DSM-II provided basic symptoms for a generic organic brain syndrome, such as impairments in orientation, memory, calculation, learning, and judgment, and lability and shallowness of affect. Although there was no specific category for secondary personality change, it would have been included in the nonpsychotic organic brain syndromes. DSM-III eliminated the unitary organic mental syndrome and allowed for a variety of organic syndromes in which an organic factor was judged etiologically related. Organic personality syndrome nonetheless required at least one of four specific characteristics, including lability, impulsivity, apathy, or suspiciousness; DSM-III-R added recurrent aggression to the list of criteria. The limitations of the nosology are clear. Personality encompasses a broad range of traits and behaviors not limited to those specified in the organic personality disorder category. The disturbance of personality is identified not from the presence of any particular behavior or trait, but rather as a change from premorbid personality. DSM-IV has dropped the category of organic personality disorder and replaced it with personality change due to a general medical condition. The specific phenomenological criteria were dropped in favor of a general persistent personality disturbance that represents a change from the individual's previous characteristic personality pattern. Subtypes based on the particular phenomenology evident include labile type, disinhibited type, aggressive type, paranoid type, apathetic type, other type, combined type, and unspecified type. Epidemiology The epidemiological difficulties in ascertaining cases of secondary personality changes are clear: No one particular behavior or trait is diagnostic; rather, a change in a patient's personality structure must be documented. Such documentation often requires recourse to an external informant because patients with personality change are frequently unreliable self-informants. The overinclusive range of personality traits enumerated in previous editions of DSM allowed researchers to pick and choose traits; in addition, the means of measuring them were not consistent from study to study. As a result, reliable incidence and prevalence figures for secondary personality change are not available. Specific personality trait changes for particular brain diseases—for example, passive and self-centered behaviors in dementia of the Alzheimer's type—have been reported; the studies reporting those results, however, have not been replicated, and it remains uncertain how the findings should be applied to other disorders. Etiology The range of etiologies of secondary personality change is vast and diverse and may involve any of the basic pathological processes described in the previous section. Diseases that preferentially affect the frontal lobes or subcortical structures are more likely to manifest with prominent personality change. Head trauma is a common cause. Strokes involving the anterior communicating or middle cerebral arteries selectively damage frontal lobe structures, often resulting in personality change. The anterior communicating artery is also a common site for aneurysms, which can result in secondary personality change. Frontal lobe tumors, such as meningiomas and gliomas, can grow to considerable size before coming to medical attention, as they may be neurologically silent (i.e., without focal signs). Degenerative disorders affecting the frontal lobes can present with personality change long before cognitive symptoms are evident. Among progressive dementia syndromes, especially those with a subcortical pattern of degeneration, such as AIDS dementia complex, Huntington's disease, or progressive supranuclear palsy, significant personality disturbance manifests often. Multiple sclerosis can impinge on the personality, reflecting subcortical white matter degeneration. Exposures to toxins with a predilection for white matter, such as irradiation, may also produce significant personality change disproportionate to the cognitive or motor impairment. Diagnosis and Clinical Features The DSM-IV diagnostic criteria for personality change due to a general medical condition are listed in Table 10-52. The diagnosis of a secondary personality change rests entirely on the history. A clear and detailed description of the patient's premorbid personality must be obtained. This history usually is collected from an external informant who knew the patient at baseline as well as currently. The first task in evaluating the history is to determine whether a change in personality has indeed occurred or whether the current disruptive behaviors represent long-standing traits that have been exacerbated by a change in circumstance. In addition, delirium must be ruled out.

Table 10-52 DSM-IV Diagnostic Criteria for Personality Change Due to a General Medical Condition

Once a diagnosis of a personality change has been established, the search for an etiological agent begins. An insidious and progressive course is suggestive of a degenerative process or a neoplasm. An abrupt onset of personality change is more suggestive of a vascular event or trauma. Risk factors for HIV infection should raise the suspicion of HIV or neurosyphilis infection. A complete history of toxic exposures, including alcohol and recreational drug use, environmental or occupational toxin exposures, and medications, should be obtained. The search for a causative agent can be aided by the presence of other evidence of brain dysfunction, such as motor abnormalities and cognitive impairment. The particular form of a personality change may be helpful in determining the locus of injury or brain dysfunction, although much research remains to be done. The prefrontal cortex is often implicated in secondary personality change disorders. Two frontal lobe personality syndromes have been described, correlating with injury to the orbitofrontal and dorsolateral frontal cortical regions. Table 10-53 outlines the behavioral and personality changes associated with each. The anatomical designations for those syndromes may be misleading because frontal regions form rich neuronal networks with subcortical and limbic structures. Subcortical dementia also is characterized by significant personality deteriorations, such as apathy, aspontaneity, and slowing. Patients with multiple sclerosis sometimes present with a euphoric personality, which probably reflects a disruption of the orbitofrontal subcortical network.

Table 10-53 Frontal Lobe Personality Change Syndromes

Global degenerative processes, such as dementia of the Alzheimer's type, involve significant personality change that has been less well characterized. In general, there is a coarsening of the personality with loss of subtlety and finesse. An exacerbation of premorbid traits is possible, with a suspicious patient becoming paranoid or a flamboyant patient becoming histrionic. Agitation or aggression is a common concomitant of brain disease. When they occur in a patient with a premorbid history of violence and a short temper, it may be difficult to determine if a secondary personality change has occurred, even when CNS dysfunction is evident. Laboratory evaluation for secondary personality change is the same as for other secondary disorders. The most important element is informed clinical suspicion

regarding specific disease processes. Differential Diagnosis Secondary personality change must be differentiated from adjustment disorders occurring, for example, in response to environmental stressors or major medical disorders. Apathetic and amotivational symptoms in patients with dorsolateral frontal lesions may be mistaken for major depressive disorder. The former can be distinguished by a lack of pervasive dysphoria, intact neurovegetative function, and the absence of self-disparagement and hopelessness. Euphoria and disinhibition with the orbitofrontal syndrome may be ascribed to mania. The orbitofrontal syndrome, however, does not display heightened motor activity, excessive energy, and disrupted sleep; neither does it follow the cyclical course of bipolar I disorder but rather produces a persistent and consistent clinical picture. Course and Prognosis The course of and prognosis of secondary personality syndromes depend on the course of the etiological systemic or cerebral disorder. Personality change secondary to mass lesions or hydrocephalus can improve dramatically with surgery, chemotherapy, or radiation therapy. However, each of these treatments may result in a different personality change syndrome. Personality change secondary to head trauma may improve slowly and gradually over the course of months or years, although residual disturbances may remain. Personality change due to degenerative processes can be most disruptive early in the disease process when the patient retains a measure of volition and control of motor capacities. Ironically, management of such patients may ease as the disease progresses, when the personality evolves into greater apathy, unresponsiveness, and akinesia. Personality change associated with epilepsy can improve dramatically with seizure control by pharmacotherapy or surgery. Treatment Treatment for secondary personality syndromes is first directed toward correcting the underlying etiology. Symptomatic treatments as a group have been marginally effective at best. Lithium carbonate, carbamazepine, and valproic acid have been used for the control of affective lability and impulsivity. Aggression or explosiveness may be treated with lithium, anticonvulsant medications, or a combination of lithium and an anticonvulsant agent. Centrally active b-adrenergic receptor antagonists, such as propranolol (Inderal), have some efficacy as well. Antipsychotic medications are no more effective in the dampening of aggression than the previously mentioned agents, induce greater discomfort, and introduce the risk of tardive dyskinesia. Apathy and inertia have occasionally improved with psychostimulant agents. Because cognition and verbal skills may be preserved in patients with secondary personality changes, they may be candidates for psychotherapy. Families should be involved in the therapy process, with a focus on education and understanding the origins of the patient's inappropriate behaviors and coarsening. Issues such as competency, disability, and advocacy are frequently of clinical concern in those patients in light of the unpredictable and pervasive behavior change.

SUGGESTED CROSS-REFERENCES A discussion of psychiatric clinical manifestations of specific neurological and systemic disorders appears in Chapter 2 on neuropsychiatry and behavioral neurology. Neuropsychological and intellectual assessment of adults is presented in Section 7.3, assessment of children in Section 7.5, and medical assessment and laboratory testing in Section 7.6. Discussions of substance-related disorders appear in Chapter 11, schizophrenia in Chapter 12, psychotic disorders in Chapter 13, anxiety disorders in Chapter 15, factitious disorders in Chapter 17, dissociative disorders (including dissociative amnesia) in Chapter 18, sexual dysfunctions in Section 19.1a on normal human sexuality and sexual dysfunctions, sleep disorders in Chapter 21, and personality disorders in Chapter 24. Primary care psychiatry is presented in Section 28.1, and the psychiatric aspects of HIV infection and AIDS in Section 2.8. Physiological aspects of normal aging (including age-related cognitive decline) is discussed in Section 51.2c and dementia of the Alzheimer's type and other dementing disorders of late life are discussed in Section 51.3e. CHAPTER REFERENCES Alexander MP: Traumatic brain injury. In Psychiatric Aspects of Neurologic Disease, vol II, D Benson, D Blumer, editors. Grune & Stratton, New York, 1982. American Academy of Neurology: Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus–type 1 (HIV-1) infection. Neurology 41:778, 1991. Avoli M: Molecular mechanisms of antiepileptic drugs. Sci Med 4(4):54, 1997. *Bradford Hill A: The environment and disease: Association or causation? Proc R Soc Med 58:295, 1965. Burns A, Levy R: Dementia. Chapman & Hall Medical, London, 1994. Caine ED, Joynt RJ: Neuropsychiatry. . . again. Arch Neurol 43:325, 1986. *Collins S, Law MG, Flecher A, Boyd A, Kaldor J, Masters CL: Surgical treatment and risk of sporadic Creutzfeldt-Jacob disease: A case-control study. Lancet 353:693, 1999. Cummings JL: Clinical Neuropsychiatry. Grune & Stratton, New York, 1985. Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR: The return of Phineas Gage: Clues about the brain from the skull of a famous patient. Science 264:1102, 1994. Evans AS: Causation and disease: A chronological journey. Am J Epidemiol 108:249, 1975. Gerard EM, Spitz MC, Tobin JA, Shantz D: Subacute postictal aggression. Neurology 50:384, 1998. *Grant I, Adams K: Neuropsychological Assessment of Neuropsychiatric Disorders, ed 2. Oxford University Press, New York, 1996. Grant I, Martin A: Neuropsychology of HIV Infection. Oxford University Press, New York, 1994. Harlow JM: Recovery after severe injury to the head. Publ Mass Media Soc 2:327, 1868. Huntington's Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971, 1993. *Janicki MP, Dalton AJ, editors: Dementia, Aging, and Intellectual Disabilities: A Handbook. Brunner/Mazel, Philadelphia, 1999. Jaspers K: General Psychopathology, J Hoenig, MW Hamilton, translators. University of Chicago Press, Chicago, 1963. *Jorm AF: The Epidemiology of Alzheimer's Disease and Related Disorders. Chapman & Hall, London, 1990. Joseph AB, Young RR, editors: Movement Disorders in Neurology and Neuropsychiatry. Blackwell Scientific, Boston, 1992. Kelly JP, Rosenberg JH: Diagnosis and management of concussion in sports. Neurology 48:575, 1997. Krauthammer C, Klerman GL: Secondary mania. Arch Gen Psychiatry 35:1333, 1978. *Lipowski ZJ: Delirium—Acute Confusional States, ed 2. Oxford University Press, New York, 1990. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squittieri F, Lin B, Bassett A, Almqvist E, Bird TD, Hayden MR: A worldwide study of the Huntington's disease mutation: The sensitivity and specificity of measuring CAG repeats. N Engl J Med 330:1401, 1994. Lezak MD: Neuropsychological Assessment, ed 3. Oxford University Press, New York, 1995. Liptzin B, Levkoff SE, Gottlieb GL, Johnson JC: Delirium. J Neuropsychiatry Clin Neurosci 5:154, 1993. *Lishman WA: Organic Psychiatry: The Psychological Consequences of Cerebral Disorder, ed 2. Blackwell Scientific, London, 1987. Lyness JM, editor: Affective Disorders from Medical Conditions. Semin Clin Neuropsychiatry 2:228, 1997. Marx OM: Nineteenth-century medical psychology. Isis 61:355, 1970. McAllister TW, Green RL, editors: Neurobehavioral Consequences of Traumatic Brain Injury. Semin Clin Neuropsychiatry 3:160, 1998.

Miller NE, Lipowski ZJ, Lebowitz BD, editors: Delirium: Advances in research and clinical practice. Int Psychogeriatr 3:97, 1991. Minden SL, Schiffer RB: Affective disorders in multiple sclerosis: Review and recommendations for clinical research. Arch Neurol 47:98, 1990. O'Donoghue JL, editor: Neurotoxicity of Industrial and Commercial Chemicals. CRC Press, Boca Raton, FL, 1985. Popkin MK: “Secondary” and drug-induced mood, anxiety, psychotic, catatonic, and personality syndromes: A review of the literature. J Neuropsychiatry Clin Neurosci 4:369, 1992. Restak R, editor: Neuropsychiatry of Minor Head Injury. Semin Clin Neuropsychiatry 2:160, 1997. Reynolds EH: Structure and function in neurology and psychiatry. Br J Psychiatry 157:481, 1990. Robinson RG, Starkstein SE: Current research in affective disorders following stroke. J Neuropsychiatry Clin Neurosci 2:1, 1990. Salloway S, Malloy P, Cummings J, editors: The Neuropsychiatry of Limbic and Subcortical Disorders. J Neuropsychiatry Clin Neurosci 9:313, 1997. Schaumburg HH, Spencer PS: Recognizing neurotoxic disease. Neurology 37:276, 1987. Shorter E: A History of Psychiatry: From the Era of the Asylum to the Age of Prozac . Wiley, New York, 1997. Silver JM, McAllister TW: Forensic issues in the neuropsychiatric evaluation of the patient with mild traumatic brain injury. Neuropsych Pract Opin 9:102, 1997. Slater E, Beard AW: The schizophrenia-like psychoses of epilepsy. Psychiatric aspects. Br J Psychiatry 109:95, 1963. Terry RD, Katzman R, Bick KL: Alzheimer Disease. Raven, New York, 1994. White BV: Stanley Cobb: A Builder of the Modern Neurosciences. Francis A. Countway Library of Medicine, Boston, 1984. Zegans LS, Coates TJ, editors: Psychiatric Manifestations of HIV Disease, vol 17. Saunders, Philadelphia, 1994.

Textbook of Psychiatry

11.1 INTRODUCTION AND OVERVIEW Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.1 INTRODUCTION AND OVERVIEW JEROME H. JAFFE, M.D. Definitions and Diagnosis Comparative Nosology History Epidemiology Etiology Treatment Suggested Cross-References

Whether a society views substance use primarily as a moral or a legal problem, when it creates difficulties for the user or ceases to be entirely volitional it becomes the concern of all the helping professions, including psychiatry. This chapter on substance-related disorders is made up of separate sections organized around the syndromes engendered by the use of each of the major groups of pharmacological agents that are commonly misused (abused). This section deals with issues that are common across categories of drugs—the nomenclature and diagnostic schemes of the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the 10th revision of International Classification of Diseases and Related Health Problems (ICD-10), the history of substance use and dependence, epidemiology, and the etiological factors and treatment principles that appear to be common to these syndromes. General Organization of DSM-IV and ICD-10 DSM-IV includes two broad categories of substance-related disorders: substance use disorders (substance dependence and substance abuse), and a diverse grouping of substance-induced disorders (such as intoxication, withdrawal, psychotic disorder, and mood disorders). Thus, in DSM-IV the topic of substance-related disorders goes beyond substance dependence and abuse and closely related problems to include a wide variety of adverse reactions not only to substances of abuse, but also to medications and toxins. The medications associated with substance-induced disorders range from anesthetics to over-the-counter medications and include such diverse drug categories as anticholinergics, antidepressants, anticonvulsants, antimicrobial drugs, antihypertensive agents, corticosteroids, antiparkinson agents, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, and disulfiram (Antabuse). In addition, several categories of substance-induced disorders can be associated with a wide range of nonmedicinal toxic materials, ranging from heavy metals and industrial solvents to insecticides and household cleaning agents. DSM-IV groups the diagnostic criteria for substance dependence, abuse, intoxication, hallucinogen persisting perception disorder, and withdrawal syndromes in a section titled “Substance-Related Disorders,” whereas the other substance-related disorders (e.g., substance-induced mood disorders and substance-induced delusional disorders) are described in the sections covering the disorders that they most closely resemble phenomenologically (Table 11.1-1).

Table 11.1-1 Substance-Induced Mental Disorders Included Elsewhere in the Textbook

The DSM-IV section dealing with substance dependence and substance abuse presents descriptions of the clinical phenomena associated with the use of 11 designated classes of pharmacological agents: alcohol, amphetamines or similarly acting agents; caffeine; cannabis; cocaine; hallucinogens; inhalants; nicotine; opioids; phencyclidine (PCP) or similar agents; and sedatives, hypnotics, and anxiolytics. A residual twelfth category includes a variety of agents, such as anabolic steroids and nitrous oxide, that are not in the 11 designated classes. ICD-10 considers the disorders due to psychoactive substance use within the confines of an alphanumeric system that allows only nine categories of pharmacological agents, with one residual category to cover both multiple drug use and use of psychoactive substances not included in the nine designated categories. DSM-IV and ICD-10 categorize substances comparably, with the following exceptions. Caffeine and PCP are considered distinct categories in DSM-IV; whereas in ICD-10, problems related to caffeine are included in the category of other stimulants such as amphetamine, and phencyclidine must be included with hallucinogens or in the residual category. Also, ICD-10 has a special category for abuse of non–dependence-producing substances ( Table 11.1-2). Specifically mentioned are antidepressants, analgesics, antacids, vitamins, and steroids or hormones.

Table 11.1-2 ICD-10 Diagnostic Criteria for Abuse of Non-Dependence-Producing Substances

DEFINITIONS AND DIAGNOSIS Substance Dependence The revised third edition of DSM (DSM-III-R), DSM-IV, and ICD-10 formulations for substance abuse and dependence closely follow the concepts and terminology developed in 1980 by an International Working Group sponsored by the World Health Organization (WHO) and the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) of the United States, which defined substance dependence as follows: A syndrome manifested by a behavioral pattern in which the use of a given psychoactive drug, or class of drugs, is given a much higher priority than other behaviors that once had higher value. The term “syndrome” is taken to mean no more than a clustering of phenomena so that not all the components need always be present or not always present with the same intensity. . . . The dependence syndrome is not absolute, but is a quantitative phenomenon that exists in different degrees. The intensity of the syndrome is measured by the behaviors that are elicited in relation to using the drug and by the other

behaviors that are secondary to drug use. . . . No sharp cut-off point can be identified for distinguishing drug dependence from non-dependent but recurrent drug use. At the extreme, the dependence syndrome is associated with “compulsive drug-using behavior.” That central notion is continued in DSM-IV, which states: The essential feature of dependence is a cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues substance use despite significant substance-related problems. The central notion in ICD-10 is virtually the same: a cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state. The DSM-IV and ICD-10 criteria for substance dependence are presented in Table 11.1-3 and Table 11.1-4. DSM-IV uses seven criteria to describe a generic concept of dependence that applies across 11 classes of pharmacological agents. ICD-10 requires that three of six criteria be met and also applies across classes of drugs.

Table 11.1-3 DSM-IV Diagnostic Criteria for Substance Dependence

Table 11.1-4 ICD-10 Diagnostic Criteria for Mental and Behavioral Disorders Due to Psychoactive Substance Use

DSM-IV and ICD-10 use a polythetic syndrome definition, in which no one specific criterion is required so long as three or more are present. However, DSM-IV asks the clinician to specify whether physiological dependence (evidence of criterion 1, tolerance, or criterion 2, withdrawal) is present or absent. Evidence indicates that physiological dependence is associated with a more severe form of the disorder. In addition to requiring the clustering of three criteria in a 12-month period, DSM-IV includes a few other qualifications. It states specifically that the diagnosis of dependence can be applied to every class of substances except caffeine. That point is admittedly controversial, and some researchers believe, on the basis of the same DSM-IV generic criteria, that caffeine produces a distinct form of dependence, although it is relatively benign for most persons. Some persons use several categories of drugs and are clearly drug dependent, according to the generic criteria, but it may not be possible to ascertain whether they are dependent on any one specific class of drugs. When at least three groups of substances are involved, DSM-IV calls the condition polysubstance dependence (Table 11.1-5). DSM-IV also makes provision for classifying substance-related disorders that cannot be classified in any of the previous categories (e.g., nitrous oxide, anticholinergics, anabolic-androgenic steroids) or for an initial diagnosis of dependence or abuse when the specific substance is not known. A similar residual category is included in ICD-10, but steroids are given a distinct code. The DSM-IV diagnostic criteria for other (or unknown) substance-related disorders are listed in Table 11.1-6.

Table 11.1-5 DSM-IV Diagnostic Criteria for Polysubstance Dependence

Table 11.1-6 DSM-IV Diagnostic Criteria for Other (or Unknown) Substance-Related Disorders

Patterns of Remission and Course Specifiers DSM-IV and ICD-10 deal with remission by providing distinct modifying terms that can be appended to a diagnosis of substance dependence. DSM-IV terms are more varied than those of ICD-10 ( Table 11.1-7). The DSM-IV course specifiers require a period of at least 1 month, after a period of active dependence, during which no criteria of dependence are present. If a patient has not met any criteria for dependence for at least 1 month but for less than 12 months, the course specifier to use is early full remission. If the period during which no criteria of dependence are met exceeds 12 months, the specifier of sustained full remission can be used. If the full criteria for dependence or abuse have not been met for less than a year, but one or more criteria have been present, early partial remission may be used. If the period exceeds 12 months, sustained partial remission may be used. Two additional remission specifiers should be used when appropriate: “on agonist therapy (includes partial agonists)” and “in a controlled environment.” Several factors, such as duration of remission and duration of period of dependence, must be considered in deciding that a person has fully recovered and no longer warrants a diagnosis of dependence. The modifiers that describe the course of dependence in ICD-10 are similar, but specific criteria for selecting them are not provided ( Table 11.1-4).

Table 11.1-7 DSM-IV Course Modifiers for Substance Dependence

Substance Abuse DSM-IV defines the essential features of substance abuse as follows: A maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances. . . . These problems must occur recurrently during the same 12-month period. . . . [T]he criteria for Substance Abuse do not include tolerance, withdrawal, or a pattern of compulsive use and instead include only the harmful consequences of repeated use. A diagnosis of Substance Abuse is preempted by the diagnosis of Substance Dependence if the individual's pattern of substance use has ever met the criteria for Dependence for that class of substances. The DSM-IV criteria for substance abuse are shown in Table 11.1-8.

Table 11.1-8 DSM-IV Diagnostic Criteria for Substance Abuse

A major difference exists between DSM-IV and ICD-10 with regard to the diagnosis of substance abuse. ICD-10 does not use the term “abuse.” Instead, it includes a category of harmful use, which substantially differs from the DSM-IV concept of “abuse.” The concept of “harmful use” is limited to mental and physical health (e.g., hepatitis and overdose, or episodes of depressive disorder resulting from heavy alcohol use). The concept specifically excludes social impairment, stating: “The fact that a pattern of use of a particular substance is disapproved of... or may have led to socially negative consequences such as arrest or marital arguments is not in itself evidence of harmful use.” Four diagnostic criteria must be met to make the ICD-10 diagnosis of harmful use. Substance Withdrawal Substance withdrawal, as used in DSM-IV, is a diagnostic term rather than a technical term. Thus minor symptoms that technically are due to cessation of substance use (e.g., the coffee drinker's early morning precoffee lethargy or minor headache) would not by themselves fulfill the criteria for substance withdrawal, unless they are accompanied by a maladaptive behavior change and cause some clinically significant distress or impairment in social, occupational, or other important area of functioning. DSM-IV does not recognize withdrawal from caffeine, cannabis, or PCP, although some observers believe that specific signs and symptoms can be observed when those agents are abruptly discontinued after a period of heavy use. ICD-10 does describe a cannabinoid withdrawal state. Withdrawal is commonly, but not invariably, associated with substance dependence. The signs and symptoms of withdrawal vary with the specific class of drug. In general, the severity of withdrawal is related to the amount of substance used and the duration and patterns of use. Withdrawal is seen not only when substance use is stopped but also when reduced use of a substance or a change in metabolism results in lower tissue levels. The DSM-IV generic criteria for substance withdrawal are shown in Table 11.1-9; the ICD-10 general criteria are shown in Table 11.1-4. Specific diagnostic criteria for withdrawal from each category of drugs, to be used when the general criteria have been met, are also provided.

Table 11.1-9 DSM-IV Diagnostic Criteria for Substance Withdrawal

Substance Intoxication Substance intoxication is defined more narrowly in DSM-IV than it might be in a pharmacology text. A variety of substances may produce unwanted physiological or psychological effects that could be construed as substance intoxication effects (e.g., excessive sleepiness following use of an antihistamine), but unless the symptoms are associated with maladaptive behavior, the effects would not constitute substance-induced intoxication as defined in DSM-IV. Furthermore, whether a behavioral effect is maladaptive depends on the social and environmental context in which it occurs. If alcohol makes a person unusually sociable, a bit garrulous, and a little uncoordinated at a family celebration this is probably not maladaptive drinking behavior, the same behavior at a formal business meeting probably is. Similarly, ICD-10 specifies that intoxication must produce disturbances in the level of consciousness, cognition, perception, affect, or behavior that are of clinical importance. However, it requests clinicians to further specify which of several common complications of intoxication (e.g., trauma, delirium, convulsions) are also present. The DSM-IV general criteria for substance intoxication are shown in Table 11.1-10. In addition, ICD-10 provides specific sets of diagnostic criteria for each of the drug categories and for multiple drugs, to be used once the generic criteria for intoxication have been met. Also shown are the additional specifiers for complications of intoxication ( Table 11.1-4).

Table 11.1-10 DSM-IV Diagnostic Criteria for Substance Intoxication

Substance-Induced Disorders In addition to dependence, abuse, intoxication, and withdrawal, the use of certain psychoactive drugs can induce syndromes that used to be called organic mental disorders. To avoid implying that other psychiatric disorders do not have an organic basis, DSM-IV designates these syndromes substance-induced disorders and recognizes the following categories: substance intoxication, substance withdrawal, substance-induced withdrawal delirium, substance-induced intoxication delirium, substance-induced persisting dementia, substance-induced persisting amnestic disorder, substance-induced mood disorder, substance-induced anxiety disorder, substance-induced psychotic disorder, substance-induced sexual dysfunction, and substance-induced sleep disorder. In recording a diagnosis of a substance-related disorder, the clinician should indicate the specific agent causing the disorder, if known, rather than the broad drug category; that is, substance-induced intoxication, pentobarbital (Nembutal) rather than substance-induced intoxication, sedative-hypnotics. However, the diagnostic code should be selected from the list of classes of substances provided in sets of criteria for the substance-induced disorder being recorded. For each of the substance-induced disorders (other than intoxication and withdrawal), the clinician is asked to specify whether the onset was during intoxication or during withdrawal. Thus, a specific substance-induced disorder would have a three-part name delineating (1) the specific substance, (2) the context (whether the disorder occurred during intoxication or during withdrawal or occurs or persists beyond those stages), and (3) the phenomenological presentation (e.g., diazepam [Valium]-induced anxiety disorder with onset during withdrawal). Table 11.1-11 shows the various disorders induced by the major categories of substances recognized by DSM-IV and indicates which disorders are seen during intoxication and during withdrawal. Although they are not included specifically in the table, anabolic-adrenergic steroids can also induce psychotic mood, anxiety, and sleep and sexual disorders, and their withdrawal can also be associated with mood and sleep disorders. ICD-10 has a distinctly different approach to recording these drug-related disorders. With the first and second digits after the letter committed to designating the drug category, additional psychiatric syndromes are indicated by the use of the third and fourth digits. For example, persistent mood disorder associated with hallucinogens is designated F16.72. For the diagnosis to be made, the mood disorder would need to meet the criteria listed for mood (affective) disorders.

Table 11.1-11 DSM-IV Diagnoses Associated With Class of Substances

Evolving Terminology The terminology used to describe the substance-related disorders has been repeatedly revised as concepts about the nature of drug-using behavior have evolved. In the 1980 third edition of the DSM (DSM-III) drug use disorders were divided into two major categories, drug abuse and drug dependence, and specific criteria for diagnosis were given. In DSM-III-R, adopted in 1987, the two categories were retained, but the diagnostic criteria were modified. Further revisions were made for DSM-IV, which adopted the terms “substance abuse” and “substance dependence,” probably to eliminate the use of the more cumbersome term “alcohol and drug dependence including tobacco.” For similar reasons, ICD-10 adopted the term “psychoactive substance dependence.” In much of the world literature on drug dependence, the term “dependence” is used to convey two distinct ideas: (1) a behavioral syndrome and (2) physical or physiological dependence. Physiological dependence can be defined as an alteration in neural systems that is manifested by tolerance and the appearance of withdrawal phenomena when a chronically administered drug is discontinued or displaced from its receptor. Because the dual use of the word causes confusion, the

1980 ADAMHA-WHO working group recommended restricting use of the term “dependence” to describe the behavioral syndrome and substituting the term “neuroadaptation” for physical dependence. Such a substitution would have emphasized several points. First, the continued use of many drugs, including tricyclic antidepressants and b-adrenergic receptor antagonists, causes neuroadaptive changes followed by withdrawal phenomena, but not by drug-seeking behavior, on their discontinuation. Second, neuroadaptive changes begin with the first dose of an opioid or sedative drug, and therefore, such changes in and of themselves are not a sufficient cause (or definition) of drug dependence as a behavioral syndrome. Why Use “Addiction”? The words “addict” and “addiction” often have pejorative connotations; they are also frequently trivialized and used to refer to ordinary activities, such as exercising and solving crossword puzzles. However, the term “addiction” continues to have the core connotation of decreased control, and some chapters in this book have retained such terms as “opioid addict” because they are less awkward to use than terms such as “severely opioid-dependent person” when referring to persons who are dependent on drugs to a severe degree. Here the word “dependent,” unmodified, is used to mean behaviorally dependent. The term “physiological dependence” or “physical dependence” is used to refer to the physiological changes that result in withdrawal symptoms when drugs are discontinued.

COMPARATIVE NOSOLOGY DSM-IV and ICD-10 The generic concept of dependence is virtually identical in DSM-IV and ICD-10. By requiring the clinician to specify whether tolerance and withdrawal are present, DSM-IV appears to recognize a special significance for tolerance and physiological dependence. Some data indicate that among alcoholics the presence of physical dependence and, to a lesser degree, tolerance is associated with a more severe variety of the syndrome. In practice, however, requiring evidence of these criteria would not substantially reduce the number of cases meeting the criteria for dependence in most drug categories, with the exception of hallucinogens, a class of drugs for which DSM-IV does not list physiological dependence as a criterion. There is generally a high level of agreement between DSM-IV and ICD-10 for making a diagnosis of dependence, although the descriptions of the criteria for determining the presence and severity of the syndrome differ. They both require that three elements of the syndrome have been present in a 12-month period. The DSM-IV categorization of drug classes differs somewhat from the one used by ICD-10, which, constrained by a new alphanumeric system, uses only nine drug categories by including caffeine with amphetamine-like stimulants and PCP with other psychoactive agents. The word “abuse” is also commonly used in ways that differ significantly from the definitions developed for use in DSM-IV. In popular and legislative contexts drug abuse means any use of an illicit substance or any nonprescribed use of a drug intended as a medicine, as well as the harmful or excessive use of legally available substances, such as alcohol and tobacco. Despite the reliability of DSM-IV and ICD-10 criteria for dependence in many European and Anglo-American cultures, several criteria (e.g., narrowing of drinking repertoire, time spent obtaining the drug, and even tolerance for the drug) have posed difficulties in other cultures, especially when dealing with alcohol. Tolerance is often understood when applied to drugs, but not to alcohol; in some cultures, holding one's liquor is a sign of manhood. Clinicians are more likely to make a diagnosis of drug dependence than alcohol dependence even when behavioral signs are comparable. In several cultures, little or no distinction is recognized between use, abuse, and harmful use of illicit drugs. Other Perspectives The criteria for diagnosis in DSM-IV and ICD-10 were developed from what is essentially a biopsychosocial model of substance dependence. In such a model multiple factors—genetic, psychological, sociological, and pharmacological—contribute to the observed clinical syndromes. Such apparent unanimity about drug dependence should not obscure the existence of dissenting perspectives, which take several forms. In one the biopsychosocial model is accused of giving too much weight to biological factors and too little recognition to the notion of human will and responsibility, of medicalizing deviant behavior for the benefit of treatment professionals, and of creating universal exculpation for all those who fail to live up to reasonable societal expectations. But some professionals have implicitly criticized the same biopsychosocial model for not giving sufficient weight to the ideas that substance dependence is a specific primary disease (i.e., not a symptom of other psychiatric difficulties), that those who develop the disease have no control over their intake of certain substances, and that denial of the presence of a problem is a major characteristic of the disease. Concepts about substance dependence can be arrayed along several dimensions that are not entirely independent or orthogonal: broad versus narrow, disease versus learned behavior, and social versus medical. The narrow concept of substance dependence accepts as disorders those maladaptive behaviors associated primarily, if not exclusively, with the ingestion of substances generally accepted as pharmacological agents. Compulsive eating, gambling, running, hair pulling, and repetitive excessive sexual activities are not included among the dependence disorders, although those problems may share certain features that resemble a decreased ability to choose and are sometimes ameliorated by participation in support groups founded on principles similar to those of Alcoholics Anonymous (AA). A broad approach would create a superclass of disorders that would include a number of such behaviors not involving pharmacological agents. At the disease end of the disease-versus-behavioral syndrome dimension is a belief that dependence is not a learned behavior that can be modified or ameliorated with relearning but is a primary disorder caused by an interaction between a substance and a person with some genetic vulnerability and that only total abstinence can arrest the progression of the disease. The medical-versus-social dimension typically describes a range of views on how best to respond to problems with substances, rather than differences about the essential nature of the problems. The medical model stresses issues of assessment—treatment, planning, and record keeping—and sometimes treatment that can be rendered only by those with professional training (not necessarily physicians). The social model emphasizes the importance of social supports and integrating the person with a problem into a network of recovering persons who can offer continuing support. The assessment and recording of progress and outcome as generally practiced by credentialed professionals is minimized.

HISTORY The most commonly abused drugs have been in use for hundreds, if not thousands, of years. For example, opium has been used for medicinal purposes for at least 3500 years, references to cannabis (marijuana) as medicinal can be found in ancient Chinese herbals, and wine is mentioned frequently in the Bible. The indigenous people of the Western Hemisphere were smoking tobacco and chewing coca leaves generations before the arrival of the Spaniards. Some of the problems caused by alcohol and other drugs, such as drunkenness, are described in the Bible and in the writings of the ancient Greeks and Romans. As new and more concentrated forms of drugs were discovered or invented or new routes of administering them were developed, new problems related to their use emerged. For instance, when cheap gin was introduced into England in the eighteenth century, the alcohol-related problems that emerged were considered more serious than those associated with beer and wine. Although opium smoking was a major problem in Asia in the eighteenth and nineteenth centuries, new problems were seen after morphine, the most active opium alkaloid, was isolated in 1806. Morphine was subject to misuse by injection from the late nineteenth century on, and intravenous morphine and heroin use began to spread in the early part of the twentieth century. Tobacco use and its associated problems did not become widespread until the nineteenth century, when new methods of curing the leaves produced a mild smoking tobacco and cigarettes were introduced, which made common the practice of inhaling tobacco smoke deeply into the lungs. By the early twentieth century, cigarette smoking was a popular practice. Medicalizing Excessive Drug Use In 1810 Benjamin Rush, who is often credited as the first American physician to suggest that excessive use of alcohol was a disease rather than exclusively a moral defect, proposed the establishment of a sober house; in 1835 Samuel Woodward, a pioneer in the establishment of asylums for the insane, advocated similar asylums for inebriates. Contemporaneous with those early moves to involve medicine in dealing with excessive alcohol use was the emergence of the temperance movement and the Washingtonians—groups of reformed drunkards concerned with helping others to adopt and maintain sobriety. In the process the Washingtonians developed many of the principles of self-help that were rediscovered by AA almost a century later. When the ideas of voluntarism and self-help as exemplified by Washingtonian societies failed to eliminate the problem of drunkenness, physicians began to debate more seriously the idea of coerced treatment in inebriate asylums supported by public funds. In 1870 advocates of the approach established the American Association for the Cure of Inebriates (AACI), dedicated to setting up hospitals for such persons, conducting research, and teaching medical students and physicians how to treat inebriety. At first those physicians who believed in a more spiritual, voluntary approach to the problem (neo-Washingtonians) were part of the AACI, but gradually the more somatically oriented factions, which advocated medically supervised asylums (and compulsory treatment when needed), gained ascendancy. Furthermore, the focus of concern was no longer limited to those who abused alcohol. Thomas Crothers, the secretary of AACI, saw inebriate asylums as places to treat all those who used any variety of intoxicant or narcotic to excess. However, very few publicly supported inebriate asylums ever opened. Early Attitudes The closing years of the nineteenth century saw growing concern about the excessive and inappropriate use of drugs, including alcohol and tobacco as well as opiates and cocaine. First isolated from the coca leaf in 1860, cocaine came into widespread use in 1885 when pharmaceutical companies began selling it in the United States and Europe. In 1884 Sigmund Freud had published a review of the potential therapeutic uses of cocaine. Some medical authorities in the United States shared his enthusiasm, and cocaine was recommended by the Hay Fever Association as a remedy for that malady. Within a few years, however, it was recognized that cocaine had the capacity to induce toxic psychosis as well as gain control over behavior. It was also recognized that long-term opiate use had dependence-inducing effects. Nevertheless, in the United States, until the beginning of the twentieth century, both the opium alkaloids and cocaine were still found in

patent medicines that were sold over the counter for a wide variety of indications, and their labeling often did not reveal their contents. Although achieving long-term cure of morphinism was reported to be exceedingly difficult, until the turn of the twentieth century neither the public nor the medical profession saw the habitual user of opium or morphine as invariably suffering from a moral deficit. Those who had developed the morphine habit represented the entire socioeconomic spectrum, with women outnumbering men by about two to one. Various political and literary figures were known to use opiates but to lead otherwise productive and exemplary lives. However, cocaine use and the morphine habit were also common among gamblers, petty thieves, prostitutes, and other disreputable members of society. Persons with emotional problems and those who had formerly used alcohol to excess were probably also overrepresented among opium users, since it was not unusual at the time for physicians to prescribe opiates to control emotional problems and alcoholism. The problem of using the same institution for treatment of drug users who had antisocial tendencies and those who led more conventional lives was as vexing to early advocates of medical treatment as it is to present-day practitioners. Many proponents of inebriate asylums did not want to take responsibility for persons who had frequent or serious encounters with the police because it was thought that such persons would make it impossible to create an atmosphere conducive to recovery. Partly to cope with the problem, even some of the proponents of a disease model of inebriety maintained the distinction between “inebriety the disease” and “intemperance the vice.” Early Control Efforts: Evolution of the Criminal Model By the late 1890s the public and the medical community were no longer indifferent to drug use and habituation. In 1893 the Anti-Saloon League was founded, reinvigorating a temperance movement that advocated the total prohibition of alcohol. Medical texts in England, Europe, and the United States contained descriptions of morphinism, theories of its causation, and recommendations for withdrawal and postwithdrawal treatment. Some texts also described problems of cocainism. Medical authorities in the United States cautioned against overly liberal prescribing of cocaine and opiates by physicians and expressed great concern about the presence of those drugs in unlabeled proprietary over-the-counter medicines. State laws were passed aimed at controlling the sale of opiates and cocaine, especially in patent medicines. In 1900 the cocaine in Coca-Cola was replaced by caffeine. Partly to support the efforts of the Chinese government to control opium use in China, representatives of the United States government led the movement to negotiate an international treaty to control traffic in opium, cocaine, and related drugs. The first such treaty was signed in The Hague in 1912. Negotiators from the United States were also interested in the international control of cannabis but could not get other nations to view the substance as sufficiently problematic to warrant it. (Such control was achieved in 1925 at the Second Geneva Convention.) The Hague Convention required the signatories to pass domestic legislation controlling opiates and cocaine. The Harrison Act of 1914, the first federal legislation to regulate opiates and cocaine, was designed to restrict access to opiates and cocaine to doctors, dentists, pharmacists, and legitimate importers and manufacturers and brought the United States into compliance with the convention. State regulations concerning the sale of opiates and cocaine, the introduction of aspirin and the barbiturates, and the Pure Food and Drug Act of 1906, which required labeling of patent medicines, were already having an impact on the use of opiates in medicine when the Harrison Act was passed in 1914. Although many medical and political leaders in the United States believed that much of the problem of drug dependence resulted from careless prescribing by physicians, the Harrison Act was not originally intended to interfere with the legitimate practice of medicine or to cause special hardship for those already dependent on opiates. For several years after the Harrison Act was passed, a few cities operated clinics that prescribed morphine to persons with established morphine habits. Most of those dependent on opiates before the Harrison Act became abstinent within a few years after it was passed, although generally not as a result of treatment at the clinics. Fluctuating Attitudes Major changes had taken place in American attitudes and practices by the 1920s. The Eighteenth Amendment to the U.S. Constitution, which prohibited the sale of alcohol, became law in 1920 and radically changed drinking behavior in the United States. Within a year after alcohol prohibition was enacted, 14 states also passed cigarette prohibition laws. Even less popular than alcohol prohibition, those laws were all repealed by 1927, and by the mid-1920s Americans were smoking 80 billion cigarettes a year. However, cocaine use, so prevalent at the turn of the century, was no longer widespread. Disillusioned by the reluctance of morphine addicts at clinics to detoxify and by repeated relapses among those who did, doctors began to recommend (not for the first time) compulsory treatment with confinement until cure. As the new laws curtailed legitimate supplies of opiates, an illicit traffic developed to provide them to morphine addicts who could not or would not use the clinics. Increasingly, the drug sold was heroin, which had been introduced for medical use in 1898 but was quickly found by drug users to have effects quite similar to those of morphine. Many who patronized the illicit traffickers and used the clinics had histories of delinquency and criminal activity, and eventually that subgroup came to predominate. Reformers, moralists, and the popular press found in the opiate habit, and in the reputation of those who continued to use morphine, proof of the evils inherent in those drugs. Negative publicity, lurid stories, medical disillusionment, and pressure from law enforcement agents combined to label the morphine clinics as medical folly and brought about their closing, the last in 1923. At the same time a series of United States Supreme Court decisions implied that prescribing even small amounts of opiates or cocaine to an addict for treatment of addiction was not proper medical practice and was thus an illegal sale of narcotic drugs. Several physicians were imprisoned, and numerous others were tried, reprimanded, or otherwise harassed. By the early 1920s persons addicted to opiates were not welcome in doctor's offices, and they were often refused treatment at hospitals. Dope addict and dope fiend had become common terms, and the average layperson, as well as some otherwise well-informed members of the medical profession, appeared to believe that the opiate molecule was inherently evil. In the late 1930s cannabis acquired a similar reputation, and in 1937 the United States Congress passed legislation prescribing criminal penalties for its use, sale, or possession. Alcohol prohibition had been repealed in 1933. New Drug Problems The first of the barbiturate sedatives, barbital, was introduced into clinical medicine in 1903, followed over the next 30 years by scores of congeners that differed primarily in their duration of action. Within a few years after the introduction of each new compound, the first case reports of abuse, dependence, and withdrawal appeared in the medical journals, a pattern that was repeated with the nonbarbiturate sedatives, such as glutethimide (Doriden), ethchlorvynol (Placidyl), and meprobamate (Miltown) in the 1950s. Amphetamine, first synthesized in 1887, was put into clinical use in 1932 as a drug to shrink mucous membranes. By 1935 its central stimulant effects had been recognized and found useful for treating narcolepsy, and dozens of other suggested uses soon followed. Reports that amphetamine was being used as a euphoriant began to appear in the late 1930s, but the full significance of its abuse potential was not appreciated until the post-World War II epidemic of intravenous methamphetamine addiction in Japan. That epidemic, precipitated by the sale of surplus methamphetamine tablets intended for combat troops, involved millions of people. Other amphetamine-like drugs, which have also been subject to abuse, were introduced during the 1950s and early 1960s. The psychological effects of mescaline were already known and written about at the end of the 19th century. However, public concern about hallucinogens did not reach a high level until the 1960s, when the use of a newly discovered and exceedingly potent compound, lysergic acid diethylamide (LSD), evolved from experimentation by a few college students to more widespread use by even younger people. Phencyclidine, a general anesthetic developed in the 1950s, also became a drug of abuse in the 1970s. Despite repeated reports of abuse and dependence associated with barbiturates, barbiturate-like sedatives, and amphetamines and related stimulants, and in spite of concerns about experimentation with LSD and related hallucinogens, there were no federal criminal sanctions related to these drugs until 1964, when authority for their control was assigned to the Food and Drug Administration (FDA). In contrast, in the 1950s, concern about heroin addiction had led to ever harsher criminal penalties for its sale or possession. Although law enforcement efforts aimed at controlling heroin use were increased, both the number of new heroin addicts and the crime rates continued to rise throughout the late 1960s. At about that time there was also a sharp increase in the nonmedical use of other substances, such as cannabis and LSD, and a major epidemic of amphetamine abuse and dependence. In addition to amphetamines diverted from medical channels, supplies came from clandestine laboratories. Drug use, especially cannabis, became linked to antiestablishment attitudes, politics, and lifestyles. Evolving Treatment Approaches Treatment for substance-related problems underwent several dramatic changes during the twentieth century. The large specialized asylums that were advocated in the nineteenth century never materialized. Toward the end of the nineteenth century physicians were primarily concerned about how to manage withdrawal syndromes and whether or not longer compulsory treatment was needed. With the advent of prohibition, the impetus to develop treatments for alcoholism declined sharply. Interest in treating opioid-dependent patients also declined as physicians became discouraged by their tendency to relapse after being detoxified and as opioid use and dependence came to be seen more as criminal behaviors than as medical disorders. A few private sanitoriums continued to provide treatment for opioid dependence. By 1930, as drug-addicted prisoners began to fill the penitentiaries, the federal government saw the need to establish two hospitals, at Lexington, Kentucky, and Fort Worth, Texas, to provide treatment for that population and also to conduct research on the problem of opiate addiction. Treatment of barbiturate and amphetamine dependence took place largely in the mainstream of medical practice and in state hospitals, but there was no consensus on what constituted effective posthospital care.

In the mid-1930s two recovering alcoholics rediscovered the principles of the Washingtonians, added some new principles, and initiated the self-help movement now known as AA. By the 1950s, this movement had begun to inspire analogous self-help efforts among other types of substance abusers. The situation changed again in the early 1960s. With new outbreaks of heroin use by young people and increasing crime, the federal government and individual states attempted to respond to the problem. California initiated a civil commitment program for addicts under the administrative control of the Department of Corrections; New York City reopened Riverside Hospital to treat juvenile heroin addicts. The first follow-up studies of patients treated at the federal hospital at Lexington revealed exceedingly high rates of relapse after treatment. Both the medical community and the general public demanded new ideas and solutions, including a reconsideration of providing addicts with legitimate opioids through medical channels. From 1958 to 1967 several major new approaches to treating opioid dependence were developed. Synanon, the prototype therapeutic community, was started in California in 1958 and was soon replicated in New York with the establishment of Daytop Village and Phoenix House. Vincent Dole and Marie Nyswander showed that maintaining selected long-term heroin addicts on large daily doses of methadone (Dolophine) was effective in reducing crime and heroin use. Several research groups demonstrated that heroin addicts would voluntarily try treatment with narcotic antagonists. In the mid-1960s, New York State and the federal government legislated civil commitment programs modeled after the program in California, with an initial period of prolonged institutional care as a key element. Although many treatment programs initiated in the early 1960s continued to focus on the treatment of opioid dependence, others, especially the therapeutic communities, viewed all nonmedical drug use as stemming from similar defects in character structure and offered a generic approach to treating drug dependence. Alcohol and Nicotine In the 1950s clinicians at Wilmar State Hospital in Minnesota developed a treatment program for alcoholism built on a synthesis of the medical model and the experiences of recovering alcohol abusers using the 12-step principles of AA. That treatment approach was refined and expanded at the Johnson Institute and Hazelden Foundation, also in Minnesota. The modified programs, widely adopted by others, are often referred to as 28-day programs, 12-step programs, or the Minnesota model. In the early 1970s the effort to recognize alcoholism as a disease gained momentum, and the decision of medical insurance carriers to provide coverage for detoxification and inpatient treatment fueled an unprecedented growth of private-sector facilities offering treatment for alcoholism. Almost without exception, they were residential programs using the Minnesota model. The decriminalization of public intoxication spurred a parallel increase in alcohol treatment programs supported by the public sector. The Surgeon General's Report of 1964 linked cigarette smoking to lung cancer and concluded that tobacco smoking was a form of dependence, although not an addiction. By the 1970s, tobacco dependence was more widely accepted as a valid clinical entity, and various treatments for it were developed. By the late 1980s, as smoking was becoming socially unacceptable, many buildings were declared smoke free, smoking was banned on most airplane flights and in many hospitals, and pharmaceutical companies began to market new products for delivering nicotine (e.g., nicotine chewing gum and transdermal patches) as aids for smoking cessation. By the late 1990s the tobacco companies were negotiating settlements in multiple civil law suits by states and by individuals who had been injured by their tobacco use, and Congress had unsuccessfully debated major tax increases on tobacco and regulation by the FDA. Two-Tiered System When the cocaine epidemic of the early 1980s struck the middle class, much of the large, private-sector system for treating alcoholism evolved into chemical dependency units offering similar treatments to persons with alcohol problems and those with other varieties of substance dependence. By 1990 it was estimated that more than 8000 recognized programs existed that deal with alcoholism and other substance dependence. The treatment methods used varied widely in terms of settings, costs, philosophical underpinnings, and populations served. New categories of substance-abuse professionals had emerged, and psychiatrists who once had considered the problems to be a low-status area successfully lobbied for the creation of a recognized subspecialty in addiction psychiatry. Treatment capacity was described as a two-tiered system with private and public sectors, in which the private sector served 40 percent of the population but received 60 percent of the total expenditures for treatment. One response to the escalating cost of substance abuse services among those with private medical insurance was the rise of a managed care industry created to control costs on behalf of employers who pay for health insurance, generally by severely limiting the length of stay in hospital settings. Managed care, by refusing to recognize (and pay for) the medical necessity of inpatient treatment for most cases of substance dependence, largely dismantled the rest of the “28-day” inpatient alcohol and drug treatment programs that had serviced patients with insurance. By the mid-1990s managed care principles were routine in the public sector as well, and little remained of the two-tiered system. Legislation and National Strategies In 1969 Congress recognized the need to give greater attention to the problem of alcoholism and established the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in the National Institute of Mental Health (NIMH). In 1970 legislation was passed, reorganizing the jumble of drug regulatory statutes that had evolved since the passage of the Harrison Act, increasing the resources for controlling the availability of illicit drugs, and assigning the task of enforcement to a new agency, the Drug Enforcement Agency (DEA), which incorporated elements of the FDA and the Bureau of Narcotic and Dangerous Drugs. All drugs subject to special controls were included in one of several categories of the Controlled Substances Act. In 1971 when United States troops in Vietnam were reported to be using heroin heavily, the Special Action Office for Drug Abuse Prevention (SAODAP) was established in the Executive Office of the President to coordinate government activities and policies relating to drug abuse and to develop and publish an overall national drug strategy. The creation of that office and the associated legislation marked a turning point in United States policy. The notion that opioid dependence was an incurable disorder, which justified the harshest of penalties in the name of prevention, was superseded by a policy that recognized that a substantial proportion of opioid addicts (as well as those with other varieties of drug dependence) could eventually reenter the mainstream of society. New commitments were made to basic research, epidemiology, development of new treatment methods, and evaluation of existing treatment approaches. Methadone maintenance was moved, by executive fiat, from the legal limbo of experimental status to a category that recognized its legitimacy. Regulations intended to prevent inappropriate prescribing of opioids were developed. Federal support for the expansion of community treatment programs was also greatly increased. By 1973 about 200,000 substance users, most of them opioid users, were in treatment in community programs. Those programs were repeatedly and intensively evaluated over the subsequent decade. The legislation that established SAODAP also provided the legislative framework for the National Institute on Drug Abuse (NIDA) in the Department of Health, Education and Welfare (HEW). When it was established in 1974 NIDA became the lead agency for implementing federal policy on treatment, research, and prevention. By the early 1980s treatment for opioid dependence was generally accepted to have demonstrable impact. However, for most patients in treatment programs, the primary drugs of abuse were no longer opioids but more typically, cannabis, stimulants, or sedatives. During the early and mid-1970s some groups had argued for the decriminalization or legalization of cannabis. The arguments lost much of their force when it was found that in 1979 almost 10 percent of high school students were using cannabis on a daily basis. In response to what they perceived as tolerance toward cannabis use, a number of parents' organizations were formed that were committed to making all drug use unacceptable. Those groups forced NIDA to review and remove from all its publications any statements that could be interpreted as tolerating drug use. This decreased tolerance for drug use grew in parallel with a more general conservative shift in public attitudes. For example, in the 1970s the public and the courts had rejected the use of urine testing as a means of detecting drug use in an effort to interrupt the heroin epidemic; but starting in 1986, federal employees were required by presidential order to undergo such tests. Similar drug testing was encouraged in private industry, giving rise to new industries for detecting the presence of drugs, interpreting test results, and placing drug users in treatment. By the 1970s it was obvious that the major drug abuse problems in the United States in terms of social and economic impact and health costs were alcoholism and tobacco dependence. Although the Surgeon General's Report of 1964 linking cigarettes to cancer had not produced any dramatic decrease in smoking, the rate of increase in cigarette consumption among men had begun to level out. In 1988 the Surgeon General's report on the Health Consequences of Smoking officially defined tobacco dependence as analogous to other varieties of drug dependence. In 1994 the FDA held hearings on the appropriateness of regulating the nicotine in tobacco as an addictive drug. Shortly thereafter, with backing from the president, the FDA assumed authority to regulate advertising of tobacco products; the White House lobbied Congress to pass legislation that would limit advertising and raise federal taxes on tobacco. In the early 1980s rising demand for the treatment of cocaine dependence, the sudden cocaine-induced deaths of several prominent athletes, and concern about the spread of the human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) among intravenous drug users led to the Anti-Drug Abuse Act of 1986, which authorized the government to spend nearly $4 billion to intensify efforts against drugs and drug abuse. Although most of that money was allocated to law enforcement activities, federal resources for the treatment of drug dependence and research were also substantially increased. Recognizing the need to do more to prevent drug dependence and provide more treatment, the federal government created a series of offices that by 1992 evolved into the Substance Abuse and Mental Health Services Administration (SAMHSA), with several constituent centers, including the Center for Substance Abuse Treatment (CSAT) and the Center for Substance Abuse Prevention (CSAP). The 1988 Anti-Drug Abuse Act and the 1989 Emergency Supplemental Appropriation created the Office of National Drug Control Policy (ONDCP) in the White House. While still devoting more than two thirds of federal resources available for drug problems to controlling drug supply, this legislation also increased funding for treatment and prevention. Critics of the emphasis on supply-control gained public attention when they were supported by several prominent conservative writers and economists and garnered the financial support of several well-endowed foundations. While the more thoughtful of these critics have stopped calling for outright legalization of drugs, they have

called for greater emphasis on reducing the harm related to drug use by medically prescribing heroin and other psychoactive drugs and more support for needle-exchange programs. Despite some evidence suggesting that availability of sterile needles can reduce HIV transmission, the federal government continues to ban the use of federal money for such programs.

EPIDEMIOLOGY A number of distinct methods have been developed to gauge the extent and medical consequences of substance use, abuse, and dependence in the United States. The major recurring surveillance instrument are the National Household Survey on Drug Abuse (Household Survey), the Drug Abuse Warning Network (DAWN), Arrestee Drug Abuse Monitoring System (ADAM—formerly known as the Drug Use Forecasting [DUF] program), and the Monitoring the Future Study (better known as the High School Survey). In addition, data on street availability and purity of illicit drugs, drug seizures, and arrests for drug offenses are collected nationally from the DEA and the Federal Bureau of Investigation (FBI) and locally from municipal police departments. Each of these data sources has strengths and limitations. For example, the Household Survey annually interviews a representative sample of individuals age 12 and older living in households, college dormitories, homeless shelters, and rooming houses. It oversamples minority populations and certain large urban areas, and focuses in detail on drug-using behaviors. It does not interview military personnel or individuals who are living on the street or in institutions (jails or hospitals). It does not attempt to determine whether respondents need treatment or meet formal criteria for drug dependence. In addition, some respondents may be reluctant to admit to certain types of drug use. The ADAM system interviews, and obtains anonymous urine specimens from, a sample of arrestees in moderate-size cities in the United States. By design, persons charged with sale or possession of drugs cannot make up more than 25 percent of the sample. Although it does not depend on self-reports to measure use, the ADAM results cannot be easily extrapolated to a national population, and the information that can be derived from a single urine test is limited. In 1989 the DAWN system, which obtains data on drug-related episodes from medical examiners and hospital emergency rooms, was modified so that the reporting emergency rooms constitute a representative sample of such facilities in the continental United States. The DAWN data provide useful information on trends in the morbidity associated with various illicit drugs; but these data need to be interpreted with caution because the DAWN system reports only episodes in which a drug is part of the presenting clinical picture. For example, a rising number of emergency room episodes associated with heroin could mean that more heroin users with AIDS-related problems are seeking primary medical care, rather than that more individuals are using heroin. Similarly, reports by medical examiners of more violent deaths associated with cocaine may signal an escalation of competition among drug dealers, rather than more people using cocaine. The analytical methods do not reveal the nature of the linkage between drug use and the presenting problem, which drugs (if any) played a causal role in the episode, or whether the user was a novice or a chronic user. The High School Survey has obtained information each year since 1975 from forms returned anonymously by high school seniors. It now includes former seniors now in college and students in the eighth and tenth grades. Although the survey depends on self-report, the trend information it provides is exceedingly useful. In addition to the recurring data-gathering efforts, important epidemiological information is available from two national studies that systematically interviewed representative samples of the population and used DSM-III or DSM-III-R criteria to develop estimates of current and lifetime prevalence of psychiatric disorders, including substance abuse and substance dependence. These studies are the NIMH Epidemiological Catchment Area (ECA) Study, conducted in the early 1980s, and the National Comorbidity Survey (NCS), conducted between 1990 and 1992. The ECA interviews in five areas of the United States included individuals in institutions (mental hospitals, jails, nursing homes, etc.) and used DSM-III criteria to develop estimates of prevalence. The NCS interviews of a nationally representative sample of noninstitutionalized people used DSM-III-R criteria. Although the ECA was conducted before the cocaine epidemic of the 1980s crested and criteria for diagnosis used were altered somewhat in DSM-III-R, it nevertheless remains a landmark study of the extent of drug abuse and dependence and co-occurring psychiatric disorders. The ECA study found that 16.7 percent of the U.S. population ages 18 and older met the DSM-III criteria for a lifetime diagnosis of either abuse or dependence on some substance, with 13.8 percent meeting the criteria for an alcohol-related disorder, and 6.2 percent meeting the criteria for abuse or dependence of a drug other than alcohol or tobacco. The NCS found a 26.6 percent lifetime prevalence of substance abuse and dependence, substantially higher than the 16.7 percent found in the ECA. Some of this is probably due to questions in the NCS about prescription drugs that were posed when a patient reported symptoms of dependence, and on differences in criteria (DSM-III versus DSM-III-R). However, there may also have been real increases in prevalence. For illegal drugs and the nonmedical use of prescription drugs, the lifetime rate for dependence in the NCS was 7.9 percent, a figure much closer to the 6.2 percent found for such drugs in the ECA study. The NCS found a 12-month prevalence estimate for any addictive disorder (including dependence and abuse) of 8.2 percent; 4.5 percent alcohol dependence, and 1.8 percent drug dependence. Except for tobacco, men are far more likely than women to use drugs and alcohol and are correspondingly more likely to develop dependence. For example, lifetime and 12-month prevalence rates of alcohol dependence are 20.1 percent and 6.6 ercent for men, but only 8.2 percent and 2.2 percent for women. Among the major achievements of the NCS analyses were the findings on the proportions of people who had used drugs at any time in their lives ( lifetime users) who became dependent (overall and for each drug category); the demographic factors that predicted use, dependence, and persistence of dependence; and the prevalence and significance of multiple psychiatric diagnoses. Dependence cannot develop if a drug is never used; thus, presenting data on the prevalence of dependence in the population as whole, including those who never used, can obscure the likelihood of dependence developing among those who do use a particular drug. In the NCS, prevalence of lifetime dependence on the broad range of illicit and nonprescribed medications was 14.7 percent, with male users only slightly more likely (16.4 percent) than female users (12.6 percent) to develop dependence. In a similar analysis of the 12-month prevalence of dependence on these drugs, the rate for the population as a whole was 1.8 percent. However, the 12-month prevalence was 3.5 percent for those who had used any of these drugs at any time in their lives; 10.3 percent for those who had used them in the past 12 months, and 23.8 percent among those who had a lifetime history of dependence. The likelihood of being drug dependent within the past 12 months, given a lifetime history of dependence, was similar for men (24.9 percent) and women (22.2 percent). Lower educational and lower income levels predicted a lifetime history of dependence (odds ratios greater than 2), but race, ethnicity, or living in an urban environment did not. There were also differences in the likelihood that users of a particular drug would become dependent on it. For example, for heroin, the lifetime opioid dependence rate was 23 percent; for tobacco, 32 percent; for cocaine, 16.7 percent; for alcohol, 15.4 percent but only 4.9 percent for psychedelics. Men who used alcohol were more likely to become dependent (21.4 percent) than women (9.2 percent), possibly because they drink more than women but genetics may also play a role. Table 11.1-12 shows data from the 1996 Household Survey on percentage of respondents who reported using various drugs. The data are shown for four age groups. Persons aged 18 to 25 years reported the highest level of use of illicit drugs during the 30 days preceding the interview; those ages 26 to 34 had the next highest rate and reported a higher lifetime experience with cocaine. Illicit drug use during the 30 days preceding the interview is far more prevalent among young adults (ages 18 to 34, and particularly those 18 to 25 years old) than among those above age 35 or below age 18. Also, whereas recent use is more common in large metropolitan areas than in rural areas, regional, racial, and ethnic differences vary with the age group considered. With the exception of tobacco dependence, all forms of substance abuse or dependence are more common among men than among women. However, recent data indicate that when adjustment is made for differences in rates of use and experimentation with illicit drugs, women are about as likely as men to become dependent. Current illicit drug use (past 30 days) was more common among male (8.1 percent) than female (4.2 percent) respondents, and among the unemployed. Among other demographic subgroups, it was slightly more common among blacks and in the western states.

Table 11.1-12 Use of Illicit Drugs, Alcohol, and Tobacco in the U.S. Population by Age Groups

The High School Survey found that self-reported use of cannabis and illicit drugs in general (mostly cannabis) in the past 30 days declined sharply from the high levels (38 to 40 percent) reported in 1977 through 1979 to much lower levels (16 percent) in 1991. The decline in cocaine use began in 1987. However, 30-day prevalence rates for cannabis increased from 1992 through 1997. Cocaine and crack cocaine 30-day prevalence rates also increased slightly from a low of 1.3 percent in 1993 to 2.3 percent in 1997. Other substance use increased also, but levels were still below the peaks observed a decade earlier. In 1997 the annual prevalence rate among high school seniors for use of any illicit drug was 42.4 percent, and for an illicit drug other than cannabis, it was 20.7 percent. The ADAM system obtains data from a population in which illicit drug use is high and thus provides trend data not readily available from other sources. In general, current drug use among arrestees is several times higher than that among those sampled by national surveys, even though urine tests detect drug use for only a few days, whereas surveys typically ask about drug use over the preceding 30 days. For example, in 1988, the peak of the cocaine epidemic, more than 60 percent of arrestees tested positive for cocaine (80 percent among male arrestees in Manhattan). More-recent data (1995) show a decline in cocaine use and low levels of heroin use. Epidemics Several major overlapping drug abuse epidemics have occurred over the past 30 years, affecting somewhat different populations. Cannabis use, which had been endemic among certain minority groups and jazz musicians, began to increase in the 1960s, especially among young people, and then spread to other segments of the population. At its peak, in 1978 to 1979, 10 percent of high school seniors were using marijuana on a daily basis. Daily use declined to 5 percent by 1984, to 2 percent by 1991, and then reversed direction and again rose. Similar changes in use rates were reflected in the Household Survey. An epidemic of heroin use also began in the early 1960s, and incidence peaked between 1969 and 1971. The population of active heroin users reached its highest levels in the early 1970s, but periodic upsurges have occurred as supplies became more available, law enforcement activity waxed and waned, and relapse rates increased among former users. In 1977 the United States government estimated that there were 500,000 opioid abusers and dependent users, and more recently, it revised the estimate to 320,000 occasional users and 810,000 chronic users. In general, the heroin-using population is an aging one, with a high and still growing prevalence of HIV in some areas. The 1996 Household Survey estimated that about 2.3 million people had tried heroin at least once and that 245 thousand had used it in the past year. However, it is believed that a large percentage of heroin users are outside the population interviewed by the survey. The cocaine epidemic began in the 1970s and reached its peak around 1985, when it was estimated that 5.8 million people in the United States (2.9 percent of the population) had used cocaine in the month prior to survey. The epidemic seems to have passed its peak in most segments of society, with current (past 30 days) use rates in 1996 at about 1.5 to 2 percent among those 18 to 34 (0.8 percent for ages 17 and older). Cocaine use among the heaviest users (weekly or almost weekly) did not decline significantly, but rates decreased among arrestees in 1995. In the early 1990s, fueled by abundant supplies of cheap illicit methamphetamine produced in many small laboratories, methamphetamine use began to increase in a number of cities in western, southwestern and northwestern parts of the United States. By 1996, gauged by drug tests on arrestees, that epidemic had passed its peak in those areas.

ETIOLOGY The model of drug dependence from which the DSM-IV and ICD-10 criteria were derived conceptualizes dependence as a result of a process in which multiple interacting factors influence drug-using behavior and the loss of flexibility with respect to decisions about using a given drug. Although the actions of a given drug are critical in the process, it is not assumed that all persons who become dependent on the same drug experience its effects in the same way or are motivated by the same set of factors. Furthermore, it is postulated that different factors may be more or less important at different stages of the process. Thus, drug availability, social acceptability, and peer pressures may be the major determinants of initial experimentation with a drug, but other factors such as personality and individual biology probably are more important in how the effects of a given drug are perceived. Still other factors, including the particular actions of the drug, may be primary determinants of whether drug use will progress to drug dependence, whereas still others may be important influences on the likelihood that drug use will lead to adverse effects or the likelihood of successful recovery from dependence. Figure 11.1-1 illustrates how various factors might interact in the development of drug dependence. The central element is the drug-using behavior itself. The decision to use a drug is influenced by immediate social and psychological situations, as well as by the person's more remote history. Use of the drug initiates a sequence of consequences that can be rewarding or aversive, and which, through a process of learning, can result in a greater or lesser likelihood that the drug-using behavior will be repeated. For some drugs, use also initiates the biological processes associated with tolerance, physical dependence, and (not shown in the figure) sensitization. In turn, tolerance can reduce some of the adverse effects of the drug, permitting or requiring the use of larger doses, which then can accelerate or intensify the development of physical dependence. Above a certain threshold, physical dependence is generally a distinct recurrent motive for further drug use. Sensitization of motivational systems may increase the salience of drug-related stimuli.

FIGURE 11.1-1 WHO schematic model of drug use and dependence. (Reprinted with permission from Edwards G, Arif A, Hodgson R: Nomenclature and classification of drug- and alcohol-related problems. A WHO memorandum. Bull WHO 99:225, 1981.)

For simplicity Figure 11.1-1 shows drug use alone as initiating that chain of consequences, but the choices a person makes over and over again are more complex. The decision is whether to use one drug or another or to engage in some behavior that does not involve drug use. Each of those decisions can initiate positive and negative consequences. Changes in the availability, costs, and consequences of alternative behaviors can also influence what appears to be compulsive use of a pharmacological agent. For example, patients in a methadone maintenance program who were using cocaine despite negative consequences (no take-home methadone) reduced their cocaine use when vouchers for goods and services were awarded for clean (negative for cocaine) urine specimens. Social and Environmental Factors Cultural factors, social attitudes, peer behaviors, laws, and drug cost and availability all influence initial experimentation with substances, including alcohol and tobacco. These factors also influence initial use of more socially disapproved drugs such as cocaine and opioids, but personality factors assume a more important role. Social and environmental factors also influence continued use, although individual vulnerability and psychopathology are probably more important determinants of the development of dependence. In general, the use of the less socially disapproved substances (alcohol, tobacco, and cannabis) precedes the use of opioids and cocaine, and those antecedent substances are sometimes referred to as gateway drugs. Substantial evidence indicates that consumption of alcohol and tobacco in a population can be altered by changes in their price and availability. When alcohol availability is increased by increasing the number of sales outlets or extending sale hours, consumption tends to rise. When the cost of either alcohol or tobacco is increased in relation to disposable income (e.g., by increased taxes), consumption falls. These factors even influence the behavior of dependent persons, although perhaps not to the same degree as for those who are not dependent. Availability can be altered independently of cost, and alterations can be limited to selected populations (e.g., prohibiting sale of alcohol and tobacco to those under a specific age). Social, cultural, and economic factors do not always operate synergistically but may sometimes influence consumption in opposite directions. For example, in the late

1980s increased public awareness of how alcohol use adversely affects health resulted in a decline in its consumption. That decline occurred even though alcohol was more freely available, its cost relative to income remained constant or actually decreased, and social pressures against women drinking (unless pregnant) also decreased. Illicit Drugs Social and cultural factors, including beliefs about the effects of a drug, frequently exert more influence on drug-use patterns than the laws that supposedly reflect such factors. For example, cannabis use increased among high school students from the early 1970s to 1979 and then fell steadily over the next decade, although use and possession were illegal throughout the entire 18-year period, and nothing indicates that it became more expensive or less available during the 1980s. An upward trend in use was noted from 1993 to 1997, although it never reached the peak levels of 1979. Some experts believe the decline in use seen during the 1980s was linked to changing perceptions about the toxic effects of cannabis on health. The rise beginning in the 1990s was correlated with a decline in the perception of the risk of harm from regular use. Similarly, cocaine use increased in the late 1970s, despite high prices for the drug and high risk of criminal penalties; but following several well-publicized deaths from cocaine in the mid-1980s, its use declined among high school seniors and in the general population, even as the price of the drug declined. Social and cultural factors profoundly influence the availability of illicit drugs, which in turn influences which groups in a society are most likely to become users. Currently, illicit opioids and cocaine are more available in the inner cities of large urban areas than in other parts of the country. Such availability not only influences initial and continued use but also affects relapse rates among those who seek treatment but must live in high-availability areas. When a significant number of users of illicit drugs live in one area, a subculture evolves that supports experimentation and continued use. Many of the areas in which illicit drugs are readily available are also characterized by a high crime rate, high unemployment, and demoralized school systems—all of which serve to reduce the sense of hope and sense of self-esteem associated with resistance to use and good prognosis once dependence develops. Social and educational factors also affect the likelihood for successful recovery from drug dependence; those who find satisfying alternatives are more likely to abstain from drug use. VIETNAM The experience of United States service personnel who used heroin in Vietnam provided a unique natural experiment in which the influences of availability, vulnerability, and social norms could be observed. From 1970 to 1972 high-grade heroin at very low cost was readily available to young persons separated from their families and usual social norms. Among Army enlisted personnel, about half of those who tried heroin became dependent (at least they developed withdrawal symptoms when they attempted to stop using heroin). Of those who used heroin at least five times, 73 percent became dependent. The background factors that predicted heroin use in the general civilian population—early deviant behavior, such as fighting, drunkenness, arrest, and school expulsion—also predicted drug use in Vietnam, but they were not the best predictors of relapse after the soldiers returned to the United States. Relapse was related to being white, being older, and having parents who had criminal histories or were alcoholic. Availability and Health Professionals The important role of availability is also illustrated by the repeated observation that physicians, dentists, and nurses have far higher rates of dependence on DEA-controlled substances, such as opioids, stimulants, and sedatives, than other professionals of comparable educational achievement (e.g., accountants or lawyers) who do not have such easy access to the drugs. Compared with controls, physicians appear to be four to five times as likely to take sedatives and minor tranquilizers without supervision by a professional other than themselves. Yet even in that situation other factors play a role. Physicians who had unhappy childhoods are more likely to self-prescribe than those who are healthier psychologically. Drugs as Reinforcers The belief that persons take drugs because of the subjective effects the drugs produce can be traced to antiquity. Different drugs produce distinctive subjective states, and extensive laboratory evidence shows that persons with experience can distinguish one drug class from another and can even rank different classes and doses on the basis of how much they like the effects. Yet the hold that drugs can eventually exert on a user's behavior is not entirely a function of its initial likeable or euphorigenic actions. For example, the effects of cocaine are typically described as powerfully euphorigenic, producing increased self-esteem, alertness, energy, and well-being; the effects of nicotine are more subtle, producing some mixture of alerting and relaxing; and the subjective effects of alcohol are more likely to be described as relaxing, are more variable, and appear to be more dependent on personality. Despite those differences, dependence (or addiction) can occur with each, and they appear to have shared or overlapping neural substrates for their reinforcing properties. Almost all of the drugs that are used for their subjective effects and are associated with the development of dependence induce some degree of tolerance. In some cases the tolerance to the toxic and aversive effects is more pronounced than the tolerance to the reinforcing and mood-elevating effects. For example, most opioid users quickly develop tolerance to opioid-induced nausea and vomiting. This may allow users to increase the dose and thus experience greater euphoric effects. Conversely, those who continue to experience aversive drug effects (such as severe flushing with alcohol) may be less likely to persist in using the drug and are at lower risk for developing dependence. Tolerant opioid users do not continue to self-administer opioids solely to prevent the highly aversive withdrawal phenomena. Interviews with heroin users have indicated that despite some tolerance to many of the drug's effects, they continue to experience a brief euphoric effect immediately after an intravenous injection. Among nonalcoholic sons of alcoholic fathers, intrinsic tolerance may be a marker of biological vulnerability to developing alcohol dependence. Sons of alcoholic fathers who were more tolerant to a test dose of alcohol were far more likely to have developed alcohol dependence at 8-year follow-up than those who were less tolerant. With a few notable exceptions, animals in experimental situations will self-administer most of the drugs that humans tend to use and abuse. Included among the drugs are µ and d opioid agonists, cocaine, amphetamine and amphetamine-like agents, alcohol, barbiturates, many benzodiazepines, a number of volatile gases and vapors (e.g., nitrous oxide and ether), and PCP. Nicotine is also self-administered, although under more specialized conditions; cannabinoid self-administration has been difficult to demonstrate; and LSD-like drugs are not generally found to be reinforcing. Biological Substrates Knowledge about the neurobiology of drug reinforcement and the mechanisms underlying tolerance and dependence has increased substantially. For opioids (and probably for other drugs as well) the neural systems involved in drug reinforcement and self-administration are distinct from those responsible for some of the other actions (e.g., opioid-induced analgesia) as well as from those that mediate the more visible signs of the withdrawal syndrome characteristic for that drug class. The pathways critical for the reinforcing actions of a number of dependence-producing drugs, such as opioids, amphetamine, cocaine, and to some degree nicotine and alcohol, have their origins in dopaminergic neurons with cell bodies in the ventral tegmental area and projections to the nucleus accumbens and the related structures that make up the “extended amygdala.” This comprises several neural structures receiving input from the limbic cortex, hippocampus, lateral amygdala and midbrain, and projecting axons to the ventral pallidum, the medial ventral tegmental area and the lateral hypothalamus. The medial part of the nucleus accumbens is a particularly important site; dopamine release here is critical for the reinforcing effects of cocaine and amphetamines. It is also important for the reinforcing effects of opioids, but there are opioid receptors on neurons in the nucleus accumbens, and opioids can exert reinforcing effects at that site even when the dopaminergic terminals are destroyed. Evidence suggests that such drugs as nicotine, cannabinoids, and alcohol also activate dopaminergic pathways linked to the nucleus accumbens. Some researchers have proposed that all positive reinforcement, including the reinforcement associated with food reward and sex, critically depends on this dopaminergic circuit. Dopamine release from mesolimbic dopaminergic neurons may play more than one role in the genesis of drug seeking and drug dependence. Dopamine release has been postulated to facilitate learning which events and behaviors lead to important consequences for the organism and to alert the organism to pay greater attention to such events. In this way, drug-induced dopamine release leads to a greater salience of drug-using opportunities and is linked to wanting and craving. However, the diverse categories of drugs that activate the mesolimbic dopaminergic system do so by distinct mechanisms, and most have actions on many other neural systems. Reinforcing mechanisms are briefly described in the chapters devoted to specific drugs; however, only a few examples are given. The ventral tegmental area dopaminergic neurons have both nicotinic and g-aminobutyric acid (GABA) receptors. These neurons normally are inhibited by GABAergic activity. The GABAergic neurons acting on the ventral tegmental area express µ- and d-opioid receptors. When these receptors are activated by µ opioids, GABAergic transmission is inhibited and the dopaminergic ventral tegmental area neurons become more active and release dopamine in the nucleus accumbens. However, opioids can also act directly on neurons in the nucleus accumbens, independent of dopamine action. As a reinforcing drug, cocaine acts primarily at the nerve endings of the serotonergic, dopaminergic, and noradrenergic neurons. When transmitters are released from these neuron into the synapse, they are transported back into the nerve endings by transporter proteins. By occupying these transporter sites, cocaine prevents the reuptake of the transmitters, thus increasing their concentration in the synapse. Cocaine's binding to the dopamine transporter is primarily responsible for its reinforcing effects, but the actions on other neurotransmitters also influence its subjective effects. Amphetamine too, increases dopamine levels at the synapse and binds to the dopamine transporter to some degree. But amphetamine actions at the transporter are not as important as its major action, which is to displace dopamine and norepinephrine from their storage sites in the neuron and thereby lead to their release. Alcohol is no longer believed to act like a general anesthetic, altering neuronal membranes. Instead, at clinically relevant concentrations its actions may be exerted more selectively on specific receptors and neurotransmitter systems. At clinically relevant concentrations these actions include enhancing the inhibitory action of GABAergic neurotransmitters (by increasing the sensitivity of the GABA receptor) and reducing the excitatory actions of glutamatergic neurotransmitters (by altering

the response of the N-methyl D-aspartate [NMDA] receptors). By its blocking actions at the NMDA receptor, ethanol can indirectly alter the release of other neurotransmitters (e.g., serotonin, dopamine, norepinephrine, glutamate, aspartate, and GABA). Low doses of alcohol increase dopamine levels in the nucleus accumbens and elevate brain serotonin concentration. Various regions of the brain differ in their sensitivity to these actions of ethanol. The endogenous opioid system may be involved in some aspects of the mood-elevating effects of alcohol, since the opioid antagonist naloxone reduces alcohol self-administration in animals and the antagonist naltrexone reduces relapse rates in treated alcoholics. Mesolimbic dopaminergic neurons have multiple nicotinic cholinergic receptors on their cell bodies and terminals in the nucleus accumbens. When activated, these receptors increase dopamine release. Interestingly, regular exposure to tobacco smoke containing nicotine may be more reinforcing than nicotine itself because other chemical entities in tobacco inhibit brain monoamine oxidase type A (MAO A) and MAOB, which are involved in the regulation of intraneuronal stores of dopamine. This inhibition increases the amount of dopamine available for release when the dopaminergic neurons are activated. Drugs can also be reinforcers by terminating aversive states; some of these actions involve dopaminergic systems, but others do not. Some researchers argue that compulsive drug use can be explained on the basis of the positive reinforcing effects of drugs without any need to invoke alleviation of withdrawal distress or any obvious source of antecedent pain or dysphoria. Furthermore, they argue, craving is primarily associated not with cues that evoke withdrawal but with those that evoke memories of positive reinforcement (euphoria). However, evidence now indicates that even when there are no obvious and dramatic withdrawal symptoms (e.g., cocaine, nicotine), adaptive changes in the reward system result in a relative dopaminergic deficiency state (measurable as decreased dopamine levels in the nucleus accumbens) when drug use is stopped or its action ceases. This deficiency state is experienced as dysphoria or anhedonia. Quite often the same drug-using behavior that terminates this dysphoria moves the system to a hyperdopaminergic state associated with euphoria. In short, the behaviors associated with chronic drug use are typically driven by both the avoidance of dysphoria (negative reinforcement) and the pursuit of euphoria (positive reinforcement). The sensitivity of neural systems to reinforcing drugs such as cocaine and opioids is enhanced by corticosteroids. In animal models, a variety of stresses acting through release of corticotropin-releasing factor (CRF) and the hypothalamic pituitary-adrenal axis can sensitize neural systems and trigger reinitiation of drug taking. There is ample clinical evidence that such stresses can act similarly in drug-dependent individuals immediately following withdrawal and for long periods thereafter. In addition, some drugs may sensitize neural systems to the reinforcing effects of the drug. Learning and Conditioning Drug use, whether occasional or compulsive, can be viewed as behavior maintained by its consequences. Any event that strengthens an antecedent behavior pattern can be considered a reinforcer of that behavior. In that sense certain drugs reinforce drug-taking behavior. Drugs can also reinforce antecedent behaviors by terminating some noxious or aversive state, such as pain, anxiety, or depression. In some social situations the use of the drug, quite apart from its pharmacological effects, can be reinforcing if it results in special status or the approval of friends. Social reinforcement can maintain drug use until the effects of primary reinforcement or reinforcement by alleviation of withdrawal symptoms come into play. Each use of the drug evokes rapid positive reinforcement, either as a result of the rush (the drug-induced euphoria), alleviation of disturbed affects, alleviation of withdrawal symptoms, or any combination of these effects. In addition, some drugs may sensitize neural systems to the reinforcing effects of the drug. With short-acting substances, such as heroin, cocaine, nicotine, and alcohol, such reinforcement occurs several times a day, day in and day out, creating powerfully reinforced habit patterns. Eventually, the paraphernalia (needles, bottles, cigarette packs) and behaviors associated with substance use can become secondary reinforcers as well as cues signaling availability of the substance, and in their presence, craving or a desire to experience the effects increases. With socially acceptable substances, such as tobacco, use becomes so woven into the matrix of daily functioning that some users are reminded of the substances when performing ordinary tasks. Stresses can also act as cues that induce drug taking, particularly in the postwithdrawal period. Classical Conditioning In addition to the operant reinforcement of drug-using and drug-seeking behaviors, other learning mechanisms probably play a role in dependence and relapse. Opioid and alcohol withdrawal phenomena can be conditioned (in the Pavlovian or classic sense) to environmental or interoceptive stimuli. Such conditioning has been demonstrated in both laboratory animals and abstinent and methadone-dependent human volunteers. For a long time following withdrawal (from opioids, nicotine, or alcohol), the addict exposed to environmental stimuli previously linked with substance use or withdrawal may experience conditioned withdrawal, conditioned craving, or both. The increased feelings of craving are not necessarily accompanied by symptoms of withdrawal. The most intense craving is elicited by conditions associated with the availability or use of the substance, such as watching someone else use heroin or light a cigarette or being offered some drug by a friend. Some workers now believe that the cues that induce memories of drug-induced euphoria are more important for stimulating craving and in predisposing to relapse than either protracted or conditioned withdrawal. Those learning and conditioning phenomena can be superimposed on any preexisting psychopathology, but preexisting difficulties are not required for the development of powerfully reinforced substance-seeking behavior. Withdrawal Syndromes and Negative Reinforcement Although positive reinforcement is a powerful etiological factor in the genesis of cocaine, amphetamine, and (in some cases) opioid dependence, aversive withdrawal phenomena and negative reinforcement may be equally important influences for a number of other drugs and dominant influences for others. One example of this is seen in most persons who become dependent on benzodiazepines taken in the course of treatment for anxiety syndromes. When drug use is interrupted, some seem to experience a reappearance of the original symptoms; others have new distressing symptoms indicating withdrawal. The use of benzodiazepines alleviates both kinds of aversive states. In either case the drug is acting as a negative reinforcer in perpetuating drug use. Benzodiazepines can induce euphoria in alcoholic patients or in persons with histories of sedative abuse, but they are not reliably euphorigenic in normal, nonalcoholic persons. Benzodiazepine anxiolytic agents may induce euphoria in nondependent, nonanxious persons, but such instances are rare relative to the number of those who experience only relief of anxiety. In most clinical situations, even among users of highly euphoric illicit drugs, the distinction between positive and negative reinforcing effects does not exist. The alcoholic, the heavy smoker, and the heroin user may experience, simultaneously or sequentially, relief of withdrawal, a sense of ease, and perhaps alleviation of dysphoria and depression. With intravenous drugs there may also be a sudden rush of intense pleasure. Long-Lasting Changes Associated With Chronic Drug Use After long-term use, most drugs of abuse produce adaptive changes in the brain that are manifested as acute and chronic withdrawal syndromes when drug use ceases. How these changes are produced, how long they persist after cessation of drug use, and how they contribute to relapse are still being explored. But much progress has occurred, as is illustrated by several examples of recent developments. Tolerance and dependence on opioids involves several mechanisms. Opioid agonist binding to the opioid receptors results in an inhibition of adenylyl cyclase and lower intracellular cyclic adenosidine monophosphate (cAMP) concentrations. Long-term exposure elicits compensatory upregulation of the cAMP pathway, internalization of µ- and d-receptors, and a decrease in the number of G proteins, which couple the receptors to the second messengers and ion channels. Upregulation of adenylyl cyclase is mediated by the transcription factor cAMP response element–binding protein (CREB), which also plays a role in the generation of distinct and persistent Fos-like proteins, which are also thought to be involved in tolerance. As a result of upregulation of cAMP, GABAergic neurons innervating the ventral tegmental area become hyperactive when opioids are withdrawn, thus inhibiting dopaminergic neurons. Such a mechanism may account, in part, for the dysphoria and anhedonia of opioid withdrawal. In addition, chronic opioid use reduces the size of dopamine neurons in the ventral tegmental area; increased production of dynorphin may also serve to inhibit dopaminergic activity at the ventral tegmental area and nucleus accumbens. The glutamatergic system is also involved in opioid adaptation, since NMDA receptor sensitivity is altered by opioids and NMDA antagonists can alter the development of opioid tolerance and physical dependence. With chronic alcohol use, affected neurons develop adaptive changes that include, among a number of others, supersensitivity or increased numbers of NMDA receptors. When the alcohol is withdrawn the actions of excitatory neurotransmitters at supersensitive NMDA receptors are postulated to produce the hyperexcitability of alcohol withdrawal, including hyperactivity in noradrenergic systems and glutamate-induced neuronal excitotoxicity. Alcohol-dependent patients tested 1 week and 1 month after cessation of alcohol use had cerebrospinal fluid with substantially lower concentrations of GABA and substantially higher concentrations of the excitatory transmitters glycine aspartate, glutamate, and N-acetylaspartylglutamate (NAAG) than that of healthy controls. Although these changes may be trait markers rather than consequences of long-term alcohol use, they are what might be expected to result from withdrawal of alcohol after adaptive changes have occurred. Most agents currently used to treat alcohol withdrawal act directly or indirectly at GABA receptors, and perhaps those that act at NMDA sites may provide alternative or even superior therapeutic agents. Nicotine tolerance may involve desensitization of nicotinic receptors. However, chronic nicotine use increases the number of nicotinic cholinergic receptors, and the mechanisms underlying the nicotine withdrawal syndrome remain unclear. From the symptoms, which include craving, inability to concentrate, irritability, increased appetite, dysphoria, and (sometimes) depression, some hypoactivity in dopaminergic systems is likely. Given the many other actions of nicotine on learning, attention, arousal, and appetite, changes in systems in addition to the mesolimbic are probably also involved.

Cocaine and amphetamines can induce tolerance, dependence, and sensitization, depending in part on whether exposure is continuous or intermittent. One way to determine the contribution of negative reinforcement to the motivation to continue using a substance or to relapse after withdrawal is to introduce agents that can modify withdrawal syndromes or aversive states. Abundant evidence shows that when psychological interventions are held constant, noninhaled nicotine (delivered by transdermal patches [Nicoderm] or nicotine gum [Nicorette]) significantly increases the probability that smokers trying to quit will be successful. Neither nicotine gum nor transdermal patches produce positive reinforcing effects, but they do alleviate aspects of the nicotine withdrawal syndrome. Thus, it is reasonable to infer that although the symptoms may not be life threatening, the avoidance of nicotine withdrawal plays a significant role in continued smoking and relapse. However, evidence suggests that for some, nicotine (or some other component of tobacco) controls negative effects other than those usually associated with withdrawal. Persons with histories of major mood disorder are more likely to become regular smokers if they try cigarettes and may experience symptoms of depression when they try to stop smoking; those symptoms are suppressed by returning to smoking. Heroin addicts treated with oral methadone or sublingual buprenorphine (Subutex) experience a reduction in opioid withdrawal symptoms but little or no euphoric effects from those agents. Yet, such treatment dramatically reduces elf-administration of heroin. Such findings support the view that acute and protracted opioid withdrawal (or opioid suppression of aversive affects) is an important factor in the perpetuation of heroin use and relapse after withdrawal. Similarly, acamprosate, a structural analogue of glutamate is postulated to reduce relapse in alcoholics following alcohol withdrawal by dampening the hyperexcitability in the glutamatergic system. Conditioned Withdrawal and Stress Sensitivity In addition to the direct contribution of withdrawal phenomena to the perpetuation of drug use are the indirect effects exerted through learning mechanisms. The regular recurrence of withdrawal-induced aversive states provides ample opportunity for those states to become linked through learning to environmental cues and other mood states, and the rapid relief of withdrawal by drug use results in repeated reinforcement of drug-taking behavior. Long after there are measurable manifestations of acute withdrawal, certain moods or environmental cues can evoke components of the original withdrawal state along with urges to use the drug again. Considerable evidence shows that in former opioid addicts, stress can trigger both craving and relapse, and dysregulation of the hypothalamic-pituitary-adrenal axis persists for long periods after drug cessation. How long withdrawal phenomena, stress sensitivity, or both continue to contribute to risk of relapse is not clear. Substantial evidence supports a withdrawal syndrome period for alcohol, opioids, and certain sedatives with subtle disturbances of mood, sleep, and cognition that persists for many weeks or months after the acute syndrome subsides. Whether the dysregulation of the hypothalamic-pituitary-adrenal axis is causally related to protracted withdrawal or has a similar time course is still uncertain. Biological Factors—Vulnerability The children of alcoholic parents are at higher risk for developing alcoholism and drug dependence than are children of nonalcoholic parents. Dependence on other drugs also shows a familial pattern. The increased risk is partly due to environmental factors (parental modeling, neglect, early child abuse), but genetic factors are also important. Numerous studies of laboratory animals have revealed genetically transmitted differences in the reinforcing effects of alcohol and various drugs such as cocaine and opioids and show that genetic factors powerfully influence sensitivity to toxic effects. The evidence for genetic factors in human vulnerability to alcoholism and other drug dependence is derived most convincingly from twin and adoption studies, but family studies are also revealing. Several studies of twins have found a higher concordance rate for alcoholism among identical twins than among fraternal twins. Although identical twins are generally believed to have more social contact than fraternal twins, when the effects of environmental factors are adjusted statistically, genetic factors are still found to have a major influence on the likelihood of becoming dependent. Indeed, in one population-based twin study 48 to 58 percent of the variation in liability to dependence was attributable to genetic factors; the remainder was due to general environmental influences not shared by family members. In studies of 3372 Vietnam-era veteran twin pairs, the concordance rates for dependence on at least one illicit drug were higher for monozygotic twins (26.3 percent) than for dizygotic (16.5 percent) twins. Generally, overall rates of dependence did not differ among these veterans and contemporary civilians. Biometric modeling identified both common (shared) and drug-specific genetic vulnerability factors as well as general and drug-specific effects of family and nonfamily environment. In the common vulnerability models, 31 percent of the variance for common (shared) vulnerability was due to additive genetic factors, 25 percent to family environmental effects, and 44 percent to nonfamily environmental effects. The importance of common (shared) genetic factors versus drug-specific genetic factors varies considerably for different categories of drugs. For marijuana, stimulant, and sedative abuse, common genetic vulnerability factors accounted for most of the genetic variance, with unique specific genetic factors accounting little. For psychedelics, no specific genetic influence was found. For heroin, 54 percent of the total variance was due to genetic factors, with 38 percent (70 percent of total genetic variance) contributed by unique genetic factors and only 16 percent by common (shared) ones. Another analysis of data from this group of veterans showed that both genetic and environmental factors influenced the initiation of cigarette smoking, but genetic effects accounted for 70 percent of the variance in the persistence of smoking for those who became regular smokers. This study, which is consistent with other genetic studies of smoking, found the genetic contribution to the persistence of smoking to be as great as or greater than the genetic contribution in the genesis of other psychiatric disorders, including alcoholism. Twin studies in women have revealed strong genetic contributions to the use of caffeine and development of caffeine tolerance, dependence, and withdrawal. Family studies also point towards general and drug-specific vulnerability factors. In a study of alcoholic probands and their siblings, about 50 percent of the brothers and 25 percent of the sisters met lifetime criteria for alcohol dependence. Compared with controls, these siblings also showed higher rates of tobacco, cocaine, and marijuana use, but the siblings of subjects who were dependent on alcohol and another drug, (presumably a more severe form of dependence), were not more likely to develop alcoholism than siblings of subjects who were dependent only on alcohol. However, siblings of probands who were dependent on both alcohol and marijuana had an elevated risk for marijuana dependence; siblings of probands dependent on alcohol and cocaine were more likely to become cocaine dependent. Statistical analysis that controlled for access to the drugs still showed specific family clustering. Studies of boys adopted soon after birth have shown higher rates of alcoholism among those whose biological fathers were alcoholics than among those whose biological fathers were not. Some adoption studies pointed toward subtypes of alcoholism among men: one is a later-onset disorder that is less severe and far more sensitive to environmental factors (type I) and the other is associated with early onset, antisocial behavior and criminality in the biological fathers, and a stronger genetic basis for the increased vulnerability (type II). The hypothesis that two genetically distinct types of alcoholism (type I and type II) exist has been criticized on the grounds that it is essentially a relabeling of the older primary-secondary categorization. In the latter, alcohol-dependent persons who do not have antisocial personality disorder are designated as having primary alcoholism; those who first exhibit antisocial personality disorder and later develop alcoholism are designated antisocial personality disorder with secondary alcoholism. Also, several groups have been unable to use the type I and type II criteria to categorize patients with alcohol dependence accurately in clinical studies. However, arguments about the validity of the type I–type II categorization do not diminish the importance of genetic factors in vulnerability to developing alcohol dependence. The results of a large-scale efforts to identify the genes that contribute to vulnerability to alcoholism are now emerging. As many as one third of alcohol-dependent persons have no family history of the disorder. Men are more likely to develop alcoholism than are women (fourfold to fivefold in the United States). This is true across every culture studied, probably reflecting, in part, social sanctions on drug use and deviant behavior by women. But it is also postulated that women are less likely to drink heavily because they are less tolerant to alcohol. Women who do drink heavily run the same risk of developing alcoholism as men who drink heavily, and women who use illicit drugs are about as likely to develop dependence as men who use such drugs. In some, but not all studies alcohol-dependent persons are at far higher risk for developing other varieties of drug dependence. A more consistent finding is that drug-dependent persons also are at high risk for alcoholism and often have a family history of alcoholism. Such findings are consistent with data from the twin studies that have found general as well as drug-specific vulnerability factors. Most researchers believe that no single gene will be found to account for the complexities of inherited risk for drug and alcohol dependence. Some genetic factors may not increase vulnerability to alcoholism but decrease it. A genetically determined variation in the activity of enzymes that metabolize alcohol (alcohol dehydrogenase and aldehyde dehydrogenase [ALDH]), common among some Asian groups, results in high levels of acetaldehyde in response to alcohol ingestion. The effect is to cause alcohol flush reaction and to exert some deterrent effect on alcohol ingestion. Alcoholism is lower among many Asian groups than among whites. Further, Asians with alcoholism are much less likely to have the inactive form of the ALDH enzyme. Biological and Behavioral Differences Studies exploring how persons with and without family histories of alcoholism might differ have involved measures of personality, drug-use and alcohol-use patterns, psychomotor and cognitive performance, electrical activity of the brain, endocrine responses to challenges with alcohol and other substances, as well as measures of receptor numbers and affinities and enzyme activities (e.g., MAO) in peripheral tissues (e.g., blood platelets and lymphocytes). One finding that has been replicated is that under some conditions, the electrical response of the brain that occurs about 300 ms after a sensory stimulus (the P300 wave) has a smaller amplitude in nondrinking sons and daughters of alcoholic fathers than in control subjects without family histories of alcoholism. The decreased amplitude is believed to reflect a decreased capacity to recognize and interpret complex environmental stimuli. Most studies have found

no differences in intelligence among subjects with and without family histories of alcoholism. However, the results of personality studies are conflicting; some find no differences and others find greater impulsivity, adventurousness, and sensation seeking among those with a positive family history. Studies of the drinking patterns of adolescent and young adult sons of alcoholic persons also have not yielded consistent results; some (but not all) studies show that sons of alcoholic parents are heavier drinkers. Other studies have compared the subjective, motoric, and endocrine responses of young men with and without family histories of alcoholism following challenge exposures to alcohol and other potentially euphoriant drugs (such as benzodiazepines). Sons of alcoholic fathers seem to be more tolerant to the intoxicating effects of modest doses of alcohol, and in some (but not all) studies, higher doses of alcohol produced smaller changes in their prolactin and cortisol concentrations. Furthermore, one study found that sons who had smaller responses to test doses of alcohol at age 20 (i.e., were more tolerant) were fourfold more likely to have developed alcoholism 8 years later. Another study of sons of alcoholic parents found that those who had exhibited smaller electroencephalographic (EEG) alpha frequency responses to alcohol were more likely to be alcohol dependent at 10-year follow-up. The results of studies using benzodiazepine challenges are also not consistent; one showed a greater euphoric response to alprazolam (Xanax) in sons of alcoholic parents, and another showed no difference between positive and negative family-history groups after a dose of diazepam. A number of studies have shown that conduct disorder and early childhood aggression are associated with a substantial increase in the likelihood of early involvement with illicit drug use and development of dependence on alcohol and illicit drugs. Considerable evidence supports a role for both genetics and environmental factors in the development of conduct disorder. Antisocial personality disorder represents an independent additional risk factor for addictive disorders. The effects of antisocial personality disorder and family history of an substance-related disorder appear to be additive rather than synergistic. It seems possible that in some of the studies of children and young people at high risk for later drug dependence, the electrophysiological differences, cognitive deficits, and personality differences reflected the presence of conduct disorder or antisocial personality disorder rather than a family history of alcoholism per se. Psychodynamic Factors and Psychopathology Early psychoanalytic formulations postulated that drug users, in general, suffered from either a special form of affective dysregulation (tense depression) that was alleviated by drug use or from a disorder of impulse control in which the search for pleasure was dominant. More-recent formulations postulate ego defects, which are evinced by the addict's inability to manage painful affects (guilt, anger, anxiety) and to avoid preventable medical, legal, and financial problems. The newer formulations postulating ego defects are to some degree the older formulations with a modest change in terminology that gives greater weight to the inability to cope with painful affects than to the intensity or abnormality of the affects per se. It is postulated that some substances pharmacologically and symbolically aid the ego in controlling those affects and that their use can be viewed as a form of self-medication. For example, it has been suggested that opioids help users control painful anger, that alcohol helps alcoholics control panic, and that nicotine may help some cigarette smokers control symptoms of depression. Although it is conceded that some of those observations may reflect problems produced by long-term use, the psychodynamic perspective is that the psychopathology is the underlying motivation for initial use, dependent use, and relapse after a period of abstinence. However, traditions of passivity and uncovering techniques derived from the psychoanalysis of neurosis are poorly suited to the treatment of most drug addicts. Further, some addicts have great difficulty differentiating and describing what they feel, a difficulty that has been called alexithymia (i.e., no words for feelings). Family Dynamics One family member's substance abuse is often influenced by substance-using behaviors of others in the family, and these complex interrelationships can profoundly affect their lives. An understanding of the relationships among substance-using patients and their families is relevant for understanding the etiology of substance dependence and its treatment and for helping other family members to cope with problems associated with the substance-using behavior. More has been written about the families of alcohol-dependent persons and heroin users than about families affected by users of other drugs. Similarities between the family dynamics in these two prototypical dependencies have led researchers and clinicians to assume that certain general principles apply to all varieties of substance dependence. The observation that alcoholism is commonly found in the families of those seeking treatment for other types of dependence, that alcohol-dependent persons are often dependent on other substances as well, and that those addicted to illicit drugs are often alcoholic suggests that there are common features among families with an addicted member. However, there are few data to suggest that the families of those dependent on tobacco or benzodiazepines are as dysfunctional as those affected by alcohol, opioids, or cocaine. It is not always clear to what degree one family member's behavior causes the substance-using behavior of another or is primarily a response to that behavior. Some writers emphasize that the addiction is a symptom that provides a displaced focus for conflict among other family members and that the user (the designated patient) may be playing a role in maintaining the homeostasis of a dysfunctional family. At the same time, addiction often arises in families in which one or both parents (and sometimes grandparents) have drug or alcohol problems and other psychopathology. Some characteristics commonly observed both in families of persons who are alcohol dependent and of those addicted to illicit drugs are multigenerational drug dependence; a high incidence of parental loss through divorce, death, abandonment, or incarceration; overprotection or overcontrol by one parent (usually the mother), whose life is inordinately dependent on the behavior of the addicted offspring (symbiotic relationships); distant, cold, disengaged, or absent father (when the father is alive); defiant drug-using child, who appears to be engaged with peers but remains unusually dependent on the family well into adult life (pseudo-independence). The actual family dynamics are difficult to characterize because the family members' self-reports about their relationships do not reliably correspond to what outsiders observe. Such families typically do not describe themselves in the way that family therapists see them. Some workers have proposed that unresolved family grief plays a role in the genesis of drug addiction in a family member and that such families cannot deal effectively with separation because of previous losses. Despite the pathological interdependence between the addict and other family members, the addict is often described as passive, dependent, withdrawn, and unable to form close relationships. Despite all the apparent pathology found in families, in many instances the family brings the substance user into treatment, and the patient often believes that it is the family that is most likely to be helpful in recovery. Furthermore, clinicians now generally believe that involving families in treatment is important, if not essential, to effective intervention. One aspect of treating families is dealing with the tendency of some members to shield the patients from the consequences of their substance use, a behavior usually labeled by clinicians as “enabling” but usually experienced by the family member as loving, supporting, accepting, and protecting. A variation on family therapy, sometimes called network therapy, involves enlisting family members and close friends as allies of the therapist to provide social support and reinforcement of drug-abstaining behaviors. The persons selected to fulfill this role function as part of a treatment team rather than as patients. CODEPENDENCE The terms “coaddiction,” “coalcoholism,” or more commonly “codependency” or “codependence” have recently come into vogue to designate the behavioral patterns of family members who have been significantly affected by another family member's substance use or addiction. The terms have been used in various ways, and there are no established criteria for codependence, a concept that some writers have expanded far beyond its origins to encompass any personality disorder that involves difficulty in expressing emotions. However, many have criticized the expanded concept of codependence as a largely invalid notion based solely on anecdote. The following summary of some characteristics frequently described as aspects of codependence is not meant to imply the validity of a unitary syndrome. Enabling Enabling was one of the first and more agreed upon characteristics of codependence or coaddiction. Sometimes family members feel that they have little or no control over the enabling acts. Either because of the social pressures for protecting and supporting family members or because of pathological interdependencies, or both, enabling behavior often resists modification. Other characteristics of codependence include an unwillingness to accept the notion of addiction as a disease. The family members continue to behave as if the substance-using behavior were voluntary and willful (if not actually spiteful) and the user cares more for alcohol and drugs than for the members of the family. This results in feelings of anger, rejection, and failure. In addition to those feelings, the family members may feel guilty and depressed because the addict, in an effort to deny loss of control over drugs and to shift the focus of concern away from their use, often tries to place the responsibility for such use on the other family members, who often seem willing to accept some or all of it. Denial Family members, like the substance users themselves, often behave as if the substance use that is causing obvious problems were not really a problem; that is, they engage in denial. The reasons for the unwillingness to accept the obvious vary. Sometimes denial is self-protecting, in that the family members believe that if there is a drug or alcohol problem, then they are responsible. Like the addicts themselves, codependent family members seem unwilling to accept the notion that outside intervention is needed and, despite repeated failures, continue to believe that greater will power and greater efforts at control can restore tranquility. When additional efforts at control fail, they often attribute the failure to themselves rather than to the addict or the disease process, and along with failure come feelings of anger, lowered self-esteem, and depression. Other Problems Some clinicians have reported high levels of somatic disorders, such as ulcers, colitis, and migraine, among family members of alcoholic persons and addicts and have attributed those illnesses to stress or a somatic expression of the feelings engendered by trying to cope with the family member's addiction. However, in light of the findings that there may be a genetic basis for somatization disorders among the daughters of certain subtypes of alcoholic persons, it is not clear that all of the illnesses seen among the family members of substance users are responses to the stresses of living with an addict.

Other Factors There are other factors that influence the pattern of use and cessation of any given substance. For example, the decision not to use a substance also has consequences that can be aversive or reinforcing, and evidence indicates that when the rewards of not using the substance are high, the likelihood of use is reduced. In addition, many of the substances associated with dependence act directly on systems that subserve both motivation and decision making, raising questions about whether use is always influenced solely by its consequences (learning processes). The cognitive processes and skills that would ordinarily subserve decision-making appear to be impaired by alcohol, barbiturates, cannabis, and several other categories of self-administered agents. Thus, whereas substance use is influenced by learning, the substances also alter the brain itself. This suggests additional problems and possibilities for intervention. Evidence is accumulating that limited cognitive skills reduce the likelihood of successful recovery from substance use and that coping skills can help a person avoid or deal with aversive affective states, environmental stresses, and situations that are associated with a high risk for substance use. Other factors that influence the course of substance use and dependence are difficult to operationalize or teach or prescribe, but they deserve mention. Studies of the natural history of substance use indicate that recovery is powerfully influenced by the support of family and friends. Many persons report that hope, faith, formal religious affiliation, or the sustaining love of some significant person was more important to their recovery than any specific treatment. Multiple Factors The biopsychosocial general model of substance dependence presented here does not attempt to assign a weight or special significance to any one factor or interaction. The implication is that for different categories of drugs, different factors may play more or less powerful causal roles in perpetuating substance use or facilitating relapse. For example, positive reinforcing effects may be more important for the development of cocaine dependence, whereas acute and protracted withdrawal phenomena may be more important in the return to opioid use following withdrawal. Even with the same substance, different factors may be more or less important for different persons. Thus, the emergence of depressive symptoms may make it difficult for some cigarette smokers to quit, particularly those with a history of major depressive disorder, and those persons may be helped by antidepressants. Such a multifactorial model implies that certain treatments or interventions may be more effective for one substance category than another and that even among persons using the same substances, different treatments may be indicated. Figure 11.1-1 also implies that the notion of dependence is not a property of any one element but an abstraction inferred from the relations among the elements of the system. While it is convenient (and required by DSM-IV) to see dependence as a disorder located within a person, any interpretation that overemphasizes one part of the system, whether the biology of the person, social influences, or behavior, is missing part of the nature of dependence. Comorbidity Comorbidity is the co-occurrence of two or more psychiatric disorders in a single patient. A high prevalence of additional psychiatric disorders is found among persons seeking treatment for alcohol, cocaine, or opioid dependence. Although opioid, cocaine, and alcohol abusers with current psychiatric problems are more likely to seek treatment, it should not be assumed that those who do not seek treatment are free of comorbid psychiatric problems; such persons may have social supports that enable them to deny the impact that drug use is having on their lives. Two large epidemiological studies have shown that even among representative samples of the population, those who meet the criteria for alcohol or drug abuse and dependence (excluding tobacco dependence) are far more likely to meet the criteria for other psychiatric disorders also. In the NCS, 51 percent of those who met the criteria for a lifetime addictive disorder received at least one additional mental disorder diagnosis; in the earlier ECA study, the comparable figure was 38 percent. In the ECA study, among those diagnosed with drug dependence the most common additional diagnosis was alcohol abuse-dependence, followed in frequency by antisocial personality disorder, phobic disorders, and major depression for men and phobic disorders, major depression, and dysthymia for women. Almost every psychiatric diagnosis was more common among those who met the criteria for drug dependence, with notable increases in odds ratios for alcoholism, antisocial personality disorder, and mania among women, and for mania, antisocial personality disorder, and dysthymia among men. Both men and women with drug abuse-dependence are at a substantially higher risk for schizophrenia. The extent of comorbidity among individuals in the ECA study is illustrated in Figure 11.1-2.

FIGURE 11.1-2 Lifetime prevalence of comobid mental and addictive disorders in the United States, combined community and institutional five-site Epidemiologic Catchment Area data, standardized to the U.S. population. (Reprinted with permission from Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK: Comorbidity of mental disorders with alcohol and other drug abuse. JAMA 264:2511, 1990.)

In general, the probability of comorbidity is higher for those with a lifetime diagnosis of an opioid or cocaine disorder than for those with a diagnosis of cannabis abuse. Among people in prison the comorbidity rates were even higher than in the general population; addictive disorders were found in 92 percent of prisoners with schizophrenia, 90 percent of those with antisocial personality disorder, and 89 percent of those with bipolar disorders. Among persons with mental disorders seeking treatment in psychiatric specialty settings, 20 percent have a current substance abuse disorder diagnosis. The findings from the NCS largely confirm the observations of the ECA study that those with substance use disorders are substantially more likely to experience other mental disorders and that those with other mental disorders are far more likely to develop substance use disorders. The NCS also underscored the finding that although 52 percent of respondents had never experienced any DSM-III-R disorder and 21 percent had one such disorder, 13 percent had two disorders and 14 percent had three or more disorders. Furthermore, the 12-month prevalence of a disorder was more likely among those with more than one disorder: 59 percent of all of 12-month disorders occurred in the 14 percent with a lifetime history of three or more disorders, and 89 percent of severe 12-month disorders occurred in the same group. These findings describe rather than explain comorbidity. They do not shed much light on the question of whether, or in which cases, drug use is at least initially an adaptive effort at self-medication, or whether those with a variety of psychiatric disorders are less able to cope with the effects of substance use and so are more likely to become dependent. It is also not clear whether psychiatric disorders increase the vulnerability to drug abuse and drug dependence or whether some common factor contributes to both. In some cases, however, there does appear to be a causal link between drug use and some psychiatric disorders. For example, evidence indicates that substance abuse (especially alcohol) can cause or increase the risk for depressive disorder; cocaine can increase the frequency of panic disorder; and cannabis, cocaine, and amphetamine use can aggravate or precipitate schizophrenic symptomatology. Some of these are drug-induced disorders (particularly some of the depressive symptoms seen in alcoholics) and clear with cessation of alcohol use. However, some psychiatric disorders (e.g., mood disorder and antisocial personality disorder) often antedate substance use and can be viewed as risk factors or predictors for substance abuse and dependence. This is particularly true of conduct disorder adult antisocial behavior, in which the symptoms often begin before the onset of problematic drug use. The NCS found that the odds of developing alcohol or drug dependence increased fivefold in the presence of conduct disorder without adult antisocial behavior and 10- to 14-fold if only adult antisocial behavior or both conduct disorder and antisocial behavior were present. Of the Axis I disorders, bipolar I disorder is more strongly related to dependence on alcohol or drugs than any other mood or anxiety disorder. In general, about 24.5 percent of those with a 12-month addictive disorder had a mood disorder as well, and 35.6 percent had an anxiety disorder. Overall, 42.7 percent of those with a 12-month addictive disorder had at least one 12-month Axis I mental disorder. In terms of lifetime disorders, 41 to 65.5 percent of those with a lifetime addictive disorder have a lifetime history of at least one Axis I mental disorder, while 51 percent of those with one or more lifetime mental disorders (Axis I or II) have a history of one or more addictive disorders. For lifetime conduct disorder or adult antisocial behavior, the rate of lifetime substance use disorder rises to 82 percent. Although the possibility of recall bias exists, those with both an affective and an addictive disorder usually report that depression began earlier than substance use. However, temporal relationship between two disorders does not prove causality, even when the development of the first disorder is a predictor of both the likelihood and course of the subsequent disorder. There is the possibility, as has been suggested for smoking and depression, that both disorders are linked to some third common factor. In the NCS, a more chronic course of an addictive disorder was found for those who reported earlier development of primary anxiety disorder, conduct

disorder, or adult antisocial behavior but was not found with earlier onset of other mental disorders. In the NCS, co-occurring mental disorders also influenced the likelihood of seeking treatment and the treatment sector from which service would be sought. As mentioned, those who had a substance dependence problem were far more likely to seek and receive treatment if they also had a co-occurring mental disorder. About one-third of people with a 12-month history of affective disorder received some treatment; but those who also had an addictive disorder were more likely to have received it in a specialty addiction treatment program. A collaborative study of the genetics of alcoholism used extensive structured interviews to separate independent mood and anxiety disorders from those that occurred only within the context of active drinking or withdrawal. This study found that over a lifetime, independent mood disorder was less common in alcoholics (14 percent) than in controls (17.1 percent), although more than twice as many alcoholics (2.3 percent) as controls (1.0 percent) met criteria for bipolar disorder. Panic disorder and social phobia were also substantially more common as independent disorders among alcoholics. In general, in this study the large majority of alcohol-dependent men and women did not have independent mood or anxiety disorders. This suggests that the higher rates of co-occurrence of most anxiety and affective disorders found in epidemiological studies or clinical populations probably reflect substance (alcohol)-induced anxiety and mood disorders that will resolve without special intervention once drug use ceases.

TREATMENT Many people who develop substance-related problems recover without formal treatment. For those who do seek help or advice, particularly those patients with less severe disorders, relatively brief interventions are often as effective as more intensive treatments. Since these brief interventions do not change the environment, alter drug-induced brain changes, or provide new skills, a change in the patient's motivation (cognitive change) probably best explains their impact on the drug-using behavior. For those individuals who do not respond or whose dependence is more severe, a variety of interventions appear to be effective. Although each section in this chapter discusses treatment relevant to the particular substance use disorder, the clinician sees few drug-dependent people who use only one drug. (Nicotine dependence may be an exception.) For example, among patients using an illicit drug, the most common additional diagnosis is alcohol dependence. It is useful to distinguish among specific procedures or techniques (e.g., individual therapy, family therapy, group therapy, relapse prevention, and pharmacotherapy) and treatment programs. Most programs use a number of specific procedures and involve several professional disciplines as well as nonprofessionals who have special skills or personal experience with the substance problem being treated. The best treatment programs combine specific procedures and disciplines to meet the needs of the individual patient after a careful assessment. However, there is no generally accepted classification either for the specific procedures used in treatment or for programs making use of various combinations of procedures. This lack of standardized terminology for categorizing procedures and programs presents a problem, even when the field of interest is narrowed from substance problems in general to treatment for a single substance, such as alcohol, tobacco, or cocaine. Except in carefully monitored research projects, even the definitions of specific procedures (e.g., individual counseling, group therapy, and methadone maintenance) tend to be so imprecise that one usually cannot infer just what transactions are supposed to occur. Nevertheless, for descriptive purposes, programs are often broadly grouped on the basis of one or more of their salient characteristics: whether the program is aimed at merely controlling acute withdrawal and consequences of recent drug use (detoxification) or is focused on longer-term behavioral change; whether the program makes extensive use of pharmacological interventions; and the degree to which the program is based on individual psychotherapy, AA or other 12-step principles, or therapeutic community principles. For example, government agencies recently categorized publicly funded treatment programs for drug dependence as either methadone maintenance (mostly outpatient), outpatient drug-free programs, therapeutic communities, or short-term inpatient programs. However, these broad descriptions mask as much as they reveal, tend to confuse the setting with the procedures, and obscure differences in the etiological models underlying the treatments used in different programs. Selecting a Treatment Not all interventions are applicable to all varieties of substance use or dependence, and some of the more coercive interventions used for illicit drugs are not applicable to substances that are legally available, such as tobacco. Changes in addictive behaviors do not occur abruptly, but rather through a series of stages. Five stages in this gradual process has been proposed: precontemplation, contemplation, preparation, action, and maintenance. For some types of addiction the therapeutic alliance is enhanced when the treatment approach is tailored to the patient's stage or readiness to change. For some drug use disorders, a specific pharmacological agent may be an important component of an intervention; for example, disulfiram, naltrexone (ReVia) or acamprosate for alcoholism; methadone, levomethadyl acetate (ORLAAM) (also called L-a-acetylmethadol [LAAM]) or buprenorphine (Buprenex) for heroin addiction; nicotine delivery devices or bupropion (Zyban) for tobacco dependence. Not all interventions are likely to be useful to health care professionals. For example, many youthful offenders with histories of drug use or dependence are now remanded to special facilities (boot camps), other programs for offenders (and sometimes for employees) rely almost exclusively on the deterrent effect of frequent urine testing, and a third group are built around religious conversion or rededication in a specific religious sect or denomination. In contrast to the numerous studies suggesting some value for brief interventions for smoking and for problem drinking, there are few controlled studies of brief interventions for those seeking treatment for dependence on illicit drugs. In general, for those persons who are severely dependent on illicit opioids, brief interventions (such as a few weeks of detoxification, whether in or out of a hospital) have limited effect on outcome measured a few months later. Among patients dependent on cocaine or heroin, substantial reductions in illicit drug use, antisocial behaviors, and psychiatric distress are much more likely following treatment lasting at least 3 months. Such a time-in-treatment effect is seen across very different modalities, from residential therapeutic communities to ambulatory methadone maintenance programs. Although some patients appear to benefit from a few days or weeks of treatment, a substantial percentage of users of illicit drugs drop out (or are dropped) from treatment before they have achieved significant benefits. Some of the variance in outcome of treatment can be attributed to differences in the characteristics of patients entering treatment and by events and conditions following treatment. However, programs based on similar philosophical principles and using what seem to be similar therapeutic procedures vary greatly in effectiveness. Some of the differences among programs that seem to be similar reflect the range and intensity of services offered. Programs with professionally trained staffs that provide more-comprehensive services to patients with more severe psychiatric difficulties are more likely to be able to retain those patients in treatment and to help them to make positive changes. Differences in the skills of individual counselors and professionals can powerfully affect outcomes. Such generalizations concerning programs serving illicit drug users may not hold for programs dealing with those seeking treatment for alcohol or tobacco or even cannabis problems uncomplicated by heavy use of illicit drugs. In such cases, relatively brief periods of individual or group counseling can produce long-lasting reductions in drug use. The outcomes usually considered in programs dealing with illicit drugs have typically included measures of social functioning, employment, and criminal activity, as well as decreases in drug-using behavior. Treatment for alcoholism and other mental health problems generally has more limited expectations (e.g., reduction in alcohol use and symptoms of psychiatric disorders), although changes in the use of health care resources subsequent to treatment is sometimes an additional measure of treatment efficacy. Measuring Treatment Outcome The latest published large multisite study of treatment, the Drug Abuse Treatment Outcome Study (DATOS, carried out from 1991 to 1993), interviewed patients at intake and 1, 3, and 12 months after treatment. As in previous multisite studies, sites selected were stable representatives of four major program types: drug-free outpatient, methadone maintenance, short-term residential (chemical dependency), and long-term residential (therapeutic community). Except at the methadone programs, which used group and individual counseling about equally, group counseling was the common element of the other treatments. Some antidepressants and antipsychotic agents were used in the nonmethadone programs, but they were incidental. This study found a lower level of services available to patients seeking treatment then were available decade earlier. Also, the patients were older and more likely to have a variety of special medical problems (e.g., HIV positive, concurrent psychiatric disorders) and social needs (homelessness). Treatment outcomes were generally consistent with those of previous studies of drug treatment in the public sector. One year after treatment there were substantial decreases in drug use. Levels of weekly or daily cocaine use at 1 year were about 50 percent of pretreatment levels, with greater reduction for those who participated in treatment for 3 months or more. Daily heroin use was lower among patients who remained in methadone maintenance treatment than among those who left. Although cocaine use among patients treated with methadone was somewhat lower, the reduction could not be attributed to treatment. Alcohol and marijuana use did not decline significantly. There was also no apparent decrease in suicidal thoughts or increase in employment, and in contrast to a number of previous multisite studies, multivariate analysis in this study did not confirm the widely reported reduction in predatory and or high-risk sexual behaviors for those in methadone programs. Those who stayed in long-term residential treatment for 6 months or longer showed a major decrease in drug use from preadmission levels for all categories of drugs—66.4 to 22 percent for cocaine; 17.2 to 5.8 percent for heroin; alcohol and marijuana use reduced by more than half. These individuals also reported a 50 percent decrease in illegal activities and about a 10 percent increase in full-time employment. In DATOS, outpatient drug-free and short-term inpatient programs had very few admissions in which the major drug problem was heroin; the most common presenting drug problem for both was cocaine, followed by alcohol and marijuana. Participation in the outpatient drug-free programs for 3 months or more was associated with a greater decrease in cocaine use at 1 year, (about 50 percent compared with those who stayed 3 months or less). But even 58 percent of those who stayed less than 3 months reported some decrease in cocaine use over preadmission levels. Patients who entered short-term inpatient programs also reported major decreases in drug use at 1 year, but there was no difference between those who stayed more than 2 weeks and those who stayed less than 2 weeks. Since the decision to enter any of the programs studied in DATOS was made by the patient, the study does not give much guidance to a clinician weighing a recommendation for a specific patient.

More guidance comes from a large-scale, random-assignment study of the treatment of alcoholics, which found that three distinct methods of delivering individual therapy over a 12-week period—12-step facilitation, cognitive-behavioral coping skills, and motivational enhancement (four sessions only)—produced comparable and generally quite favorable outcomes. Patient characteristics interacted significantly with the treatment in only one area, alcoholics with low-level psychiatric problems had better outcomes in terms of days of abstinence if assigned to 12-step facilitation rather than cognitive behavioral therapy. Patients who received individual therapy after a brief period of inpatient and intensive day-care treatment (aftercare) had better 1-year outcomes than those who began individual treatment as outpatients. Currently, entry into treatment rarely reflects a truly informed choice aimed at matching the characteristics and needs of the patient with the capacities and skills of a provider. Findings from studies of public-sector programs serving drug users with relatively few social supports show that more-intensive services, such as vocational, health, and mental health services, increase retention and produce better outcomes at follow-up. Influence of Philosophical Orientation The kinds of therapeutic procedures deemed valuable or essential by treatment professionals are profoundly affected by their philosophical orientation. For example, one study found that many professionals who adhere to a disease model of substance dependence view reduction of denial, acceptance of disease, need for lifelong abstinence, commitment to recovery, and affiliation with AA as the most important elements of intervention. In contrast, dealing with responsibility, instilling motivation and confidence, teaching relapse prevention, and avoiding high-risk situations were rated highest by psychologists espousing a behavioral model of dependence. Until quite recently, even physicians were unlikely to view pharmacological interventions as having significant value in treating alcoholism or most other forms of drug dependence, although some physicians did prescribe various forms of nicotine for tobacco dependence. Many controlled studies over many years have shown that the use of illicit opioids (heroin) can be markedly reduced by supervised administration of oral methadone or LAAM. Because of government regulations, the use of these agents is currently limited to practitioners and programs who have obtained special licenses; such programs and practices are rigidly regulated. Buprenorphine, a partial opioid agonist, is also effective. Data also show that naltrexone can reduce relapse rates for alcoholics following withdrawal. Controlled studies conducted in Europe show that acamprosate, a drug believed to act via actions on the glutamatergic system, can also reduce alcoholism relapse rates. However, to date, the pharmacological agents available to treat substance-related disorders have not been widely used, even when there are few regulatory barriers. The relatively indifferent or negative attitudes of physicians toward the use of pharmacological agents in the treatment of alcoholism and drug dependence may change if new and more effective medications become available at reasonable cost and unencumbered by burdensome government regulations. However, at present there seems to be only a modest correlation between the evidence showing that a given intervention or procedure is effective and the likelihood that it will be widely used. Treatment of Comorbidity—Integrated Versus Concurrent The treatment of the severely mentally ill (primarily those with schizophrenia and schizoaffective disorders) who are also drug dependent continues to pose problems for clinicians. Although some special facilities have been developed that use both antipsychotic drugs and therapeutic community principles, for the most part specialized addiction agencies have difficulty treating these patients. Generally, integrated treatment in which the same staff can treat both the psychiatric disorder and the addiction is more effective than either parallel treatment (a mental health and a specialty addiction program providing care concurrently) or sequential treatment (treating either the addiction or the psychiatric disorder first and then dealing with the comorbid condition.) Services and Outcome The extension of managed care into the public sector has produced a major reduction in the use of hospital-based detoxification and virtual disappearance of residential rehabilitation programs for alcoholics. Unfortunately, managed-care organizations tend to assume that the relatively brief courses of outpatient counseling that are effective with private-sector alcoholic patients are also effective with patients who are dependent on illicit drugs and who have minimal social supports. For the present, the trend is to provide the care that costs least over the short term and to ignore studies showing that more services can produce better long-term outcomes. Treatment is often a worthwhile social expenditure. For example, treatment of antisocial illicit drug users in outpatient settings can produce decreases in antisocial behavior and reductions in rates of HIV seroconversion that more than offset the treatment cost. Treatment in a prison setting can produce favorable decreases in postrelease costs associated with drug use and rearrests. Despite such evidence there are problems maintaining public support for treatment of substance dependence, both in the public and private sectors. This lack of support suggests that these problems continue to be viewed, at least in part, as moral failings rather than as medical disorders.

SUGGESTED CROSS-REFERENCES Individual sections discuss in detail the relevant substances and treatment for their related disorders: alcohol-related disorders in Section 11.2; amphetamine-related disorders, Section 11.3; caffeine-related disorders, Section 11.4; cannabis-related disorders, Section 11.5; cocaine-related disorders, Section 11.6; hallucinogen-related disorders, Section 11.7; inhalant-related disorders, Section 11.8; nicotine-related disorders, Section 11.9; opioid-related disorders, Section 11.10; PCP-related disorders, Section 11.11; sedative-hypnotic–related disorders, Section 11.12, and anabolic-androgenic steroid abuse, Section 11.13. Brief psychotherapy is covered in Section 30.8; alternative therapies, in Section 30.10; and methadone (and other maintenance therapies) in Section 31.23. Drug and alcohol abuse among elderly persons is discussed in Section 51.3h. SECTION REFERENCES Akil H, Owens C, Gutstein H, Taylor L, Curran E, Watson S: Endogenous opioids: Overview and current issues. Drug Alcohol Depend 51:127, 1998. Anglin MD, Hser Y-I, Grella CE: Drug addiction and treatment careers among clients in the Drug Abuse Treatment Outcome Study (DATOS). Psychol Addict Behav 11:308, 1997. Anthenelli RM, Smith TL, Irwin MR, Schuckit MA: A comparative study of criteria for subgrouping alcoholics: The primary/secondary diagnostic scheme versus variations of the type 1/type 2 criteria. Am J Psychiatry 151:1468, 1994. Anthony JC, Warner LA, Kessler RC: Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Clin Exp Psychopharmacol 2:244, 1994. Baumohl J, Jaffe JH: History of alcohol and drug abuse treatment in the United States. In Encyclopedia of Drugs and Alcohol, vol 3, JH Jaffe, editor. Macmillan, New York, 1995. Beirut LJ, Dinwiddie SH, Begleiter H, Crowe RR, Hesselbrock V, Nurnberger JI Jr, Porjesz B, Schuckit MA, Reich T: Familial transmission of substance dependence: Alcohol, marijuana, cocaine, and habitual smoking. Arch Gen Psychiatry 55:982, 1998. Edwards G, Arif A, Hodgson R: Nomenclature and classification of drug- and alcohol-related problems. A WHO Memorandum. Bull WHO 99:225, 1981. *Gerstein DR, Harwood HJ, editors: Treating Drug Problems, vol 1. Committee for the Substance Abuse Coverage Study, Division of Health Care Services, Institute of Medicine. National Academy Press, Washington, DC, 1990. Goldman D, Bergen A: General and specific inheritance of substance abuse and alcoholism. Arch Gen Psychiatry 55:964, 1998. Harrison PA, Fulkerson JA, Beebe TJ: DSM-IV substance use disorder criteria for adolescents: A critical examination based on a statewide school survey. Am J Psychiatry 155:486, 1998. Hubbard RL, Craddock SG, Flynn PM, Anderson J, Etheridge RM: Overview of 1-year follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychol Addict Behav 11:261, 1997. *Institute of Medicine: Broadening the Base of Treatment for Alcohol Problems. National Academy Press, Washington, DC, 1990. Institute of Medicine: Pathways of Addiction. National Academy Press, Washington, DC, 1996. Inturrisi CE: Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependence. Semin Neurosci 9:110, 1997. Jaffe JH: Current concepts of addiction. In Addictive States, CP O'Brien, JH Jaffe, editors. Research Publications: Association for Research in Nervous and Mental Disease, vol 70. Raven, New York, 1992.

Jaffe JH, Knapp CM, Ciraulo DA: Opiates: Clinical aspects. In Substance Abuse: A Comprehensive Textbook, ed 3, JH Lowinson, P Ruiz, RB Millman, JG Langrod, editors. Williams & Wilkins, Baltimore, 1997. *Johnston LD, O'Malley PM, Bachman JG: National survey results on drug use from the Monitoring the Future Study. College Students and Young Adults. National Institute on Drug Abuse, Rockville, MD, 1999. Kaufman E: The family in drug and alcohol addiction. In Comprehensive Handbook of Drug and Alcohol Addiction, NS Miller, editor. Marcel Dekker, New York, 1991. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC: Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the national comorbidity survey. Arch Gen Psychiatry 54:313, 1997. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, Kendler KS: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry 51:8, 1994. Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, Leaf PJ: The epidemiology of co-occurring addictive and mental disorders: Implications for prevention and service utilization. Am J Orthopsychiatry 66:17, 1996. Koob GF, Le Moal M: Drug abuse: Hedonic homeostatic dysregulation. Science 278:52, 1997. Kreek MH, Koob GF: Drug dependence: Stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23, 1998. McLellan AT, Grissom GR, Zanis D, Randall M, Brill P, O'Brien CP: Problem-service ‘matching' in addiction treatment. Arch Gen Psychiatry

54:730, 1997.

Miller WR: Why do people change addictive behavior? The 1996 H. David Archibald lecture. Addiction 93:163, 1998. Musto DF: The American Disease. Origins of Narcotic Control. Oxford University Press, New York, 1987. Nesse RM, Berridge KC: Psychoactive drug use in evolutionary perspective. Science 278:63, 1997. Nestler EJ, Aghajanian GK: Molecular and cellular basis of addiction. Science 278:58, 1997. Nyman DJ, Cocores J: Coaddiction: Treatment of the family member. In Comprehensive Handbook of Drug and Alcohol Addiction, NS Miller, editor. Marcel Dekker, New York, 1991. *Prescott CA, Kendler KS: Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 156:34, 1999. Prochaska JO, DiClemente CC, Norcross JC: In search of how people change. Applications to addictive behaviours. Am Psychol 47:1102, 1992. Project MATCH Research Group: Matching alcoholism treatment to client heterogeneity: Project MATCH posttreatment drinking outcomes. J Stud Alcohol 58:2, 1997. *Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK: Comorbidity of mental disorders with alcohol and other drug abuse. JAMA 264:2511, 1990. Robinson TW, Berridge KC: The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Res Rev 18:241, 1993. Rounsaville BJ, Bryant K, Babor R, Kranzler H, Kadden R: Cross system agreement for substance use disorders: DSM-III-R, DSM-IV and ICD-10. Addiction 88:337, 1993. Schuckit MA, Smith TL: An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch Gen Psychiatry 53:202, 1996. Schuckit MA, Tipp JE, Bucholz KK, Nurnberger JI Jr, Hesselbrock VM, Crowe RR, Kramer J: The life-time rates of three major mood disorders and four major anxiety disorders in alcoholics and controls. Addiction 92:1289, 1997. Schulteis G, Gold LH, Koob GF: Preclinical behavioral models for addressing unmet needs in opiate addiction. Semin Neurosci 9:94, 1997. Self DW, Nestler EJ: Relapse to drug-seeking: Neural and molecular mechanisms. Drug Alcohol Depend 51:49, 1998. Simpson DD, Joe GW, Brown BS: Treatment retention and follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychol Addict Behav 11:294, 1997. Substance Abuse and Mental Health Services Administration Office of Applied Studies: Preliminary Results from the 1996 National Household Survey on Drug Abuse. National Household Survey on Drug Abuse Series: H-3. DHHS publ no. (SMA) 97-3149. SAMHSA, Office of Applied Studies, Rockville, MD, 1997. True WR, Heath AC, Scherrer JF, Waterman B, Goldberg J, Lin N, Eisen SA, Lyons MJ, Tsuang MT: Genetic and environmental contributions to smoking. Addiction 92:1277, 1997. Tsai G, Gastfriend DR, Coyle JT: The glutamatergic basis of human alcoholism. Am J Psychiatry 152:332, 1995. Tsai GE, Ragan P, Chang R, Chen S, Linnoila MI, Coyle JT: Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry 155:726, 1998. Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J, True W, Lin N, Toomey R, Eaves L: Co-occurrence of abuse of different drugs in men. Arch Gen Psychiatry 55:967, 1998. *Uhl GR: Molecular genetics of substance abuse vulnerability: A current approach. Neuropsychopharmacology 20:1, 1999. Wise RA: Drug-activation of brain reward pathways. Drug Alcohol Depend 51:13, 1998.

Textbook of Psychiatry

11.2 ALCOHOL-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.2 ALCOHOL-RELATED DISORDERS MARC A. SCHUCKIT, M.D. Definition and Comparative Nosology Epidemiology Pharmacology Etiology Biological Theories Diagnosis and Clinical Features Differential Diagnosis Course and Prognosis Treatment Suggested Cross-References

An understanding of the effects of alcohol and the clinical importance of alcohol-related disorders is essential for the practice of psychiatry. Alcohol intoxication is capable of causing irritability, violent behavior, feelings of depression, and in rare instances, hallucinations and delusions. Longer-term, escalating levels of consumption of alcohol can produce tolerance as well as such intense adaptation of the body that cessation of use can precipitate a withdrawal syndrome usually marked by insomnia, evidence of hyperactivity of the autonomic nervous system, and feelings of anxiety. Therefore, the adequate evaluation of life problems and psychiatric symptoms in a patient requires that the clinician consider the possibility that the clinical situation reflects the effects of alcohol. The clinical importance of the relation between alcohol use patterns and psychiatric symptoms is amplified by the high prevalence of alcohol intake and related problems in the general population. Ninety percent of people in most Western societies consume alcohol at some time during their lives, and perhaps 30 percent or more of drinkers develop temporary alcohol-related life problems. Severe, repetitive alcohol-related life impairment (i.e., alcohol dependence) is observed at some time during the lives of approximately 10 percent of men and 3 to 5 percent of women, with an additional 5 to 10 percent of each sex developing persistent but less intense alcohol-related life problems that are diagnosed as abuse. Because high levels of alcohol intake can cause diverse medical and psychiatric problems, it has been estimated that 20 to 35 percent of people seeking help from a health care provider have alcohol abuse or dependence. Thus, alcohol-related problems are very common in society. Despite the diverse nature of the symptomatology and the high prevalence of alcohol-related disorders, the alcoholic is rarely easy to identify. Alcohol abuse and dependence are seen in both genders, all races and ethnic groups, and in all socioeconomic strata. The alcoholic individual usually has a job, functions moderately well in a family setting, and often appears in the psychiatrist's office with general complaints that rarely point directly toward the alcoholism. The clinician establishes the contribution of alcohol to the clinical complaints by avoiding the false stereotype of the alcoholic as a nonfunctional street person, recognizing the high prevalence of this disorder, and considering the diagnosis in all psychiatric patients.

DEFINITION AND COMPARATIVE NOSOLOGY Alcohol Use Disorder In all diagnostic systems, the definition of alcoholism indicates evidence of repeated impairments from alcohol in multiple areas of life functioning, despite which the person returns to drinking. These basic elements were present in the third edition (1980) and the revised third edition (1987) of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-III, DSM-III-R) and have continued into the fourth edition (DSM-IV) published in 1994. In the most recent manual, dependence is diagnosed as the presence of at least three of seven major areas of life impairment related to alcohol occurring repeatedly and clustering together in the same 12-month period. These difficulties include tolerance, evidence of a withdrawal syndrome when the drug is discontinued or intake is decreased, potential interference with life functioning associated with spending a great deal of time using the substance, and returning to use despite evidence of physical or psychological problems. It is the syndrome of dependence for which the best data are available regarding the usual clinical course of problems, appropriateness of treatment, and potential importance of genetic factors. DSM-III-R and DSM-IV do not require evidence of tolerance or withdrawal for the definition of dependence. Recognizing the large change in the concept of “alcoholism” associated with the absence of the centrality of these physiological components of the disorder, DSM-IV allows clinicians to subtype dependence into those syndromes with evidence of a physiological component (i.e., tolerance or withdrawal) and those without these phenomena. Some recent data support the clinical importance of withdrawal, and it is hoped that the request for subtyping will facilitate the accrual of data to determine if it is appropriate to continue to emphasize these physiological conditions in DSM-V. Thus, all patients with a possible alcohol use disorder should first be evaluated for the presence of alcohol dependence. For those who do not meet the criteria for this disorder, however, there is a second potential syndrome to consider, abuse. Here an individual who is not dependent on alcohol demonstrates repeated problems within any 12-month period in any one or more of four potential areas of difficulties. These include repeated legal, interpersonal, social, or occupational impairments related to alcohol, as well as use of alcohol in physically hazardous situations. DSM-IV reformulated the concept of abuse in order to identify criteria that were independent of those noted for dependence. However, it is likely that if they continue to drink, the majority of individuals with abuse will go on to develop dependence in the future. A similar definition of dependence occurs in the tenth revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10). Here, however, the threshold for diagnosis is any three of six (rather than seven) items. The items in ICD-10 dependence include all the concepts in DSM-IV, although they are expressed and numbered differently and some concepts are combined into one criterion. ICD-10 also lists a second and less intense alcohol use disorder, known as harmful use. The definition of this second syndrome is quite different from DSM-IV because the ICD-10 approach is based on evidence of repeated interference with psychological and physical health functioning, and does not include social impairment, legal problems, or use in physically hazardous situations. Thus, although the definitions of dependence are quite similar in the United States and ICD-10 systems, there is less obvious overlap between abuse and harmful use. Attempts have been made to further divide alcohol-dependence into clinically meaningful subgroups. One such approach is demonstrated in DSM-IV where persons with dependence syndromes are to receive an additional notation of whether a physiological component (i.e., tolerance, withdrawal, or both) is present. Other authors have called for the recognition of a more severe early-onset alcohol dependence syndrome, often accompanied by criminality and dependence on other drugs, which has been labeled as type II or type B alcoholism. These latter approaches are consistent with the recognition that an earlier-onset alcohol dependence syndrome, like most medical and psychiatric disorders, is likely to have a more severe course, but it appears as if some of the prognostic significance of type II or B alcoholism rests with an elevated risk for a concomitant antisocial personality disorder in the early-onset group. Severity and Remission The DSM-IV definition of dependence also attempted to better clarify the concepts of severity and remission. Regarding the former, no reliable criteria could be developed, and the manual offers the clinician the possibility of incorporating the relatively imprecise divisions of mild (with few symptoms), moderate (with functional impairment intermediate between mild and severe), and severe (with many symptoms); ICD-10 has no formal notation of severity. Remission is a more complex phenomenon, and the definition was created from data gathered in a field trial that was incorporated into the DSM-IV process. The diagnostic criteria distinguish between the high-risk period in the first 12 months of recovery and at later time points and ask the clinician to specify whether the patient is totally free of substance-related problems. The criteria also consider whether or not the individual is living in a controlled environment such as prison or a hospital; ICD-10 makes similar but not identical distinctions.

EPIDEMIOLOGY Psychiatrists need to be concerned about alcoholism because this condition is common, and the usual alcoholic person resembles most other patients (i.e., does not fit a stereotype). Thus, it is always important to evaluate the drinking patterns of all patients because alcohol can interact with medications and intensify pre-existing major psychiatric disorders. Clinicians also need to recognize that a high proportion of their patients have temporary but potentially important alcohol-induced

psychiatric syndromes. Prevalence of Drinking At some time during their lives, 90 percent of the population in the United States drinks, with most persons beginning their alcohol intake in the early to mid-teens years (Table 11.2-1). At any time two out of three men are current drinkers, with a ratio of persisting alcohol intake of approximately 1.3 men to 1 woman. A current drinker is defined most commonly as anyone who has used alcohol during the preceding 1 to 3 months, and is differentiated from persons with alcohol problems. The age of highest prevalence of drinking and of greatest alcohol intake is from the middle or late teens years to the mid 20s.

Table 11.2-1 Alcohol Epidemiology

Different groups in the United States have different proportions of drinkers. Generally, those who have high education and high socioeconomic status have the highest proportion who are current drinkers. Among religious groups, Jews have the highest proportion who consume alcohol, but the lowest number of persons with alcohol problems. Conservative Protestants and Catholics use alcohol less frequently than liberal Protestants and Catholics. Other groups, such as the Irish, have higher rates of severe alcohol problems, but they also have significantly higher rates of abstention. High rates of alcohol problems are also found among Native Americans and Eskimos. In the United States in the early 1990s the average person over the age of 14 years consumed 2.31 gallons of absolute alcohol a year. This amount sounds substantial, but it is considerably less than the over 5 gallons of absolute ethanol consumed each year at the time of the American Revolution. The current figure also represents a significant decrease from the amounts consumed during the mid 1970s, and the 2.7 gallons per capita in 1981. Alcohol Problems Because a high proportion of persons are drinkers, especially in their middle teens to mid-20s, and because the per-capita consumption of alcohol is high, it is not surprising that a large proportion of persons have alcohol-related problems sometime in their lives. A recent 10-year follow-up study of almost 500 men evaluated at age 33 found that during the preceding decade between one quarter and one third had alcohol-related blackouts, approximately one third admitted to driving after consuming enough alcohol to be impaired, and 20 percent reported missing school or work because of either a hangover or a desire to party with alcohol rather than work. As common as these problems are and as much as they contribute to lost work time and to physical morbidity and mortality, most people appear to mature out of alcohol problems with the passage of time. Thus, people probably experience fewer alcohol-related difficulties during their 30s than during their 20s, and even fewer difficulties in their 40s and 50s. Both per-capita consumption and the proportion of persons with problems related to alcohol appear to decrease with increasing age beyond middle adulthood. Alcohol Abuse or Dependence The lifetime risk for alcohol dependence is approximately 10 percent for men and 3 to 5 percent for women. The rate of alcohol abuse and dependence combined may be as high as 20 percent for men and 10 percent for women. Those figures translate to perhaps a total of 200,000 deaths a year in the United States from accidents (perhaps 25,000 persons a year alone), suicide, cancer, and heart disease—the leading causes of death among alcoholic men and women. Cirrhosis is also found at increased rates; 15 percent of alcoholic persons meet the criteria for cirrhosis. Because alcoholism is associated with numerous medical and psychiatric problems, alcoholic persons are overrepresented in psychiatric settings, where they make up one quarter to one third of the usual patient load, even in facilities that serve the affluent. The age of peak onset of alcohol problems severe enough to lead to a diagnosis of alcohol dependence is probably in the middle 20s to approximately age 40. Despite multiple difficulties in social relationships, families, and jobs, high functioning in some areas is likely to remain. Thus, the stereotypical alcoholic person who is a homeless bum is very much the exception rather than the rule, representing only 5 percent of all persons with severe, recurring alcohol-related difficulties. Age-related differences are found in the pattern of alcohol-related problems. As is true with almost all psychiatric and many medical disorders, the earlier the onset of alcoholism, the greater the chance that the disorder is severe and that another psychiatric disorder pre-existed. Therefore, when alcohol dependence is noted in a teenager, the person probably has another problem, usually conduct disorder (i.e., early antisocial personality disorder). In that instance, the alcohol-related problems are likely to be associated with severe drug difficulties and antisocial problems in school and with family or peers that occurred before the onset of alcohol dependence. At the other extreme, although most alcoholic persons have their problems early in life, perhaps 10 percent or so have an onset of recurring difficulties after the age of 55. The late onset of the disorder tends to be associated with less severe social difficulties and more subtle signs and symptoms, but a greater likelihood of associated medical problems than among younger alcoholic persons. Comorbid Conditions The alcohol-related disorders are highly prevalent conditions, and psychiatric symptoms are common during intoxication and withdrawal. Therefore, if diagnoses were to be used to indicate prognosis and optimal treatment, an algorithm had to be developed to help the clinician disentangle temporary substance-related psychopathology from independent psychiatric syndromes. Alcohol is an organic agent, and most diagnostic algorithms formulated from the time of Emil Kraepelin through DSM-IV have recognized the potential dangers of labeling psychiatric disorders when the symptoms develop during a condition strongly influenced by an organic cause. This hierarchical approach has many parallels in medicine. For example, pneumonias that develop de novo are recognized as having a cause and a long-term prognosis different from similar clinical conditions superimposed on congestive heart failure, a bronchus blocked by a carcinoma, or during the course of a severe immune deficiency. The symptoms of pneumonia must be recognized, but the treatment and the prognostic implications of the condition are quite different in the diverse situations. Similarly, in psychiatry depressive episodes that are observed during hypothyroid states; tremor and symptoms of anxiety seen in hyperthyroidism; and psychotic symptoms observed in connection with a brain tumor must be recognized and are likely to require intervention. However, in each instance the prognostic and treatment implications of the syndrome are quite different from major depressive episodes, panic disorder, or schizophrenia that developed in the absence of those major preexisting disorders. This is also true of the alcohol-related disorders. All the diagnostic manuals since DSM-III have warned the clinician that psychiatric syndromes developing only during intoxication or withdrawal from substances do not necessarily indicate an independent psychiatric disorder. Recognizing that those caveats are easy to overlook in clinical pratice, DSM-IV has added an overall statement about the inadvisability of labeling independent psychiatric disorders based on symptoms observed only during alcohol intoxication or within 4 weeks of abstinence from alcohol. Depressions, panic attacks, and psychotic thought processes occurring in the context of alcohol problems usually improve rapidly and then disappear. Thus, they do not usually carry the same prognostic implications as actual major depressive episodes, panic disorders, and schizophrenia. Similarly, DSM-IV reminds clinicians that such symptoms of mood, anxiety, or psychotic disorders that are documented before severe life problems from alcohol or that remain beyond 4 weeks of total abstinence should be carefully evaluated as possible indicators of true comorbidity with the occurrence of two or more independent psychiatric syndromes. These issues are discussed in greater detail in sections on alcohol-induced mood, anxiety, and psychotic disorders. Finally, three psychiatric syndromes—bipolar I disorder, schizophrenia, and antisocial personality disorder—carry well established heightened risks for subsequent alcohol-related disorders. Individuals with panic disorder or generalized social phobia might also carry a small but statistically significant risks for alcohol abuse or dependence.

PHARMACOLOGY Including a discussion of pharmacology in a section on alcohol-related disorders is not meant to imply that a disorder can be defined solely through the use of a substance. Most drinkers do not have serious problems related to alcohol and only a minority of drinkers have difficulties severe and pervasive enough to be labeled abuse or dependence. However, all alcoholic persons have a problem with that potent substance. As a result, clinicians cannot understand the disease or its syndromes without knowing something about alcohol itself. Ethanol (beverage alcohol) is a simple molecule that is well absorbed through the mucosal lining of the digestive tract in the mouth, the esophagus, and the stomach. The most prominent area of absorption, however, is in the proximal small intestine, which is also the site of absorption of many of the B vitamins. Ethanol rapidly enters the bloodstream and, as a result of its high solubility in water, is distributed to almost every body system. As a consequence of its modest fat solubility, alcohol is likely to have effects on body membranes rich in fat, including neurons. Wine, beer, and such distilled spirits as whiskey, gin, and vodka differ in their content of congeners. Congeners are responsible for much of the characteristic taste of the beverage, and consist of combinations of methanol, butanol, aldehydes, phenols, tannins, lead, cobalt, iron, and other substances. Under certain circumstances congeners can have physiological effects, but their potency pales in comparison with the potency of alcohol. A drink of an alcoholic beverage is usually defined as containing 10 to 12 grams of ethanol. In round figures this is the amount of alcohol contained in approximately 12 ounces of beer (which in the United States has approximately 3.6 percent ethanol), 4 ounces of table wine (containing about 12 percent ethanol), and between 1 and 1.5 ounces of 80-proof spirits (containing 40 percent ethanol). For the average 70-kg (155-pound) person who has an average amount of body fat, one drink is likely to raise the blood alcohol level by approximately 15 to 20 mg/dL. The body subsequently metabolizes and excretes approximately one drink an hour. The rate of absorption of alcohol from the digestive tract is likely to be faster on an empty stomach than after a full meal, especially one rich in fats and carbohydrates. After absorption into the bloodstream from the small intestine, between 2 and 10 percent of the alcohol is then excreted unchanged from the lungs or the kidneys or through sweat; the majority is metabolized in the liver. Liver metabolism occurs mostly through four pathways, with each resulting in the production of acetaldehyde. Most of the process occurs through the actions of alcohol dehydrogenase (ADH) in the cytosol of hepatic cells. Especially at high blood alcohol levels, some of the alcohol is also broken down in the microsomes of the smooth endoplasmic reticulum (the microsomal ethanol oxidizing system [MEOS] system). The ADH process is the usual rate-limiting metabolic step, occurring relatively slowly because of the liver's need to handle the produced hydrogen ions through use of a cofactor that is in relatively short supply, nicotinamide adenine dinucleotide (NAD). The acetaldehyde produced by ADH and MEOS is then destroyed by the enzyme aldehyde dehydrogenase (ALDH) in both the liver cell cytosol and mitochondria. This step occurs rapidly, with the result that the average person does not have substantial levels of this substance; this is fortunate because at high levels acetaldehyde can produce histamine release, which through a variety of mechanisms contributes to falling blood pressure, nausea, and vomiting. The ALDH isoenzyme pattern of an individual is related to the risk for developing alcoholism. Approximately 10 percent of Asian (e.g., Japanese, Chinese, Korean) men and women fully lack the low km ALDH form responsible for metabolizing low blood concentrations of acetaldehyde—that is they are homozygotes for the inactive form of this specific isoenzyme. An additional approximately 40 percent of Asian men and women are heterozygotes, being able to produce low concentrations of this most efficient ALDH form. In homozygote individuals, even one half of a standard drink is likely to cause a severe reaction, resulting in intense facial flushing, rapid heartbeat, nausea, and vomiting. Consequently, most such people rarely drink, and have an associated alcoholism risk that is close to zero. Individuals who are heterozygotes regarding this low k m ALDH form are more likely to drink but demonstrate relatively high levels of sensitivity to alcohol, and are likely to consume relatively low amounts of alcohol compared to other individuals. Thus, the genetically controlled ALDH isoenzyme pattern is an important factor in the alcoholism risk, although one that applies only to Asians because the absence of the low k m ALDH is not found in other racial groups. ALDH activity is also important in another context. A variety of medications, such as disulfiram (Antabuse), inhibit the functioning of this low k m ALDH form. Thus, when alcoholic individuals regularly take disulfiram, even relatively small amounts of alcohol are likely to produce facial flushing, a rapid heartbeat, and nausea within 20 minutes or so of having consumed the alcoholic beverage. Such drugs, known as alcohol-sensitizing agents, have been considered for the treatment of alcohol dependence. Neuropharmacology All substances of abuse share the ability to produce changes in feeling states and subsequently increase the likelihood that a person will have a psychological drive to continue to take the substance despite potentially severe adverse consequences (psychological dependence). That effect is distinct from the physical dependence that produces the withdrawal or abstinence syndrome that characterizes drugs like alcohol. However, the 300 or so diverse psychoactive drugs differ in many important ways. For example, only a few produce physiological tolerance and clinically relevant levels of withdrawal symptoms when the substance is discontinued. Some drugs markedly increase the chances that a person will have temporary psychoses or depressions; other drugs do not. Some are likely to be lethal in overdose; others appear to be relatively safe at high levels. Clinicians therefore are presented with a daunting challenge if they attempt to memorize all the attributes for each of the hundreds of psychoactive substances. A useful shortcut is to place drugs of abuse into categories on the basis of their most prominent effects at the usual doses at which they are taken. In this scheme, substances that have as their most prominent usual effects the production of somnolence and decreased neuronal activity but that are not powerful in attenuating pain are labeled as depressants or sometimes as sedative-anxiolytics. They include alcohol, all the benzodiazepines, all the barbiturates, and the carbamate antianxiety drugs, such as meprobamate (Miltown). These substances produce a similar profile of symptoms during intoxication, are potentially lethal in overdose (especially when multiple depressant drugs are taken at the same time), are cross-tolerant, are physically addicting, and produce similar withdrawal syndromes. The behavioral and physiological changes observed with any substance differ with the dose, the patient's prior history of exposure to the drug, and clinical conditions, including physiological disorders and the patient's state of fatigue. With a drug like alcohol, the effects also change over time after intake, with more pronounced symptoms observed while the blood alcohol levels are rising then when the blood alcohol levels are falling, a phenomenon called acute tolerance or the Mallenby effect. Debate continues about the most important mechanisms of action of alcohol on the brain. One of the problems occurs because the drug has a major effect on most neurochemical systems, demonstrating different effects at different doses and sometimes opposite effects during intoxication and withdrawal. One series of theories on the mechanisms underlying intoxication relates to the effects that alcohol has on the cell membrane: alcohol tends to fluidize or decrease the levels of rigidity of the membrane, with subsequent impairments in the cell's ability to control the influx and the efflux of electrolytes. Other research focuses on changes in dopamine, attempting to tie in the effects of alcohol to the pleasure centers of the limbic system, or on serotonin, a neurotransmitter related to appetitive behaviors. Still other investigators point to the potential importance of the neurochemical compounds that may, at least theoretically, be formed between acetaldehyde and the neurotransmitters serotonin and dopamine, producing alkaloids that have properties resembling opioids. Another set of investigations point out the indirect effects that alcohol can have on the benzodiazepine-receptor complexes in the brain. Finally, alcohol has potent effects on glutamate-gated ionophoric receptors, especially those that bind N-methyl-D-aspartate (NMDA). With such a diverse range of effects and the absence of an obvious receptor system reacting specifically to alcohol, many leads are promising but few answers are definitive regarding the most clinically relevant effects of alcohol on the nervous system or the way in which the alterations may relate to abuse or dependence on alcohol. Tolerance With repeated administration of alcohol, larger and larger doses of the drug are required to produce the desired effect. That phenomenon, called tolerance, is the ability to tolerate higher and higher doses of the substance and is the result of at least three processes. Behavioral tolerance reflects the ability of a person to learn how to perform tasks effectively despite the effects of alcohol. It is a learned behavior and the result of repeated practice. Pharmacokinetic tolerance is an adaptation of the metabolizing system to rid the body of alcohol rapidly. After several weeks of daily drinking, the liver produces more ADH than usual and expands the MEOS system, with a resulting increase of up to 30 percent in the rate of breakdown of ethanol. Finally, pharmacodynamic or cellular tolerance is an adaptation of the nervous system so that it can function, despite high blood alcohol concentrations, by resisting the actions of alcohol on the cell. Thus, persons have been observed to be awake, relatively alert, and relatively coordinated despite blood alcohol concentrations of 250 mg/dL, and some people have been awake at blood alcohol concentrations above 600 mg/dL. Once tolerance has developed for one of the brain depressants, a person often shows a similar reaction to a second drug of that class ( cross-tolerance). Therefore, a person who has been drinking heavily, has tolerance for alcohol, and then stops drinking can be expected to require a higher dose of benzodiazepines for sleep

induction. If the person took two depressant drugs at the same time, tolerance is not likely to be observed and the mixing of the two substances can have lethal effects. Just as tolerance requires a period of days or weeks to develop, the phenomenon is likely to disappear within a similar period of time after the intake of any depressant drug has ceased. Some clinicians and researchers have described a phenomenon of reverse tolerance or sensitization. This is a complex situation that might involve multiple physiological components. For example, whether alcoholic or not, as persons grow older they have increasing levels of sensitivity to most brain depressants, including alcohol. This is because of several age-related changes in the body, including a decrease in the rate at which alcohol is metabolized in the liver and a relative decrease in body water as a consequence of an increasing percentage of body fat. The result of these changes is that higher blood alcohol levels develop in older people, whose neurons also have an enhanced sensitivity to the effects of alcohol. Even more dramatic examples of increased sensitivity to alcohol are seen after severe brain damage (e.g., the consequence of an auto accident or alcohol-related brain deterioration) and after impairment in any of the major alcohol-metabolizing systems, as occurs in cirrhosis. Effects on the Body Some data indicate that alcohol use is not always harmful and may under certain circumstances even have some beneficial effects. However, any amount of alcohol is considered harmful to the developing fetus, to recovering alcoholics, to people taking medications that may adversely interact with alcohol, and to individuals with certain medical disorders or psychiatric syndromes (such as major depressive disorder or schizophrenia) that might be intensified by alcohol. For other people a maximum of one or two drinks a day appears to be associated with a decreased risk of cardiovascular disease. This association may be caused by an alcohol-induced decrease in platelet adherence or to an increase in at least one portion of high-density lipoprotein (HDL) cholesterol, although the fraction affected does not appear to be the one most potent in protecting against heart disease. Unfortunately, the intake of more than two drinks a day is likely to increase low-density lipoprotein (LDL) cholesterol and triglycerides and to raise blood pressure, with the overall result of increasing the risk of cardiac disorders. Also, even low levels of alcohol intake may increase the risk for breast cancer. Central and Peripheral Nervous Systems BLACKOUT Blackout indicates a memory impairment (anterograde amnesia) for the period of time when the person was drinking heavily but remained awake. This common difficulty is related to the ability of any brain depressant to interfere with the acquisition of memory at high enough doses. Perhaps 40 percent of teenaged and young adult males have blackouts, and memory loss does not by itself indicate a high likelihood of alcohol abuse or dependence. The blackout, which is temporary and limited to memory problems involving a short period of time, is not a DSM-IV diagnosis, and is distinct from alcohol-induced persisting amnestic disorder, formerly known as Wernicke-Korsakoff syndrome. SLEEP IMPAIRMENT Alcohol intoxication can help a person fall asleep more quickly, but it tends to depress rapid eye movement sleep and inhibit stage 4 sleep. It is likely to be associated with frequent alternations between sleep stages, a process sometimes referred to as sleep fragmentation. PERIPHERAL NEUROPATHY A more serious and potentially permanent problem is seen in perhaps 10 percent of alcoholic persons after years of heavy drinking. The deterioration of nerve functioning to the hands and feet, called peripheral neuropathy, arises through an apparent combination of vitamin deficiencies and the direct effects of alcohol or its metabolites. The symptoms include numbness of the hands and feet, often bilateral, frequently accompanied by tingling and paresthesias. Although the condition is usually relatively mild and often improves with abstinence, the pain and the numbness can result in a permanent impairment. CEREBELLAR DEGENERATION Characterized by unsteadiness of gait, problems with standing, and mild nystagmus, cerebellar degeneration is probably caused by a combination of the effects of ethanol and acetaldehyde, along with vitamin deficiencies. Treatment usually consists of total abstinence and vitamin supplementation, although complete recovery is not common. OTHER EFFECTS ON THE CENTRAL NERVOUS SYSTEM A series of temporary but intense psychiatric symptoms are likely to be observed during alcohol intoxication and withdrawal, including depressed mood, severe anxiety, and psychoses. These symptoms often mimic psychiatric disorders but are likely to disappear within weeks of abstinence. Severe amnestic disorders and dementias may also occur. Gastrointestinal Problems Second only to the nervous system, the gastrointestinal system is most severely affected by heavy drinking. Probably the most common gastrointestinal problem associated with alcohol intake is an acute and at times severe inflammation of the esophagus or the stomach, with stomach inflammation often accompanied by vomiting and bleeding. If gastritis occurs in the presence of dilated esophageal veins seen with cirrhosis, it can induce potentially lethal bleeding. The liver and the pancreas are especially vulnerable to alcohol. In the liver, increasing alcohol doses result in the accumulation of fats and proteins in the cells, producing a reversible swelling often described as a fatty liver. Inflammation of the liver cells accompanied by a subsequent intense rise in some liver function tests and other signs of alcoholic hepatitis can lead to the deposition of excessive amounts of hyalin and collagen near blood vessels, an early stage of cirrhosis. As damage progresses, the normal flow of blood through the liver is impaired, dilated veins or varices develop from the increased abdominal venous pressure, and fluid seeps from the liver capsule, accumulating in the abdomen as ascites. As liver failure progresses, secondary cognitive impairment can develop as various levels of hepatic encephalopathy. Perhaps 15 percent of alcoholic persons respond to large doses of alcohol with an inflammation of the pancreas that can present as the abdominal emergency of acute pancreatitis. This can lead to a chronic irreversible condition of pancreatic destruction, with associated signs of insufficiency in sugar metabolism (a form of diabetes) and digestive enzymes. Cerebrovascular and Cardiovascular Problems Heavy intake of alcohol increases the blood pressure and elevates both LDL cholesterol and triglycerides, thus enhancing the risk for myocardial infarction and thrombosis. At high doses, alcohol is also a striated-muscle toxin with a resulting production of what is usually but not always a reversible deterioration in the heart muscle that manifests itself as beating irregularities and signs of heart failure (alcoholic cardiomyopathy). Similar levels of swelling of muscle cells and subsequent muscle pain can be observed in the skeletal muscles. Blood-Producing Systems High levels of alcohol intake, often in the range of four to eight drinks a day, decrease the production of white blood cells and impairs the ability of those cells to migrate to sites of infection. Such drinking can also affect the stem cells that produce the red blood components, significantly increasing the average size of the red cell (the mean corpuscular volume [MCV]), and can impair the production and the efficiency of blood platelets. Cancer High rates of many types of cancer are seen in alcoholic persons, especially cancers of the head, neck, esophagus, and stomach; additional areas of enhanced risk include the liver, the colon, and the lungs. The risks probably reflect alcohol-related immune system suppression, but might also be a result of the direct effects of ethanol on mucosal membranes. The heightened rates of malignant tumors in alcoholic persons remain significant even when the possible effects of smoking and poor nutrition are considered. Fetal Alcohol Effect Alcohol and acetaldehyde can have deleterious effects on the developing fetus. Both substances cross the placenta with ease, and in high enough doses can produce fetal death and spontaneous abortion. Surviving infants of heavy-drinking mothers can evidence any mixture of the components of a syndrome that in its full-blown form can include severe mental retardation, a small head, a diminished physical size, facial abnormalities (including a flat bridge of the nose, an absent philtrum, and an epicanthal eye fold), an atrial septal heart defect, and syndactyly. None of these problems is reversible; once present, the cognitive defects, physical irregularities, and behavioral problems remain throughout life. Because the exact amount of alcohol required and the most vulnerable periods of pregnancy have not been definitively established all pregnant women are advised to abstain from any use of alcohol.

ETIOLOGY Many factors affect the decision to drink, the development of temporary alcohol-related difficulties in the teenage years and the 20s, and the development of alcohol dependence. The initiation of alcohol intake probably depends on social, religious, and psychological factors, although the high rate of persons who have tried alcohol at some time during their lives indicates that drinking is an almost ubiquitous phenomenon in most Western societies. However, it is important to remember that the factors that influence the decision to drink or those that contribute to temporary problems might be different from those that contribute to the severe, recurring problems of alcohol dependence. Psychological Theories A variety of theories relate to the use of alcohol to reduce tension, increase feelings of power, and decrease the effects of psychological

pain. Perhaps the greatest interest has been paid to the observation that persons with alcohol-related problems often report that alcohol decreases their feelings of nervousness and helps them cope with the day-to-day stresses of life. The psychological theories are built in part on the observation among nonalcoholic persons that the intake of alcohol in a tense social setting or after a difficult day can, especially in low doses, be associated with an enhanced feeling of well-being and an improved ease of interactions. However, data indicate that in high doses, especially at falling blood alcohol levels, most measures of muscle tension and psychological feelings indicate that heavy drinking is likely to be associated with increased nervousness and tension. The theories that focus on alcohol's potential to enhance feelings of being powerful and sexually attractive and to decrease the effects of psychological pain are difficult to evaluate definitively. Psychodynamic Theories Perhaps related to the disinhibiting or anxiety-lowering effects of alcohol, at least at rising blood alcohol concentrations, is the hypothesis that some persons may use alcohol to help them deal with self-punitive harsh superegos as a way of decreasing unconscious stress levels. Also, classical psychoanalytical theory hypothesizes that at least some alcoholic persons have become fixated at the oral stage of development and use alcohol to relieve their frustrations by taking the substance by mouth. Alcoholic persons may also use the drug as part of a need for enhanced feelings of power. However, hypotheses regarding arrested phases of psychosexual development, although heuristically useful, have had little effect on the usual treatment approaches and are not the focus of extensive ongoing research. Similarly, several hypotheses have questioned the potential importance of addictive personality attributes because they may reflect levels of impulsiveness and sensation-seeking behavior. However, careful studies have failed to identify a unique personality profile that is prone to addictions, with the exception of antisocial personality disorder. Behavioral Theories Expectations about the rewarding effects of drinking and subsequent actual reinforcement after alcohol intake contribute to the decision to drink again after the first experience with alcohol. These issues are important in efforts to modify drinking behaviors in the general population, and they contribute to some important aspects of alcoholic rehabilitation. Sociocultural Theories Sociocultural theories are often based on observations of social groups that have high and low rates of alcoholism. Theorists hypothesize that ethnic groups such as Jews that introduce children to modest levels of drinking in a family atmosphere and that eschew drunkenness have low rates of alcoholism. Some other groups such as Irish men, with high rates of abstention but a tradition of drinking to the point of drunkenness among drinkers, are thought to have high rates of alcoholism. However, these theories often depend on stereotypes that are frequently erroneous and there are several exceptions to these rules. For example, some theories based on observations of the Irish and the French would have predicted high rates of alcoholism among the Italians, although alcohol problems are not generally observed at a high level in this group. In the final analysis, social and psychological theories probably have more than heuristic value. They outline factors that contribute to the onset of drinking, the development of temporary alcohol-related life difficulties, and even alcoholism. The problem is how to find a way to gather relatively definitive data to support or refute the theories.

BIOLOGICAL THEORIES Genetic Theories The best supported of the biological theories of alcoholism centers on genetics ( Table 11.2-2). One finding supporting the genetic conclusion is the threefold to fourfold increased risk for severe alcohol problems in close relatives of alcoholic persons. The rate of alcohol problems increases with the number of alcoholic relatives, the severity of their illness, and the closeness of their genetic relationship to the person under study. The family investigations do little to separate the importance of genetics and environment, but twin studies take the data a step further. The rate of similarity or concordance for severe alcohol-related problems is significantly higher in identical twins of alcoholic individuals than in fraternal twins in most studies. The adoption-type studies have all revealed a significantly enhanced risk for alcoholism in the offspring of alcoholic parents, even when the children had been separated from their biological parents close to birth and raised without any knowledge of the problems within the biological family. The risk for severe alcohol-related difficulties is not further enhanced by being raised by an alcoholic adoptive family.

Table 11.2-2 Data Supporting Genetic Influences in Alcoholism

These data not only support the importance of genetic factors in alcoholism, but also highlight the complexity of the phenomenon. The absence of evidence of a single major locus indicates the possibility that a limited number of genes operate with incomplete penetrance, or that a combination of genes is required before the disorder expresses itself (a polygenic mode of inheritance). Making matters even more complex is the likelihood that the disorder is solely an expression of environmental events in some families, and the probability that different genetic factors operate in different families to produce a picture of genetic heterogeneity. Despite these problems, studies have identified men and women at high future risk of alcoholism, usually defined as having an alcoholic parent. Persons at high and low future risk are then compared on psychological and biological parameters. Some protocols then expose young adults to an alcohol challenge, and several investigations have subsequently followed them over time. Related Biological Theories Different approaches have highlighted several potential leads to biological factors that may affect the risk of developing alcoholism. Investigations of early-teenage children of alcoholic parents, usually including inner-city families or children of persons with antisocial personality disorder, have shown the potential importance of several neurocognitive test results as possible predictors of a risk for alcoholism. Additional leads have come from electrophysiological evaluations of children of alcoholic persons, including the finding that perhaps one third of the sons of severely alcoholic men may have a decreased amplitude of the positive wave observed 300 milliseconds after a rare but unexpected sensory stimulus, the P3 wave of event-related potential (ERP). Other studies have shown a potential decrease in the amount of power in the slow alpha range on the background cortical electroencephalogram (EEG), or relative deficiencies in beta waves. An additional potential phenotypic marker involves the intensity of a person's reaction to an alcohol challenge. An ongoing study involves 453 sons of alcoholics and controls who were originally evaluated at approximately age 20, at which time they were all drinkers but none was alcohol dependent. At the time of initial evaluation, despite matching the two family history groups on drinking and drug use histories, and despite identical blood alcohol concentrations during the drinking experiment, 40 percent of the sons of alcoholics but less than 10 percent of the controls showed remarkably low levels of response to alcohol. The intensity of the reaction was measured by a combination of subjective feelings of intoxication, changes in motor performance while under the influence of alcohol, as well as alcohol-induced changes in blood hormones and electrophysiological functioning of the brain. An average of 8.2 years later, all 453 subjects were located, and information about functioning during the follow-up period was obtained from the subject and an additional informant for 450 individuals (99.3 percent). The low level of response to alcohol at approximately age 20 was a potent predictor of future alcoholism, with 60 percent of the sons of alcoholics who had a low response developing alcoholism by approximately age 30, whereas the same was true for only 15 percent of the sons of alcoholics who showed high levels of response to the alcohol challenge. Sons of nonalcoholics showed a similar pattern of relationship between the low response to alcohol and the future risk of alcoholism. The data revealed that for this relatively highly functional, often white-collar population the low response to alcohol was responsible for a large proportion of the ability of the family history to predict the risk of alcoholism. These follow-up data underscore some of the important issues related to genetic influences in this disorder. First, it is unlikely that anyone inherits a predestination for alcoholism. Rather, there are likely to be a variety of different genetically influenced characteristics that interact with the environment to increase the risk for severe

and repetitive alcohol-related life problems. Second, identification of traits that enhance the alcoholism risk, and possibly the genes related to these characteristics, might help to pinpoint the social and cultural factors that interact with a biological predisposition to produce the final level of risk for this disorder. It is possible that more knowledge about environmental and potentially changeable influences might help to develop more precise prevention approaches that can be applied to individuals who carry the highest risk.

DIAGNOSIS AND CLINICAL FEATURES Alcohol use disorders are probably the most common of the serious diagnosable behavioral or psychiatric disorders, and the diagnosis of alcohol dependence or abuse requires a high index of suspicion for the disorder in any patient. The average man or woman presenting with severe and repetitive alcohol problems is likely to be neatly dressed, to show no signs of severe alcohol withdrawal, to have a job and a family, and to complain of a variety of physical conditions or temporary but potentially severe psychiatric complaints. Thus, the clinician must gather a history of alcohol-related life problems from the patient and, whenever possible, a resource person, and must try to determine whether alcohol has caused or contributed to the psychiatric or physiological syndrome. Table 11.2-3 lists the alcohol-related disorders in DSM-IV, and also presents a comparable listing from ICD-10.

Table 11.2-3 DSM-IV Alcohol-Related Disorders and Corresponding ICD-10 Disorders

For patients presenting with psychiatric symptoms (e.g., anxiety, depression, or psychoses) as well as evidence of alcohol-related problems, the first step is to obtain a careful history from both the patient and a resource person who knows the patient well. Second, in taking the information the clinician must emphasize syndromes that meet diagnostic criteria for major depressive disorder or full anxiety syndromes or other disorders, not just symptoms such as sadness or nervousness. Third, the clinician must establish a time line from birth to the present, noting (1) the approximate age of onset of alcohol problems severe and repetitive enough to justify a diagnosis of alcohol dependence; (2) periods of abstinence of several months or more; and (3) the ages at which the patient met the criteria for any major psychiatric disorders, taking care to emphasize full-blown psychiatric clinical conditions, not isolated symptoms. If a review of the time line reveals no evidence that the additional psychiatric syndromes either antedated the severe alcohol problems or persisted for 4 or more weeks during a period of abstinence, alcoholism is the major disorder. Under these conditions the other psychiatric syndromes are important but temporary conditions that occurred during alcohol intoxication or withdrawal. Depressive, anxiety, and psychotic syndromes are often seen in people with alcohol-related disorders. However, even if the psychiatric symptoms are intense, they do not indicate a separate psychiatric syndrome when seen only during intoxication or withdrawal (i.e., they can be temporary alcohol-induced conditions). In an effort to encourage clinicians and researchers to consider the entire span of clinical conditions that might be relevant to any syndrome being observed, in DSM-IV all important diagnostic entities related to a specific phenomenon (e.g., depressive disorders, anxiety disorders, psychotic disorders) are now listed within the clinically relevant sections (e.g., the mood disorder section). For the sake of clarity, disorders associated with substances are now labeled as substance-induced disorders. To be termed a substance-induced condition, the syndrome must be clinically meaningful and must resemble the type of disorder described within that DSM-IV section (e.g., a mood disorder). There must be evidence indicating a likelihood that the clinical condition developed during, or within a month of, substance intoxication or withdrawal from a specific substance (such as alcohol) that would be capable of producing a relevant temporary clinical condition (such as a severe mood disturbance). The clinician and researcher are warned that the substance-induced condition should only be diagnosed when the psychiatric symptoms (e.g., depression) are in excess of those usually associated with intoxication or withdrawal. The diagnostic criteria further list the specific substances involved and ask that, if possible, the clinician specify whether the condition had an onset during intoxication or withdrawal. These latter modifiers are important to indicate to the clinician when additional medical and psychiatric treatment might be required. For alcohol-induced mood disorders, diagnoses can also be subtyped regarding the presence or absence of depressive, manic, or mixed features. DSM-IV offers similar information regarding a substance-induced anxiety disorder, which is listed in the section on anxiety disorders. Again, the condition must be clinically relevant; there must be evidence that a substance, such as alcohol, capable of producing a severe temporary anxiety condition was involved; and a distinction regarding an onset during intoxication or withdrawal is encouraged. The anxiety conditions can be further subdivided regarding the relevance of generalized anxiety symptoms, repetitive panic attacks, obsessive-compulsive symptoms, or phobic symptoms. The documentation of hallucinations and delusions associated with intoxication or withdrawal from relevant substances is covered in DSM-IV section on psychotic disorders. When the condition is clinically relevant and when evidence exists that a substance (such as alcohol) capable of causing the psychotic symptoms was involved, a diagnosis of a substance-induced psychotic disorder (in this instance alcohol-induced psychotic disorder) can be made. Additional criteria have been developed for alcohol-induced sexual dysfunction (see Table 19.1a-20) and alcohol-induced sleep disorders (see Table 21-18). Alcohol Dependence DSM-IV provides general criteria for all substance use disorders (see Table 11.1-3). Dependence concerns a history of a broad array of problems, including compulsive intake of alcohol, an increasingly important place in life occupied by the substance, and possibly evidence of physical withdrawal symptoms. Dependence criteria also concern life impairment related to the substance. Physical dependence or is a phenomenon that appears to be related to tolerance. As the body changes to resist the effects of alcohol, it is likely to reach a condition in which it cannot function optimally unless the brain depressant is present. That condition takes days or weeks to develop. DSM-IV substance dependence criteria include seven items that are subsets of the nine originally listed in DSM-III-R. These seven items are similar to the ICD-10 dependence syndrome criteria, although ICD-10 deals more directly with evidence of a compulsion to use (see Table 11.1-4). In addition, while maintaining the broad concept of dependence that appeared in DSM-III-R, DSM-IV asks the clinician to use the two items that deal with tolerance or withdrawal to further classify dependent persons into those with and those without evidence of physiological symptoms. This division allows clinicians and researchers to determine the treatment and the prognostic implications of tolerance and withdrawal. The framers of the fifth edition of DSM (DSM-IV) in the twenty-first century will then have data to help them decide whether to return to the emphasis on physiological symptoms that characterized earlier manuals (e.g., DSM-III). A 23-year-old graduate student in physics was referred for evaluation by her adviser who was concerned about tardiness at work and recent problems with a lack of clarity of thinking. As he discussed these difficulties with her, the student admitted to being concerned about her drinking, which had been dramatically emphasized to her in a recent intervention carried out by her father and mother. She related that for the last 5 years or so she has regularly consumed 1.5 to two or three bottles of wine each evening (approximately 9 to 18 drinks). In the last 2 years she has noted a marked increase in the need for more alcohol to get the same effects, reported giving up activities with her family in order to drink, spending a great deal of her time drinking, and driving long distances to obtain alcohol. She has repeatedly tried to cut down, often setting a limit of two drinks in an evening, but regularly going on to nine or more standard drinks before stopping. Despite her high general level of functioning, her active participation in a graduate education program, and close interpersonal relationships, this history of alcohol dependence is fairly typical among alcohol-dependent individuals. Alcohol Abuse The DSM-IV diagnostic criteria for abuse focus on the impairment of social, legal, interpersonal, and occupational functioning in a person who is not alcohol dependent (see Table 11.1-8). ICD-10 presents a diagnosis of harmful use that is only roughly similar to DSM-IV. The major difference is the restriction of the international system to issues of physical or psychological problems. The DSM-IV criteria were developed through careful comparisons of DSM-III and DSM-III-R

concepts, and were refined through a series of reanalysis of existing data sets and a large field trial of the criteria for abuse and dependence. The field trial involved comparisons of clinical coverage and demographic correlates of DSM-III-R and possible DSM-IV criteria, as applied to more than 1000 men and women from diverse groups and representing persons from the general population as well as those with diverse substance problems in six centers in the United States and four locations in other countries. Alcohol Intoxication The DSM-IV diagnostic criteria for alcohol intoxication are based on evidence of recent ingestion of ethanol, maladaptive behavior, and at least one of six possible physiological correlates of intoxication ( Table 11.2-4). The ICD criteria for acute alcohol intoxication are generally similar to the DSM-IV criteria. There are seven physiological signs of intoxication listed in the international system, some of which, such as conjunctival injection, are not listed in the DSM-IV criteria.

Table 11.2-4 DSM-IV Diagnostic Criteria for Alcohol Intoxication

As a conservative approach to identifying blood levels that are likely to have major effects on driving abilities in the majority of people, the legal definition of intoxication in most states in the United States requires a blood concentration of 80 or 100 mg ethanol per dL of blood (mg/dL), which is the same as 0.08 to 0.10 grams per deciliter (g/dL). For most people, a rough estimate of the levels of impairment likely to be seen at various blood alcohol concentrations can be outlined. Evidence of behavioral changes, a slowing in motor performance, and a decrease in the ability to think clearly occurs at doses as low as 20 to 30 mg/dL, as shown in Table 11.2-5. Blood concentrations between 100 and 200 mg/dL are likely to produce a progression of the impairment in coordination and judgment to severe problems with coordination (ataxia), increasing lability of mood, and progressively greater levels of cognitive deterioration. Anyone who does not show significant levels of impairment in motor and mental performance at about 150 mg/dL probably has significant pharmacodynamic tolerance. In that range most persons without significant tolerance also experience relatively severe nausea and vomiting. With blood alcohol concentrations in the 200 to 300 mg/dL range, the slurring of speech is likely to become more intense, and memory impairment (anterograde amnesia or alcoholic blackouts) becomes pronounced. Further increases in blood alcohol concentration result in the first level of anesthesia, and the nontolerant person who reaches 400 mg/dL or higher risks respiratory failure, coma, and death.

Table 11.2-5 Impairment Likely to Be Seen at Different Blood Alcohol Concentrations

Prior editions of DSM also described alcohol idiosyncratic intoxication. Currently termed pathological alcohol intoxication in ICD-10, it was characterized by extreme aggressive behavior occurring within minutes of ingesting relatively small amounts of alcohol, such as two drinks. According to DSM-III-R the person was usually amnestic for the episode, and the aggressive behavior was atypical of the person's usual sober comportment. However, a literature review before the publication of DSM-IV revealed little convincing evidence that such a disorder really exists, and it was deleted from the manual. The status of the condition in ICD-10 is being examined and must be regarded as tentative. Alcohol Withdrawal In persons who have been drinking heavily over a prolonged period of time, a rapid decrease in the amount of alcohol in the body might produce a variety of physical symptoms. This withdrawal or abstinence syndrome is characterized by a group of symptoms that are the opposite of what was initially experienced with intoxication. Therefore, after a person is physically dependent on alcohol, abstinence is likely to be accompanied by a coarse tremor of the hands, insomnia, anxiety, and increased blood pressure, heart rate, body temperature, and respiratory rate—a condition labeled in DSM-IV as alcohol withdrawal and described in Table 11.2-6. In ICD-10 the criteria for alcohol withdrawal are similar to those listed in DSM-IV, although there are differences in the items listed as physiological correlates of withdrawal as well as in the number of signs required (i.e., three) to make a diagnosis. The DSM-IV criteria for alcohol withdrawal also require that the symptoms must cause clinically significant distress or impairment in an important area of functioning.

Table 11.2-6 DSM-IV Diagnostic Criteria for Alcohol Withdrawal

Although 95 percent or more of withdrawals are limited to these mild or moderate symptoms, for 3 to 5 percent the symptoms include convulsions or delirium. Withdrawal phenomena are likely to begin within 8 hours of abstinence, reach a peak intensity on the second or third day, and markedly diminish by the fourth or fifth day. The symptoms can persist in a mild form for 3 to 6 months or more as part of a protracted withdrawal syndrome.

This 23-year-old graduate student in physics with alcohol dependence was unable to establish even 24 hours of sobriety as an outpatient. Therefore, reflecting her continued drinking, she was referred for inpatient care. Following approximately 10 hours of abstinence, and with a documented blood alcohol concentration of 0 mg/dL, she was noted to be mildly diaphoretic, with a respiratory rate of 25 breaths per minute, blood pressure of 130/90, a mild bilateral tremor of the hands, and a pulse rate of 85 beats per minute. She had a history of jogging 2 to 5 miles a day and these figures represented moderate elevations in her usual vital signs. Treated with multiple vitamins, good nutrition, oral fluids, and benzodiazepines, the symptoms rapidly improved, and her vital signs were close to normal by day four of abstinence. Alcohol Intoxication and Alcohol Withdrawal Delirium For the small proportion of intoxications and withdrawals that are accompanied by severe cognitive symptoms, both DSM-IV and ICD-10 contain the diagnoses of alcohol intoxication delirium and alcohol withdrawal delirium (see Table 10-22 and Table 10-23). When the symptoms of withdrawal are accompanied by a state of severe agitated confusion or delirium, sometimes associated with tactile or visual hallucinations, the diagnosis of alcohol withdrawal delirium (also called delirium tremens [DTs]) can be made. During withdrawal, some alcoholic persons show one or several grand mal convulsions, sometimes called rum fits. A 73-year-old professor emeritus at a university was thought to be in good health when he entered the hospital for an elective hernia repair. Perhaps reflecting his status in the community, the relatively brief history contained no detailed notes of his drinking pattern, and made no mention that his g-glutamyltransferase (GGT) values of 55 units per liter, along with the mean corpuscular volume (MCV) of 93.5 cubic microns. Eight hours postsurgery the nursing staff noted a sharp rise in the pulse rate to 110, an increase in blood pressure to 150/100, prominent diaphoresis, and a tremor to both hands, following which the patient demonstrated a brief but intense grandmal convulsion. He awoke after approximately 15 minutes extremely agitated and disoriented to time, place, and person. A reevaluation of the history and a separate interview with the wife documented alcohol dependence with a consumption of at least six to nine standard drinks per night. Over the following 4 days, the patient's autonomic nervous system dysfunction decreased as his cognitive impairment disappeared. His condition is classified as alcohol withdrawal delirium in DSM-IV. Alcohol-Induced Persisting Amnestic Disorder One of the most intensely studied alcohol-related central nervous system (CNS) syndromes is the relatively rare DSM-IV diagnosis of alcohol-induced persisting amnestic disorder (see Table 10-39), which is the result of a relatively severe deficiency in the B vitamin thiamine. Similar criteria are offered in ICD-10 as an amnesic syndrome. Some persons are at higher risk for this syndrome than are others because of a genetically influenced transketolase deficiency. The condition has been historically subdivided into (1) Wernicke's encephalopathy, with prominent ataxia and palsy of the sixth cranial nerve, a condition that tends to reverse fairly rapidly with vitamin supplementation, and (2) Korsakoff's syndrome, which is permanent in at least a partial form in perhaps 50 to 70 percent of the persons affected. Korsakoff's syndrome is characterized by a pronounced anterograde and retrograde amnesia and potential impairment in visuospatial, abstract, and other types of learning. In most cases the level of recent memory is out of proportion to the global level of cognitive impairment. The 25 percent or so of patients with Korsakoff's syndrome who are likely to recover fully and the 50 percent or so who recover partially appear to respond to 50 to 100 mg of oral thiamine a day, usually administered for many months. Alcohol-Induced Persisting Dementia An alcohol-related CNS diagnosis relevant to psychiatry is the relatively heterogeneous and poorly studied long-term cognitive problem that can develop in the course of alcoholism, namely alcohol-induced persisting dementia (see Table 10-31). Similar syndromes are described in ICD-10 as residual and late-onset psychotic disorder or as other persisting cognitive impairment. Global decreases in intellectual functioning, cognitive abilities, and memory are observed. Recent memory difficulties are consistent with global cognitive impairment, an observation that helps to distinguish the syndrome from alcohol-induced persisting amnestic disorder. The decreased brain functioning, including problems with psychomotor performance, tends to improve with abstinence, but perhaps half of all affected patients have long-term and even permanent memory and thinking disabilities. Perhaps 50 to 70 percent of these patients evidence increased size of the brain ventricles and shrinkage of the cerebral sulci, although these changes appear to be partially or completely reversible during the first year of complete abstinence. In the final analysis, it is unlikely that there is a single alcoholic dementia syndrome; rather, the problem seems to represent the combined effects of trauma, vitamin deficiencies, and the direct actions of alcohol and acetaldehyde. Alcohol-Induced Mood Disorder In the context of heavy and repetitive intake of any brain depressant, such as alcohol, symptoms of severe depression are common and may be labeled as an alcohol-induced mood disorder (Table 14.6-18). Like DSM-III-R, ICD-10 retains this and most related substance-induced syndromes in the section on organic mental disorders labeled as an organic mood [affective] disorder. For long-lasting mood disturbances, ICD-10 also has the labels of other persistent mood [affective] disorders and persistent mood [affective] disorder. The diagnosis in DSM-IV or ICD-10 focuses on either sadness or mania-like symptoms severe enough to impair functioning that occur only in the context of repeated heavy drinking and continue for several days to 4 weeks after abstinence. Heavy intake of alcohol over several days results in many of the symptoms observed in major depressive disorder, but the intense sadness improves within days to weeks of abstinence. Consistent with the theory that intoxication with brain depressants can cause severe symptoms of depression is the documentation that 80 percent of alcoholic persons report histories of intense depression; 30 to 40 percent were depressed for 2 or more weeks, during which they had symptoms that resembled a major depressive episode. However, when information from patients and resource persons was carefully evaluated, only 5 percent of alcoholic men and 10 percent of alcoholic women ever had depressions that met the criteria for major depressive disorder when they had not been drinking heavily. Clinical data reveal that when even severe depression develops in alcoholic persons, they are likely to improve fairly rapidly without medications or intensive psychotherapy aimed at the depressive symptoms. A recent study of almost 200 alcoholic men found that 40 percent had severe levels of depression after 1 week of abstinence. However, the percentage with pervasive depressive symptoms decreased to about 5 percent after 3 additional weeks of abstention from alcohol, even though no treatment was given for the mood symptoms. At the end of several weeks, most alcoholic patients are left with mood swings or intermittent symptoms of sadness that can resemble cyclothymic disorder or dysthymic disorder. Even those mild and intermittent depressive symptoms are likely to diminish and disappear with time. The presence of the dysthymic symptoms usually indicates the normal course of a withdrawal syndrome and not an independent mood disorder. A consultation was requested on a 42-year-old woman with alcohol dependence who complained of persisting severe depressive symptoms despite 5 days of abstinence. In the initial stage of the interview she noted that she had “always been depressed” and felt that she “drank to cope with the depressive symptoms.” Her current complaint included a prominent sadness that had persisted for several weeks, difficulties concentrating, initial and terminal insomnia, and a feeling of hopelessness and guilt. In an effort to distinguish between an alcohol-induced mood disorder and an independent major depressive episode, a time-line based history was obtained. This focused on the age of onset of DSM-IV alcohol dependence, periods of abstinence that extended for several months or more since the onset of dependence, and the ages of occurrence of clear major depressive episodes lasting several weeks or more at a time. Despite this patient's original complaints, it became clear that there had been no major depressive episodes prior to her mid-20s when alcohol dependence began, and that during a 1-year period of abstinence related to the gestation and neonatal period of the birth of her son, her mood had significantly improved. A provisional diagnosis of an alcohol-induced mood disorder was made. The patient was offered education, reassurance, and cognitive therapy to help her to deal with the depressive symptoms, but no antidepressant medications were prescribed. The depressive symptoms remained at their original intensity for several additional days, and then began to improve. By approximately 3 weeks abstinent the patient no longer met criteria for a major depressive episode, although she demonstrated mood swings similar to dysphemia for several additional weeks. This case is a fairly typical example of an alcohol-induced mood disorder in an individual with alcohol dependence. Alcohol-Induced Anxiety Disorder Anxiety symptoms fulfilling the diagnostic criteria for alcohol-induced anxiety disorder are also common in the context of acute and protracted alcohol withdrawal (see Table 15.6-18). In ICD-10 these are listed as organic anxiety disorders resembling generalized anxiety or panic disorders. Almost 80 percent of alcoholic persons report panic attacks during acute withdrawal; their complaints can be intense enough for the clinician to consider diagnosing a panic disorder. Similarly, during the first 4 to 6 weeks of abstinence, persons with severe alcohol problems are likely to avoid some social situations for fear of being overwhelmed by anxiety (i.e., they have symptoms resembling social phobia); their problems can at times be severe enough to resemble agoraphobia. The symptoms of nervousness during acute and protracted withdrawal can also include many of the problems seen in generalized anxiety disorder. However, when psychological or physiological symptoms of anxiety are observed in alcoholic persons only in the context of heavy drinking or within the first several weeks or months of abstinence, the symptoms are likely to diminish and subsequently disappear with time alone. If one correctly identifies temporary substance-induced syndromes, alcoholic persons are no more likely than people in the general population to have most independent major anxiety disorders. They are, however, much more likely to have temporary but intense symptoms of anxiety. Two anxiety disorders that might be more closely tied to alcoholism are panic disorder and social phobia.

A 52-year-old African-American male lawyer entered treatment for alcohol dependence with the chief complaint of “panic attacks” as well as alcohol problems. In light of evidence of concomitant panic disorder and alcohol dependence, a time-line history was established. This individual first met criteria for panic disorder by approximately age 18, and an intensification of occasional panic attacks occurred as he went off to college. After several visits to an emergency room during his freshman year, the diagnosis of panic disorder was made, and the current retrospective history revealed no evidence of dependence on alcohol or any other substance at that time. His panic disorder was treated with behavioral therapy and antidepressant medication, and was under good control when, at approximately age 33, he experienced an intensification of his alcohol intake and developed associated problems. He appears to have fulfilled criteria for alcohol dependence. During the course of his alcoholism, his panic disorder symptoms increased and decreased in intensity over time, with obvious exacerbations whenever he attempted to cut back on his alcohol intake. The diagnosis was alcohol dependence along with an independent panic disorder. Treatment focused on a continuation of the cognitive-behavioral therapy, antidepressant medications (when needed) for the panic disorder, as well as alcohol rehabilitation. Alcohol-Induced Psychotic Disorder About 3 percent of alcoholic persons have psychotic symptoms in the context of heavy drinking and withdrawal. In DSM-III-R those problems were labeled organic hallucinosis or delusional disorders. In ICD-10 they are presented as organic delusional disorders in the organic section and as a psychotic disorder in the substance use disorders section. Many of the symptoms resemble those seen in schizophrenia, but when the psychotic features develop only in the context of alcohol problems they are likely to clear spontaneously. The syndromes are likely to recur only if heavy alcohol intake resumes. A 39-year-old male letter carrier was brought to an emergency room by the police after he behaved in an unusual fashion at home and complained that his neighbors were trying to kill him. The history obtained from the patient and his wife revealed that his psychotic thinking developed slowly over the preceding 3 weeks; he began with feelings that people were looking at him at work, progressed to vague feelings that people were against him, and went on to frank auditory hallucinations that people at work and in the neighboring houses were talking about their plans to kill him. He had no insight into those paranoid delusions and auditory hallucinations. The relatively abrupt onset of the syndrome—he was in his late 30s—pointed to a potential organic cause, and further probing documented his daily drinking of between 6 and 18 beers for at least the preceding 10 weeks. A diagnosis of alcohol-induced psychotic disorder with onset during intoxication was made, and both hallucinations and delusions disappeared after 3 weeks of abstinence. After alcohol treatment, the man stayed sober for the next 8 months. Unfortunately, he later resumed heavy drinking and had a recurrence of both hallucinations and delusions. Alcohol-Related Disorder Not Otherwise Specified DSM-IV allows for the diagnosis of alcohol-related disorder not otherwise specified for alcohol-related disorders that do not meet the diagnostic criteria for any of the other diagnoses ( Table 11.2-7). ICD-10 offers the listings of other or unspecified mental and behavioral disorders induced by alcohol.

Table 11.2-7 DSM-IV Diagnostic Criteria for Alcohol-Related Disorder Not Otherwise Specified

Laboratory and Physical Examination Establishing the diagnosis for alcohol abuse or dependence centers on obtaining from the patient and a resource person a history of the patient's life problems and the possible role played by alcohol. Up to one third of all psychiatric patients are likely to have an alcohol problem that either caused or exacerbated the presenting clinical condition. The process of identification can also be facilitated by a series of blood tests, outlined in Table 11.2-8. Those state markers of heavy drinking reflect physiological alterations likely to be observed if the patient regularly ingests four or more drinks a day over many days or weeks. One of the most sensitive and specific of the markers (perhaps 60 to 80 percent sensitivity and specificity) is a level of 30 or more units per liter of g-glutamyltransferase (GGT), an enzyme that aids in the transport of amino acids and that is found in most areas of the body. Because this enzyme is likely to return to normal levels after 2 to weeks of abstinence, even 20 percent increases in enzyme levels above those observed after 4 weeks of abstinence can be useful in identifying patients who have returned to drinking after treatment. Equally impressive results have been reported for the measure of a deglycosylated form of the protein transferrin, known as carbohydrate-deficient transferrin (CDT). Using a commercially available assay, CDTect, and employing a cutoff of 20 mg/L, this test has both a sensitivity and a specificity of 65 to 80 percent for the identification of the heavy consumption of alcohol (e.g., 5 to 8 drinks per day for a week); these figures might be slightly lower for women. With a biological half-life of about 16 days, this test can also be useful in monitoring abstinence in alcoholics. It appears that patients not identified by higher GGT values might still have elevations in CDT so that both tests should be used for identification and abstinence-monitoring functions in alcoholics.

Table 11.2-8 State Markers of Heavy Drinking Useful in Screening for Alcoholism

The MCV blood test, with perhaps 70 percent sensitivity and specificity, is a state marker when the size of the red blood cell is 91 or more cubic micrometers. The 120-day life span of the red cell does not allow the test to be used as an indicator of a return to drinking after about 1 month of abstinence. Other tests that can be helpful in identifying patients who are regularly consuming heavy doses of alcohol include those for high normal concentrations of uric acid (greater than 6.4 mg/dL, with a range that depends on the sex of the person); mild elevations in the usual liver function tests, including aspartate aminotransferase and alanine aminotransferase; and elevated levels of triglycerides or LDL cholesterol. A number of physical findings can also be useful in identifying the alcoholic patient. These findings include modest elevations in blood pressure, frequent bruising, cancer of the head and neck and upper digestive tract, an enlarged liver, evidence of cirrhosis, and symptoms consistent with pancreatitis.

A 41-year-old mechanic consulted a physician for a physical examination related to his application for an insurance policy. The history revealed a prior divorce along with some problems in the current marriage, difficulties getting along with his foreman at work who complained about the patient's occasional absences, and some difficulties with insomnia and restless sleep. The patient denied symptoms of intense depression, but did admit to moodiness. The physical examination revealed a mild elevation in blood pressure (140/90), but was otherwise within normal limits. The panel of laboratory results included a MCV of 94.8 cubic microns, a CDT value of 25 mg/L, and a GGT of 55 units per liter. Although the patient had initially reported himself to be a “moderate social drinker,” a more detailed history revealed that he drank 6 to 8 beers on weeknights, and 12 to 20 beers a day on weekends. The physician shared her impressions regarding the pattern of life problems, noted the elevation in the state markers of heavy drinking, and told the patient that she felt that he had reached a point where alcohol was causing repeated problems, while noting in the chart the diagnosis of alcohol dependence. The objective data available to the physician regarding laboratory values helped her efforts to optimize this patient's motivation for abstinence.

DIFFERENTIAL DIAGNOSIS Once the pattern of alcohol-related life problems has been established, the diagnosis of alcohol abuse or dependence is fairly obvious. A substantial proportion of the information presented in this chapter also helps the clinician to take the next logical step: determining whether an independent major psychiatric disorder exists. Briefly, individuals who present with clinically significant levels of depression, anxiety, or psychotic symptoms in addition to their alcoholism should be evaluated using the time-line approach in order to determine whether the psychiatric symptoms are likely to have been substance-induced (and are thus temporary) or represent independent and longer-term psychiatric disorders. In addition, the clinical course of the psychiatric symptoms should be closely observed during the subsequent several weeks to a month or so of abstinence, in order to determine whether the depression, anxiety, and other symptoms decrease in intensity over time. Although some symptoms might remain as part of a protracted withdrawal syndrome, if the disorder is substance-induced the individual should no longer fulfil criteria for the full diagnostic syndrome after a month or so of abstaining from alcohol. Antisocial Personality Disorder When the emphasis on the chronological development of symptoms is used, at least three diagnoses— antisocial personality disorder, schizophrenia, and bipolar I disorder—are likely to predate alcohol abuse or dependence and to be true comorbid conditions. Antisocial personality disorder, listed on Axis II, begins early in life and has major effects on many aspects of life functioning. The diagnosis is based on evidence of severe antisocial behaviors in many areas beginning before the age of 15 years and continuing into adulthood. Persons with antisocial personality disorder are described as impulsive, frequently violent, highly likely to take risks, and unable to learn from their mistakes or to benefit from punishment. A person who carries these characteristics into adolescence, the typically time for experimentation with alcohol and drugs, can be expected to have difficulty controlling substance use. Thus, perhaps 80 percent or more of persons with antisocial personality disorder are likely to have severe secondary alcohol problems in the course of their lives. A diagnosis of pre-existing antisocial personality disorder with subsequent alcohol abuse or dependence indicates someone who is more likely than the average alcoholic person to have severe coexisting drug problems, to be violent, to discontinue treatment prematurely, and to have a much less than optimistic prognosis. Debate continues on the optimal manner of viewing the co-occurrence of antisocial personality disorder and alcoholism, but most researchers agree that the personality disorder is a separate entity worthy of diagnosis. The genetic factors that increase the risk for antisocial personality disorder may be separate from those that affect the development of alcoholism. In most treatment programs, perhaps 5 percent of alcoholic women and between 10 and 20 percent of alcoholic men have preexisting antisocial personality disorder. Other Axis II-type symptoms are often observed during intoxication and as part of the acute and protracted abstinence syndromes, but they have not been documented to predate the alcohol-related disorders. Schizophrenia A second disorder in which secondary alcohol problems are more common than in the general population is schizophrenia. Characterized by what is usually a slow onset of paranoid delusions and auditory hallucinations in a clear sensorium and typically beginning in the mid-teens to the 20s, schizophrenia is likely to be severe and debilitating. Possibly because of a lack of long-term treatment facilities, persons with schizophrenia are likely to live in inner-city areas and to spend a great deal of time on the streets. Perhaps because they use alcohol to decrease feelings of isolation or to self-medicate their symptoms, persons with schizophrenia are more likely than those in the general population to go on to have severe alcohol-related life problems. Their alcohol intake is likely to undercut the effectiveness of appropriate antipsychotic medications, to increase mood swings and signs of psychoses, and to contribute to a downward course of schizophrenia that entails repeatedly revolving into and out of inpatient care. Because most alcohol treatment programs exclude actively psychotic patients, schizophrenia persons rarely appear in inpatient alcohol treatment programs. However, severe alcohol-related disorders are observed in 30 percent or so of schizophrenic persons being treated in public mental health facilities. A 34-year-old unemployed, divorced white male entered treatment for alcohol dependence. His history revealed seven prior hospitalizations since the age of 23, with most discharge diagnoses including schizophrenia, and some noting alcohol dependence. The patient was a poor historian, and no additional informants were available. However, the information from prior hospitalizations revealed that at the time of the initial inpatient stay the patient had experienced approximately 1 year of auditory hallucinations and paranoid delusions. During that time he had not yet demonstrated severe enough problems related to alcohol or other drugs to fulfill criteria for dependence. Subsequently, a hospitalization at age 28 was followed by a 6-month stay in a recovery home during which the records indicated that there had been no alcohol or illicit drug use, despite which the patient continued to demonstrate auditory hallucinations and paranoid delusions without insight. The current hospitalization involved a thorough physical examination and initiation of treatment of alcohol withdrawal while re-evaluating and stabilizing the antipsychotic medication level for this individual who demonstrated both alcohol dependence and an independent schizophrenia disorder. Bipolar I Disorder The third disorder in which severe alcohol problems are overrepresented is bipolar I disorder. In a manic episode, the patient is hyperexcited and impulsive, carries out most activities to excess, has poor judgment, and is likely to develop temporary alcohol problems. The severity of the manic symptoms usually precludes inpatient alcohol rehabilitation while the patient is actively manic. However, alcohol-related difficulties must be evaluated in histories taken from persons with manic features entering mental health facilities. Major Anxiety Disorders Finally, there are data from recent studies that support a small but statistically significant association between independent (i.e., not alcohol-induced) panic disorder and perhaps independent social phobia and alcohol dependence. One large investigation involved over 3000 personal interviews carried out across six centers in different parts of the United States. While about 90 percent of alcohol-dependent men and women did not have a major anxiety disorder there was no evidence for a significant increased risk for most major anxiety disorders, the rates of independent panic disorder and independent social phobia were significantly higher than in controls. Other Disorders Debate in the literature continues about whether major depressive disorder, agoraphobia, obsessive-compulsive disorder, and other major psychiatric diagnoses are overrepresented in the histories of alcoholic persons. Several studies indicate that, when the time-line method is used and a history is obtained from many informants, little evidence is found for very high rates of most independent psychiatric disorders among alcoholic persons, other than the three disorders noted above. Therefore, although the majority of alcoholic persons have temporary psychiatric symptoms, they are not more likely than are persons in the general population to carry an independent psychiatric syndrome other than the three exceptions discussed above. There are interesting and complex relations between alcohol dependence and dependence on other drugs. Men and women with the antisocial personality disorder demonstrate a marked increased risk for dependence on multiple substances, including alcohol. It is also probable that individuals with dependence on opiates and stimulants (such as cocaine and amphetamines) exhibit an increased risk for alcohol dependence even in the absence of antisocial personality disorder. However, most alcohol-dependent people do not meet the criteria for dependence on other drugs. Several recent investigations of children of alcohol-dependent men and women, as well as the large Collaborative Study on the Genetics of Alcoholism (COGA) indicated that once the effects of the antisocial personality disorder were controlled, alcohol dependence appeared to run relatively true within families, without evidence of a marked crossover between alcoholism and other dependencies. An exception to this general rule is nicotine dependence, which has long been noted to be elevated among alcohol-dependent individuals, a finding that has been hypothesized to relate to either attempts to use nicotine to try to moderate some of the effects of high doses of alcohol or withdrawal, or a possible genetic relationship between nicotine and alcohol-dependence syndromes.

COURSE AND PROGNOSIS Details of a clinical course that fit the great majority of persons with any disorder are difficult to describe. However, sufficient data regarding alcohol-related disorders are available to offer a general outline of the typical pattern of problems. Several recent evaluations of large numbers of alcohol-dependent individuals suggest that most subgroups of alcoholics are more similar than different on the time course and prevalence of alcohol-related life difficulties. The differences that do exist reflect characteristics of individuals in society in general and do not appear to

indicate any unique aspects of their alcoholism as such. Thus, for example, similar to women in the general population, compared to male alcoholics, female alcoholics have higher rates of independent depressive episodes, and slightly lower proportions of women who have ever engaged in alcohol-related violence or have had severe alcohol-related driving problems. However, in general, the clinical courses of alcohol-dependent men and women are relatively similar. Older as compared to younger alcohol-dependent individuals are more likely to have medical problems, to take multiple medications, to experience more severe withdrawal syndromes, probably to have a less extensive social support system. Again, these characteristics reflect differences between older versus younger individuals in general more than they indicate potential unique aspects of alcoholism in the geriatric population. Thus, while the reader is advised to take the following information as general guidelines that must be applied with common sense to subgroups of individuals, it is possible to present generalities regarding the usual clinical course of alcoholism and its treatment. Early Course Patients with antisocial personality disorder who later go on to develop alcoholism have an early onset of drinking, intoxication, and alcohol-related problems, but that scenario is not applicable to the other 80 to 90 percent of alcoholic men and 95 percent of alcoholic women. Usually, alcoholic persons have their first drink (other than taking a sip from a parent's glass) between the ages of 13 and 15 years, the first intoxication is likely to occur at 15 or 16 years, and the first evidence of a minor alcohol-related problem is usually observed in the late teenage years. These milestones do not differ significantly from what is expected for people in the general population who do not later go on to develop alcohol abuse or dependence. For the average person the pattern of severe difficulties becomes apparent in the middle 20s to the middle 30s when a constellation of symptoms of relatively great severity is likely to be observed: an alcohol-related breakup of a significant relationship, a second alcohol-related driving or public intoxication arrest, evidence of alcohol withdrawal, being told by a physician that alcohol has harmed the person's health, or significant interference with functioning at school or work. This pattern probably does not vary much with the type of beverage used—beer, wine, or spirits. The landmarks in Table 11.2-9 are only rough estimates and can differ greatly between people and among various groups. Women, for example, are likely to begin drinking later than men, but their subsequent escalation of symptoms is likely to be slightly more rapid than that seen in men.

Table 11.2-9 Clinical Course of Alcohol Dependence

Later Course Once alcohol's interference with life functioning has become apparent, the future is likely to include periods of drinking problems that repeatedly alternate with periods of abstinence and periods of alcohol intake unassociated with problems (temporary controlled drinking). Abstinence often develops in response to some interpersonal, social, or legal crisis and is likely to produce only mild withdrawal symptoms. Average alcoholic persons are then likely to use the temporary cessation of drinking problems to convince themselves that alcohol is not really a cause for concern after all. Those periods of abstinence, lasting days to months, are common in the course of most persons with alcoholism and are usually followed by periods during which drinking rules are established and are temporarily followed. The person is likely to consume only beer or wine (forgetting that a glass of beer, a glass of wine, and a shot of whiskey have similar amounts of alcohol) and tries to drink only at certain times of the day and under certain conditions. This period of temporary control soon leads to an escalation of alcohol intake, the accumulation of a new set of problems, and a subsequent crisis. These events, in turn, are likely to precipitate a new period of abstinence, and the cycle begins again. Thus, controlled drinking is a common but temporary condition for most alcoholic persons. Those who have less severe alcohol problems, such as those who may fulfill the diagnostic criteria for alcohol abuse in DSM-IV, are probably more likely to have long-term and even permanent periods of control. However, several research projects have indicated that long-term continued control is not likely to be seen once a person meets the diagnostic criteria for alcohol dependence. An additional attribute important in the course of alcohol dependence is the phenomenon of spontaneous remission. Perhaps in response to nonspecific events or to a crisis, the alcoholic person promises to abstain and keeps the promise forever. Whatever the cause of the abstinence, about 20 percent or more of alcoholic persons, if followed over a long enough period of time, probably do achieve permanent abstinence, even without formal treatment or participation in such self-help groups as Alcoholics Anonymous (AA). Even in the average blue- or white-collar alcohol-dependent person, the life span is likely to be decreased. This foreshortening of 10 to 15 years is associated with many causes, including the marked increased risks for heart disease, cancer, accidents, and suicide among alcoholic individuals. Prognosis Between 10 and 40 percent of alcoholic persons enter some kind of formal treatment program during the course of their alcohol problems. A number of prognostic signs are favorable. First is the absence of preexisting antisocial personality disorder or a diagnosis of other substance abuse or dependence. Second, evidence of general life stability with a job, continuing close family contacts, and the absence of severe legal problems also bodes well for the patient. Third, if the patient stays for the full course of the initial rehabilitation (perhaps 2 to 4 weeks), the chances of maintaining abstinence are good. The combination of these three attributes predicts at least a 60 percent chance for 1 or more years of abstinence. Few studies have documented the long-term course, but researchers agree that 1 year of abstinence is associated with a good chance for continued abstinence over an extended period of time. However, alcoholic persons with severe drug problems (especially intravenous drug use or cocaine or amphetamine dependence) and those who are homeless may have only a 10 to 15 percent or so chance of achieving 1 year of abstinence. Accurately predicting whether any specific person will achieve or maintain abstinence is impossible, but the prognostic factors listed above are associated with an increased likelihood of abstinence. However, the factors reflecting life stability probably explain only 20 percent or less of the course of alcohol use disorders. Many forces that are difficult to measure have significant effects on the clinical course; they are likely to include such intangibles as levels of motivation and the quality of the patient's social support system. In general, alcoholic persons with preexisting independent major psychiatric disorders—such as antisocial personality disorder, schizophrenia, and bipolar I disorder—are likely to run the course of their independent psychiatric illness. Therefore, for example, clinicians must treat the patient with bipolar I disorder who has secondary alcoholism with appropriate psychotherapy and lithium (Eskalith), use relevant psychological and behavioral techniques for the patient with antisocial personality disorder, and offer appropriate antipsychotic medications on a long-term basis to the patient with schizophrenia. The goal is to keep the symptoms of the independent psychiatric disorder as minimal as possible in the hope that a greater level of life stability will be associated with a better prognosis for the patient's alcohol problems.

TREATMENT The elements of treatment appropriate for patients with severe alcohol problems are fairly straightforward. Much of the clinical challenge comes in recognizing how prevalent the alcohol-related disorders are, how often those conditions present with symptoms of other psychiatric syndromes, and how to use clinical clues, physical findings, and laboratory tests to identify alcoholism. Three general steps are involved in treating the alcoholic person once the disorder has been diagnosed—intervention, detoxification, and rehabilitation. Those approaches assume that all possible efforts have been made to optimize medical functioning and to address psychiatric emergencies. Thus, for example, the alcoholic person with symptoms of depression severe enough to be suicidal requires inpatient hospitalization for at least several days until the suicidal ideation disappears.

Similarly, the person presenting with cardiomyopathy, liver difficulties, or gastrointestinal bleeding first needs adequate attention paid to the medical emergency. The patient with alcohol abuse or dependence must then be brought face-to-face with the reality of the disorder (intervention), be detoxified if needed, and begin rehabilitation. The essentials of these three steps for an alcoholic person with independent psychiatric syndromes are quite similar to the approaches used for the primary alcoholic person without independent psychiatric syndromes. However, in the former case the treatments are applied after the psychiatric disorder has been stabilized to the maximum degree possible. Intervention The goal in this step, which has also been called confrontation, is to break through feelings of denial and to help the patient recognize the adverse consequences likely to occur if the disorder is not treated. Intervention is as a process aimed at increasing to as high a level as possible the levels of motivation for treatment and for continued abstinence. This step often involves convincing patients that they are responsible for their own actions while reminding them how alcohol has created significant life impairments. The psychiatrist often finds it useful to take advantage of the person's chief presenting complaint, whether it is insomnia, difficulties with sexual performance, an inability to cope with life stresses, depression, anxiety, or psychotic symptoms. The psychiatrist can then teach the patient how alcohol has either created or contributed to these problems, and can reassure the patient that abstinence can be achieved with a minimum of discomfort. A physician was consulted by a 43-year-old businessman who was concerned about his wife. He had recently been confronted by their 21-year-old daughter who felt that her mother was an alcoholic. The daughter noted her mother's slurred speech on several recent occasions when the daughter called home, times during the day when the mother was apparently home but did not answer the telephone, and observed high levels of alcohol consumption. A more detailed history revealed that the husband had been concerned about the wife's drinking pattern for at least 5 years, relating her practice of staying up after he went to bed, retiring later with alcohol on her breath. He also noted her consumption of 10 to 12 drinks at parties, with the resulting tendency to isolate herself from the remaining guests, her panic-like behavior regarding the need to pack liquor when they go on trips where alcohol might not be readily available, and what he observed to be a tremor of her hands some mornings during breakfast. The husband was given several potential courses of action, including the possibility of referring the spouse for treatment with the physician. The husband was advised to share his concern with his wife at a time when she was not actively intoxicated, emphasizing specific times and events where her impairment with alcohol was noted. He was also asked to consider whether a close friend of many years and the adult daughter might be included in this intervention, and it was suggested that a tentative appointment might be made with the clinician (or with an alcohol and drug treatment program) so that a next step could be established if the intervention was successful. A physician intervening with a patient can use the same nonjudgmental but persistent approach each time an alcohol-related impairment is identified. It is the level of persistence rather than exceptional interpersonal skills that usually gets results. A single intervention is rarely enough. Most alcoholic persons need a series of reminders of how alcohol contributed to each developing crisis before they seriously consider abstinence as a long-term option. Family The family can be of great help in the intervention. Family members must learn not to protect the patient from the problems caused by alcohol otherwise the patient may not be able to gather the energy and the motivation necessary to stop drinking. During the intervention stage, the family can also suggest that the patient meet with persons who are themselves recovering from alcoholism, perhaps through AA, and they can meet with groups, such as Alanon, that reach out to family members. Those support groups for families meet many times a week and help family members and friends see that they are not alone in their fears, worry, and feelings of guilt. Members share coping strategies and help each other find community resources. The groups can be most useful in helping family members rebuild their lives, even if the alcoholic person refuses to seek help. Detoxification Most persons with alcohol dependence have relatively mild symptoms when they stop drinking. If the patient is in relatively good health, adequately nourished, and has a good social support system the depressant withdrawal syndrome usually resembles a mild case of the flu. Even intense withdrawal syndromes rarely approach the severity of symptoms described by some early textbooks in the field. The essential first step in detoxification is a thorough physical examination. In the absence of a serious medical disorder or combined drug abuse, severe alcohol withdrawal is unlikely. The second step is to offer rest, adequate nutrition, and multiple vitamins, especially those containing thiamine. Mild or Moderate Withdrawal Withdrawal develops because the brain has physically adapted to the presence of a brain depressant and cannot function adequately in the absence of the drug. Giving enough of a brain depressant on the first day to diminish symptoms and then weaning the patient off the drug over the next 5 days offers most patients optimal relief and minimizes the possibility that a severe withdrawal will develop. Any depressant—including alcohol, barbiturates, or any of the benzodiazepines—can work, but most clinicians chose a benzodiazepine for its relative safety. Adequate treatment can be given with either short-acting drugs, such as lorazepam (Ativan), or long-acting substances, such as chlordiazepoxide (Librium) and diazepam (Valium). An example of treatment is the administration of 25 mg of chlordiazepoxide by mouth three or four times a day on the first day, with a notation to skip a dose if the patient is asleep or feeling sleepy. An additional one or two 25-mg doses during the first 24 hours can be used if the patient is jittery or shows signs of increasing tremor or autonomic dysfunction. Whatever the dosage required on the first day, the benzodiazepine can be decreased by 20 percent of it each subsequent day, with a resulting need for no further medication after 4 or 5 days. When using a long-acting agent, such as chlordiazepoxide, the clinician must avoid producing excessive sleepiness through overmedication; if the patient is sleepy, the next scheduled dose should be omitted. When taking a short-acting drug, such as lorazepam, the patient must not miss any dose because rapid changes in blood benzodiazepine concentrations may precipitate a severe withdrawal. A social model program of detoxification saves money by avoiding medications while using social supports. This less expensive regimen can be helpful for mild or moderate withdrawal syndromes. Some clinicians have also recommended b-adrenergic receptor antagonists, such as propranolol (Inderal), or a-adrenergic receptor such as agonists, clonidine (Catapres), although these medications do not appear to be superior to the benzodiazepines. Unlike the brain depressants, these other agents do little to decrease the risk of seizures or delirium. Severe Withdrawal For the approximately 1 to 3 percent of alcoholic patients with extreme autonomic dysfunction, agitation, and confusion—that is, those with alcoholic withdrawal delirium, also called delirium tremens—no optimal treatment has yet been developed. The first key step is to ask why such a severe and relatively uncommon withdrawal syndrome has occurred; the answer often relates to a severe concomitant medical problem that needs immediate treatment. The withdrawal symptoms can then be minimized either through the use of benzodiazepines (in which case high doses are sometimes required), or through antipsychotic agents, such as haloperidol (Haldol) and thioridazine (Mellaril). Once again, doses are used on the first or second day to control behavior, and the patient can be weaned off the medication by about the fifth day. Another 1 to 3 percent of patients may have a single grand mal convulsion; the rare person has multiple fits and the peak incidence is on the second day of withdrawal. Such patients require a neurological evaluation, but in the absence of evidence of a seizure disorder they do not benefit from anticonvulsant drugs. Rehabilitation For most patients, rehabilitation includes three major components: (1) continued efforts to increase and maintain high levels of motivation for abstinence, (2) work to help the patient readjust to a life-style free of alcohol, and (3) relapse prevention. Because these steps are carried out in the context of acute and protracted withdrawal syndromes and life crises, treatment requires repeated presentations of similar materials that remind the patient how important abstinence is and that help the patient develop new day-to-day support systems and coping styles. No single major life event, traumatic life period, or identifiable psychiatric disorder is known to be a unique cause of alcoholism. In addition, the effects of any causes of alcoholism are likely to have been diluted by the effects of alcohol on the brain and the years of an altered life-style, so that the alcoholism has developed a life of its own. This is true even though many alcoholic persons believe that the cause was depression, anxiety, life stress, or pain syndromes. Research, data from records, and resource persons usually reveal that the alcohol contributed to the mood disorder, accident, or life stress, not vice versa. The same general treatment approach is used in inpatient as well as outpatient settings. The selection of the more expensive and intensive inpatient mode often depends on evidence of additional severe medical or psychiatric syndromes, the absence of appropriate nearby outpatient groups and facilities, and the patient's history of having tried but failed in outpatient care. The treatment process in either setting involves intervention, optimizing physical and psychological functioning, enhancing motivation, reaching out to family, and using the first 2 to 4 weeks of care as an intensive period of help. Those efforts must be followed by at least 3 to 6 months of less frequent outpatient care. Outpatient care uses a combination of individual and group counseling, the judicious avoidance of psychotropic medications

unless needed for independent disorders, and involvement in such self-help groups as AA. Counseling Counseling efforts in the first several months should focus on day-to-day life issues to help patients maintain a high level of motivation for abstinence and to enhance their levels of functioning. Psychotherapy techniques that provoke anxiety or that require deep insights have not been shown to be of benefit during the early months of recovery and, at least theoretically, may actually impair efforts at maintaining abstinence. Therefore, this discussion focuses on the efforts likely to characterize the first 3 to 6 months of care. Counseling or therapy can be carried out in an individual or group setting; few data indicate that either approach is superior to the other. The technique used is not likely to matter greatly, and usually boils down to simple day-to-day counseling or almost any behavioral or psychotherapeutic approach focusing on the here and now. To optimize motivation, treatment sessions should explore the consequences of drinking, the likely future course of alcohol-related life problems, and the marked improvement that can be expected with abstinence. Whether in an inpatient or an outpatient setting, individual or group counseling is usually offered for a minimum of three times a week for the first 2 to 4 weeks, followed by less intense efforts, perhaps once a week, for the subsequent 3 to 6 months. Much time in counseling deals with how to build a life-style free of alcohol. Discussions cover the need for a sober peer group, a plan for social and recreational events without drinking, and approaches for reestablishing communication with family members and friends. The third major component, relapse prevention, begins with identifying situations in which the risk for relapse is high. The counselor must help the patient to develop modes of coping to be used when the craving for alcohol increases or when any event or emotional state makes a return to drinking likely. An important part of relapse prevention is reminding the patient about the appropriate attitude toward slips. Those short-term experiences with alcohol can never be used as an excuse for returning to regular drinking. The efforts to achieve and maintain a sober life-style are not a game in which all benefits are lost with that first sip. Rather, recovery is a process of trial and error; patients use slips when they occur to identify high-risk situations and to develop more appropriate coping techniques. Most treatment efforts recognize the effects that alcoholism has on the significant people in the patient's life and an important aspect of recovery involves helping family members and close friends to understand alcoholism and how rehabilitation is an ongoing process that lasts for 6 to 12 or more months. Couples and family counseling and support groups for relatives and friends help the persons involved to rebuild relationships, to learn how to avoid protecting the patient from the consequences of any drinking in the future, and to be as supportive as possible of the alcoholic patient's recovery program. Medications If detoxification has been completed and the patient is not one of the 10 to 15 percent of alcoholic persons who have an independent mood disorder, schizophrenia, or anxiety disorder, there is little evidence in favor of prescribing psychotropic medications for the treatment of alcoholism. Lingering levels of anxiety and insomnia as part of a reaction to life stresses and protracted abstinence should be treated with behavior modification approaches and reassurance. Medications, including benzodiazepines, for these symptoms are likely to lose their effectiveness much faster than the insomnia disappears; as a result the patient may increase the dose and have subsequent problems. Similarly, sadness and mood swings can linger at low levels for several months. However, controlled clinical trials indicate no benefit in prescribing antidepressant medications or lithium to treat the average alcoholic person who has no independent or long-lasting psychiatric disorder. The mood disorder will clear before the medications can take effect, and patients who resume drinking while on the medications face significant potential dangers. With little or no evidence that the medications are effective, the dangers significantly outweigh any potential benefits from their routine use. One possible exception to the proscription against the use of medications is the alcohol-sensitizing agent disulfiram. Disulfiram is given in dosages of 250 mg a day before the patient is discharged either from the intensive first phase of outpatient rehabilitation or from inpatient care. The goal is to place the patient in a condition in which drinking alcohol precipitates an uncomfortable physical reaction, including nausea, vomiting, and a burning sensation in the face and stomach. Unfortunately, few data convincingly prove that disulfiram is more effective than a placebo, probably because most people stop taking the disulfiram when they resume drinking. Many clinicians have stopped routinely prescribing the agent, partly in recognition of the dangers associated with the drug itself: mood swings, rare instances of psychosis, the possibility of an increase in peripheral neuropathies, the relatively rare occurrence of other significant neuropathies, and a potentially fatal hepatitis. Moreover, patients with pre-existing heart disease, cerebral thrombosis, diabetes, and a number of other conditions cannot be given disulfiram because an alcohol reaction to the disulfiram could be fatal. Two additional promising pharmacological interventions have recently been studied. The first involves the opiate antagonist naltrexone (ReVia), which is at least theoretically believed to possibly decrease the craving for alcohol or blunt the rewarding effects of drinking. In any event, two relatively small (i.e., approximately 90 patients on the active drug across the studies) and short-term (i.e., 3 months of active treatment) investigations using 50 mg per day of this drug had potentially promising results. However, it is difficult to evaluate the full impact of this medication unless longer-term studies of relatively large groups of more diverse patients are evaluated. The second medication of interest, acamprosate (Campral), has been tested in over 5000 alcohol-dependent patients in Europe, this drug is not yet available in the United States. Used in dosages of approximately 2000 mg per day, this medication was associated with an approximately 10 to 20 percent higher rate of positive outcome than placebo when used in the context of the usual psychological and behavioral treatment regimen for alcoholism. Once again, the mechanisms of actions of acamprosate are not known but might relate to an impact on g-aminobutyric acid (GABA) or on the NMDA system craving or the rewarding effects of alcohol. Another medication with potential promise in the treatment of alcoholism is the nonbenzodiazepine antianxiety drug, buspirone (BuSpar), although the effect of this drug on alcohol rehabilitation is inconsistent between studies. However, at the same time, there is no evidence that antidepressant medications such as the SSRIs, lithium, or antipsychotic medications, are significantly effective in the treatment of alcoholism. Self-Help Groups Clinicians must recognize the potential importance of self-help groups like AA. Members of AA have help available 24 hours a day, associate with a sober peer group, learn that it is possible to participate in social functions without drinking, and are given a model of recovery by observing the accomplishments of sober members of the group. Learning about AA usually begins during inpatient or outpatient rehabilitation. The clinician can play a major role in helping patients understand the differences between specific groups. Some groups are composed only of men or women, and others are mixed; some meetings are composed mostly of blue-collar men and women whereas others are mostly for professionals; some groups place great emphasis on religion, and others are eclectic. Patients with coexisting psychiatric disorders may need some additional education about AA. The clinician should remind them that some members of AA may not understand their special need for medications and should arm the patients with ways of coping when group members inappropriately suggest that the required medications be stopped.

SUGGESTED CROSS-REFERENCES Classification of mental disorders is discussed in Chapter 9, epidemiology in Section 5.1, and the sociocultural sciences in Chapter 4. Delirium and amnestic disorders are discussed in Chapter 10. Other substance-related disorders are discussed in Chapter 11; mood disorders are discussed in Chapter 14, anxiety disorders are discussed in Chapter 15, personality disorders are discussed in Chapter 24, and schizophrenia is presented in Chapter 12. Psychotherapies are discussed in Chapter 30. SECTION REFERENCES Bierut LJ, Dinwiddie SH, Begleiter H, Crowe RR, Hesselbrock V, Nurnberger JI, Jr Schuckit MA, Reich T: Familial transmission of substance dependence: Alcohol, marijuana, cocaine, and habitual smoking: A report from the Collaborative Study on the Genetics of Alcoholism. Arch Gen Psychiatry 55 (11): 982, 1998. *Blane HT, Leonard KE, editors: Psychological Theories of Drinking and Alcoholism, ed 2. Guilford, New York, 1999. Brown SA, Gleghorn A, Schuckit MA, Myers MG, Mott MA: Conduct disorder among adolescent alcohol and drug abusers. J Stud Alcohol 57:314, 1996. *Brown SA, Irwin M, Schuckit MA: Changes in anxiety among abstinent male alcoholics. J Stud Alcohol 52:55, 1991. *Carmelli D, Swan GE, Page WF, Christian JC: World War II-veteran male twins who are discordant for alcohol consumption: 24-year mortality. Am J Public Health

85:99, 1995.

Council on Scientific Affairs: Alcoholism in the elderly. JAMA 275:1, 1996. Helander A, Carlsson AV, Borg S: Longitudinal comparison of carbohydrate-deficient transferrin and gamma-glutamyl transferase: Complementary markers of excessive alcohol consumption. Alcohol

Alcohol 31:101, 1996. Hillbom M: Alcohol and cardiovascular disease. Stroke 26:40, 1995. Kabel DI, Petty F: A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: Adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Res 1996.

20:780,

Kendler KS, Walters EE, Neale MC, Kessler RC, Heath AC, Eaves LJ: The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Arch Gen Psychiatry 52:374, 1995. Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, Leaf PJ: The epidemiology of co-occurring addictive and mental disorders: Implications for prevention and service utilization. Am J Orthopsychiatry 66:17, 1996. *Koob GF, Roberts AJ. Brain reward circuits in alcoholism. CNS Spectrums 4:23, 1999. Kozaric-Kovacic D, Folnegovic-Smalc V, Folnegovic Z, Marusic A: Influence of alcoholism on the prognosis of schizophrenic patients. J Stud Alcohol 56:622, 1995. Kranzler HR, Burleson JA, Del Boca FK, Babor TF, Korner P, Brown J, Bohn MJ: Busipirone treatment of anxious alcoholics: A placebo-controlled trial. Arch Gen Psychiatry 51:720, 1994. Martin PR, McCool BA, Singleton CK: Genetic sensitivity to thiamine deficiency and development of alcoholic organic brain disease. Alcohol Clin Exp Res 17:31, 1993. Nathan PE: Psychoactive substance dependence. In The DSM-IV Source Book, T Widiger, A Frances, editors. American Psychiatric Press, Washington, 1994. Pfefferbaum A, Lim KO, Desmond JE, Sullivan EV: Thinning of the corpus callosum in older alcoholic men: A magnetic resonance imaging study. Alcohol Clin Exp Res

20:752, 1996.

*Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 156:34, 1999. *Project MATCH Research Group: Matching alcoholism treatments to client heterogeneity: Project MATCH posttreatment drinking outcomes. J Stud Alcohol 58:7, 1997. Schuckit MA: Recent developments in the pharmacotherapy of alcohol dependence. J Consult Clin Psychol 64:669, 1996. Schuckit MA: Are the costs of alcoholism treatment justified? Drug Abuse Alcohol News 25:1, 1996. Schuckit MA: Biological, psychological, and environmental predictors of the alcoholism risk: A longitudinal study. J Stud Alcohol 59:485, 1998. Schuckit MA: Educating Yourself About Alcohol and Drugs. Plenum, New York, 1998. *Schuckit MA, Daeppen J-B, Danko GP, Tripp ML, Smith TL, Li T-K, Hesselbrock VM, Bucholz KK: Clinical implications for four drugs of the DSM-IV distinction between substance dependence with and without a physiological component. Am J Psychiatry 156:41, 1999. Schuckit MA, Daeppen J-B, Tipp JE, Hesselbrock M, Bucholz KK: The clinical course of alcohol-related problems in alcohol dependent and nonalcohol dependent drinking women and men. J Stud Alcohol 59:81, 1998. Schuckit MA, Smith TL, Daeppen J-B, Eng M, Li T-K, Hesselbrock VM, Nurnberger JI Jr, Bucholz KK: Clinical relevance of the distinction between alcohol dependence with and without a physiological component. Am J Psychiatry 155:733, 1998. Schuckit MA, Hesselbrock V: Alcohol dependence and anxiety disorders: What is the relationship? Am J Psychiatry 151:1723, 1994. *Schuckit MA, Smith TL: An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch Gen Psychiatry 53:202, 1996. Schuckit MA, Tipp JE, Bergman M, Reich W, Hesselbrock VM, Smith TL: Comparison of induced and independent major depressive disorders in 2945 alcoholics. Am J Psychiatry 154:948, 1997. Schuckit MA, Tipp JE, Bucholz KK, Nurnberger JI Jr, Hesselbrock VM, Crowe RR, Kramer J: The lifetime rates of three major mood disorders and four major anxiety disorders in alcoholics and controls. Addiction 92:1289, 1997. Schuckit MA, Tipp JE, Reich T, Hesselbrock VM, Bucholz KK: The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects. Addiction 90:1335, 1995. Sullivan EV, Rosenbloom MJ, Deshmukh A, Desmond JE, Pfefferbaum A: Alcohol and the cerebrum: Effects on balance, motor coordination, and cognition. Alcohol Health Res World

19:138, 1995.

Thun MJ, Peto R, Lopez AD, Monaco JH, Henley J, Heath CW Jr, Doll R: Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med 337:1705, 1997. Tsai G, Gastfriend DR, Coyle JT: The glutamatergic basis of human alcoholism. Am J Psychiatry 152:332, 1995. *Vaillant GE: A long-term follow-up of male alcohol abuse. Arch Gen Psychiatry 53:243, 1996. Van den Brandt PA, Goldbohn A, van't Veer P: Alcohol and breast cancer. Am J Epidemol 141:907, 1995. Volpcelli JR, Alterman AI, Hayashida M, O'Brien CP: Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876, 1992. Winokur G, Coryell W, Akiskal HS, Maser JD, Keller MB, Endicott J, Mueller T: Alcoholism in manic-depressive (bipolar) illness. Am J Psychiatry

152:365, 1995.

Yeastedt J, La Grange L, Anton RF: Female alcoholic outpatients and female college students: A correlational study of self-reported alcohol consumption and carbohydrate-deficient transferrin levels. J Stud Alcohol 59:555, 1998.

Textbook of Psychiatry

11.3 AMPHETAMINE (OR AMPHETAMINE-LIKE)-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.3 AMPHETAMINE (OR AMPHETAMINE-LIKE)-RELATED DISORDERS JEROME H. JAFFE, M.D. Definitions History Comparative Nosology Epidemiology Etiology Diagnosis and Clinical Features Pathology and Laboratory Examinations Differential Diagnosis Course and Prognosis Treatment Other Agents Suggested Cross-References

Amphetamines are the most widely used illicit drugs, second only to cannabis, in Great Britain, Australia, and several countries of western Europe. In the United States, lifetime and current cocaine use still exceeds the nonmedical use of amphetamines; but in some parts of the country methamphetamine use increased significantly in the 1990s and became a matter for serious concern. Despite the important pharmacological differences between amphetamine and amphetamine-like drugs and cocaine, the patterns of use, dependence, and toxicity associated with them are similar, as are the treatment approaches currently used. Among the drugs that produce subjective effects quite similar to those of amphetamine and methamphetamine and also have abuse potential, are methylphenidate (Ritalin) and phendimetrazine (Preludin), which are included in Schedule (Control Level) II of the Controlled Substance Act (CSA), and diethylpropion (Tenuate), benzphetamine (Didrex), and phentermine (Ionamin), which are included in Schedules III or IV of the CSA.

DEFINITIONS Amphetamine use may be associated with a number of distinct disorders, of which dependence and abuse are but two. In the case of amphetamine and amphetamine-like agents, at least 10 other substance-related disorders have been described. Amphetamine dependence is defined in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a cluster of physiological, behavioral, and cognitive symptoms that, taken together, indicate that the person continues to use amphetaminelike drugs despite significant problems related to such use (see Table 11.1-3). This brief definition emphasizes the drug-using behavior itself, its maladaptive nature, and how the choice to engage in that behavior shifts and becomes constrained as a result of interaction with the drug over time. Amphetamine abuse is a term used to categorize a pattern of maladaptive use of amphetamine or an amphetaminelike drug leading to clinically significant impairment or distress and occurring within a 12-month period in which the symptoms have never met the criteria for amphetamine dependence (see Table 11.1-8). The amphetamine-induced disorders include amphetamine intoxication, amphetamine withdrawal, amphetamine-induced psychotic disorder with delusions and amphetamine-induced psychotic disorder with hallucinations, amphetamine intoxication delirium, amphetamine-induced mood disorder, (amphetamine-induced anxiety disorder, amphetamine-induced sleep disorder, amphetamine-induced sexual dysfunction, and amphetamine-related disorder not otherwise specified. The coding scheme of DSM-IV provides distinct numbers for amphetamine dependence and amphetamine abuse, but the codes for the other amphetamine-induced disorders are common to several other substance-related disorders.

HISTORY Amphetamines were introduced into clinical use in the early 1930s. By late in the decade, there was some concern about amphetamine dependence, and in 1938 the first reports of amphetamine psychosis appeared. Nevertheless, between 1932 and 1946 almost three dozen clinical uses of amphetamine were proposed and tried by the medical profession, and some amphetamines were available in over-the-counter nasal inhalers until as late as 1971. Immediately following World War II, Japan experienced an epidemic of intravenous methamphetamine abuse and dependence, but until the end of the 1960s there was reluctance in the United States to believe that amphetamine and related drugs could cause addiction. However, because of growing concern over their misuse and overuse, the Food and Drug Administration (FDA) placed them under regulatory control in the mid-1960s. Despite these controls the quantity of drugs smuggled into the country or produced illegally in clandestine laboratories increased. There were enough drugs on the street, (which up to that time had come primarily from diversion of legitimately produced drugs), to fuel a major epidemic of amphetamine and methamphetamine abuse in the late 1960s. This epidemic made clear the potential toxicity of the amphetamines, especially when used intravenously, and such terms as “speed freaks” and “speed kills” left an enduring legacy in the popular vocabulary. Over the next decade regulatory controls on legitimately produced amphetamines were progressively tightened. Some misuse of amphetamines and amphetamine-like drugs persisted in the United States, with much of the supply coming from illicit laboratories. When it became illegal to obtain the commonly used precursor phenyl-2-propanone, (P2P), illicit manufacturers found ways to produce methamphetamine from ephedrine and/or pseudoephedrine widely available in over-the-counter medications for colds and asthma. The new method of synthesis actually yields a higher percentage of the active d-isomer of methamphetamine and was adopted both by criminal organizations using large-scale laboratories and by independent producers whose small laboratories, usually located in remote rural areas, are more difficult to detect and eliminate. In the late 1980s there were reports that smoking of crystalline methamphetamine (“ice”) was on the rise, especially in Hawaii, but through the mid-1990s the use of amphetamine-like stimulants continued to be overshadowed by cocaine abuse in most parts of the United States. Over this same period in the United Kingdom, Australia, and Western Europe amphetamine use always exceeded cocaine use. In the mid-1990s, methamphetamine use rose sharply in several areas of the United States, especially in California and several states in the southwest and northwest. This increased use was evident from surveys, drug testing of arrestees, and emergency room visits for methamphetamine toxicity. Amphetamines are used legitimately almost exclusively for the treatment of narcolepsy and attention-deficit/hyperactivity disorder, although methylphenidate is more widely prescribed for the latter indication. Some amphetaminelike agents are still prescribed as appetite suppressants, but the use of amphetamine itself for that purpose has been discouraged and is illegal in some states. Amphetamines may be useful in the treatment of atypical depression, but concern about abuse potential has discouraged the controlled clinical studies that would be necessary to define just which patients (if any) might benefit more from amphetamine-like agents than from tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs).

COMPARATIVE NOSOLOGY The DSM-IV diagnostic criteria for amphetamine dependence are the same generic criteria applied to other substances ranging from opioids and cocaine to alcohol. The notion of a generic concept of dependence is shared with the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10). In making a diagnosis of dependence there is generally a high level of agreement between DSM-IV and ICD-10: they use similar concepts (the dependence syndrome varying in severity), although the wording of the criteria for determining the presence and severity of the syndrome differ. Both require that three elements of the syndrome occur within a 12-month period. Although DSM-IV appears to lay greater stress on tolerance and physiological dependence by asking clinicians to specify if these elements are present, it is not certain whether patients who exhibit these phenomena have a distinct form of the disorder. Patients diagnosed with alcohol dependence who exhibit tolerance or withdrawal have a more severe syndrome. One study of cocaine users found that even if tolerance and physical dependence had been required to make the diagnosis there would have been about the same number of patients meeting the criteria for dependence. There is a major difference between ICD-10 and DSM-IV in the classification of what is called substance abuse in DSM-IV. ICD-10 does not use the term “abuse.” Instead, it includes a category of harmful use, which is substantially different from the concept of “abuse” used in DSM-IV. The concept of “harm” is limited to physical

and mental health (e.g., hepatitis, cardiac damage, episodes of depression, or toxic psychosis). It specifically excludes social impairments as follows: Harmful patterns of use are often criticized by others and frequently associated with adverse social consequences of various kinds. The fact that a pattern of use of a particular substance is disapproved of by another person or by the culture, or may have led to socially negative consequences such as arrest or marital arguments, is not in itself evidence of harmful use. Another difference between ICD-10 and DSM-IV is in the coding systems, which limit the number of distinct drug categories that can be recorded. ICD-10 separates cocaine-related disorders from those caused by other stimulants. Because of the limits of the system the code for stimulants includes caffeine with the amphetamines and amphetamine-like stimulants. It is not clear whether 3,4-methylenedioxymethamphetamine (MDMA)-related disorders would be included under stimulants or other drugs.

EPIDEMIOLOGY The National Household Survey on Drug Abuse (NHSDA) conducted in 1997 found that 4.5 percent of adults (ages 12 and older) reported lifetime nonmedical use of stimulants, a slight decline from the previous year. Past-30-day use was 0.3 percent in 1997. The highest rates of use in the past year (1.5 percent) were among 18to 25-year-olds, followed by 12- to 17-year-olds. The sample was not large enough to detect increases in methamphetamine use in the western and southwestern states that are reflected in emergency room visits for amphetamine-related toxicity or drug testing programs for arrestees The Monitoring the Future Study (High School Survey) considers amphetamines and similar drugs together as stimulants. Among high school seniors self-reported use of stimulants has been consistently higher than use of cocaine and crack cocaine. Despite the recent increases in methamphetamine use in some parts of the United States, stimulant use for the country as a whole has fallen from the high past-30-days rate of 15.8 percent seen in 1981 to a past-30-days rate of 4.8 percent in 1997. Two population surveys that used accepted diagnostic criteria to measure the extent of drug abuse and dependence were the Epidemiologic Catchment Area (ECA) study, carried out in the early 1980s using criteria from the third edition of DSM (DSM-III) Survey (NCS), carried out from 1990 to 1992 using criteria from the revised third edition of DSM (DSM-III-R). The ECA report combined categories of dependence and abuse for amphetamine and amphetamine-like drugs. The 1-month, 6-month, and lifetime prevalences of amphetamine abuse or dependence were 0.1, 0.2, and 1.7 percent, respectively. The NCS lifetime dependence rate for 15- to 54-year-olds was 1.7 percent; about 15 percent of respondents gave a history of some nonmedical use of stimulants. Among those who reported nonmedical use about 11 percent met criteria for dependence.

ETIOLOGY Drug dependence, including amphetamine and amphetamine-like substance dependence, is viewed as resulting from a process in which multiple interacting factors (social, psychological, cultural, and biological) influence drug-using behavior. This process, in some cases, leads to the loss of flexibility with respect to drug use that is the hallmark of drug dependence. According to this biopsychosocial perspective, the actions of the drug are seen as critical. However, not everyone who becomes dependent experiences the effects of a given drug in the same way or is influenced by the same set of factors. Even with the same class of pharmacological agents, different factors, (social, biological, cultural) may be more or less important at different stages of the process. As with most substances, largely social and cultural factors influence availability and initial use of amphetamines and amphetamine-like drugs; however, pharmacological factors are believed to be very important in perpetuating use and progressing to dependence on these drugs. Amphetamines have potent mood-elevating and euphorigenic actions in humans and are powerful reinforcers in animal models, particularly when the drug effects have rapid onset, as when they are injected or inhaled. Although some physical dependence develops, in contrast to the opioids and sedatives, an aversive withdrawal syndrome probably plays a less prominent role in perpetuating the use of amphetamines and amphetamine-like drugs. Comorbidity Additional psychiatric diagnoses are quite common among those dependent on amphetamines and amphetamine-like drugs. How this comorbidity is linked etiologically to amphetamine dependence is not always clear, but epidemiological evidence shows that the presence of psychiatric disorders not related to substance abuse (e.g., mood disorders, schizophrenia, and antisocial personality disorder) substantially increases the odds of developing substance abuse or dependence. Those with conduct disorder or antisocial personality disorder are more likely to take risks and to disregard social prohibitions against using illicit drugs. Amphetamines and amphetamine-like drugs may alleviate various psychiatric disorders or dysfunctional states in some persons. For example, some users (a relative few) may find relief from adult attention-deficit disorders. The drugs may alleviate a persistent dysthymic disorder in others, and for such users the anhedonic state following amphetamine cessation may be experienced as more intense. Still others may have found that the drug facilitated sexual activity. Although such factors may explain drug use on more than one occasion, they do not account for progression to dependence or abuse. In the United States more is known about the characteristics of young people who experiment with, and become dependent on, cocaine and “crack” than about those who use amphetamines. High school juniors and seniors who use illicit drugs in general perform less well in school, have poorer family relationships, report more psychological symptoms and health problems, and exhibit more delinquent behavior. Those who use cocaine and crack are the most delinquent, but reported anxiety and depression is no greater among this group than among those whose illicit drug use does not include cocaine or crack. Research on the temporal appearance of the syndromes indicates that in some instances and for some syndromes drug use antedates the psychiatric disorders. In one component of the ECA study subjects were reinterviewed 1 year later. Those who reported using amphetamines, amphetamine-like drugs, or cocaine in the time between interviews were almost 8 times more likely than nonusers to have developed a depressive disorder and 14 times more likely to have experienced a panic attack. Amphetamine users report a wide range of psychiatric symptoms, most of which are correlated with high levels of drug use. These are discussed more fully below. Genetic Factors A study of Vietnam era twins found higher concordance rates for stimulant dependence among monozygotic twins than dizygotic twins. The analyses indicated that genetic factors and unique (unshared) environmental factors contributed about equally to the development of dependence. In this study, cocaine, amphetamines, and amphetamine-like drugs were all considered stimulants. Other Factors Social, cultural, and economic factors are powerful determinants of initial use, continued use, and relapse. Excessive use is far more likely to occur where amphetamines are readily available; this is amply demonstrated by the epidemics of amphetamine use in Japan and the United States and by more recent sharp increases in use that have followed the emergence of illicit large-scale and “kitchen” laboratories synthesizing cheap, relatively pure methamphetamine. Since in both human and animal studies alternative positive reinforcers compete with drugs as reinforcers, the absence of such nondrug alternatives can be seen as a factor contributing to their use, especially in communities where drugs are available and the social pressures against using them are not strong. Alternative positive reinforcers are not limited to material rewards but include the kinds of psychological rewards associated with satisfactory interpersonal relationships and the self-esteem that derives from achievements in socially acceptable roles. Learning and Conditioning Learning and conditioning are also believed to be important in perpetuating amphetamine use. Each ingestion, inhalation, or injection of the drug reinforces prior drug-taking behavior. In addition, the environmental cues associated with amphetamine use become associated with the euphoric state so that long after cessation, such cues (e.g., paraphernalia, friends who use drugs) can elicit memories that reawaken a craving for the drug. Also, other drug effects may become cues, so that the effects of alcohol, often consumed with amphetamines, can become a cue eliciting an urge to use amphetamines. Pharmacological Factors The reinforcing and toxic effects of amphetamines and amphetamine-like drugs play an important role in the genesis of amphetamine dependence and other amphetamine-related disorders. Amphetamines produce subjective effects very similar, if not identical, to those produced by cocaine. Both categories of drugs can produce a sense of alertness, euphoria, and well-being. Performance impaired by fatigue is usually improved. There may be decreased hunger and decreased need for sleep. Patterns of toxicity are also similar, although not identical. Both the amphetamines and cocaine can induce paranoia, suspiciousness, and overt psychosis that can be difficult to distinguish from paranoid-type schizophrenia; both can produce major cardiovascular toxicities. However, the amphetamines and cocaine differ distinctly in their mechanisms of action at the cellular level, their duration of action, and their metabolic pathways. Amphetamines enhance talkativeness, self-confidence, and sociability. Some people's beliefs about the capacity of these drugs to increase sexual drive and performance also play an important, if indirect, role in their reinforcing effects. Evidence for the enhancement of sexual performance by amphetamines is still largely

anecdotal but seems convincing to some well-trained observers. Amphetamine users, both heterosexual and homosexual, report more frequent sexual activity with more partners than heroin users. Mechanisms of Action Although amphetamines inhibit reuptake of monoamines to a small degree, their major action is the release of monoamines from storage sites in axon terminals, which in turn increases monoamine concentrations in the synaptic cleft. The release of dopamine in the nucleus accumbens and related structures is thought to account for their reinforcing and mood-elevating effects; the release of norepinephrine is probably responsible for the cardiovascular effects. In contrast to cocaine, which binds to neurotransporters and inhibits reuptake of the neurotransmitters released into the synapse, amphetamine-like drugs are taken into the neurons where they are transported into the neurotransmitter storage vesicles. By changing the internal environment of the vesicles, the drugs cause the neurotransmitters to leak out into the cytoplasm and into the synaptic cleft. The dopamine released into the cytoplasm may undergo oxidation, which results in the production of several highly toxic and reactive chemicals (oxygen radicals, peroxides, and hydroxylquinones). Some of the neuronal toxicity of methamphetamine is due, therefore, not to the drug per se, but to the intracellular accumulation of dopamine. Methylphenidate, widely used for the treatment of attention-deficit/hyperactivity disorder, has a mechanism of action quite distinct from that of the other amphetamine-like drugs, but is generally grouped with them. Like cocaine, methylphenidate produces actions in the central nervous system (CNS) largely by blocking the dopamine transporters responsible for the reuptake of dopamine from synapses following its release. Recent studies suggest that the relatively low abuse potential of orally administered methylphenidate is due to slow occupation of dopamine transporters in the brain: it takes about 60 minutes for an oral dose to produce peak concentrations in the brain. In clinical studies only one of seven normal adults reported a “high” after doses that produced blockade of 50 percent of the dopamine transporters—a degree of blockade comparable to that achieved with intravenous doses of cocaine. These studies and studies on other drugs show that reinforcing effects depend critically on the rate of change in dopamine concentrations in relevant brain circuits. Furthermore, unlike cocaine, which leaves the brain relatively rapidly, methylphenidate occupies the transporter sites for a much longer time. Common Routes of Administration Amphetamines and amphetamine-like drugs can be taken orally, by injection, by absorption through nasal and buccal membranes, or by heating, inhalation of the vapors, and absorption through the pulmonary alveoli. As with nicotine, opioids, freebase cocaine, and phencyclidine (PCP), inhaled amphetamine or methamphetamine is almost immediately absorbed with a rapid onset of effects. Unlike cocaine, amphetamine and methamphetamine salts can be vaporized without much destruction of the molecule, thus obviating the need for preparing a freebase form for smoking. As with the opioids the rapid onset of amphetamine effects from intravenous injection or inhalation produces an intensely pleasurable sensation referred to as a “rush.” The duration of the amphetamine rush has not been studied in the laboratory, but it is presumed to be shorter than the duration of elevated mood. Despite the rapid onset of action following smoked amphetamines, some users, particularly young users in Australia and Great Britain, make a transition from oral to intravenous use. Amphetamine injectors seem to be more likely than injectors of other drugs, such as heroin, to share injection equipment. Metabolism Amphetamine and methamphetamine are extensively metabolized in the liver, but much of what is ingested is excreted unchanged in the urine. The half-lives of amphetamine and methamphetamine (weak bases) are considerably shortened when the urine is acidic. The half-life of amphetamine after therapeutic doses ranges from 7 to 19 hours and that of methamphetamine appears slightly longer. Thus, after toxic dosage, resolution of symptoms may take far longer (up to several days) with amphetamines than with cocaine, depending on the pH of the urine. Tolerance and Sensitization Most amphetamine users who seek treatment report needing progressively more amphetamine to get the same euphoric effect; they have developed tolerance. Some tolerance also develops to the cardiovascular effects of amphetamine. In animal models, chronic administration of amphetamine or amphetamine-like drugs (as well as cocaine) also produces a form of sensitization in which the response to a given dose is actually enhanced. One theory holds that sensitization to drug effects is attributable to a variety of kindling in the CNS. In the classic studies of kindling, electrical stimulation of the limbic system, which initially has little effect, is applied repeatedly; after a matter of days the threshold for effects decreases and major, long-lasting seizures appear. Animals show similar effects with CNS stimulants, so that repeated doses of amphetamine eventually elicit seizures or stereotyped behaviors not seen with initial doses. The sensitization can be long lasting. The paranoid states and toxic psychoses that chronic amphetamine users commonly develop are believed to be phenomena to which sensitization develops. Those who have experienced amphetamine psychosis may do so more rapidly with subsequent exposures. Withdrawal States Although the amphetamine withdrawal syndrome has aversive qualities (e.g., dysphoria and anhedonia), it is generally not deemed as aversive as opioid withdrawal. In most cases it is probably not as critical in perpetuating amphetamine use, although withdrawal anhedonia and fatigue may contribute to an urge to use after brief withdrawal. Postdrug-use anhedonia and dysphoria may be more important for users who have come to depend on the drugs for high energy or helping to project a confident persona, who may be temporarily unable to function without them. For others, withdrawal dysphoria may exaggerate the intensity of an antecedent mood disorder. There does not appear to be a protracted amphetamine withdrawal syndrome. Mechanisms of CNS Changes Chronic administration of amphetamines results in several adaptive changes in the brain. For example, stimulation of dopamine receptors activates cyclic adenosine monophosphate (cAMP) within neurons in the nucleus accumbens and striatum. This activation initiates a chain of intracellular events that results in altered expression of a number of genes, some of which is mediated by phosphorylation of the transcription factor cAMP response element binding protein (CREB). One of the actions of CREB is to increase transcription of dynorphin in ribonucleic acid (RNA). This action is significant because dynorphin is a selective k-opioid agonist. k-receptor agonists inhibit release of dopamine. Recurrent collateral axons from neurons in the nucleus accumbens are thought to release dynorphin on k-receptors at dopaminergic terminals, thus dampening excessive dopaminergic activity. However, when amphetamine use is stopped and the excessive dopamine release ceases, the compensatory high levels of dynorphin persist and further diminish dopaminergic activity, thus exaggerating the anhedonia and dysphoria of amphetamine withdrawal. Additionally, neurons of the nucleus accumbens exhibit decreases in the concentration of G i protein (which inhibits adenylyl cyclase) and increases in levels of cAMP-dependent protein kinase. Both of these changes may persist for weeks and would be expected to upregulate the cAMP pathway. In animal models, manipulations that upregulate the cAMP pathway produce increased self-administration of cocaine (and probably of amphetamine). The persistent changes in the cAMP pathway appear to represent one mechanism of tolerance to the reinforcing effects of stimulants. Repeated administration of amphetamine results in induction and accumulation of Fos-like proteins, chronic fos-related antigens (FRAs) (mediated by phosphorylation of CREB). These chronic FRAs are long-lived and are distinct from Fos-like proteins seen after a single drug exposure. In addition to persistent changes in gene transcription, repeated amphetamine administration produces persistent morphological changes in neurons of the nucleus accumbens. Glutamate transmission, which appears to play an important role in modulating the rewarding and behavior-sensitizing effects of cocaine, does not appear to be involved in these actions of amphetamine. This difference may be important, distinguishing the adaptive changes induced by these two classes of stimulants. Other Actions Neither the actions of amphetamine nor those of amphetamine-like drugs are selective for dopamine. Amphetamine-like drugs release norepinephrine and serotonin. Some of those actions are relevant to the toxic actions of amphetamine, especially its cardiovascular toxicity.

DIAGNOSIS AND CLINICAL FEATURES DSM-IV lists a number of amphetamine (or amphetamine-like)-related disorders ( Table 11.3-1) but specifies diagnostic criteria only for amphetamine intoxication (Table 11.3-2), amphetamine withdrawal (Table 11.3-3), and amphetamine-related disorder not otherwise specified ( Table 11.3-4) in the section on amphetamine (or amphetaminelike)-related disorders. The diagnostic criteria for the other amphetamine (or amphetaminelike)-related disorders are contained in the DSM-IV sections dealing with the primary phenomenological symptom (e.g., psychosis).

Table 11.3-1 DSM-IV Amphetamine (or Amphetamine-like)-Related Disorders

Table 11.3-2 DSM-IV Diagnostic Criteria for Amphetamine Intoxication

Table 11.3-3 DSM-IV Diagnostic Criteria for Amphetamine Withdrawal

Table 11.3-4 DSM-IV Diagnostic Criteria for Amphetamine-Related Disorder Not Otherwise Specified

Amphetamine Use Disorders The DSM-IV generic criteria for dependence and abuse are applied to amphetamine and related substances (see Table 11.1-3 and Table 11.1-8). Depending on the dose, the route of administration, and the pattern of use, amphetamine dependence has quite variable effects on behavior, the capacity to work, and toxic consequences. With relatively low doses taken orally, behavior may be within normal limits and dependence is manifested only by the fatigue and depressive symptoms that ensue when drug use is interrupted and by the effort devoted to ensuring a supply. With higher doses, in addition to preoccupation with getting the drug, there is often hyperactivity, restlessness, bruxism, hypertalkativeness, irritability and short-tempered behavior, decreased sleep, and decreased appetite often accompanied by weight loss. Generally, mood is elevated; the amphetamine user is gregarious and may express confidence, even some grandiosity. With very high doses and intravenous or pulmonary routes behavior and judgment can be severely disrupted, dependence can develop quickly, and the likelihood of developing toxic paranoid states is high. There may also be repetitive behaviors that appear to have no rational basis, such as taking objects apart or rearranging objects. Such behaviors are probably analogous to the stereotypy seen when animals are repeatedly dosed with amphetamine. Severe aggressive behavior is uncommon, but it may occur during episodes of intoxication or during amphetamine-induced psychosis. Likelihood of Progression Patients with narcolepsy and children with attention-deficit/hyperactivity disorder can take amphetamine-like drugs or methylphenidate daily for many years without developing significant tolerance to their therapeutic effects and with little escalation of dose or toxicity. When amphetamine and amphetamine-like drugs were more widely used in the treatment of obesity, relatively few patients who took them daily developed dependence. Even when amphetamine-like drugs are taken for nonmedical reasons (e.g., to reduce fatigue or for euphorigenic effects), not all users progress to abuse or dependence. Although the absolute risk of such progression is not precisely known, all estimates suggest that it is high enough to justify a policy that discourages experimentation. One estimate of risk comes from a classic study, carried out in 1974 and published in 1976, of drug use among a representative sample of young men. Seventy-three percent reported having had no experience with amphetamines, but of the 27 percent who had some experience, almost 10 percent (3 percent of the total) reported daily use. Findings from the NCS conducted in the early 1990s were remarkably similar. About 15 percent of interviewees had used a stimulant other than cocaine for extramedical reasons. Of these users, 11.2 percent had become dependent on them (DSM-III-R criteria) by the time of the interview. Varied Patterns of Use There are several patterns of abuse of amphetamines and similar agents. Some persons may use the drugs intermittently in relatively low doses; for example, truck drivers or students may use them to overcome fatigue or the need for sleep or to derive some positive mood effects. Some intermittent users become dependent and find it difficult to stop; some may eventually escalate the dosage. Since the drugs are no longer available legitimately for these purposes, persons with that pattern of use are likely to obtain them from illicit sources. Some persons use amphetamines primarily to induce euphoria. Such users often progress to high dosages, especially if they use the drugs intravenously or by

inhalation. These are obviously the most dangerous patterns of use, and they commonly lead to compulsive use or toxic effects. Although intravenous use initially may be intermittent, with days or weeks elapsing between episodes, such high-dose use often progresses to sprees or speed runs, during which several grams of amphetamine might be smoked or injected. The runs can last for days or weeks and are commonly punctuated by episodes of toxicity (amphetamine-induced psychotic disorder with delusions or amphetamine intoxication delirium) or by brief periods of abstinence (crashing), generally precipitated by an interruption in the supply of the drug or exhaustion. Some clinicians have observed that in contrast to cocaine users who prefer to smoke cocaine and use in binges interrupted by periods of cocaine abstinence, methamphetamine users are more likely to use on a daily basis and tend to change routes of administration because the drug is irritating to the nasal mucosa and lungs. High-dose amphetamine users often combine amphetamine with sedatives, benzodiazepines, or opioids to modulate the stimulant effects. Alcohol use and alcohol abuse are common concomitants of high-dose amphetamine abuse and dependence. Methamphetamine is sometimes used to reduce the sedating effects of alcohol and facilitate and prolong socializing and sexual activity. Some observers believe that methamphetamine use increases the likelihood of multiple sex partners and the transmission of human immunodeficiency virus (HIV). In a study of gay and bisexual men who were methamphetamine injectors (and were not seeking treatment), 54 percent reported sharing needles within the preceding 30 days, and 74 percent reported exchanging sex for money or drugs. The recent increase in the use of methamphetamine in California and several western states has been predominantly among white men 25 to 34 years old. Comorbidity The frequent co-occurrence of other psychiatric disorders and amphetamine dependence was first noted in the 1950s. The presence of other psychiatric disorders sharply increases the odds of drug dependence in general, and drug-dependent persons are more likely than the general population to meet the criteria for additional psychiatric disorders. Patients with schizophrenia commonly use amphetamine or cocaine and develop both dependence and toxic syndromes. It has been suggested that schizophrenia patients use stimulants to alleviate negative symptoms or adverse effects of antipsychotic agents. Special programs involving peer-based support groups seem to be effective in linking drug-using schizophrenia patients with outpatient treatment programs. Amphetamine-Induced Disorders All of the disorders listed in DSM-IV for cocaine (intoxication, psychotic disorder, intoxication delirium, mood disorder, anxiety disorder, sleep disorder, and sexual dysfunction) may occur in association with the use of amphetamine or amphetamine-like drugs. The clinical pictures are similar, if not identical; the DSM-IV diagnostic criteria and codes are identical except for substitution of the word “amphetamine” for the word “cocaine.” Amphetamine Intoxication The intoxication syndromes of cocaine and amphetamines are similar. Amphetamine intoxication can occur as a result of single doses in non-tolerant individuals, but it is most commonly seen in those who are amphetamine-abusers or are dependent. Some of the manifestations are exaggerated effects of the drug, including euphoria, grandiosity, restlessness, hypervigilance, talkativeness, and stereotyped repetitive behaviors. The patient is generally oriented to time, place, and situation. However, intoxication may be accompanied by visual and tactile hallucinations or illusions. Generally, patients recognize that the symptoms are drug induced. When they do not, a diagnosis of amphetamine-induced psychotic disorder should be considered. Symptoms of amphetamine intoxication usually resolve as the drug is excreted over a period of 24 to 48 hours. In DSM-IV, the diagnostic criteria for amphetamine intoxication ( Table 11.3-2) and cocaine intoxication (see Table 11.6-2) are separated but are virtually the same. DSM-IV allows for noting the presence of perceptual disturbances as a symptom of amphetamine intoxication. Amphetamine Withdrawal The severity of the amphetamine withdrawal syndrome is presumably related to the intensity and duration of the antecedent drug use. Some elements of the syndrome (dysphoria and fatigue) can be seen after relatively brief binges or “runs” of only a few days, with some less severe aspects of “crashing” reported to occur even after 24 hours of use. During phases of the amphetamine withdrawal syndrome users may experience severe depression that tends to resolve without special treatment when sleep normalizes. Amphetamine users stabilized on amphetamine prior to withdrawal have been studied. Among the findings noted as early as 1963 were a marked shortening of time to first rapid eye movement (REM) sleep and a marked rebound in total REM sleep. A return to normal levels in some cases required several weeks. The DSM-IV criteria for amphetamine withdrawal and those for cocaine withdrawal are identical; the ICD-10 criteria are virtually identical. Less is known about the later stages of amphetamine withdrawal, but it is likely that there are periods of increased vulnerability when stimuli previously associated with use elicit memories of drug effects and craving. Amphetamine-Induced Psychotic Disorder and Intoxication Delirium Although amphetamine-induced psychotic disorder or intoxication delirium are usually seen only when high doses are used for a long time, such syndromes have been reported in apparently vulnerable persons even after therapeutic doses given for a short time. Haloperidol (Haldol) and phenothiazines have been used to treat the psychotic syndrome. Although with cocaine the delusional syndrome is typically of short duration, with the amphetaminelike drugs it may not resolve for many days after drug cessation. Following recovery from either a psychotic or delirium syndrome there may be amnesia for the entire episode or some part of it. Psychiatrists in Japan have presented data showing that amphetamine-induced psychosis may persist for several years and that in the acute stage there may be disturbance of consciousness (confusion, disorientation) in addition to the more typical mood and delusional symptoms. Following recovery persons who have experienced an amphetamine-induced psychosis seem to be sensitized and will experience acute paranoid psychosis on reexposure to small doses of amphetamines, and some have exacerbations in response to stress. Rhesus monkeys show hallucinatory-like behaviors and stereotypies in response to low-dose amphetamine challenge as long as 28 months after a 12-week course of low-dose amphetamine exposure. Amphetamine-Induced Mood Disorder According to DSM-IV, the onset of amphetamine-induced mood disorder can occur during intoxication or withdrawal (see Table 14.6-18). In general, intoxication is associated with manic or mixed mood features, whereas withdrawal is associated with depressive mood features. The manic and hypomanic symptoms often seen during amphetamine use rarely (if ever) persist beyond the period of drug use, but hypophoria, depressive, and anhedonic symptoms that persist well beyond the period of withdrawal are not uncommon. Patients may seek treatment for such persisting symptoms. In such situations the clinician should consider a diagnosis of amphetamine-induced mood disorder. However, it is often difficult to distinguish a substance-induced mood disorder from a primary mood disorder, especially in patients who have a history of depressive symptoms antedating the onset of amphetamine use. Given the pharmacology of amphetamine it is possible that drug-induced changes could aggravate and intensify a primary depressive disorder. Amphetamine-Induced Anxiety Disorder In DSM-IV, the onset of amphetamine-induced anxiety disorder can also occur during intoxication or withdrawal (see Table 15.6-18). Amphetamine, like cocaine, can induce symptoms similar to those seen in obsessive-compulsive disorder, with repetitive, stereotyped behaviors. However, these ordinarily do not persist beyond the period of drug intoxication and rarely merit a distinct diagnosis. Amphetamine-like drugs can also induce panic attacks in individuals with no previous history of panic attacks. When such episodes persist well beyond the period of drug use and require clinical attention a distinct diagnosis should be entertained. Amphetamine-Induced Sexual Dysfunction Although amphetamine is often used to enhance sexual experiences, high doses and long-term use are associated with impotence and other sexual dysfunctions. These dysfunctions are classified in DSM-IV as amphetamine-induced sexual dysfunction with onset during intoxication (see Table 19.1a-20). Amphetamine-Induced Sleep Disorder The diagnostic criteria for amphetamine-induced sleep disorder with onset during intoxication or withdrawal are found in the DSM-IV section on sleep disorders (see Table 21-18). Amphetamine use can produce insomnia and sleep deprivation; persons undergoing amphetamine withdrawal can experience hypersomnolence and nightmares. However, unless these disturbances persist beyond the period of drug use or well beyond withdrawal and are severe enough to merit clinical attention they do not require a separate diagnosis. Disorder Not Otherwise Specified If an amphetamine (or amphetamine-like)-related disorder does not meet the criteria of one or more of the previous discussed categories, it can be diagnosed as an amphetamine-related disorder not otherwise specified ( Table 11.3-4). With the increasing illicit use of designer amphetamines, syndromes may arise that do not meet the criteria outlined in DSM-IV and that necessitate the frequent use of the not otherwise specified category. Toxicity and Complications Subjects in a survey of amphetamine users in Australia reported various physical and psychological problems that they attributed to

amphetamine use. Commonly reported physical symptoms were tiredness (89 percent), loss of appetite (85 percent), dehydration (73 percent), and jaw clenching (73 percent). Also reported were headaches, muscle pains, shortness of breath, and tremors. The most frequently reported psychological symptoms were mood swings (80 percent), sleep problems (78 percent), anxiety, difficulty concentrating, depression, and paranoia (each about 70 percent), hallucinations, and episodes of aggression and violence (each about 45 percent). Daily use, heavier use, and being male and unemployed were correlated with reporting more symptoms. Amphetamines produce their most dramatic toxic effects on the CNS and the cardiovascular system. In animal models (rodents and primates), chronically administered high doses of amphetamines produce long-lasting depletion of brain norepinephrine, and more selective but even longer-lasting depletion of dopamine, alterations in dopamine uptake sites, and reduction in serotonergic activity. Because these effects involve damage to both axons and axon terminals, largely sparing the cell bodies, it is not known to what degree these long-lasting effects are permanent. Methamphetamine in particular seems capable of inducing damage to serotonergic fibers, but the noradrenergic system is largely unaffected. These effects may be due to toxic biotransformation products of excessive dopamine within the neuron. The long-lasting dopaminergic changes probably account for the altered, elevated threshold for self-stimulation in animals and the anhedonia reported by chronic amphetamine users for prolonged periods following cessation. It is not known to what degree methamphetamine use causes neuronal damage in humans, but data from patients with Parkinson's disease suggest that there must be considerable damage to the dopaminergic pathways before it becomes evident in function and behavior. In monkeys the toxic effects of chronic amphetamine use include damage to cerebral blood vessels, neuronal loss, and microhemorrhages. In humans high doses of amphetamine have also been associated with lethal hyperpyrexia and with destructive deterioration of arterioles. High doses can also produce convulsions and ultimately coma and death. Amphetamine-like drugs can cause catastrophes of the cardiovascular system (e.g., intracranial hemorrhage, arrhythmias, and acute cardiac failure) because of their capacity to release norepinephrine, dopamine, and serotonin, and to raise blood pressure. With amphetamines, considerable tolerance develops to the effect on blood pressure. The likelihood of such cardiovascular effects is related to dose and the rapidity with which the drug is absorbed. The use of methamphetamine by smoking or intravenous injection is likely to result in greater cardiovascular toxicity. Amphetamine-induced hyperthermia and free radical formation are believed to be involved in causing rhabdomyolosis and the consequent renal tubular obstruction that is occasionally reported. Because amphetamine use can be associated with increased sexual activity, often accompanied by poor judgment, amphetamine users are at increased risk for venereal diseases, including infection with HIV.

PATHOLOGY AND LABORATORY EXAMINATIONS Amphetamine and amphetaminelike drugs can be detected for varying lengths of time in urine (several days, depending on dose and sensitivity of the method). Metabolites can also be detected in blood, saliva, and hair. Blood and saliva furnish a better index of current levels, whereas urine provides a longer window of opportunity for detecting use over the previous few days. Hair analysis can reveal drug use over a period of weeks to months but has little applicability in clinical situations. Such procedures as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have not yet been used during the immediate postamphetamine cessation period, but given the findings seen at autopsy and the pharmacology of amphetaminelike agents, it would not be surprising if there were arteriolar pathology and alterations in dopamine systems.

DIFFERENTIAL DIAGNOSIS The disorders associated with the use of amphetamine and amphetamine-like drugs need to be distinguished from both primary mental disorders and disorders induced by other classes of drugs. A history of the drug ingestion is important for making these distinctions. However, given the unreliability of self-reports about drug use and the likelihood that many users will deny any drug use at all, laboratory testing for drugs in body fluids and histories from collaterals are very important. Disorders associated with amphetamine use cannot be easily distinguished from those associated with cocaine except by a reliable history or laboratory tests. Users of amphetamine or cocaine and related drugs may exhibit inappropriate optimism, euphoria, and expansiveness; excessive talkativeness; and a decreased need for sleep sometimes associated with irritability in the context of a clear sensorium, a pattern that is also observed in manic and hypomanic episodes of bipolar I disorder and bipolar II disorder, respectively. Those symptoms, however, may not be obvious enough to suggest their relation to drug use, and the first indication of drug dependence may be financial difficulties, an arrest for selling drugs or possessing them, or some drug-induced toxicity. Intoxication Amphetamine intoxication is diagnosed when the effects of the drug exceed the mood-elevating effects that users typically seek when they use amphetamines. The diagnosis of intoxication would be appropriate when the drug effects are problematic enough to require differentiation from hypomanic or manic behavior. Amphetamine and amphetamine-like drug intoxication can also be confused with PCP intoxication, although the latter is usually associated with nystagmus, motor incoordination, and some cognitive impairment. Endocrine disorders (such as Cushing's disease) and the excessive use of steroids should also be considered. Psychotic Disorders Amphetamine-induced toxic psychosis can be exceedingly difficult to differentiate from schizophrenia and other psychotic disorders characterized by hallucinations or delusions. Paranoid delusions occur in about 80 percent of patients, and hallucinations in 60 to 70 percent. Consciousness is clear and disorientation is uncommon. The presence of vivid visual or tactile hallucinations should raise suspicion of a drug-induced disorder. In areas and populations where amphetamine use is common it may be necessary to provide only a provisional diagnosis until the patient can be observed and drug test results are obtained. Even then, there may be difficulties because in some urban areas a high percentage of persons with established diagnoses of schizophrenia also use amphetamines or cocaine. Typically symptoms of amphetamine psychosis remit within a week, but in a small proportion of patients, psychosis may last for more than a month. Anxiety Disorders Amphetamine-induced anxiety disorder must also be distinguished from panic disorder and generalized anxiety disorder. Other Symptoms The symptoms that may emerge during withdrawal—depression, dysphoria, anhedonia, disturbed sleep—need to be distinguished from those of primary mood disorders and primary sleep disorders. Unless the symptoms are more intense or more prolonged than is typical of amphetamine withdrawal and require independent treatment, the diagnosis should be limited to withdrawal rather than amphetamine-induced mood disorder. When a diagnosis of amphetamine-induced mood disorder is made, one must specify whether its onset was during intoxication or in withdrawal. It is also possible to specify the subtype of mood disorder (with depressive, manic, or mixed features). In differentiating amphetamine-induced mood disorder from the primary mood disorder the critical factor is the clinician's judgment that the mood disorder was caused by the drug. An amphetamine-induced mood disorder or mood disorder with onset during intoxication or withdrawal usually remits within a week or two. It is appropriate, therefore, to withhold judgment about the diagnosis during the early phase of withdrawal. If depressed mood and related symptoms persist beyond a few weeks, the possibility of alternative causes should be entertained. In considering diagnostic possibilities the clinician should consider the age of the patient at the onset of symptoms and a history of episodes of mood disorder that developed before the onset of drug use or during any long intervals when there was no significant drug abuse.

COURSE AND PROGNOSIS The natural history of amphetamine dependence in the United States is less well documented than that of opioids or cocaine. Some researchers believe that some intravenous amphetamine users in the 1960s moved on to heroin use in the 1970s. However, it seems likely that many whose use was less severe simply stopped or recovered, whereas others intensified their use of alcohol. Japanese clinicians believe that some amphetamine users may develop persistent psychosis and that those who recover remain at high risk of reexperiencing psychosis if they use amphetamines again (sensitization). A 3- to 8-year follow-up study of 110 methamphetamine users hospitalized for drug-related problems in Japan in the 1980s found that 12 former patients had died, a mortality rate 11 times that of age- and sex-matched general population controls. However, 56 percent of those still alive had not used amphetaminelike drugs in the year before interview, and most of them also showed improvements in work and family relationships. Twenty-five percent were thought to have highly or moderately unfavorable outcomes in terms of drug use, work, and family relationships. Findings from treatment programs in California suggest that the course and prognosis for amphetamine dependence are probably similar to those for cocaine dependence. The prognosis for Japanese convicted and imprisoned for crimes related to stimulant drug use seems as bleak as that in the United States; 58 percent committed crimes within 1 year after release and 98 percent committed crimes within 5 years.

TREATMENT

There are no specific, well-established treatments for dependence on amphetamine or amphetamine-like drugs and few controlled studies on the treatment of amphetamine dependence. Most casual users do not need or seek treatment. Those with moderately severe dependence obtain treatment in a variety of settings (mostly outpatient drug free) that were not designed specifically to treat amphetamine dependence. The most severe cases, those within the criminal justice system, and the homeless generally drop out of outpatient treatment because of their complex needs or are unable to access treatment at all. Some data on treatment seeking and outcome are available for the state of California where amphetamine abuse began to increase in the early 1990s. In general, methamphetamine users in the state gave reasons for entering treatment similar to those of other substance users—personal motivation (69 percent) and pressure from the criminal justice system (31 percent) and from family or other significant persons (22 percent). Treatment received ranged from residential and ambulatory detoxification to day treatment, 12-step activities, and case management. Although those leaving 12-step programs were more likely to have been considered treatment completers, at follow-up, patients reported similar reductions in drug use (unverified by urine tests) regardless of the treatment received and were neither more nor less successful in this respect than those receiving treatment for heroin, cocaine, or marijuana use. One program that provided a highly structured and manualized cognitive-behavioral treatment making use of a combination of group and individual counseling initially developed for crack cocaine users found that this type of treatment produced equal levels of participation in treatment and equally good outcomes for those dependent on methamphetamine. A wide variety of pharmacological agents have been explored as adjuncts to, or major elements in, the treatment of amphetamine dependence. Some have been studied in controlled trials. Virtually all of these agents had been previously tried in the treatment of cocaine dependence and produced comparably disappointing results. For example, although imipramine (Tofranil) (150 mg a day) improved treatment retention, it had no significant effect on methamphetamine use. Although an open-label trial of fluoxetine (Prozac) (20 mg a day) was reported to be useful in amphetamine dependence, success in dozens of open-label trials with cocaine-dependent patients has rarely been confirmed when the same agents were studied in double-blind controlled trials. In Europe and Australia the ethics and efficacy of prescribing oral amphetamines for amphetamine users are hotly debated. This practice is allowed in Great Britain, although it varies from region to region, and virtually no safeguards exist against diversion of prescribed amphetamines to the illicit market. No outcome studies exist that evaluate the values and risks of this practice. Selection of Treatment Setting The general principles of treatment for amphetamine dependence are not very different from those for cocaine and opioid dependence, but there are fewer replicated studies on the efficacy of any particular treatment approach. As with cocaine and opioid dependence, amphetamine dependence severe enough to require formal treatment is often associated with other psychiatric diagnoses. Patient heterogeneity requires thoughtful selection among available alternatives. Not all amphetamine users require extensive treatment; some users who are not dependent respond to external pressures, as when employers insist on careful monitoring of drug use. The executive with little history of psychopathology, a supportive social network, economic assets, and personal skills has a different prognosis and a wider range of options than does a patient who is unemployed, alienated from the family, and perhaps also using opioids. Severe depression, psychotic manifestations beyond the initial withdrawal period, and drug use that is completely out of control (i.e., repeated failure to respond to outpatient efforts) seem to be the major accepted criteria for hospitalization.

OTHER AGENTS Substituted Amphetamines MDMA (“Ecstasy,” “Adam”) is one of a series of substituted amphetamines that also includes 3,4-methylenedioxyethylamphetamine (MDEA, “Eve”), 3,4-methylenedioxyamphetamine (MDA), 2,5-dimethoxy-4-bromoamphetamine (DOB), paramethoxyamphetamine (PMA), and others. These drugs produce subjective effects resembling those of amphetamine and lysergic acid diethylamide (LSD), and in that sense, MDMA and similar analogues may represent a distinct category of drugs (“entactogens”). A methamphetamine derivative that came into use in the 1980s, MDMA was not technically subject to legal regulation at the time. Although it has been labeled a designer drug in the belief that it was deliberately synthesized to evade legal regulation, it was actually synthesized and patented in 1914. Several psychiatrists used it as an adjunct to psychotherapy and concluded that it was of value. At one time it was advertised as legal and was used in psychotherapy for its subjective effects. However, it was never approved by the FDA. Its use raised questions of both safety and legality, since the related amphetamine derivatives MDA, DOB, and PMA had caused a number of overdose deaths, and MDA was known to cause extensive destruction of serotonergic nerve terminals in the CNS. Using emergency scheduling authority, the Drug Enforcement Agency made MDMA a Schedule I drug under the CSA, along with LSD, heroin, and marijuana. Despite its illegal status MDMA continues to be manufactured, distributed, and used in the United States, Europe, and Australia. Its use is common in Australia and Great Britain at extended dances (“raves”) popular with adolescents and young adults. Mechanisms of Action The unusual properties of the drugs may be a consequence of the different actions of the optical isomers: the R(–) isomers produce LSD-like effects and the amphetamine-like properties are linked to S(+) isomers. The LSD-like actions, in turn, may be linked to the capacity to release serotonin. The various derivatives may exhibit significant differences in subjective effects and toxicity. Animals in laboratory experiments will self-administer the drugs, suggesting prominent amphetamine-like effects. Subjective Effects After taking usual doses (100 to 150 mg), MDMA users experience elevated mood and, according to various reports, increased self-confidence and sensory sensitivity; peaceful feelings coupled with insight, empathy, and closeness to people; and decreased appetite. Difficulty in concentrating and an increased capacity to focus have both been reported. Dysphoric reactions, psychotomimetic effects, and psychosis have also been reported. Higher doses seem more likely to produce psychotomimetic effects. Sympathomimetic effects of tachycardia, palpitation, increased blood pressure, sweating, and bruxism are common. The subjective effects are reported to be prominent for about 4 to 8 hours, but they may not last as long or may last longer, depending on the dose and route of administration. The drug is usually taken orally, but it has been snorted and injected. Both tachyphylaxis and some tolerance are reported by users. The acute adverse effects reported include precipitation of episodes of panic and anxiety. More-severe brief psychiatric disturbances can also occur, and preexisting pathology does not appear to be a requisite for severe reactions. A healthy drug-free subject, known to be without personal and family psychiatric illness was given a 140-mg dose of the drug and developed a psychosis lasting 2½ hours that included vivid auditory and visual hallucinations and a belief that people were making noise to annoy him intentionally. Following the acute effects of MDMA there may be a combination of some diminishing residual effects gradually superseded by feelings of drowsiness, fatigue, depression, and difficulty concentrating, somewhat comparable to the crash after cessation of amphetamine use. When young adults who were Saturday night MDMA users were compared with alcohol-only users who frequented the same club, the MDMA users reported elevated mood on the following day but feelings of depression (Beck Depression Inventory scores of about 12) by the fifth day. In contrast, alcohol-only users showed relatively little mood change over the 5-day period; their highest Beck depression scores (about 8) occurred on the second day. In a double-blind placebo-controlled study of normal volunteers given 1.7 mg per kg of body weight of MDMA, some subjects continued to report symptoms typical of MDMA actions (suppressed appetite, jaw clenching, restlessness, heaviness in the legs, difficulty concentrating) 24 hours later. More-persistent neuropsychiatric adverse effects associated with MDMA use include anxiety, depression, flashbacks, irritability, panic disorder, psychosis, and memory disturbance. Toxicity Although it is not as toxic as MDA, various somatic toxicities attributable to MDMA use have been reported, as well as fatal overdoses. It does not appear to be neurotoxic when injected into the brain of animals, but it is metabolized to MDA in both animals and humans. In animals MDMA produces selective, long-lasting damage to serotonergic nerve terminals. It is not certain if the levels of the MDA metabolite reached in humans after the usual doses of MDMA suffice to produce lasting damage. Nonhuman primates are more sensitive than are rodents to MDMA's toxic effects and show more prolonged or permanent neurotoxicity at doses not much higher than those used by humans (Fig. 11.3-1). Users of MDMA show differences in neuroendocrine responses to serotonergic probes, and studies of former MDMA users show global and regional decreases in serotonin transporter binding, as measured by positron emission tomography. Although psychological assessment of a small sample of users did not reveal evidence of current anxiety or a mood disorder, eight of nine subjects had at least some impairment on at least one test of neuropsychological function.

FIGURE 11.3-1 Neurotoxic effects of MDMA. MDMA damages serotonin-producing neurons in the brains of nonhuman primates. The left illustration shows a normal neuron. The shaded area in the middle illustration shows the axon terminals of the neurons that are damaged by MDMA. The right illustration shows how, 12 to 18 months after being damaged by MDMA, serotonin-producing nerve fibers have regrown excessively in some areas and not at all in others. (Reprinted with permission from Mathias R: Like methamphetamine, “ecstasy” may cause long-term brain damage. NIDA Notes 11:7, 1996.)

Other reported toxicities include arrhythmias, cardiovascular collapse, hyperthermia, rhabdomyolysis, disseminated intravascular coagulation, acute renal failure, and hepatotoxicity. The role that contaminants in illicit MDMA played in the toxic reactions is uncertain, but significant elevations of blood pressure and temperature have been observed after administration of pure MDMA. MDMA dependence does not appear to be a significant problem in the United States, but cases of dependence have been reported in England. Among a sample of MDMA users in Australia, 28 percent reported that problems related to the use of the drug were mostly acute reactions, such as panic, paranoia, loss of reality, and hallucinations. Only 2 percent reported feeling dependent (needing to use it every day to cope), but 22 percent claimed that they knew someone who had been dependent, and 47 percent believed it was possible to become addicted. MDA, MDMA, PMA, and MDEA have all been linked to psychosis and overdose deaths. The toxic manifestations of overdose include restlessness, agitation, sweating, rigidity, high blood pressure, tachycardia, hyperpyrexia, and convulsions. Chlorpromazine (Thorazine) prevented lethality in dogs, but there are no clinical reports of its use for this purpose in humans. There are currently no established clinical uses for MDMA, although before its regulation, there were several reports of its beneficial effects as an adjunct to psychotherapy. Khat The fresh leaves of Catha edulis, a bush native to East Africa, have been used as a stimulant in the Middle East, Africa, and the Arabian peninsula for at least 1000 years. Khat is still widely used in Ethiopia, Kenya, Somalia, and Yemen. The amphetamine-like effects of khat have long been recognized, and although efforts to isolate the active ingredient were first undertaken in the nineteenth century, only since the 1970s a has cathinone ( S(–)a-aminopropriophenone or S-2-amino-1-phenyl-1-propanone) been identified as the substance responsible. Cathinone is a precursor moiety that is normally enzymatically converted in the plant to the less active entities norephedrine and cathine (norpseudoephedrine), which explains why only the fresh leaves of the plant are valued for their stimulant effects. Cathinone has most of the CNS and peripheral actions of amphetamine and appears to have the same mechanism of action. In humans it elevates mood, decreases hunger, and alleviates fatigue. Like amphetamine, it is self-administered by laboratory animals and produces increased locomotor activity and stereotypy. At high doses it can induce an amphetamine-like psychosis in humans. Because it is typically absorbed buccally after chewing the leaf and because the alkaloid is metabolized relatively rapidly, high toxic blood levels are not frequently reached. Concern about khat use is linked to its dependence-producing properties rather than to its acute toxicity. It is estimated that five million doses are consumed each day, despite prohibition of its use in a number of African and Arab countries. In the 1990s several clandestine laboratories began synthesizing methcathinone, a drug with actions quite similar to those of cathinone. Known by a number of street names (e.g., CAT, goob, and crank), its popularity is due primarily to its ease of synthesis from ephedrine or pseudoephedrine, which were readily available until placed under special controls. Methcathinone has been moved to Schedule (Control Level) I of the CSA. The patterns of use, adverse effects, and complications are quite similar to those reported for amphetamine.

SUGGESTED CROSS-REFERENCES The neural sciences are presented in Chapter 1 and neuropsychiatry and behavioral neurology in Chapter 2. A classification of mental disorders appears in Chapter 9. An introduction to and overview of substance-related disorders is presented in Section 11.1, cocaine-related disorders in Section 11.6, and various drugs in Chapter 31 on biological therapies, particularly sympathomimetics in Section 31.27. Schizophrenia is discussed in Chapter 12, other psychotic disorders in Chapter 13, and attention-deficit disorders in Section 39.1 SECTION REFERENCES Anthony JC, Warner LA, Kessler RC: Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 2:244, 1994. Battaglia G, Napier TC: The effects of cocaine and the amphetamines on brain and behavior: A conference report. Drug Alcohol Dependence 52:41, 1998. *Castner SA, Goldman-Rakic PS: Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys. Neuropsychopharmacology 20:10, 1999. *Center for Substance Abuse Treatment: Proceedings of the National Consensus Meeting on the Use, Abuse and Sequelae of Abuse of Methamphetamine with Implications for Prevention, Treatment and Research. DHHS publ. no. SMA 96-8013. Substance Abuse and Mental Health Services Administration, Rockville, MD, 1997. Curran HV, Travill RA: Mood and cognitive effects of +/–3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”): Weekend “high” followed by mid-week low. Addition

92:821, 1997.

*Gawin FH, Ellinwood EH: Cocaine and other stimulants. N Engl J Med 318:1173, 1988. *Gorelick DA: Pharmacologic therapies for cocaine and other stimulant addiction. In Principles of Addiction Medicine, ed 2, AW Graham, TK Schultz, editors. American Society of Addiction Medicine, Chevy Chase, MD, 1998. Gruber AJ, Pope HG Jr: Psychiatric and medical effects of anabolic-androgenic steroid use in women. Psychother Psychosom, in press. Hall W, Hando J: Patterns of amphetamine use in Australia. In Amphetamine Misuse. International Perspectives on Current Trends, H Klee, editor. Harwood Academic Publishers, Reading, Australia, 1997. *Hall W, Hando J, Darke S, Ross J: Psychological morbidity and route of administration among amphetamine users in Sydney, Australia. Addiction 91:81, 1996. Hyman SE, Nestler EJ: Initiation and adaptation: A paradigm for understanding psychotropic drug action. Am J Psychiatry 153:151, 1996. *Jaffe JH: Drug addiction and drug abuse. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed 8, AG Gilman, TW Rall, AS Nies, P Taylor, editors. Pergamon, New York, 1990. Jansen KLR: Ecstasy (MDMA) dependence. Drug Alcohol Depend 53:121, 1999. Johnston LD, Bachman JG, O'Malley PM: Monitoring the Future Study. University of Michigan, Ann Arbor, 1997. *Kalant OJ: The Amphetamines. Charles C Thomas, Springfield, IL, 1973. Kalix P: Pharmacological properties of the stimulant khat. Pharmacol Ther 48:397, 1990. Kandel DB, Davies M: High school students who use crack and other drugs. Arch Gen Psychiatry 53:71, 1996.

Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshelman S, Wittchen H-U, Kendler KS: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry 51:8, 1994. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA: Positron emission tomographic evidence of toxic effects of MDMA (“Ecstasy”) on brain serotonin neurons in human beings. Lancet 352:1433, 1998. *Meng Y, Dukat M, Bridgen DT, Martin BR, Lichtman AH: Pharmacological effects of methamphetamine and other stimulants via inhalation exposure. Drug Alcohol Depend

53:111, 1999.

Office of Applied Studies: Preliminary Results from the 1997 National Household Survey on Drug Abuse. National Household Survey on Drug Abuse Series: H6, DHHS publ. no. SMA 98-3251. Substance Abuse and Mental Health Services Administration, Rockville, MD, 1998. Pope HG Jr, Kouri EM, Hudson JI: The effects of supraphysiologic doses of testosterone on mood and aggression in normal men: A randomized controlled trial. Arch Gen Psychiatry, in press. Seiden LS, Sabol KE, Ricaurte GA: Amphetamine: Effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639, 1993. *Self DW, Nestler EJ: Relapse to drug-seeking: Neural and molecular mechanisms. Drug Alcohol Dependence 51:49, 1998. Solowij N, Hall W, Lee N: Recreational MDMA use in Sydney: A profile of “ecstasy” users and their experiences with the drug. Br J Addict 87:1161, 1992. *Steele TD, McCann UD, Ricaurte GA: 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”): Pharmacology and toxicology in animals and humans. Addiction 89:539, 1994. Strang J, Sheridan J: Prescribing amphetamines to drug misusers: Data from the 1995 national survey of community pharmacies in England and Wales. Addiction 92:833, 1997. Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J, True W, Lin N, Toomey R, Eaves L: Co-occurrence of abuse of different drugs in men. Arch Gen Psychiatry 55:967, 1998. Volkow ND, Wang G-J, Fowler JS, Gatley SJ, Logan J, Ding Y-S, Hitzemann R, Pappas N: Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155:10, 1998. Vollenweider FZ, Gamma A, Liechti M, Huber T: Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naive healthy volunteers. Neuropsychopharmacology 19:241, 1998. White FJ, Kalivas PW: Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Dependence 51:141, 1998.

Textbook of Psychiatry

11.4 CAFFEINE-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.4 CAFFEINE-RELATED DISORDERS ERIC C. STRAIN, M.D. AND ROLAND R. GRIFFITHS, PH.D. History Comparative Nosology Epidemiology Etiology Pharmacology and Effects in the Central Nervous System Dsm-IV Disorders Suggested Cross-References

The most widely consumed psychoactive substance in the world is caffeine. It is estimated that over 80 percent of adults in the United States consume caffeine regularly, and throughout the world caffeine consumption is well integrated into daily cultural practices (e.g., the coffee break in the United States, tea time in the United Kingdom, and kola nut chewing in Nigeria). Because caffeine use is so pervasive and widely accepted, disorders associated with caffeine use may be overlooked. However, it is important to recognize that caffeine is a psychoactive compound that can produce a wide variety of syndromes, and the fourth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) recognizes several caffeine-related disorders (such as caffeine intoxication, caffeine-induced anxiety disorder, and caffeine-induced sleep disorder). In addition, other caffeine-related disorders, such as caffeine withdrawal and caffeine dependence, are not official diagnoses in DSM-IV, but can be of clinical interest.

HISTORY Caffeine-containing foods and beverages have been consumed for hundreds if not thousands of years. Tea has been cultivated and consumed in China since at least 350 AD, and coffee cultivation spread from Ethiopia to Arabia in the fifteenth century and subsequently became a popular beverage in Arabic cultures during the sixteenth century. However, most caffeine consumption occurred in restricted geographical regions, and it was not until the seventeenth century that caffeine use began to spread, eventually becoming nearly universally available, as it is today. The Dutch imported caffeine in the form of coffee from Arabic countries to Europe, where it first became popular around the middle to end of the seventeenth century (along with tea, tobacco, and chocolate). Medical literature during this time period described coffee as a useful beverage for a wide variety of conditions, although it is notable that coffee's use to induce sobriety was a particularly attractive feature. However, considerable controversy about whether the use of coffee was beneficial or detrimental to health was associated with its expansion into Western cultures—a controversy that is mirrored in the contemporary concerns over the use of caffeine. The expansion of coffee consumption during the seventeenth and eighteenth centuries can be demonstrated by the estimate that there were between 2000 and 3000 coffeehouses in London by the early part of the seventeenth century (about 1 coffeehouse for 200 to 300 people). The spread and popularity of coffeehouses in Europe highlights how coffee was initially a beverage consumed in public; it was only later that coffee became a beverage consumed in the home. Perhaps the most famous of the coffeehouses in London was operated by Edward Lloyd. Like most coffeehouses, Lloyd's was a center of business, especially for insurance agents, and by the end of the eighteenth century Lloyd's actually became the well-known Lloyd's of London insurance company. However, in England, coffee use was eventually supplanted by tea consumption, with the shift in beverage preference occurring in the first half of the eighteenth century. In the United States a shift from tea to coffee use occurred in 1773 when colonists protesting British taxes threw cargoes of tea overboard in the Boston harbor—the Boston tea party. The repercussions of this event continue to the present day; the United States is the major consumer of coffee in the world. In the late nineteenth century caffeine began appearing in various soft drink beverages. While some caffeine contained in soft drink beverages is derived from the cola nut, most caffeine in sodas is added. In the United States caffeine is also added to noncola sodas and to some bottled waters, and consumption of soda has been increasing markedly in the past 25 years. In the contemporary world caffeine is integral to the economic activity of several countries. For example, only crude oil produces more foreign exchange earnings than coffee for developing countries. In the United States coffee is the major agricultural import and is second only to oil among all imports. This economic and trade activity underscores the extent to which caffeine use has spread over the past four centuries, so that caffeine is now available and accepted virtually everywhere in the world.

COMPARATIVE NOSOLOGY There is no mention made of caffeine-related disorders in the first edition of DSM (DSM-I), which was published in 1952. In the second edition of DSM (DSM-II), published in 1968, caffeine (and interestingly, tobacco) are explicitly excluded from consideration for a diagnosis of drug dependence, and no other mention of caffeine use disorders is included in this edition. The American Psychiatric Association first included caffeine (and tobacco) use disorders in the third edition of DSM (DSM-III) in 1980. At that time caffeine intoxication—the only caffeine-related disorder in DSM-III—was included as a discrete syndrome with specific criteria for its diagnosis. Over successive editions of the DSM, caffeine intoxication has remained and DSM-IV has included criteria for caffeine withdrawal in the appendix. The text suggests that further research is needed to establish caffeine withdrawal as a discrete syndrome. The DSM-IV has also included diagnoses of caffeine-induced anxiety and caffeine-induced sleep disorders—that is, conditions in which specific caffeine-induced symptoms (anxiety, sleep disturbance) require clinical attention. Caffeine abuse and caffeine dependence are not included in DSM-IV, although there is evidence that some patients can exhibit a caffeine dependence syndrome. The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) contains criteria for caffeine intoxication (“Acute intoxication due to the use of other stimulants, including caffeine”), and also includes several other diagnostic categories that can be applied to caffeine such as “harmful use,” “dependence syndrome,” and “withdrawal states from other stimulants, including caffeine.” Thus, while DSM has tended to restrict the clinical syndromes associated with caffeine use, it is important to note ICD-10, another prominent diagnostic system for psychiatric disorders, has a more inclusive set of conditions associated with caffeine use.

EPIDEMIOLOGY It is difficult to determine the average amount of caffeine used on a daily basis, partly because of the multiple sources of caffeine available to consumers. Caffeine is found in beverages (coffees, teas, sodas), foods (chocolate), and medications (both prescription and over-the-counter drugs), although most caffeine consumed is derived from coffee and tea. Some sources of caffeine such as coffees and colas, are readily identifiable, others are less easily recognized. Thus, for example, noncola sodas can contain caffeine, and certain over-the-counter analgesics also contain caffeine. Estimates of caffeine consumption require knowledge of the caffeine content of these different sources of caffeine. Also, there can be variability within categories, so that different colas, for example, may have different caffeine contents, and the procedure used to prepare a beverage (i.e., brewed versus instant coffee) can also influence the caffeine content. Table 11.4-1 provides a list of the typical caffeine content of selected caffeine-containing products, although these values represent estimates and amounts may vary.

Table 11.4-1 Typical Caffeine Content of Foods and Medications

Caffeine consumption also varies by age. Figure 11.4-1 shows estimates of per capita caffeine consumption, by those who consume caffeine, for different age groups in the United States. These estimates demonstrate the wide variability in caffeine consumption for different ages. As shown in Fig. 11.4-1, the average daily caffeine consumption for all ages of caffeine consumers is 2.79 mg/kg in the United States. It is worth noting that there is substantial caffeine consumption even by young children (i.e., over 1 mg/kg for children between the ages of 1 to 5 years). Worldwide it is estimated the average daily per capita caffeine consumption is about 70 mg.

FIGURE 11.4-1 Mean daily caffeine consumption (mg/kg) for different age groups and all ages, in the United States of America. (Adapted from Barone JJ, Roberts HR: Caffeine consumption. Food Chem Toxicol 34:119, 1996.)

In the United States, the major source of caffeine is coffee, although coffee use peaked in 1962 with a gradual decline throughout the 1980s and 1990s ( Fig. 11.4-2). Fifty-two percent of the United States population 10 years of age or older drank coffee in 1993. While coffee is the most popular form in which caffeine is consumed, caffeine use in children was equally divided between tea and coffee until the late 1980s, when there was a decrease in tea use and a compensatory increase in coffee use. Estimates of soda-related caffeine use are more difficult to determine, although it is notable that soda use (predominantly caffeinated) has been steadily increasing in the United States ( Fig. 11.4-2). It is estimated that approximately 70 percent of the soda consumed in the United States is caffeinated.

FIGURE 11.4-2 Consumption by year for soda, coffee, and tea in the United States of America (gallons per person). Values represent both caffeinated and noncaffeinated products. (Adapted from Liebman B: The changing American diet. Nutr Action Healthlett 24(3):8, 1997.)

The average daily caffeine consumption for all adults in the United States is generally estimated to be 3 mg/kg, and for adult consumers of caffeine it is estimated to be 4 mg/kg (the equivalent of about 3 or more cups of brewed coffee in a man of average weight). Among the heaviest adult consumers of caffeine, caffeine intake is at least 5 to 7 mg/kg per day (the equivalent of about 6 cups of brewed coffee in a man of average weight).

ETIOLOGY It is not uncommon for the first exposure to caffeine to occur during childhood. Following exposure to caffeine, continued caffeine consumption may be influenced by several different factors, such as the pharmacological effects of caffeine, caffeine's reinforcing effects, genetic predispositions to caffeine use, and personal attributes of the consumer (e.g., age).

PHARMACOLOGY AND EFFECTS IN THE CENTRAL NERVOUS SYSTEM Caffeine is a methylxanthine, as are theobromine (found in chocolate) and theophylline (Theo-Dur), typically used in the treatment of asthma. It is well absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 hour after ingestion. Caffeine crosses the blood-brain barrier and is metabolized by the liver. Caffeine metabolism is increased by smoking, and it is not uncommon to find higher rates of caffeine consumption in people who smoke tobacco. Caffeine (and the methylxanthines in general) exert several different effects, including the relaxation of smooth muscle (hence their therapeutic application in the treatment of asthma, where they relax the smooth muscle of bronchi), complex but probably only modest actions on heart rate and blood pressure (which depend in part upon whether or not the person is tolerant to the effects of caffeine), and increased production of urine (although the mechanism of these diuretic effects is not clear). Numerous investigations have examined the effects of caffeine in the central nervous system in order to understand the molecular basis for caffeine's effects. Mechanisms proposed as mediating caffeine's effects have included the inhibition of phosphodiesterases and effects on intracellular calcium (although these effects may only occur with higher doses of caffeine), and antagonism at the adenosine receptor. This latter action—adenosine receptor antagonism—appears to be the primary site of action for caffeine's effects at doses typically ingested by humans. Recent studies also suggest an important role of dopamine in mediating some of the behavioral effects of caffeine.

Subjective Effects and Reinforcement Single low to moderate doses of caffeine (i.e., 20 to 200 mg) can produce a profile of subjective effects in humans that is generally identified as pleasurable. Thus, studies have shown that such doses of caffeine result in increased ratings on measures such as well-being, energy and concentration, and motivation to work. In addition, these doses of caffeine produce decreases in ratings of feeling sleepy or tired. Doses of caffeine in the range of 300 to 800 mg (the equivalent of several cups of brewed coffee ingested at once) produce effects that are rated as being unpleasant, such as anxiety and nervousness. Although animal studies have generally found it difficult to demonstrate that caffeine functions as a reinforcer, well-controlled studies in humans have shown that people choose caffeine over placebo when given the choice under controlled experimental conditions. Thus, the profile of caffeine's subjective effects and its ability to function as a reinforcer can contribute to the regular use of caffeine. Genetics and Caffeine Use Studies examining the possibility of genetic influences on caffeine use have generally focused only on coffee use (rather than on all sources of caffeine), and thus conclusions from these studies need to be viewed with caution. However, several investigations comparing coffee use in monozygotic versus dizygotic twins have shown higher concordance rates for monozygotic twins, suggesting that there may be some genetic predisposition to continued coffee use following exposure to coffee. Age, Sex, and Race The relation between long-term chronic caffeine use and demographic features such as age, sex, and race has not been widely studied. There is some evidence that suggests that older people may use more caffeine, although caffeine use in adolescents is not uncommon. There is no known evidence that caffeine use differs for men versus women, and there is no data that specifically addresses caffeine use for different races. There is some evidence suggesting that in the United States whites consume more coffee and tea than African-Americans although the survey that found this difference did not distinguish between caffeinated and noncaffeinated products. This survey found no difference in the rates of soda consumption by race. Special Populations Caffeine's metabolism is increased in people who smoke tobacco, and several studies have shown higher amounts of daily caffeine consumption in people who smoke. Caffeine metabolism is decreased in women who take oral contraceptives, so that lower daily caffeine consumption in this population may simply reflect compensation because of decreased metabolism. There have also been several studies showing high daily amounts of caffeine use in psychiatric patients. For example, several studies have found such patients consume the equivalent of an average of five or more cups of brewed coffee each day. Finally, high daily caffeine consumption has also been noted in prisoners. Personality Although attempts have been made to link preferential use of caffeine to particular personality types, results from these studies do not suggest that any particular personality type is especially linked to caffeine use.

DSM-IV DISORDERS Caffeine use can be associated with five discrete syndromes. Three of these conditions—caffeine intoxication, caffeine-induced anxiety disorder, and caffeine-induced sleep disorder—are described in DSM-IV ( Table 11.4-2). A fourth syndrome—caffeine withdrawal—is included in the appendix of DSM-IV, and a final condition—caffeine dependence—is not included in DSM-IV but will be discussed here. These latter two conditions can be diagnosed using the category caffeine-related disorders not otherwise specified, which is included in DSM-IV as a substance-related disorder.

Table 11.4-2 DSM-IV Caffeine-Related Disorders

Caffeine Intoxication Caffeine intoxication has long been recognized as a discrete syndrome associated with the use of a significant amount of caffeine ( Table 11.4-3). Intoxication can be the result of an ingestion of a large amount of caffeine in a person who has not regularly consumed caffeine (a nontolerant individual), and thus may represent an overdose of caffeine. Alternatively, caffeine intoxication can occur in the context of a person who chronically consumes large amounts of caffeine, which produces a more complicated clinical picture. Interestingly, while intoxication by some psychoactive substances, such as alcohol, is sought out by some people, it appears that most individuals do not actively seek repeated episodes of caffeine intoxication.

Table 11.4-3 DSM-IV Diagnostic Criteria for Caffeine Intoxication

Epidemiology There have been few studies examining the prevalence of caffeine intoxication, and most of these studies have looked at selected populations (e.g., psychiatric inpatients, college students) and used ambiguous criteria. Notably, one random-digit telephone survey of caffeine use in the general community found that 12 percent of respondents had met the revised third edition of DSM (DSM-III-R) criteria for caffeine intoxication in the past year. Comorbidity Given the limited number of studies of caffeine intoxication, it is not surprising that there is even less known about comorbid disorders associated with this condition. However, it is notable that there appear to be some associations between the amount of caffeine typically consumed by individuals and certain psychiatric conditions (although it should be stressed that these are associations between the amount of caffeine consumed, not a specific diagnosis of caffeine intoxication). Thus, for example, high caffeine consumption has been noted in patients with psychiatric disorders such as bipolar I disorder, schizophrenia, and personality disorders. Excessive caffeine consumption has also been noted in people who smoke tobacco and may be due to increased metabolism of caffeine in smokers. Finally, although rare, it may be possible for a patient to develop delirium from ingesting an acute, extremely high dose of caffeine, and rare cases of suicide have been noted with excessive caffeine consumption. There are some patient populations that tend to not consume caffeine—patients with anxiety disorders. It has been shown that patients with generalized anxiety disorder and patients with panic disorder can be more sensitive to the effects of caffeine, and that patients with panic disorder tend to have lower caffeine

consumption. Thus, these may be patient populations in whom there is less likelihood that caffeine intoxication will be observed. Diagnosis and Clinical Features Caffeine intoxication can present with a variety of clinical features, as shown in the criteria from DSM-IV ( Table 11.4-3). In addition to these signs and symptoms, reports have found patients with caffeine intoxication can have fever, irritability, tremors, sensory disturbances, tachypnea, and headaches. It appears that the most common features of caffeine intoxication are anxiety, nervousness, insomnia, gastrointestinal disturbances, tremors, tachycardia, and psychomotor agitation. Differential Diagnosis Caffeine intoxication severe enough to come to clinical attention is probably a relatively rare condition, and several other disorders should be considered for patients who present with features suggesting caffeine intoxication. These include other substance-related disorders, such as intoxication with other stimulants (e.g., cocaine or amphetamines), and withdrawal from drugs such as sedative-hypnotics (e.g., benzodiazepines), alcohol, or nicotine. In addition, medication adverse effects such as akathisia can present with features suggestive of caffeine intoxication. The final diagnosis of caffeine intoxication depends upon demonstrating the ingestion of a significant quantity of caffeine prior to the onset of symptoms. Course and Prognosis Caffeine has a relatively short halflife (3-6 hours), so caffeine intoxication will typically resolve quickly and with no significant sequelae. Patients with caffeine intoxication generally have a good prognosis, although there have been isolated reports of people who have completed suicide by ingesting a massive amount of caffeine. Treatment The first step in treating a patient presenting with evidence suggesting caffeine intoxication is to confirm the diagnosis. It is important to consider all possible sources of caffeine when considering a diagnosis of caffeine intoxication, including medications and beverages that may not be initially recognized as containing caffeine (e.g., some noncola sodas). Because caffeine has a relatively short half-life, short-term management of the patient can be supportive while the syndrome resolves spontaneously. For the patient who habitually consumes large amounts of caffeine and repeatedly experiences episodes of caffeine intoxication, it may be helpful to aid the patient to recognize their total daily caffeine consumption through the use of daily diaries, and then to teach the patient about the adverse effects associated with caffeine use. Caffeine-Induced Anxiety Disorder A caffeine-induced anxiety disorder can be panic disorder, generalized anxiety disorder, social phobia, or obsessive-compulsive disorder, although the patient does not need to fulfill all the criteria for one of these disorders to quality for a diagnosis of caffeine-induced anxiety disorder (see Table 15.6-18). There has been no work examining this caffeine-related disorder, although there have been investigations examining the relationship between caffeine use and anxiety. Patients with anxiety disorders generally consume less caffeine than control patients, and experience greater self-reports of anxiety after consuming caffeine. In addition, caffeine has been used as a pharmacological probe in subjects without an anxiety disorder, and a sufficiently high dose can produce panic attacks in subjects. The diagnosis of caffeine-induced anxiety disorder depends upon linking the use of caffeine to the anxiety symptoms of concern. For a patient with a suspected caffeine-induced anxiety disorder, a trial of caffeine abstinence may aid in clarifying the diagnosis. Mr. B. was a 28-year-old single African-American male graduate student who was in good health and had no history of previous psychiatric evaluation or treatment. He took no medications, did not smoke or consume alcohol, and had no current or past history of illicit drug use. His chief complaint was that he had begun feeling mounting “anxiety” when working in the laboratory where he was pursuing his graduate studies. His work had been progressing well, he felt his relationship with his advisor was good and supportive, and he could not identify any problems with staff or peers that might explain his anxiety. He had been working long hours, but found the work interesting and had recently had his first paper accepted for publication. Despite these successes, he reported feeling a “crescendoing anxiety” as his day would progress. He noted that by the afternoon he would be experiencing palpitations, bursts of his heart racing, tremors in his hands, and an overall feeling of “being on the edge.” He also noted a nervous energy in the afternoons. These experiences were occurring daily, and seemed confined to the laboratory (although he admitted he was in the laboratory every day of the week). When reviewing Mr. B.'s caffeine intake, it was found he was consuming excessive amounts of coffee. Staff made a large urn of caffeinated coffee each morning, and Mr. B. routinely started with a large mug of coffee. Over the course of the morning he would consume 3 to 4 mugs of coffee (the equivalent of about 6 to 8 5-ounce cups of coffee), and continued this level of use throughout the afternoon. He occasionally had a single can of caffeinated soda, and used no other forms of caffeine on a regular basis. Mr. B. estimated he drank a total of 6 to 8 or more mugs of coffee per day (which was estimated to be at least 1200 mg of caffeine per day). Once pointed out to him, he realized this level of caffeine consumption was considerably higher than at any other time in his life. He admitted he liked the taste of coffee, and felt a burst of energy in the morning when he drank coffee that helped him start his day. Mr. B. and his physician developed a plan to decrease his caffeine use by tapering off caffeine. Details of such a tapering schedule can be found in the section on treatment of caffeine dependence. Mr. B. was successful in decreasing his caffeine use, and had good resolution of his anxiety symptoms once his daily caffeine use had been markedly decreased. Caffeine-Induced Sleep Disorder Forms of a caffeine-induced sleep disorder can be insomnia, hypersomnia, parasomnia, or mixed. However, caffeine use is most frequently associated with insomnia (although there are case reports of patients who have hypersomnia in response to caffeine). Caffeine-induced sleep disorder should be diagnosed in patients with caffeine intoxication only if the sleep disturbance is in excess to that which would be expected from intoxication (see Table 21-18). Although there are essentially no studies directly examining caffeine-induced sleep disorder, there has been work on the relationship between caffeine use and sleep. In general, ingestion of caffeine prior to bedtime results in a delay in sleep onset and poorer sleep quality. For some people, it has been shown that consuming 200 mg of caffeine before bedtime (the equivalent of about 2 cups of brewed coffee) can delay the onset of sleep for up to 4 hours. Sleep disturbances secondary to caffeine use are more likely in people who are not regular consumers of caffeine. For people who consume caffeine on a daily basis, there is evidence to suggest that some tolerance occurs to the sleep-inhibiting effects of caffeine. Caffeine-Related Disorder Not Otherwise Specified This category is included in DSM-IV as a substance-related disorder, and is to be used when the patient has a condition that is caffeine-related but not diagnosable as caffeine intoxication, caffeine-induced anxiety disorder, or caffeine-induced sleep disorder ( Table 11.4-4). Thus, for example, caffeine withdrawal or caffeine dependence could be coded as a caffeine-related disorder not otherwise specified.

Table 11.4-4 DSM-IV Diagnostic Criteria for Caffeine-Related Disorder Not Otherwise Specified

Caffeine Withdrawal Caffeine withdrawal was not included in DSM-III-R, apparently because the symptoms of caffeine withdrawal were believed to be mild. Caffeine withdrawal has been included in the appendix of DSM-IV with a set of diagnostic criteria to be used for further evaluation of the disorder ( Table 11.4-5). It is not included in the body of DSM-IV, despite evidence for a discrete caffeine withdrawal syndrome, because of concerns that there were only a limited number of symptoms (three), some symptoms were similar, and the symptoms have a high prevalence in the general population and can be frequently associated with other circumstances besides caffeine withdrawal.

Table 11.4-5 DSM-IV Research Criteria for Caffeine Withdrawal

Epidemiology Several studies have examined caffeine withdrawal under conditions where it is experimentally induced in a population of subjects. In a study of normal community volunteers whose average daily caffeine consumption was similar to that of the general population, one half of the subjects had moderate or severe headache when they had experimentally induced caffeine withdrawal; 8 to 11 percent of subjects in that study also experienced anxiety, fatigue, and depression while in withdrawal. Other similar studies have found that one third to one half of subjects will experience symptoms of caffeine withdrawal when it is experimentally induced (i.e., subjects undergo a double-blind discontinuation of their daily caffeine use). There have been relatively few attempts to conduct population-based studies on caffeine withdrawal. Such studies have usually been surveys, and found a wide range of reports of caffeine withdrawal (i.e., from 8–42 percent). In the United States it is estimated that over 80 percent of the adult population are regular consumers of caffeine, and even if the incidence of caffeine withdrawal is low, this still would suggest there are large numbers of people who could experience caffeine withdrawal. Comorbidity There have been no studies that have specifically sought to determine conditions that are comorbid with caffeine withdrawal. However, patients with higher daily consumption of caffeine may be at increased risk for developing caffeine withdrawal if they miss consuming their typical dose of caffeine. Diagnosis and Clinical Features A withdrawal condition associated with the cessation of caffeine use has been long recognized, and the most common feature noted with caffeine withdrawal has been headache. DSM-IV also includes marked fatigue or drowsiness, marked anxiety or depression, and nausea or vomiting in the diagnostic criteria. However, several other signs and symptoms of caffeine withdrawal have been noted, such as impaired concentration, yawning, decreased sociability, lassitude, work difficulty, irritability, muscle aches, stiffness, and other flu-like symptoms ( Table 11.4-6). In addition, performance on psychomotor tasks has shown to be impaired when subjects are experiencing caffeine withdrawal.

Table 11.4-6 Clinical Features of Caffeine Withdrawal

CAFFEINE WITHDRAWAL HEADACHE Headache is the most common feature associated with caffeine withdrawal. It is usually described as a generalized, throbbing headache that is worsened by exercise and Valsalva's maneuver, and responds best to caffeine consumption. It typically begins 12 to 24 hours after the last ingestion of caffeine, although the onset can occur as long as 40 hours after the last dose. It usually resolves in 2 to 4 days, although sporadic headaches can continue for up to 11 days. CAFFEINE WITHDRAWAL HEADACHE AND OTHER SIGNS AND SYMPTOMS OF CAFFEINE WITHDRAWALThere are several other signs and symptoms associated with caffeine withdrawal. Patients can experience these signs and symptoms even without the concurrent presence of headache, suggesting that the other features of caffeine withdrawal are not simply secondary to the headache. CAFFEINE WITHDRAWAL AND POSTOPERATIVE HEADACHE Headache is a frequent postoperative symptom. Patients undergoing operative procedures are required to abstain from all oral intake prior to the procedure, including daily dietary caffeine they would typically consume, and several studies have examined whether postoperative headache could reflect caffeine withdrawal. Interestingly, patients with higher daily caffeine consumption are at increased risk for developing postoperative headache, and the consumption of a caffeinated beverage on the day of an operative procedure has been shown to lower the rate of postoperative headache. CAFFEINE WITHDRAWAL AND DOSAGE OF CAFFEINE The risk of developing caffeine withdrawal, and the severity of the withdrawal syndrome are both related to the daily dosage of caffeine consumed (with risk and severity increasing as the dose of caffeine increases). However, it should be noted that caffeine withdrawal can occur with relatively low dosages of caffeine, such as 100 mg per day (the equivalent of about one cup of brewed coffee). CAFFEINE WITHDRAWAL AND AGE Most studies of caffeine withdrawal have determined the presence and features of caffeine withdrawal in adults. However, caffeine withdrawal has also been shown to occur in children. Like caffeine withdrawal in adults, headache and other caffeine withdrawal symptoms can occur in children. Differential Diagnosis There are a wide variety of medical conditions and psychiatric disorders that can overlap with the symptoms of caffeine withdrawal. In part, it was this relative nonspecificity of the criteria for caffeine withdrawal that contributed to the decision to not include it in the body of DSM-IV. When considering a patient who may have caffeine withdrawal, disorders as diverse as viral illnesses, sinus conditions, drug withdrawal states (e.g., from amphetamines, cocaine), other types of headaches such as tension or migraine, and medication reactions should be considered in the differential diagnosis. The final determination of caffeine withdrawal should rest upon a determination of the pattern and amount of caffeine consumption, the time interval between the last ingestion of caffeine and the onset of symptoms, and the particular clinical features presented by the patient. Resolution of symptoms by a dose of caffeine may also be useful in clarifying the diagnosis.

Course and Prognosis Caffeine withdrawal typically begins 12 to 24 hours after the last dose of caffeine, and usually resolves in 2 to 7 days. Most symptoms reach their maximal intensity within the first 48 hours after cessation of caffeine use, with subsequent decreasing intensity over the following days. However, it should be noted that there can be considerable variability between people in the manifestations, severity, and time course of caffeine withdrawal. Furthermore, it has been shown that the same person can experience different symptoms and different degrees of severity of symptoms across different episodes of caffeine withdrawal. Treatment There has been little work systematically investigating the optimal treatment for caffeine withdrawal. The symptoms of caffeine withdrawal typically resolve with the ingestion of a dose of caffeine, and a person with a provisional diagnosis of caffeine withdrawal who continues to be symptomatic after caffeine consumption has been terminated for more than 2 weeks should be carefully re-evaluated and considered for other possible diagnoses. Caffeine withdrawal headaches may also respond to aspirin. If caffeine withdrawal occurs because a person is attempting to abruptly stop all caffeine use, it may be better to attempt a tapering caffeine dosage schedule. Ms. E. was a 32-year-old single white woman employed full-time at a local factory. She occasionally used nonsteroidal anti-inflammatory drugs, but was taking no regular prescription medications. She had a history of alcohol dependence, in remission for 9 years, and was otherwise in good health. She first began consuming caffeine when she started college, and her current beverage of choice was coffee. She typically drank 4 to 5 mugs of coffee each day, and preferred to drink it without cream, milk, or sugar. She estimated that 5 minutes elapsed between the time she got up in the morning and the time she had her first cup of coffee; her roommate made a pot before Ms. E. got up, and Ms. E. immediately poured a mug when she got out of bed. She spaced her mugs over the course of the day, with her last mug either after lunch or with dinner. Physicians had recommended she cut down or stop her coffee use because of complaints of mild indigestion, but she had been unable to do so. Her roommate had also complained about her coffee use at times. Ms. E. routinely drank hot coffee in her car, and had spilled it and burned herself on one occasion. When she had stopped caffeine abruptly, Ms. E. experienced marked irritability; poor concentration; and a severe, generalized headache. When asked to rate the severity of the headache, she replied that “on a scale of 1 to 10 it's a 12.” She also had muscle aches, low energy, lethargy, and a craving to drink a mug of coffee. On the day that she had stopped coffee use abruptly, she left work 2 hours early because of problems with concentrating on the job, and went to bed several hours earlier than usual. She then returned to her usual pattern of coffee use. Caffeine Dependence Caffeine dependence is not included in DSM-IV, and it is explicitly stated that “A diagnosis of Substance Dependence can be applied to every class of substance except caffeine.” Despite the absence of caffeine dependence in DSM-IV, there is evidence supporting a diagnosis of caffeine dependence in some people with problematic caffeine consumption. Before reviewing the features of caffeine dependence, it is important to clarify the use of the word “dependence.” Dependence is sometimes used to indicate the presence of physical dependence—a condition characterized by physiological adaptation to the effects of a drug, and usually indicated by the presence of a withdrawal syndrome when drug ingestion is discontinued. There is considerable evidence that caffeine can produce physical dependence, as indicated by the presence of caffeine withdrawal. The term dependence is also used in a second way—to indicate a clinical diagnosis of dependence. Clinical diagnoses of dependence typically have included a constellation of diagnostic criteria that are loosely linked by the theme of problematic use of the drug. Included in these criteria can be evidence of physical dependence, although physical dependence is usually neither necessary nor sufficient to make a diagnosis of a clinical syndrome of dependence. The DSM criteria are used to make a clinical diagnosis of dependence. Although there are numerous studies and reports on caffeine's ability to produce physical dependence, as evidenced by caffeine withdrawal, there is little research on whether or not some people who consume caffeine can develop a clinical syndrome of dependence. This is a question that only a few studies have addressed. Epidemiology Caffeine use is common throughout the world. Over 80 percent of adults in the United States consume caffeine regularly, and their average daily caffeine consumption has been estimated to be 280 mg (the equivalent of about 3 cups of brewed coffee). Given the substantial number of people who consume caffeine regularly, and their use of daily dosages that produce psychoactive effects, even a low prevalence rate of caffeine dependence could represent substantial numbers of people. However, there has only been one study that has examined the prevalence of caffeine dependence in the general population—a random-digit telephone survey that used the generic criteria from DSM-III-R. That study found that 3 percent of respondents fulfilled criteria for severe dependence (7–9 criteria), 14 percent fulfilled criteria for moderate dependence (5–6 criteria), and 27 percent fulfilled criteria for mild dependence (3–4 criteria). Comorbidity The only study that has reported on comorbid conditions in patients with caffeine dependence was a selected series of case reports and thus it is difficult to generalize to the general population using those results. The study found that about two thirds of patients had a psychiatric disorder in remission, most commonly another substance abuse disorder. However, nearly one half had a mood disorder in remission, one quarter had an anxiety disorder in remission, and one fifth had an eating disorder in remission. Notably, there was a clustering of nicotine dependence, caffeine dependence, and a history of an alcohol use disorder in several subjects, and this clustering of these three disorders has been noted in other studies. CAFFEINE USE AND NONPSYCHIATRIC ILLNESSES There has been considerable interest in determining whether caffeine use is associated with other physical illnesses (analogous to findings of the relationship between nicotine use and conditions such as heart disease and cancer). Numerous studies have sought to determine whether caffeine use might be associated with heart disease, cancer, breast disease, osteoporosis, and other physical illnesses. In general, no such associations have been found, although large epidemiological studies continue to seek such relationships. When patients question a clinician about the possible association of caffeine with various such physical conditions, they can generally be reassured that there is no evidence of a strong relationship between caffeine use and physical illnesses. Interestingly, despite this lack of association between caffeine use and physical illnesses, a survey of medical specialists found that over three quarters recommended that patients decrease or eliminate their caffeine use for certain conditions (such as anxiety, arrhythmias tachycardia, esophagitis or hiatal hernia, and fibrocystic disease). It may be that there is a mild association between higher daily caffeine use in women and delayed conception and slightly lower birth weight. However, there are studies that have not found such associations, and effects when found are usually with relatively high daily dosages of caffeine (e.g., the equivalent of 5 cups of brewed coffee per day). For a woman who is considering pregnancy, especially if there is some difficulty in conceiving, it may be useful to counsel eliminating caffeine use. Similarly, for a woman who becomes pregnant and has a high daily caffeine consumption, a discussion about decreasing her daily caffeine use may be warranted. Diagnosis and Clinical Features DSM-IV provides a generic set of diagnostic criteria that are to be used for determining the presence of a substance dependence syndrome (see Table XX-X). There is little work examining the particular clinical features of caffeine dependence, although there is one report of a series of 16 cases of subjects who fulfilled the DSM-IV criteria for caffeine dependence. Only 4 of the 7 criteria were used in that study, and most of the cases had evidence of the 4 criteria (withdrawal, use continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance use, persistent desire or unsuccessful efforts to cut down or control substance use, and tolerance). In a telephone survey of caffeine users, the most common DSM-III-R dependence criterion reported by respondents was a persistent desire or unsuccessful efforts to cut down or control substance use. Differential Diagnosis When considering a possible diagnosis of caffeine dependence, it is useful to include other substance dependence syndromes in the differential diagnosis. A clinical syndrome of dependence upon caffeine probably goes overlooked by most clinicians because it is not included in DSM-IV and it is not widely recognized and acknowledged as a substance-related abuse disorder. Most people have no problems associated with being dependent upon caffeine so long as their supply is available on a daily basis. Even if they are unable to obtain caffeine for some reason, the withdrawal syndrome is relatively short-lived and is not life

threatening. Course and Prognosis No studies have examined the course and prognosis for patients with a diagnosis of caffeine dependence. Subjects with caffeine dependence have reported continued use of caffeine despite repeated efforts to discontinue their caffeine use. Treatment There have been case reports describing the treatment of patients with problematic caffeine use, although there have been no systematic studies of treating patients with a confirmed diagnosis of caffeine dependence. In general these approaches have used a combination of three techniques to aid patients to decrease or eliminate their caffeine use: gradual tapering of the daily dose, self-monitoring of daily use, and reinforcement for decreased use. The first step in reducing or eliminating caffeine use is to have patients determine their daily consumption of caffeine. This can best be accomplished by having the patient keep a daily food diary. It is important for the patient to recognize all sources of caffeine in the diet, including different forms of caffeine (e.g., beverages, medications) and to accurately record the amount consumed. After several days of keeping such a diary, the clinician can meet with the patient, review the diary, and determine the average daily caffeine dose in milligrams. The patient and clinician should then decide upon a fading schedule for caffeine consumption. Such a schedule could involve decreases in increments of 10 percent every few days. Since caffeine is typically consumed in beverage form, the patient can use a substitution procedure in which decaffeinated beverage is gradually used in place of caffeinated beverage. A diary should continue to be maintained during this time, so that the patient's progress can be monitored. The fading schedule should be individualized for the patient so that the rate of decrease in caffeine consumption minimizes withdrawal symptoms. Abruptly stopping all caffeine use should probably be avoided because withdrawal symptoms are likely to develop with sudden discontinuation of all caffeine use. Ms. G. was a 35-year-old married white homemaker with three children ages 8,6, and 2 years old. She took no prescription medications, took a multivitamin and vitamins C and E on a daily basis, did not smoke, and had no past history of psychiatric problems. She drank moderate amounts of alcohol on the weekends, had smoked marijuana in college but had not used it since, and had no other history of illicit drug use. She had started consuming caffeinated beverages while in college, and her current beverage of choice was caffeinated diet cola. Ms. G. had her first soda early in the morning, shortly after getting out of bed, and she jokingly called it her “morning hit.” She spaced out her bottles of soda over the course of the day, with her last bottle at dinner time. She typically drank 4 to 5 20-ounce bottles of caffeinated diet cola each day. She and her husband had argued about her caffeinated soda use in the past, and her husband had felt she should not drink caffeinated soda while pregnant. However, she had continued to do so during each of her pregnancies. Despite a desire to stop drinking caffeinated soda, she was unable to do. She described having a strong desire to drink caffeinated soda, and if she resisted this desire she found that she could not think of anything else. She drank caffeinated soda in her car, which had a manual transmission, and noted that she would fumble while shifting and holding the soda, and spill soda in the car. She also noted that her teeth had become yellowed, and she suspected this was related to her tendency to swish soda in her mouth before swallowing it. When asked to describe a time when she stopped using soda, she reported that she had run out of it on the day one of her children was to have a birthday party, and she did not have time to leave her home to buy more. In the early afternoon of that day, a few hours before the scheduled start of the party, she felt extreme lethargy, a severe headache, irritability, and craving for a soda. She called her husband and told him she planned to cancel the party. She then went to the grocery store to buy soda, and after drinking two bottles she felt well enough to host the party. While initially expressing interest in decreasing or stopping her caffeinated soda use, Ms. G. failed to attend scheduled follow-up appointments after her first evaluation. When finally contacted at home, she reported she had only sought help initially at her husband's request, and she had decided to try to cut down on her caffeine use on her own.

SUGGESTED CROSS-REFERENCES Chapter 11 discusses substance-related disorders, anxiety disorders are discussed in Chapter 15, and sleep disorders are discussed in Chapter 21. SECTION REFERENCES *Barone JJ, Roberts HR: Caffeine consumption. Food Chem Toxicol 34:119, 1996. Bernard ME, Dennehy S, Keefauver LW: Behavioral treatment of excessive coffee and tea drinking: A case study and partial replication. Behav Therapy

12:543, 1981.

Boulenger JP, Uhde TW, Wolff EA, Post RM: Increased sensitivity to caffeine in patients with panic disorder. Arch Gen Psychiatry 41:1067, 1984. Bruce M, Scott N, Shine P, Lader M: Anxiogenic effects of caffeine in patients with anxiety disorders. Arch Gen Psychiatry 49:867, 1992. Charney DS, Heninger GR, Jatlow PI: Increased anxiogenic effects of caffeine in panic disorder. Arch Gen Psychiatry 42:233, 1985. Comer SD, Haney M, Foltin RW, Fischman MW: Effects of caffeine withdrawal on humans living in a residential laboratory. Exp Clin Psychopharmacol

5:399, 1997.

*Dager SR, Layton ME, Strauss W, Richards TL, Heide A, Friedman SD, Artru AA, Hayes CE, Posse S: Human brain metabolic response to caffeine and the effects of tolerance. Am J Psychiatry 156:229, 1999. Dreisbach RH, Pfeiffer C: Caffeine-withdrawal headache. J Lab Clin Med 28:1212, 1219, 1943. Evans SM, Griffiths RR: Dose-related caffeine discrimination in normal volunteers: Individual differences in subjective effects and self-reported cues. Behav Pharmacol

2:345, 1991.

*Evans SM, Griffiths RR: Caffeine withdrawal: A parametric analysis of caffeine dosing conditions. J Pharmacol Exp Ther 289:285, 1999. Garrett BE, Griffiths RR: The role of dopamine in the behavioral effects of caffeine in animals and humans. Pharmacol Biochem Behav Garriott JC, Simmons LM, Poklis A, Mackell MA: Five cases of fatal overdose from caffeine-containing “look-alike” drugs. J Anal Toxicol

57:1, 1997. 9:141, 1985.

Gilbert RM: Caffeine consumption. In The Methylxanthine Beverages and Foods: Chemistry, Consumption, and Health Effects, GA Spiller, editor. Alan R. Liss, New York, 1984. Goldstein A: Wakefulness caused by caffeine. Naunyn-Schmiedebergs Arch Pharmacol 248:269, 1964. Goldstein A, Kaizer S, Whitby O: Psychotropic effects of caffeine in man. IV. Quantitative and qualitative differences associated with habituation to coffee. Clin Pharmacol Ther

10:489, 1969.

Goldstein A, Wallace ME: Caffeine dependence in schoolchildren? Exp Clin Psychopharmacol 5:388, 1997. Greden JF, Fontaine P, Lubetsky M, Chamberlin K: Anxiety and depression associated with caffeinism among psychiatric inpatients. Am J Psychiatry 135:963, 1978. Greden JF, Victor BS, Fontaine P, Lubetsky M: Caffeine-withdrawal headache: A clinical profile. Psychosomatics 21:411, 1980. Griffiths RR, Bigelow GE, Liebson IA: Human coffee drinking: Reinforcing and physical dependence producing effects of caffeine. J Pharmacol Exp Ther 239:416, 1986. *Griffiths RR, Woodson PP: Caffeine physical dependence: A review of human and laboratory animal studies. Psychopharmacology 94:437, 1988. Griffiths RR, Woodson PP: Reinforcing effects of caffeine in humans. J Pharmacol Exp Ther 246:21, 1988. Griffiths RR, Evans SM, Heishman SJ, Preston KL, Sannerud CA, Wolf B, Woodson PP: Low-dose caffeine physical dependence in humans. J Pharmacol Exp Ther 255:1123, 1990. *Griffiths RR, Mumford GK: Caffeine—A drug of abuse? In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven, New York, 1995. Hughes JR, Amori G, Hatsukami DK: A survey of physician advice about caffeine. J Subst Abuse 1:67, 1988.

Hughes JR, Higgins ST, Bickel WK, Hunt WK, Fenwick JW, Gulliver SB, Mireault GC: Caffeine self-administration, withdrawal, and adverse effects among coffee drinkers. Arch Gen Psychiatry 48:611, 1991. *Hughes JR, Oliveto AH, Helzer JE, Higgins ST, Bickel WK: Should caffeine abuse, dependence, or withdrawal be added to DSM-IV and ICD-10? Am J Psychiatry 149:33, 1992. Hughes JR, Oliveto AH, Helzer JE, Bickel WK, Higgins ST: Indications of caffeine dependence in a population-based sample. In Problems of Drug Dependence, 1992: Proceeding of the 54th Annual Meeting The College on Problems of Drug Dependence, Inc., L Harris, editor. NIDA Research Monograph 132, US Dept of Health and Human Services, National Institute on Drug Abuse, Rockville, MD, 1993. Hughes JR, Oliveto AH: A systematic survey of caffeine intake in Vermont. Exp Clin Psychopharmacol 5:393, 1997. Infante-Rivard C, Fernández A, Gauthier R, David M, Rivard G: Fetal loss associated with caffeine intake before and during pregnancy. JAMA 270:2940, 1993. James JE, Stirling KP, Hampton BAM: Caffeine fading: Behavioral treatment of affeine abuse. Behav Therapy 16:15, 1985. *James JE: Understanding Caffeine: A Biobehavioral Analysis. Sage, Thousand Oaks, CA, 1997. Liguori A, Hughes JR, Grass JA: Absorption and subjective effects of caffeine from coffee, cola and capsules. Pharmacol Biochem Behav 58:721, 1997. Nehlig A, Daval J, Debry G: Caffeine and the central nervous system: Mechanism of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev

17:139, 1992.

Parsons WD, Niems AH: Effect of smoking on caffeine clearance. Clin Pharmacol Ther 24:40, 1978. Pedersen N: Twin similarity for usage of common drugs. In Twin Research 3, Part C: Epidemiological and Clinical Studies, L Gedda, P Parisi, W Nance, editors. Alan R. Liss, New York, 1981. Schuh KJ, Griffiths RR: Caffeine reinforcement: The role of withdrawal. Psychopharmacology 130:320, 1997. Silverman K, Evans SM, Strain EC, Griffiths RR: Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med

327:1109, 1992.

Stanton CK, Gray RH: Effects of caffeine consumption on delayed conception. Am J Epidemiol 142:1322, 1995. Strain EC, Mumford GK, Silverman K, Griffiths RR: Caffeine dependence syndrome: Evidence from case histories and experimental evaluations. JAMA Weber JG, Ereth MH, Danielson DR: Perioperative ingestion of caffeine and postoperative headache. Mayo Clin Proc 68:842, 1993.

Textbook of Psychiatry

272:1043, 1994.

11.5 CANNABIS-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.5 CANNABIS-RELATED DISORDERS WAYNE MACFADDEN, M.D. AND GEORGE E. WOODY, M.D. History Epidemiology Pharmacology Diagnosis and Clinical Features Adverse Effects Laboratory Examination Treatment Suggested Cross-References

Known in central Asia and China for at least 4000 years, the Indian hemp plant Cannabis sativa is a hardy, aromatic annual herb (Fig. 11.5-1). The bioactive substances derived from it are collectively referred to as cannabis. By most estimates, cannabis remains the world's most commonly used illicit drug, with approximately 200 to 300 million regular users. It occupies fourth place in worldwide popularity among psychoactive drugs, after caffeine, nicotine, and alcohol.

FIGURE 11.5-1 Marijuana (Cannabis sativa).

Cannabis sativa is widely cultivated for its fiber, which is used to make rope and cloth; for its seeds, which are used to make oil; and for its psychoactive resin. This resin contains over 60 structurally similar compounds called cannabinoids, of which D 9-tetrahydrocannabinol (THC) is responsible for most of its psychoactive effects. The term marijuana most commonly refers to the upper leaves, flowering tops, and stems of the plant, which are cut, dried, and chopped and usually formed into cigarettes. Hashish is the dried black-brown resinous exudate from the tops and undersides of the leaves of the female plant. Other names for cannabis or its products include bhang, charas, dagga, and ganja; common slang terms are “grass,” “pot,” and “weed.” The THC content and concentration of different parts of the plant and between species varies greatly. The effects of THC depend on dosage, frequency, and route of administration; setting; and the experience and expectations of subjects. Most marijuana purchased illicitly varies from about 1 to 5 percent THC content; sinsemilla, a more potent variety made from just the buds and flowering tops of female plants may contain 7 to 14 percent THC. Hashish, a sticky resin obtained from the female plant flowers, contains up to 10 percent THC, and hashish oil, a concentrated distillate of hashish, has been assayed at up to 15 to 70 percent THC. In addition to genetic variability, the amount of THC produced by the plant is related to environmental conditions such as the amount of sunlight received, humidity, and soil condition. Other factors that affect the amount of THC actually consumed are smoking technique, the amount destroyed by pyrolysis (about 75 percent), and how quickly the drug is used, because THC deteriorates by about 5 percent per month at room temperature. Assertions that the marijuana available today is much more potent than it was 15 to 20 years ago are difficult to validate. THC content in some specimens confiscated in the mid-1970s was reported to be 5 percent or higher, which most investigators consider relatively potent. Cannabis is most commonly smoked in marijuana cigarettes, or joints, and experienced users inhale deeply and hold their breath for as long as possible to extract the THC. Amounts ranging from 2 to 50 percent of the THC in the smoke may be absorbed in this manner. Its intoxicating effects may be increased by mixing other drugs or chemicals into the cigarette, such as opium, cocaine paste, or phencyclidine (PCP). It may also be eaten and is often baked in lipid-rich foods, such as brownies.

HISTORY Archeological evidence suggests that cannabis was introduced to western Europe in approximately 500 BC. There are reports of its widespread use for pleasure-seeking purposes in the early 19th century by Napoleon's soldiers in Egypt. Although previous knowledge of its use existed in the United States, it may have been more widely introduced by Mexican immigrants in the 1920s. Soon afterward Western states pressured the federal government to control cannabis use because it was linked to violence from foreign (often unwelcome) laborers, who were allegedly growing the plant. The Marijuana Tax Act of 1937 established government control over sale and transfer of the drug, and no stamps or licenses were available for its public use. During that time its use was associated with jazz musicians or minority groups who were not well assimilated into the overall culture. Marijuana's image shifted during the 1960s when the youthful counterculture rediscovered cannabis. It became associated with social protest, and its use spread rapidly throughout the general society. Occasional use, even by adolescents, became common. The use of cannabis became “normalized” in many parts of the United States culture, a fact contributing to the initial difficulty many investigators encountered in associating cannabis with health problems. The favorable attitude toward cannabis reached a peak in about 1978. Since that time its use declined yearly in the overall population until 1993 when it began rising again. In attempts to suppress its use, penalties have risen against users and dealers, but enforcement varies widely among states and municipalities. As possible medicinal uses of cannabis are being explored, with strong advocates for its use in acquired immune deficiency syndrome (AIDS) patients and patients receiving chemotherapy, attempts to provide compassionate use have been undertaken by various constituencies. In 1996, referendums in California and Arizona approved ballot measures allowing the use of marijuana as a medical treatment. In California, this measure allowed possession and use of marijuana by patients or caregivers if recommended by two medical doctors. Controversy continues, as some lawmakers and law enforcement agencies have attempted to curb this practice by enacting preventive legislation to prosecute physicians who recommend use of substances such as cannabis that lack approval of the federal Food and Drug Administration (FDA). The World Health Organization (WHO) and other governmental advisory and regulatory agencies have consistently maintained that cannabis is a drug requiring close monitoring and stringent control. In 1965 WHO declared that “the harm to society derived from abuse of cannabis rests in the economic consequences of the impairment of the individual's social functions and his enhanced proneness to asocial and antisocial behavior.” In 1969 WHO considered cannabis not physically habit forming but a drug of dependence and recommended keeping it under legal control. The classification of cannabis as a highly controlled (class I) substance by the United States Drug Enforcement Administration is consistent with that view. Comparative Nosology The diagnostic criteria for cannabis intoxication in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) are similar. Both require at least one of the following four signs of intoxication: conjunctival injection, increased appetite, dry mouth and tachycardia, though DSM-IV requires them to develop within 2 hours of cannabis use. (1) Maladaptive or dysfunctional behavior or (2) psychological or perceptual changes are also required for both manuals. However, ICD-10 identifies 12 specific symptoms for the examiner to choose (one) from, where DSM-IV does not specify but notes it should be “clinically significant.” DSM-IV does not recognize a clinically significant cannabis withdrawal state. Withdrawal from cannabis is identified in ICD-10, but definite diagnostic criteria are

omitted. It is noted as lasting several hours to up to 7 days, and describes several nonspecific signs and symptoms.

EPIDEMIOLOGY Prevalence and Recent Trends The Monitoring the Future survey of adolescents in school indicates recent increases in lifetime, annual, current (use within the past 30 days) and daily use of marijuana by eighth and tenth graders, continuing a trend that began in the early 1990s. In 1996, 23.1 percent of eighth graders and 39.8 percent of tenth graders reported lifetime marijuana use. By 1996, past-month marijuana use had increased over 250 percent since 1991 for eighth graders and over 150 percent since 1992 for 10th graders. Lifetime use for high school seniors peaked at 60 percent in 1979, then began decreasing yearly until 1993, when rates began to rise again. Some investigators believe that softening attitudes about the hazards associated with cannabis may be responsible for these recent increases. In evaluating these trends, one should note that occasional use does not imply abuse or dependence. The percentage of users who fulfill criteria for either of these diagnoses is unclear at this time, though it is likely to be relatively low, somewhat analogous to the case with alcohol. Another measure of the prevalence of marijuana use comes from the National Household Survey on Drug Abuse, a population-based random sample of households throughout the United States. Marijuana was the most commonly used illicit drug in the 1995 study, which found that approximately 77 percent of current illicit drug users were marijuana or hashish users. About one third (31 percent) of the population reported that they had used marijuana one or more times in their lifetime, 8 percent had used it in the past year, and 5 percent had used it in the past month. Those percentages translate to approximately 66 million persons who had used marijuana in their lifetime, 18 million in the past year, and 10 million in the past month. Lifetime prevalence of marijuana use increased with each age group until 34 years, then decreased gradually. Those aged 18 to 21 were the most likely to have used marijuana in the past year (25 percent) or the past month (14 percent), and use was lowest among those age 50 or older, where it was at or below 1 percent. Demographic Correlates The rate of past year and current marijuana use by males was almost twice the rate for females overall among those age 26 and older. This gap between the sexes narrows with younger users; at ages 12 to 17, there are no significant differences. Race and ethnicity were also related to marijuana use, but the relationships varied by age group. Among those ages 12 to 17, whites had higher rates of lifetime and past-year marijuana use than blacks. Among 17- to 34-year-old adults, whites reported higher levels of lifetime use than blacks and Hispanics. But among those 35 and older, whites and blacks reported the same levels of use. The lifetime rates for black adults were significantly higher than those for Hispanics. There were no differences in past-month use between whites and blacks among those 12 to 34 years old. Among females, whites reported the highest levels of lifetime use (30 percent), followed by blacks (20 percent) and Hispanics (15 percent). Variations in patterns of marijuana use by geographic region were small as were variations in use between metropolitan and nonmetropolitan areas. For younger adults (18 to 25), marijuana use was similar across all educational levels, except for lower rates of current use among college graduates. For those ages 26 to 34, current use decreased significantly at higher educational levels. Individuals with less than a high school diploma had higher rates of past-year and current marijuana use than those all in other education categories. Among adults 35 and older, however, this trend was reversed for lifetime use; 33 percent of college graduates reported having ever used marijuana versus 12 percent of those with less than a high school diploma. Among the total adult surveyed population, past-year and past-month marijuana use were substantially higher among the unemployed than in those in any other employment category. Current users of marijuana were more likely than nonusers to drink alcohol, smoke cigarettes, and use other illicit drugs. This finding was most marked in younger adults and adolescents; in every age group up to age 35, current marijuana users were 10 to 12 times more likely to use other illicit drugs than those who were not current users.

PHARMACOLOGY The THC dose needed to produce pharmacological effects in humans from smoking range from 2 to 22 mg. THC is lipid soluble and rapidly absorbed after inhalation. It is highly protein bound and quickly redistributed from blood into other tissues. The percentage of ingested THC that reaches the brain is small; about 1 percent penetrates the blood-brain barrier. The THC that reaches the liver is almost completely metabolized, primarily into active 11-hydroxy-THC and inactive 9-carboxy-THC. More-extensive metabolism in the liver converts 11-hydroxy-THC to many inactive metabolites, including 11-norcarboxy-D-THC, which is detected minutes after smoking. It is the most abundant metabolite in plasma and urine, and also the primary cannabinoid metabolite excreted in the urine; typically it can be detected 2 to 3 days after smoking a single cannabis cigarette. Blood levels of THC peak in about 30 minutes and then decline precipitously as it redistributes through the body to lipid-rich tissues, reaching nearly undetectable levels within 3 to 4 hours. After some equilibrium between concentrations in the blood and other tissues is established, THC slowly and unevenly reenters the bloodstream from its tissue stores. Its concentration declines slowly in this second phase, with a half-life of 3 days. This low concentration of THC or its active 11-hydroxy-THC metabolite is believed to be below the threshold to produce an effect and is thus clinically insignificant. However, the half-life of these metabolites is at least 50 hours. About two thirds of the drug is excreted via the enterohepatic circulation into the feces, and the remaining one third is removed through the kidney. Most of the metabolites of THC are produced by the liver. Among these compounds, 11-norcarboxy-THC has the highest concentration in the urine and is the metabolite usually screened for in routine toxicological analyses. This and other cannabinoid metabolites can be detected in the urine for 2 to 3 days after casual use; for daily heavy users, detectable levels can persist for up to 4 weeks. Cardiovascular and central nervous system (CNS) effects, such as mood-altering properties, begin less than 1 minute after inhalation. Peak clinical effects may be delayed for 20 to 30 minutes and persist for at least 2 to 3 hours. Immediately after smoking marijuana, plasma concentrations of cannabinoids are high while effects are low; this reverses at later times. Peak blood concentrations of THC are reached rapidly, within 10 minutes of smoking and decline to 5 to 10 percent of their initial level within 1 hour. Because of this delay between peak blood concentrations and peak drug effects, establishing a relationship between blood levels of THC or its metabolites and the degree of impairment has been difficult. The precise method and time of cannabis use must be known before any useful prediction of impairment from THC can be made. The apparent half-life of THC in both plasma and body fat is about 4 days. However, concentrations of THC in blood correlate only modestly with cannabis intoxication, and there is no consistently demonstrated correlation between concentration of THC in blood and effects on performance. The pharmacological effects of orally ingested cannabis begin after 30 minutes, peak in 2 to 3 hours, and last 3 to 6 hours. Residual effects, such as subtle changes in mood and fine motor control, can be measured for a longer period if very sensitive testing procedures are used. An oral dose of approximately 20 mg of marijuana or smoking a cigarette containing about 0.5 to 2 percent THC usually produces intoxication. Orally ingested marijuana requires about three times as much THC as smoked marijuana to produce equivalent effects because only 3 to 6 percent of ingested THC is absorbed. THC demonstrates weak barbiturate-like actions such as anticonvulsant activity and opioid-like effects, including analgesia, increased catecholamine synthesis, hypothermia, and antidiarrheal activity. Increased limbic system activity has been noted with cannabis use, suggesting that THC may stimulate pleasure-reward mechanisms in the brain. Cannabis is often used in combination with other drugs. It may alter the effects of amphetamines, atropine, barbiturates, clomipramine (Anafranil), cocaine, ethanol, nicotine, opiates, and phencyclidine. Because of shared hepatic metabolic systems, ethanol and phenobarbital (Donnatal, Quadrival) can inhibit metabolism of THC. Similarly, THC can slow the metabolism of a variety of drugs, including theophylline (Theo-Dur), ethanol, and pentobarbital (Nembutal). Some limited cross-tolerance exists between THC and CNS-depressant drugs. However, there is no evidence that THC is useful for detoxification from sedatives, although they both can enhance or prolong the other's behavioral and psychological effects. Mechanism of Action The creation and radiolabeling of certain cannabinoids led to identification of a receptor in rat brain membranes. A single binding site was identified that displayed saturable and reversible binding and selectivity for cannabinoids. The pharmacological potency of cannabinoids correlates with their affinity for the cannabinoid binding site. Receptor binding was also found in the peripheral B lymphocyte–enriched areas including the marginal zone of the spleen, the nodular corona of Peyer's patches, and the cortex of the lymph nodes. Another advance has been the recent isolation of an endogenous cannabinoid-like ligand within the brain, named anandamide, from a Sanskrit word meaning “bliss.” Soon after, a cannabinoid antagonist was discovered that antagonizes cannabinoid-induced inhibition of adenyl cyclase and smooth muscle contraction. This recent

progress suggests the presence of a cannabinoid neurochemical pathway. The function of such a system is unclear, but cannabinoids exert many of their actions by influencing several neurotransmitter systems and their neuromodulators. These include acetylcholine, dopamine, g-aminobutyric acid (GABA), histamine, serotonin, norepinephrine, opioid peptides, and prostaglandins. Cannabinoids enhance the formation of norepinephrine, dopamine, and serotonin. Notably, they stimulate the release of dopamine from rat brains by activating opiate receptors; after THC infusions, dopamine levels in the nucleus accumbens increase as much as twofold, analogous to the surge seen with other addictive drugs. GABA turnover is enhanced by cannabinoids. Catalepsy can result from the interaction of THC with neurotransmitter systems in the basal ganglia. Studies of catalepsy and depression of spontaneous locomotor activity caused by cannabinoids suggest that these effects are mediated by acetylcholine, GABA, and prostaglandins. Despite these advances, interpretation of the actions of cannabinoids on neurotransmitter systems is often unclear, as evidence suggests that cannabinoids both inhibit and stimulate uptake of transmitters. Recent evidence suggests that few, if any, irreversible effects on brain chemistry are caused by THC administration. Cannabinoid receptor location and density in animal models has corresponded with its clinical effects in humans. The highest density of receptors occurs in the basal ganglia and molecular layer of the cerebellum, which correlate with its interference in motor coordination. Intermediate levels of binding were found in the hippocampus, the dentate gyrus, and layers I and IV of the cortex, consistent with cannabinoid effects on short-term memory and cognition. Low receptor density is noted in the brainstem areas controlling cardiovascular and respiratory functions, which is consistent with the cannabinoids' lack of lethality. After binding to receptors, cannabinoids also produce effects through second-messenger systems including inhibition of adenyl cyclase and calcium channels, and by possibly enhancing potassium channels activity. In summary, the biological bases for the multiple effects of cannabis are beginning to be understood, but as expected, they are complex and not yet fully elucidated.

DIAGNOSIS AND CLINICAL FEATURES Patterns of use vary widely; the most common is intermittent use of marijuana cigarettes, such as smoking one or two joints on a weekly or monthly basis, often on social occasions. As with alcohol, a small proportion of cannabis users develop the pattern of intermittent or daily use of high doses that is typically associated with abuse or dependence. The proportion of users who progress to dependence is unknown but is probably similar to alcohol. Marijuana has mild-to-moderate reinforcing effects, and benign experiences with it may lead users to try more reinforcing drugs in the belief that drug effects are pleasurable and not to be feared. In fact, initial marijuana usage is a common behavioral pattern in patients who eventually progress to so-called harder drugs such as opiates, stimulants, and stronger psychedelics. It is unlikely that the relationship is causal, however. The purchase or use of marijuana may imply a willingness to use other illicit substances and may also put the user in contact with people who distribute them. From self-report data, marijuana use has been associated with problematic alcohol use and a pattern of general deviance that leads to poor workplace performance. New studies have postulated a neurobiological basis for the “gateway hypothesis,” in which smoking marijuana is thought to cause some people to abuse harder drugs. Marijuana and heroin both produce dopamine surges in rat brains by activating opiate receptors; marijuana, however, presumably does so indirectly by causing the release of an endogenous opiate. Some speculate that marijuana may thus prime the brain to seek substances like heroin that act in a similar way. Additionally, long-term cannabis use increases release of corticotropin-releasing factor during antagonist-precipitated withdrawal in rats. As corticotropin-releasing factor is believed to be a key element of withdrawal syndromes from alcohol, opiates, and cocaine, causing stress reactions and anxiety, some also speculate that marijuana users may seek these harder drugs to provide relief from the similar neurochemically induced stress and anxiety noted in cannabis withdrawal syndromes. DSM-IV lists the cannabis-related disorders ( Table 11.5-1) but has specific criteria only for cannabis intoxication ( Table 11.5-2). The diagnostic criteria for the other cannabis-related disorders are general and are contained in the DSM-IV sections that focus on the major phenomenological symptom—for example, cannabis-induced psychotic disorder in the schizophrenia and other psychotic disorders.

Table 11.5-1 DSM-IV Cannabis-Related Disorders

Table 11.5-2 DSM-IV Diagnostic Criteria for Cannabis Intoxication

Cannabis Dependence and Cannabis Abuse DSM-IV includes the diagnoses of cannabis dependence and cannabis abuse (see Table 11.1-3 and Table 11.1-8). The experimental data clearly show tolerance to many of the effects of cannabis with sustained use of high doses. Tolerance develops to most of the physical effects of cannabis, including tachycardia, decreased skin temperature, increased body temperature, decreased intraocular pressure, sleep disturbance (decreased rapid eye movement [REM] sleep), electroencephalogram (EEG) changes (increased alpha waves), and impairment of performance on psychomotor tests. There is less agreement about tolerance to the common mood and behavioral changes, but progressive loss of the so-called high has been reported. Cannabis Intoxication DSM-IV formalizes the diagnostic criteria for cannabis intoxication ( Table 11.5-2). These criteria specify that the diagnosis can carry the phrase “with perceptual disturbances.” If perceptual disturbances are present but reality testing is impaired, the diagnosis becomes cannabis-induced psychotic disorder. Acute intoxication due to use of cannabinoids as outlined in ICD-10 closely mirrors the descriptive themes in DSM-IV. Cannabis intoxication commonly heightens the user's sensitivity to external stimuli, reveals new details, makes colors seem brighter and richer than before, and makes time seem to pass more slowly. With high doses, the user may also experience depersonalization, derealization, illusions, hallucinations, suspiciousness or paranoid ideation. Cannabis Intoxication Delirium Cannabis intoxication delirium is a DSM-IV diagnosis ( Table 10-22). The delirium associated with cannabis intoxication is

characterized by marked impairment on cognition and performance tasks. Even modest doses of cannabis impair memory, reaction time, perception, motor coordination, and attention. High doses that also impair the user's level of consciousness have even more marked effects on these cognitive measures. However, a cannabis-induced, longer-lasting toxic-organic delirium characterized by confusion with disorganization of thought processes, affective lability, delusions, and hallucinations has been reported. This reaction, similar to the delirium produced by other psychomimetics, hallucinogens, or toxins, may last up to 10 days. Whether cannabis is the primary etiological agent in these cases has been questioned by some investigators, however. Cannabis-Induced Psychotic Disorder High doses of cannabis are more likely than low doses to induce brief psychotic symptoms such as persecutory delusions or auditory and visual hallucinations, especially in persons with underlying psychiatric disorders. Such cases may fulfill the DSM-IV criteria for cannabis-induced psychotic disorder (see Table 13.3-4). It is uncertain whether persons with unstable character structures are more susceptible to these brief psychotic episodes. Cannabis-induced psychotic disorder is rare; transient paranoid ideation is more common. Florid psychosis is somewhat common in countries where persons have long-term access to cannabis of particularly high potency. The psychotic episodes are sometimes referred to as “hemp insanity.” Cannabis use is rarely associated with a bad-trip experience, such as that associated with hallucinogen intoxication. No persistent cannabis psychosis has been identified, even in chronic heavy users. However, it appears likely that cannabis can exacerbate schizophrenia, as is the case with other drugs that have hallucinogenic properties, though there is no conclusive evidence that cannabis is a causative factor in the development of schizophrenia. Thus, despite worldwide reports associating cannabis with mental illness, chronic psychosis has not yet been reliably and consistently demonstrated to result from cannabis use. Chronic psychotic disorders that may be precipitated by cannabis appear to be related to premorbid vulnerability or psychopathology. Cannabis-Induced Anxiety Disorder Cannabis-induced anxiety disorder is a common diagnosis (see Table 15.6-18) for acute cannabis intoxication, which in many persons induces short-lived anxiety states that are often provoked by paranoid thoughts. In such circumstances, panic attacks may be induced, based on ill-defined and disorganized fears. The appearance of anxiety symptoms is correlated with the dose and is the most frequent adverse reaction to the moderate use of smoked cannabis. Some cannabis users report occasional unpleasant adverse experiences, most often described as anxiety reactions of mild-to-moderate intensity. Inexperienced users are much more likely to experience anxiety symptoms than are experienced users. Cannabinoid Withdrawal State ICD-10 notes cannabinoid withdrawal state; DSM-IV does not. It is described as an “ill-defined syndrome for which definitive diagnostic criteria cannot be established at present,” substantiating the lack of systematic nosological research in this area. Symptoms and signs noted in ICD-10 include anxiety, irritability, tremor of outstretched hands, sweating, and muscle aches. Cannabis-Related Disorder Not Otherwise Specified DSM-IV does not formally recognize cannabis-induced mood disorders; therefore, such disorders are classified as cannabis-related disorders not otherwise specified ( Table 11.5-3). Cannabis intoxication can be associated with depressive symptoms, although such symptoms may suggest long-term cannabis use. Hypomania, however, is a common symptom in cannabis intoxication.

Table 11.5-3 DSM-IV Diagnostic Criteria for Cannabis-Related Disorder Not Otherwise Specified

DSM-IV also does not formally recognize cannabis-induced sleep disorders or cannabis-induced sexual dysfunction; therefore, both are classified as cannabis-related disorders not otherwise specified. When either sleep disorder symptoms or sexual dysfunction symptoms are present and related to cannabis use, they almost always resolve within days or a week after the cessation of cannabis use. Flashbacks Flashbacks, in which feelings and perceptions experienced in the intoxicated state are suddenly thrust into consciousness in the nondrugged condition, have also been reported with cannabis use, although not as often as with lysergic acid diethylamide (LSD). It has been suggested that flashbacks result from intermittent release of psychoactive components from the CNS, where they are stored during periods of active use, but that explanation remains highly speculative. A few clinical reports suggest that marijuana use may precipitate flashbacks in persons who have previously used LSD. Amotivational Syndrome An amotivational syndrome associated with chronic cannabis use was described in the older clinical literature from the Middle East, the Orient, and the United States. The syndrome is marked by apathy, poor concentration, social withdrawal, and loss of interest in achievement. Those features may correlate with the reversible decrement in cerebral blood flow that has been documented as an effect of marijuana. However, most of the reports are not rigorously scientific and lack controls that distinguish between the effects of cannabis and preexisting psychological and social conditions. Subsequent reports using different populations and better scientific methods have failed to demonstrate the syndrome. Several authors have noted that it is difficult to determine which came first, the drug or the amotivation. Most plausible perhaps is the suggestion that in certain persons the pharmacological effects of the drug interact with psychological and social factors to retard motivation and productivity. Thus, the direct causal role of marijuana in the amotivational syndrome has been seriously questioned. Symptoms may indicate ongoing intoxication or represent normal psychosocial variants that predispose to the use of cannabis and other substances. However, because persistent functional and structural changes in hippocampal neurons in animals subjected to long-term THC administration have been observed, the concept that a developing personality can be altered by chronic intoxication should not be entirely dismissed. In any event, cessation may lead to gradual improvement. Despite those potential adverse effects, many regard cannabis as a relatively safe drug because lethal doses are unknown in humans. Physical Dependence Although DSM-IV provides no criteria for a cannabis withdrawal syndrome, withdrawal signs elucidated in rats after administration of the newly developed cannabinoid antagonist provide strong evidence that cannabinoids produce physical dependence. In humans, the withdrawal signs and symptoms that result from abrupt cessation of chronic high-dose cannabis abuse are not severe. They may reach their peak about 8 hours after last use and persist for 2 to 3 days. The most prominent symptoms reported are increased irritability and restlessness. Other less reliable signs and symptoms include anxiety, sleep disturbances, anorexia, perspiration, nausea, and muscle pain. Objective signs include increased body temperature, diarrhea, vomiting, weight loss, and hand tremors. No specific treatment is generally required. Recent animal research has linked corticotropin-releasing factor to these stress-like negative affective states typical of cannabis withdrawal. Corticotropin-releasing factor concentrations are markedly elevated in the brains of chemically treated rats after antagonist-induced withdrawal. This stress hormone may mediate a similar final common pathway of anxiety and emotional stress in withdrawal states produced by various drugs of abuse (opiates, cocaine, and alcohol). Tolerance Animal species develop tolerance to a variety of pharmacological effects, including antinociception, anticonvulsant activity, catalepsy, depression of locomotor activity, hypothermia, hypotension, corticosteroid release, and ataxia. Tolerance may reach 100-fold. Other psychoactive cannabinoids including nabilone also produce tolerance. Neuronal changes such as downregulation, conformational change, and internalization of receptors have been postulated to produce this tolerance. Because of tolerance and learned behavior, detecting cannabis intoxication in an experienced user by motor performance may be difficult. In an inexperienced user, intoxication can be detected by many performance tests.

Several factors contribute to tolerance, including potency, expectations, environmental influences, individual differences, and frequency of use. There is evidence for the development of tolerance in humans to THC-induced decreases in intraocular pressure, sleep disturbances, and mood changes. High doses over long periods of time are necessary to produce behavioral tolerance.

ADVERSE EFFECTS CNS THC exerts prominent effects on the CNS that are highly variable and depend on the user, the dose, and the environment. An initial stimulant effect commonly produces an increased sense of well-being and euphoria and is associated with spontaneous laughter, disinhibition, or quiet reverie. Some experience heightened imagination and creative thinking. Mood changes vary, and anxiety and depression may be induced. These initial effects are often followed by relaxation or lethargy and drowsiness, especially at higher doses. Many users report perceptual and sensory changes, such as a sense that time is passing slowly, accentuation of auditory and visual perceptions, or actual sensory distortions, occasionally involving hallucinations. Because of these perceptual changes (usually only at very high doses), some consider marijuana a hallucinogen with very low potency. Dry mouth and throat and increased hunger are also common. Most psychoactive adverse marijuana-induced effects disappear when the acute intoxication has ended, depending on individual vulnerability, environmental factors (whether the user is in a nonthreatening area), and dose. Less common adverse effects are changed sensations of bodily perceptions, depersonalization, derealization, acute panic, and frank paranoia. THC has well-known deleterious effects on higher cognitive functions, related to the duration of cannabis use. It reliably impairs short-term memory but not retrieval of previously learned facts. Attention span, recall, the ability to store knowledge, and the ability to perform tasks requiring multiple mental steps are also adversely affected. In addition, the ability to verbalize is often diminished. The term “temporal disintegration” has been coined to characterize THC's effects on the CNS. Intoxicated persons may have difficulty integrating earlier experiences, expectations, and current perceptions into goal-directed action (e.g., learning new material is usually impaired). College students who used marijuana regularly had impaired skills related to attention, memory, and learning 24 hours after they had last used the drug. Acute neurophysiological changes include suppression of REM sleep and diffuse slowing of background activity on the EEG. Those acute effects last for minutes up to a few hours, depending on dose and individual sensitivity to the drug. However, they can measurably impair performance if higher levels of cognitive or psychomotor skills are required. THC increases cerebral blood flow in experienced users, correlating with intoxication. Acute THC also increases cerebral metabolic rate, primarily in the cerebellum and prefrontal cortex. Chronic effects have been more elusive, but long-term use has been hypothesized to impair the frontal lobe, which functions in the temporal organization of behavior. Frontal lobe impairment is consistent with the altered perception of time and also with cerebral blood flow studies that demonstrate greatest effects in the frontal lobe region. Some studies suggest that impairment assessed by sensitive measures of brain function can be detected after 5 years of use, but research has yet to demonstrate conclusively that chronic heavy marijuana use results in cognitive deficits that persist after prolonged abstinence. Studies of cerebral morphological changes in humans have not been compelling, though animal studies have shown structural damage to the hippocampus, a structure critical in learning and memory. Quantitative EEG studies have reported increased alpha power, decreased alpha frequency, and decreased beta activity following acute exposure, which is consistent with a state of drowsiness. Quantitative EEG changes such as increased frontal-central theta wave activity in association with increased alpha wave activity may occur following long-term (5 years or more) exposure. Psychomotor A variety of motor skills are affected by acute use, including decreased muscle strength, hand steadiness, and performance of simple motor tasks and reflex responses. At higher doses coordination and balance are impaired in a dose-related way. These effects may last several hours after subjective effects have subsided, and they are additive to those produced by alcohol or other sedatives. Simple reaction time has not been shown to be adversely affected, but response to complex and unforeseen situations is impaired. As these skills are functional components important to driving, they may be related to marijuana-induced impairment of automobile driving. Some data suggest that marijuana produces a significant decrease in speeding and other risk-taking behavior, effects opposite those that often result from alcohol consumption. Few studies are available on marijuana's effect in causing auto or airplane accidents. In one report of roadside sobriety tests, trained observers found that 94 percent of subjects were intoxicated 90 minutes after smoking moderate amounts of marijuana, and 60 percent after 2 hours. Despite numbers like these, several studies indicate that marijuana use by itself is a relatively minor risk factor in fatal traffic accidents. Although some observations suggest an increased accident risk for THC-positive drivers, interpretation of the data is confounded by concurrent alcohol use, which may synergistically worsen impairment. Some authors speculate that because persons with substance use disorders commonly use cannabis, marijuana testing may be of value as a monitor for more serious types of drug use—particularly, heavy drinking. Several controlled studies indicate that cannabis intoxication impairs the ability to fly airplanes more than driving ability. That finding can be explained by the increased complexity of the tasks involved in flying. For both flying and driving, no correlation has been established between the degree of impairment and blood or urine levels of THC, rendering it difficult to establish reliable legal levels of intoxication as has been done for alcohol. Cardiovascular Effects One of the first effects of the drug is a predictable dose-dependent increase in heart rate, probably due to an inhibition of vagal tone. Along with conjunctival reddening from dilation of blood vessels, the heart rate increase correlates with the appearance and duration of psychic effects as well as plasma concentrations of the drug. Myocardial oxygen demand is increased, and exercise tolerance decreased. These effects can lead to myocardial ischemia if a person with coronary artery disease exercises when intoxicated. Cannabinoids may exacerbate preexisting cardiovascular conditions such as angina and congestive heart failure. Orthostatic hypotension can also occur, especially at high doses. Tolerance appears to develop to all these cardiovascular effects. Pulmonary Effects Smoking is by far the most popular route of cannabis administration. Although not yet subject to the same large-scale, long-term epidemiological analyses that identified tobacco as a carcinogen, cannabis is known to induce pulmonary pathology. Chronic smokers often experience bronchitis, pharyngolaryngitis, and asthma, most likely from marijuana smoke's highly irritating effect on the bronchial epithelium. Marijuana cigarettes contain far more tar (particulates) and respiratory irritants than tobacco. Tar produced by burning marijuana is more carcinogenic to animals than that derived from tobacco, and some workers predict that marijuana smoking will result in malignancies. Adding to the long-term toxic potential is the fact that marijuana smoke is usually inhaled longer and more deeply than cigarette smoke, delivering up to four times more tar to the lungs. Heavy marijuana smoking causes mild, but significant, large airway obstruction, probably through chronic irritation or inflammation of the bronchial lining. THC itself causes bronchodilation to which little tolerance develops. Immunological and Carcinogenic Effects Marijuana smoke inhibits pulmonary antibacterial defense systems, primarily alveolar macrophages, neutrophils, and lymphocytes. Cannabinoids may also suppress cellular and humoral immune responses in animals. The clinical significance of these effects has not been demonstrated. In vitro and in vivo animal studies using relatively high doses of cannabinoids have shown them to have mutagenic and carcinogenic effects and to impair the synthesis of nucleic acids and proteins. While it is impossible to dismiss the potential clinical significance of those reports, no cytogenic abnormalities have yet been consistently documented in human marijuana smokers. Hormonal and Reproductive Effects In animals, cannabis disrupts all phases of reproductive functioning by direct action on both the hypothalamic-pituitary axis and the gonads. In humans, all aspects of these effects have been suspected but are difficult to confirm. Cannabis has been reported to reversibly inhibit spermatogenesis, with a reduction in the number of sperm cells and an increased prevalence of abnormal cells. Decreased levels of testosterone and decreased size of the testes and prostate after heavy use are also seen but are believed to be reversible. A single marijuana cigarette can suppress plasma leutinizing hormone during the luteal phase of the menstrual cycle. This may account for the higher frequency of anovulatory cycles often associated with marijuana smoking. These phenonema may be due to THC's central effect of interfering with the release of gonadotropin-releasing hormone at a suprapituitary site, thereby disrupting the release of circulating luteinizing and follicle-stimulating hormones. Cannabinoids cross the placental barrier and appear in maternal milk. Experimentally, cannabis is teratogenic at high doses in some species of animals. However,

cannabis's deleterious effects on the human fetus have been difficult to assess because of the frequent concurrent use of other drugs, cigarettes, and alcohol. Studies that have attempted to control for these variables have frequently associated marijuana with low birth weight. Its effects on other types of human fetal abnormalities have been reported, but the correlation is not well documented.

LABORATORY EXAMINATION Urine testing for marijuana and other drugs has become common in many settings, including drug treatment programs and places of employment. Most laboratories use the enzyme-multiplied immunoassay (EMIT), although a radioimmunoassay is also commonly used. Both tests, while relatively sensitive and inexpensive, provide an unacceptable level of false-positive results. Thus confirmation by gas chromatography–mass spectrometry is routinely used. Cannabis and its metabolites may be detected in urine at the usual cutoff level of 100 ng/mL for 42 to 72 hours after the psychological effects subside. Passive inhalation that occurs under unusually crowded conditions may also reveal cannabis metabolites in the urine but only if the cutoff level used in the urine test is decreased to 20 to 25 ng/mL, a procedure that increases the frequency of false-positive results. No clear linear relation between psychoactive effects and urine levels has been demonstrated. Urine that contains cannabis metabolites only implies that cannabis exposure occurred at an indeterminate time prior to testing. To avoid problems that may be associated with identifying very low levels of metabolites in the urine, such as can occur with passive inhalation, most laboratories use a cutoff point of 100 ng/mL or above.

TREATMENT Persons who use marijuana are often referred for treatment. Referrals are made for persons with widely varying use patterns and treatment needs. At one extreme is the person who uses cannabis intermittently at low doses who was identified by a random drug screening test. At the other extreme is the person who uses high doses daily and meets criteria for dependence. The first person may need only periodic urine testing and infrequent supportive counseling. The second probably requires referral to a specialized, intensive drug rehabilitation program. Thus, as in other clinical situations involving substance use, treatment should begin only after a complete history is taken and a diagnosis is established. A psychiatric examination helps reveal any underlying psychopathology and determine the relation of drug use to mood states and psychiatric symptoms. Cannabis dependence and abuse are usually treated by the psychosocial methods typically used in drug-free rehabilitation programs. These include attempts to promote realistic and rewarding alternatives to the drug and the associated lifestyles along with a commitment to abstinence from self-administered or unprescribed psychotropic drugs. Treatment usually involves a combination of interventions, including urine testing, participation in 12-step programs, education about drug effects, drug counseling, psychotherapy, and family therapy. Drug-focused group therapy is perhaps the most common treatment for all substance-related disorders, including cannabis-related disorders. Common strategies used by the group are social pressure to reinforce abstinence, teaching socialization and problem-solving skills, reducing stress and the sense of isolation often associated with drug use, relapse-prevention exercises, and varying degrees of confrontation. A trial comparing group-based relapse prevention and social support yielded results comparable to those obtained for treatment of alcohol or nicotine dependence. Relative to those seeking treatment for alcohol or other substance use disorders, few adults seek treatment for cannabis abuse and dependence alone. Other drug abuse usually precipitates treatment and cannabis dependence is treated along with the other drug problems. However, cannabis use is one of the more common presenting problems among youth seeking treatment for substance abuse. Denial of a drug problem appears commonly in many persons with cannabis abuse or dependence, as it does in persons with other substance use disorders. Treatment of unpleasant adverse reactions, usually anxiety, consists of calm and gentle reassurance in a warm and supportive atmosphere. Short-term use of anxiolytic agents, such as benzodiazepines, is necessary in some instances when anxiety symptoms are prominent or severe. Short-term use of low doses of antipsychotic medication may be justified if the patient has more-persistent and more-troubling symptoms, such as delusional ideas or frightening flashbacks. Treatment of toxic-delirious states is similarly supportive, symptomatic, and short-term because of their self-limited nature. Therapeutic Uses Cannabis has been tried as a therapeutic agent for a variety of ailments. Data in this field are exceedingly difficult to collect for a variety of reasons including obtaining regulatory approval and support for research and difficulty in matching placebo against smoked marijuana. Synthetic THC (e.g., drobinol) which can be orally administered, contains the principal psychoactive component of the cannabis leaf. But cannabis contains over 400 chemicals, and it is difficult to ascertain with certainty which have therapeutic properties. THC has antiemetic effects on the nausea and vomiting caused by chemotherapy. A synthetic oral cannabinoid (dronabinol [Marinol]) has been shown to be generally equal or superior to prochlorperazine (Compazine) but inferior to metoclopramide (Reglan). The relative efficacy of cannabinoids versus newer antiemetics such as ondansetron (Zofran) combined with dexamethasone (Decadron) has not been evaluated. The data on smoked marijuana versus these older and newer agents are limited, but reports suggest that it may be effective in a certain percentage of patients who had no benefit from older agents. Dronabinol can also reduce the nausea and diarrhea associated with AIDS or with chemotherapy used to treat human immunodeficiency virus (HIV) infection. It also increases appetite and produces weight gain in AIDS and cancer patients, although the weight gain is not in lean body mass. As a result, THC has gained orphan drug status from the FDA to treat nausea and vomiting from chemotherapy and to stimulate appetite in AIDS patients. However, there are no controlled studies of smoked marijuana for this condition, nor any systematic studies of the effects of smoked marijuana on immunological status in HIV-infected patients. With repeated smoking, patients may be expected to experience the typical symptoms of intoxication, such as mood changes and decreases in concentration, coordination, and the ability to estimate time. Separating the undesired side effects of cannabis from its therapeutic effects has been difficult. More controlled studies are needed. Smoked marijuana lowers intraocular pressure. This has stimulated interest in its use as a treatment for glaucoma. The mechanism of action for this feature is unknown, which limits development of similar agents. This effect is mostly short-lived (3 to 4 hours) and there is no evidence that cannabis is more effective than several other agents in treating patients suffering from glaucoma. Preclinical and clinical studies of the use of cannabinoids in neurological and movement disorders have been reported. Currently, there is no evidence that cannabinoids are superior to available therapies for multiple sclerosis and partial spinal cord injury. Case studies have reported some benefit of smoked marijuana in treatment of dystonic states, and some evidence suggests a possible role for cannabinoids in the treatment of the epilepsies, but studies are lacking. Oral THC has analgesic efficacy for cancer pain, but there is a narrow therapeutic margin between the doses that produce useful analgesia and those producing unacceptable adverse CNS effects. Mild hypothermia, prolongation of barbiturate anesthesia, and hyperglycemia are other disorders for which cannabis has not yet demonstrated clinical utility.

SUGGESTED CROSS-REFERENCES An overview of the substance-related disorders, including substance abuse and substance dependence, appears in Section 11.1. Substance intoxication delirium is discussed in Chapter 10 on cognitive disorders and mental disorders due to a general medical condition. Substance-induced psychotic disorder is discussed in Section 13.3 on acute and transient psychotic disorders and culture-bound syndromes. Substance-induced anxiety disorder appears in Section 15.6. SECTION REFERENCES *Adams IB, Martin BR: Cannabis: Pharmacology and toxicology in animals and humans. Addict 91:1585, 1996. Andreasson S, Allebeck P, Engstrom A, Rydberg U: Cannabis and schizophrenia: A longitudinal study. Lancet 2:1483, 1987. Chait LD, Pierri J: Effects of smoked marijuana on human performance: A critical review. In: Marijuana/Cannabinoids: Neurobiology and Neurophysiology, A Murphy, J Bartke, editors. CRC Press, Boca Raton, FL, 1992. Compton DR, Dewey WL, Martin BR: Cannabis dependence and tolerance production. Adv Alcohol Subst Abuse 9:129, 1990. Devane WA, Dysarz FA III, Johnson MR, Melvin LS, Howlett AC: Determination and characterization of a cannabinoid receptor in the rat brain. Mol Pharmacol 34:605, 1988.

Gieringer DH: Marijuana, driving and accident safety. J Psychoact Drugs 20:93, 1988. Gruber AJ, Pope HG: Cannabis psychotic disorder: Does it exist? Am J Addict 3:72, 1994. *Hall W, Solowij N, Lemon J: The health and psychological consequences of cannabis use. In National Drug Strategy Monograph Series, no. 25. Australian Government Publishing Services, Canberra, 1994. *Hall W, Solowij N: Adverse effects of cannabis. Lancet 352:1611, 1998. *Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW: Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 141:395, 1999. Hollister LE: Cannabis—1988. Acta Psychiatr Scand 345:108, 1988. Imade AGT, Ebie JC: A retrospective study of symptom patterns of cannabis induced psychosis. Acta Psychiatr Scand 83:134, 1991. *Johnson BA: Psychopharmacological effects of cannabis. Br J Hosp Med 43:114, 1990. Miller NS, Gold MS: The diagnosis of marijuana dependence. J Subst Abuse Treat 6:183, 1989. Millman RB: Cannabis abuse and dependence. In Treatments of Psychiatric Disorders, BT Karasu, editor. American Psychiatric Association, Washington, DC, 1989. *Millman RB, Sbriglio R: Patterns of use and psychopathology in chronic marijuana users. Psychiatr Clin North Am 9:533, 1986. Musto DF: Opium, cocaine and marijuana in American history. Sci Am 265:20, 1991. O'Brien CO: Drug addiction and drug abuse. In The Pharmacological Basis of Therapeutics, ed 9, AG Gilman, TW Rall, AS Nies, P Taylor, editors. McGraw-Hill, New York, 1996. Pope HG, Yergelen-Todd D: The residual cognitive effects of heavy marijuana use in college students. JAMA 275:521, 1996. Rinaldi L: Marijuana: A research overview. Alaska Med 36:107, 1994. Rodriguez de Fonseca F, Carrera MRA, Navarro M, Koob GF, Weiss F: Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050, 1997. Roffman RA, Stephens RS, Simpson EE, Whitaker DL: Treatment of marijuana dependence: Preliminary results. J Psychoact Drugs 20:129, 1988. Seldon BS, Clark RF, Curry SC: Marijuana. Emerg Med Clin North Am 8:527, 1990. Seth R, Sinha S: Chemistry and pharmacology of cannabis. Prog Drug Res 36:71, 1991. Substance Abuse and Mental Health Services Administration: National survey results on drug use from the monitoring the future study. U.S. Department of Health and Human Services, U.S. Government Printing Office, Washington, DC, 1997. Tanda G, Pontieri FE, Di Chiara G: Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu-1 opioid receptor mechanism. Science 276:2048, 1997. Thomas H: Psychiatric symptoms in cannabis users. Br J Psychiatry 163:141, 1993. Thornicroft G: Cannabis and psychosis. Br J Psychiatry 157:25, 1990. Tunving K: Psychiatric effects of cannabis use. Acta Psychiatr Scand 72:209, 1985. Tunving K: Psychiatric aspects of cannabis use in adolescents and young adults. Pediatrician 14:83, 1987. Voth EA, Schwartz RH: Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 126:791, 1997. Weinrieb RM, O'Brien CP: Persistent cognitive deficits attributed to substance abuse. Neurol Clin 11:663, 1993. Wert RC, Raulin ML: The chronic cerebral effects of cannabis use. Int J Addict 21:605, 1986. Wickelgren I: Marijuana: Harder than thought? Science 276:1967, 1997.

Textbook of Psychiatry

11.6 COCAINE-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.6 COCAINE-RELATED DISORDERS JEROME H. JAFFE, M.D. Definitions History Comparative Nosology Epidemiology Etiology Diagnosis and Clinical Features Differential Diagnosis Course and Prognosis Treatment Suggested Cross-References

More than 25 million people in the United States used cocaine at least once in the 1980s and 1990s. For many of those people, use progressed to abuse and dependence. In the early 1990s it was more common to have a lifetime history of cocaine dependence than of bipolar disorder (2.7 percent versus 1.6 percent). While the epidemic appears to have passed its peak, cocaine use is still prevalent, and people with cocaine abuse and dependence disorders continue to come for treatment. A wealth of information now exists on the effects of cocaine on the brain and behavior, and on cocaine toxicity, cocaine dependence, and the efficacy of treatment.

DEFINITIONS Substance use may be associated with a number of distinct disorders of which dependence and abuse are but two. In the case of cocaine, the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) describes 10 other substance-related disorders. Cocaine dependence is defined in DSM-IV as a cluster of physiological, behavioral, and cognitive symptoms that, taken together, indicate that the person continues to use cocaine despite significant problems related to such use. It is defined in the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) as a cluster of physiological, behavioral, and cognitive phenomena in which the use of cocaine takes on a much higher priority for a given individual than do other behaviors that once had a greater value. Central to these definitions is the emphasis placed on the drug-using behavior, its maladaptive nature, and how over time the voluntary choice to engage in that behavior shifts and becomes constrained as a result of interactions with the drug. Cocaine abuse is a term used in DSM-IV to categorize a pattern of maladaptive cocaine use leading to clinically significant impairment or distress within a 12-month period, but one in which the symptoms have not met criteria for cocaine dependence. ICD-10 does not use the term. Other cocaine-related disorders include cocaine intoxication, cocaine withdrawal, cocaine-induced psychotic disorder with delusions or with hallucinations, cocaine intoxication delirium, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced sleep disorder, cocaine-induced sexual dysfunction, and cocaine-related disorder not otherwise specified ( Table 11.6-1). The DSM-IV coding scheme provides distinct code numbers for cocaine dependence and cocaine abuse, but the codes for the other substance-related disorders do not differentiate cocaine-induced disorders from the other substance-induced disorders, with the exception of those related to alcohol use.

Table 11.6-1 DSM-IV Cocaine-Related Disorders

HISTORY Purified cocaine first became commercially available in 1884. Reports of compulsive cocaine use and cocaine psychosis appeared in the European medical literature within the decade. By the beginning of the twentieth century, cocaine use and dependence were not uncommon in the United States. Cocaine was an ingredient of Coca-Cola until 1900; nonprescription proprietary nostrums containing cocaine were widely promoted until the Harrison Act was passed in 1914; and 100 mg of illicit cocaine could still be bought for a quarter in the 1920s. With growing public awareness in the United States of the physical and legal risks of drug use, cocaine use and dependence declined gradually. It remained fairly common in Europe, however. Hans Maier's classic Der Kokainismus, published in 1926, included descriptions of relatively contemporaneous clinical cases. There appears to have been little cocaine use and dependence from the late 1930s to the early 1970s. Although some heroin users also used cocaine, virtually no cocaine-dependent patients entered the U.S. Public Health Service Hospital at Lexington, Kentucky, in the 1960s. Starting in the 1970s and continuing throughout the 1980s, the availability of cocaine increased noticeably. For the first few years of its renewed popularity among affluent young adults, there were few reports of cocaine toxicity or of persons seeking treatment. Some observers who were apparently unaware of previous epidemics, in which the compulsive nature of cocaine use and its serious toxicity had been repeatedly documented, declared cocaine to be a relatively benign drug. Its use spread from those affluent young adults (who tended to use it intranasally) throughout all economic and age levels of society. More-hazardous routes of administration, including injection and inhalation of freebase forms such as “crack,” became common. By 1985, owing to its increasing availability and declining price, 20 million people had tried cocaine. Its toxicity became quite apparent as the number of emergency room visits for cardiovascular, neurological, and psychiatric complications rose sharply; and its capacity to induce dependence was apparent from the escalating number of requests for treatment. Increasing numbers of drug users, overdose deaths, crime, and the images of “crack babies” damaged in utero by cocaine-using pregnant women gave national visibility to the drug problem, particularly to cocaine use. Federal expenditures for law enforcement escalated. Penalties for drug selling and possession were increased, and national prevention campaigns were initiated. Drug (urine) testing in the workplace became more common. Toward the end of the 1980s casual use declined, as did the number of cocaine-related medical emergency cases seen in hospital emergency rooms. The number of heavy users did not decline as sharply, however, and urine tests of people who were arrested showed that a substantial number of criminals were still using cocaine. The drug continued to be relatively available, less costly than in the 1970s, and by the early 1990s emergency room visits began to increase slightly. However, by the mid-1990s arrestee drug testing indicated that in some large cities people who got in trouble with the law, particularly the younger ones, were using cocaine less.

COMPARATIVE NOSOLOGY The DSM-IV criteria for cocaine dependence are the same generic criteria as are applied to other psychoactive drugs. The notion of a generic concept of dependence is shared with the revised third edition of DSM (DSM-III-R) and ICD-10. Despite some changes in wording, the syndromes and criteria for making the diagnosis of

dependence are similar in DSM-III-R and DSM-IV. A generally high level of agreement also exists between DSM-IV and ICD-10: they use similar concepts (the dependence syndrome varying in severity), although the wording of the criteria for determining the presence and severity of the syndrome differs. Both require that three elements of the syndrome be noted within a 12-month period. Although DSM-IV appears to place greater stress than ICD-10 on tolerance and physiological dependence (because it asks clinicians to specify if these criteria are present), in practice this has little impact on the proportion of patients seeking treatment who meet diagnostic criteria for dependence. Most patients who meet current DSM-IV criteria for dependence report some tolerance, withdrawal, or both. ICD-10 and DSM-IV differ in the classification of what is called substance abuse in DSM-IV. ICD-10 does not use the term “abuse” but includes instead the category of harmful use, which differs substantially from the concept of “abuse” used in DSM-IV. However, the concept of harm is limited to physical and mental health (e.g., hepatitis, cardiac damage, episodes of depression, or toxic psychosis). It specifically excludes social impairments, as follows: Harmful patterns of use are often criticized by others and frequently associated with adverse social consequences of various kinds. The fact that a pattern of use or a particular substance is disapproved of by another person or by the culture, or may have led to socially negative consequences such as arrest or marital arguments is not in itself evidence of harmful use.

EPIDEMIOLOGY Cocaine use has fluctuated dramatically over the past three decades, not just in the United States, but also in South America and in western Europe. In the United States the various activities aimed at estimating the extent and consequences of psychoactive drug use are the annual Monitoring the Future Study (MTF) (formerly known as the High School Senior Survey); the National Household Survey on Drug Abuse (NHSDA); the Drug Abuse Warning Network (DAWN), which obtains reports from a selected group of hospital emergency rooms and medical examiners' offices on drug-related adverse effects and deaths; and the Arrestee Drug Abuse Monitoring (ADAM) program (formerly DUF), which obtains its data from urine tests of arrestees at selected jails. All of those estimating techniques have sampling limitations, and none apply standardized diagnostic criteria to substance-use patterns or adverse effects. Consequently, although they provide a picture of use over time, these methods do not reveal changes in the incidence and prevalence of specific substance-related disorders, such as dependence and abuse In the annual MTF study all indicators of self-reported cocaine use among high school seniors (lifetime, past-year, and past-month use) declined substantially from the high annual prevalence level of 13.1 percent in 1985 to 3.1 percent in 1992, the lowest since the survey began in 1975. Cocaine use then gradually rose again, reaching an annual prevalence rate of 5.5 percent in 1997. The NHSDA found steady declines in the annual use of cocaine, from peak levels of more than 5 percent, from 1982 to 1985, to 2.1 percent in 1992, and then a slower decline to 1.9 percent by 1997. There was relatively little decline in the number of heavy (weekly) cocaine users between 1985 and 1993, but by 1997 past-30-day use was down from an estimated 3.0 percent in 1985 (5.7 million users) to 0.7 percent (1.5 million users). The use of crack cocaine and the incidence of new crack users also declined. Two population surveys used accepted diagnostic criteria to measure the extent of substance abuse and dependence: the Epidemiologic Catchment Area (ECA) Study, carried out in the early 1980s, used third edition of DSM (DSM-III) criteria; the National Comorbidity Survey (NCS), carried out from 1990 to 1992, used DSM-III-R criteria. The ECA report combined categories of dependence and abuse for cocaine. The 1-month and 6-month prevalence rates for cocaine abuse-dependence were too low to be measurable; the lifetime rate was 0.2 percent. The NCS carried out just after the peak of the cocaine epidemic reported a lifetime prevalence rate for cocaine dependence of 2.7 percent among 15- to 54-year-olds; 16 percent of respondents reported a history of some use of cocaine.

ETIOLOGY Substance dependence is currently viewed as the result of a process in which social, psychological, cultural, and biological factors influence substance-using behavior. The actions of the drug are seen as critical, but it is recognized that not everyone who becomes dependent experiences the effects of a given drug in the same way. Further, depending on the individual, different factors may be more or less important at different stages of the process, even with the same class of pharmacological agents. Social and cultural factors largely influence the availability and initial use of cocaine and other substances. In the case of cocaine, pharmacological factors are believed important in perpetuating use and progression to dependence. Cocaine has potent mood-elevating and euphorigenic actions, especially when its effects have rapid onset, as when cocaine is injected or inhaled. Although some physical dependence develops, an aversive withdrawal syndrome probably is less prominent in perpetuating cocaine use than that of opioids and sedatives. Comorbidity Additional psychiatric diagnoses are quite common among those dependent on cocaine. It is not always evident how this comorbidity is linked etiologically to cocaine, but the epidemiological evidence clearly shows that the presence of a psychiatric disorder not related to substance abuse (e.g., mood disorders, schizophrenia, and antisocial personality disorder) substantially increases the odds of developing substance abuse and dependence. For some persons cocaine may serve to alleviate various psychiatric disorders or dysfunctional states. Some users, for example, may find relief from dysthymic disorder. Others may find that cocaine facilitates sexual activity, permits extended socializing, or counteracts the sedative effects of alcohol. However, while such factors may explain substance use on more than one occasion, they do not account for progression to dependence or abuse. Cocaine use may induce psychiatric syndromes (e.g., panic disorders) that may persist even after drug use is stopped. Persons with certain types of psychiatric disorders may be prone to experiment with cocaine or other substances, and factors that predispose to psychiatric disorders may also predispose cocaine users to become cocaine dependent. Research on the temporal appearance of the syndromes indicates that in some instances and for some syndromes, substance use antedates the psychiatric disorder. In one component of the ECA study subjects were reinterviewed 1 year later. Those who reported cocaine or stimulant use in the interval were almost eight times more likely than nonusers to experience depression and 14 times more likely to have had a panic attack. Cocaine users were almost 12 times more likely to experience a manic episode. The ECA data also show a relation between the extent of cocaine use and other psychiatric disorders. Among men 18 to 44 years of age, those who had never used cocaine or had used it fewer than five times had a lifetime prevalence of major depression of 7.6 percent; it was 11 percent for users who were never daily users and almost 26 percent for those who met the DSM-III criteria for cocaine abuse. Similarly, the lifetime prevalence of panic disorder was related to the extent of cocaine use. Genetic Factors Laboratory animal strains differ greatly in their willingness to self-administer psychoactive drugs, including cocaine, and strains can be developed that differ even more markedly. The most convincing evidence to date of a genetic influence on cocaine dependence comes from studies of twins. A study of male twins who served in the U.S. military between 1965 and 1975 found higher concordance rates for stimulant dependence (cocaine, amphetamines, and amphetamine-like drugs) among monozygotic than dizygotic twins. The analyses indicated that genetic factors and unique (unshared) environmental factors contributed about equally to the development of stimulant dependence. Other studies have shown genetic contributions to attention-deficit/hyperactivity syndrome, conduct disorder, and antisocial personality disorder. Since these disorders are important risk factors for drug use and dependence, these findings also support genetic involvement in the etiology of drug dependence in general. Other Factors Social, cultural, and economic factors are powerful determinants of initial use, continuing use, and relapse. Excessive use is far more likely in countries where cocaine is readily available. Different economic opportunities may influence certain groups more than others to engage in selling illicit drugs, and selling is more likely to be carried out in familiar communities than in those where the seller runs a high risk of arrest. Since in both human and animal studies alternative positive reinforcers compete with drugs as reinforcers, the absence of such nondrug alternatives can be seen as a causal factor for use, especially where drugs are available and the social pressures against using them are not strong. Alternative positive reinforcers are not limited to material rewards but include psychological rewards associated with satisfying interpersonal relationships and the self-esteem that derives from achievements in socially acceptable roles. In animal models, chronic stress mediated by high levels of cortisol increases sensitivity to the reinforcing effects of cocaine and induces relapse to drug self-administration in withdrawn animals. Learning and Conditioning Learning and conditioning are also considered important in perpetuating cocaine use. Each inhalation or injection of cocaine yields a rush and a euphoric experience that reinforce the antecedent drug-taking behavior. In addition, the environmental cues associated with substance use become associated with the euphoric state so that long after a period of cessation, such cues (e.g., white powder and paraphernalia) can elicit memories of the euphoric state

and reawaken craving for cocaine. In cocaine abusers (but not in normal controls), cocaine-related stimuli activate brain regions subserving episodic and working memory and produce electroencephalographic (EEG) arousal (desynchronization). Increased metabolic activity in the limbic-related regions such as amygdala, parahippocampal gyrus, and dorsolateral prefrontal cortex correlated with reports of craving for cocaine, but the degree of EEG arousal did not. Pharmacological Factors As a result of actions in the central nervous system (CNS), cocaine can produce a sense of alertness, euphoria, and well-being. There may be decreased hunger and less need for sleep. Performance impaired by fatigue is usually improved. Some users believe that cocaine enhances sexual performance. Mechanisms of Action Cocaine inhibits the normal reuptake of monamines from the synaptic cleft by binding to transporter proteins. Its reinforcing effects are primarily due to its actions at the dopamine transporter, producing high levels of dopamine in the synapse. Evidence suggests that stimulation of both dopamine (D 1) and D2 receptors plays some role in dopamine's reinforcing and salience-enhancing actions. Cocaine also inhibits reuptake of norepinephrine and serotonin. The increase in norepinephrine concentration is important for some of cocaine's toxic effects. In animals cocaine is considered the most powerful pharmacological reinforcer of drug-taking behavior known. Given free access, animals choose to self-administer cocaine rather than have food, water, or access to other animals. Death from starvation or drug toxicity is the typical consequence of unlimited cocaine access. With limited access (2 to 6 hours a day), cocaine does not gain such control over behavior, and animals may select food in preference to cocaine, depending on the dose, the amount of work they must do to get the dose, and the type and amount of food offered as alternative reinforcers. Common Routes of Administration Cocaine can be taken orally, by injection, by absorption via nasal and buccal membranes, or by inhalation and absorption through the pulmonary alveoli. Cocaine hydrochloride, the water-soluble form typically used for snorting or injection, is largely destroyed by the heat of burning and so is not well suited for smoking. Cocaine as freebase sublimates before it is destroyed by heat. The hydrochloride salt can be converted to the freebase form by treatment with alkali and extraction with organic solvents. Inhalation of freebase cocaine produces almost immediate absorption and a rapid onset of effects. In the 1980s users learned to avoid the fire hazard of extracting organic solvents and still produce a crude form of freebase cocaine by heating the cocaine with sodium bicarbonate to yield crack, a hard, white mass that is freebase plus impurities. When smoked, this material gives off a crackling sound. In cocaine-producing countries some users may smoke a crude intermediate product, cocaine sulfate (coca paste, pasta basica, basuca), which is usually contaminated with solvents. As with the opioids, the rapid onset of cocaine's effects after intravenous injection or freebase inhalation produces an intensely pleasurable sensation, or rush. The cocaine rush lasts only a few minutes, whereas other psychological and physiological effects tend to decline more slowly, in parallel with declining concentrations in plasma. Metabolism The half-life of a single dose of cocaine in the blood is only about 30 to 90 minutes. It is typically hydrolyzed by butyrylcholinesterase (plasma pseudocholinesterase) and liver esterase into inactive metabolites, most significantly benzoylecgonine and ecgonine methylester. The metabolite is generally detectable in urine for 24 to 72 hours after brief periods of use. With repeated high dosages (e.g., 1 to 2 grams daily), cocaine or its metabolites may accumulate in body compartments (e.g., fat and the CNS), from which it is then slowly released. Consequently, using sensitive measures, cocaine may be detectable in the urine of heavy users for 2 weeks. In a study of cocaine-dependent patients admitted to an inpatient treatment unit, the average time from last reported cocaine use to first negative urine test (using a cutoff of 300 ng/mL) was 105 hours, and 20 percent had positive tests for 120 hours or longer. The concurrent use of cocaine and alcohol may result in the accumulation of a distinct metabolite, cocaethylene. This metabolite is active and longer lasting than cocaine itself and may account for the enhancement of subjective effects and toxicity when the two are used simultaneously. Tolerance and Sensitization Patients seeking treatment often report needing progressively more cocaine to get the same effect. In laboratory studies, occasional users of cocaine have more marked cardiovascular, subjective, and endocrine responses to intravenous challenge doses of cocaine than subjects who are cocaine dependent. Despite the evidence for some tolerance to blood pressure–elevating effects, even experienced users may sustain significant cardiovascular toxicity. Chronic use of cocaine also produces a form of sensitization in which the response to a given dose is actually enhanced. In animals repeated doses of CNS stimulants such as cocaine or amphetamine eventually elicit seizures or stereotyped behaviors not seen with initial doses. Sensitization is produced more reliably by intermittent dosing than by continuous dosing. The sensitization can be long lasting. The paranoid states and toxic psychoses that commonly develop among chronic cocaine users are believed to be among the phenomena to which sensitization develops. Cocaine psychosis develops more rapidly in those who have been chronic users or had developed psychoses previously. Withdrawal States The cocaine withdrawal syndrome has aversive qualities (e.g., dysphoria and anhedonia). Although withdrawal anhedonia and fatigue are not generally reported to be the most important reasons for relapse after brief withdrawal, some users who have come to depend on cocaine for high energy or to project a confident persona may be temporarily unable to function without it. For others, withdrawal dysphoria may exaggerate the intensity of an antecedent mood disorder. If a protracted cocaine withdrawal syndrome exists, it is more subtle than the syndrome associated with opioid withdrawal. It is in some ways puzzling that patients do not usually attribute craving for cocaine and relapse to withdrawal, since there is considerable evidence that chronic cocaine use produces significant long-lasting changes in many parts of the brain. COCAINE-INDUCED BRAIN CHANGES The repeated finding of perfusion deficits in the brains of cocaine-dependent subjects recently withdrawn from cocaine is probably not related to tolerance or withdrawal; however, several other findings probably are. Many, but not all, studies using positron emission tomography (PET) and single positron emission computed tomography (SPECT) to study the brains of cocaine-dependent subjects have found an increased number of dopamine transporters in the striatum, a finding consistent with postmortem studies. Within a few days of withdrawal, cocaine abusers show higher than normal cerebral metabolic rates in orbitofrontal cortex and basal ganglia that correlate with craving. At 1 to 4 weeks and at 3 to 4 months postwithdrawal, cocaine abusers have lower metabolic rates in the frontal cortex that correlate with symptoms of depression, and decreased availability of D 2 receptors that correlates with decreased cerebral metabolic rates and years of cocaine use. An increase in µ-opioid receptor binding after 4 weeks of cocaine abstinence also correlated with severity of cocaine craving. Chronic cocaine use induces a wide range of changes in the brains of animal models; many of these changes appear to be adaptive responses, while others may be linked to sensitization. After a period of chronic, binge-like cocaine administration, the threshold for reinforcement increases, and dopaminergic and serotonergic transmission in the nucleus accumbens decreases. In addition, the density of D 1 receptors increases. Messenger ribonucleic acid (mRNA) for corticotropin-releasing factor (CRF) increases, µ- and k-opioid receptors are upregulated, and the concentration of mRNA encoding for prodynorphin in the striatum and nucleus accumbens increases. Dynorphin, acting on k-receptors, probably serves as a negative feedback mechanism, dampening excessive dopaminergic activity. When cocaine use ceases, enhanced dynorphin activity could contribute to reduced dopaminergic activity manifested in dysphoria and anhedonia. Neurons bearing dopamine receptors in these same brain areas show upregulation of cyclic adenosine monophosphate (cAMP)-dependent kinase and decreased concentrations of Gi protein. Both of these changes contribute to upregulation of the cAMP pathway and activation of various transcription factors, (e.g., CRE-binding protein [CREB]), which results in the production of long-lasting Fos-like proteins that are distinct from those seen after acute cocaine administration. The persistent changes in the cAMP pathway probably represent one mechanism underlying tolerance.

DIAGNOSIS AND CLINICAL FEATURES Table 11.6-1 lists the DSM-IV cocaine-related disorders. Patterns of Use and Abuse There are several patterns of cocaine use and abuse. For example, Indians in the Andes chew coca leaves daily, but apparently very few progress to excessive use or toxicity. Although some cocaine users can use it intermittently without becoming dependent, it is not clear how long such intermittent, nondependent use can continue and for what proportion of users. Cocaine use that does not cause problems for the user does not meet the DSM-IV criteria for either dependence or abuse. Most cocaine users seeking treatment report initial intermittent use. However, at some stage the use escalated, with episodes of high-dose usage becoming more

frequent. Unlike opioid dependence, daily use is not the most common pattern among persons seeking treatment for cocaine dependence. A small percentage of such patients report using high doses, but for only a few days a month over a long period; such persons may still meet the criteria for dependence. That pattern is atypical, but intermittent use is not. Intermittent use consists of episodes or binges of use, often starting on weekends and paydays and lasting until the drug supply is exhausted or toxicity develops. The runs, or binges, during which the drug may be used every 15 to 30 minutes, can last 7 or more consecutive days but typically are shorter. Although there appears to be little tolerance between binges, changes in the response to the drug occur during the binge. Euphoric effects seem less prominent, and anxiety, fatigue, irritability, and depression increase. Any pause in the drug use causes blood concentrations to drop; typically, there is dysphoria rather than a return to normal mood. If cocaine is still available, it is used to dispel the dysphoria. When the binge is interrupted or supplies have been depleted, a cocaine crash quickly follows. Patients report the sense of needing more cocaine to get the same effect (tolerance) more commonly than the experience of pronounced withdrawal. Some users distinguish between a brief crash and withdrawal. A substantial proportion of cocaine users seeking treatment report daily or almost daily use, often associated with daily heroin use. In the early stages, cocaine use may cause little interference with normal activities. Some persons may even find that the sense of energy and heightened sense of self-confidence facilitate productive activity. Others may find that the cocaine facilitates social interaction, particularly enhancing sexual arousal and enjoyment, at least initially. The development of sexual dysfunction later in the course of use is better documented than is the enhancement. In addition to feelings of euphoria, cocaine use may also induce concurrent feelings of anxiety, irritability, and suspiciousness. Users may commit crimes to obtain money to buy cocaine, and such crimes may involve violence. In addition, cocaine can induce paranoid ideation, and there are numerous reports of homicide and attempted homicide during such cocaine-induced toxic states. Cocaine is an especially powerful reinforcer when it is taken in ways that produce a rapid onset of effects. Not only do intravenous and intrapulmonary routes of administration produce a rapid rise in blood and brain drug concentrations and an intense rush, but especially with the smoking of freebase cocaine, an almost equally rapid decline in blood and brain drug concentration occurs as the cocaine is redistributed and metabolized. Compared with those who use it intranasally, users who inhale freebase cocaine or inject the salt intravenously seem more likely to move from experimentation to regular, compulsive use, limited only by the availability of the drug or the money to buy it. Even in the laboratory setting it can be shown that craving for cocaine is briefly intensified a few minutes after intravenous use when brain and blood concentrations are falling. However, while intravenous and pulmonary cocaine use are far more likely to result in compulsive use and dependence, the intranasal route can also lead to dependence and to the full range of cocaine toxicity (including fatalities). Cocaine abusers frequently use sedatives or opioids to modulate the stimulant and toxic effects of the cocaine, a practice that can lead to concurrent dependence on sedatives or opioids. Sometimes an opiate, such as heroin, and cocaine are injected intravenously simultaneously; the mixture (speedball) is reportedly especially euphorigenic. Similar synergistic effects are seen when cocaine and buprenorphine (Buprenex) are taken simultaneously. Alcohol is probably the substance most commonly used in conjunction with cocaine, and its use may become associated with cocaine use and can trigger cocaine craving in former users trying to abstain from cocaine. Cocaine Dependence As the drug use progresses, greater priority is often given to obtaining and using cocaine than to meeting other social obligations or avoiding toxicity or arrest. The user may engage in illegal activities to raise money for cocaine or trade sex for it. At this stage the use of cocaine is considered maladaptive and probably meets the DSM-IV criteria for cocaine abuse or dependence. The DSM-IV criteria for cocaine dependence are the same generic criteria applied to other substances (see Table 11.1-3). A diagnosis of dependence requires a maladaptive drug-use pattern that leads to clinically significant impairment or distress, as indicated by at least three of seven criteria presented in the table. DSM-IV instructs the clinician to specify whether physiological dependence is present (i.e., evidence of either tolerance or withdrawal as defined in the diagnostic criteria). Drug use to prevent withdrawal is not as dominant with cocaine dependence as with opioid dependence. However, the other criteria for dependence are common among heavy users of cocaine. Tolerance to some drug actions (e.g., euphorigenic effects) can coexist with increased sensitization to other actions (e.g., anxiogenic and psychotogenic effects). Cocaine Abuse Some cocaine users develop problems or adverse effects related to their drug use (i.e., their use is maladaptive), even though such use does not meet the three-criteria requirement for the diagnosis of dependence. Examples of such recurrent maladaptive patterns include use that leads to multiple legal problems; failure to meet major social, school, or work-related obligations; and continued use despite social or vocational difficulties caused by, or aggravated by, cocaine use. When one or more such substance-related problems occur in a 12-month period but the pattern has never met the criteria for dependence, the diagnosis of cocaine abuse (see Table 11.1-8) should be made. Cocaine Intoxication Among those who meet the criteria for cocaine abuse or dependence, certain psychiatric toxicities are common. Just as alcohol-dependent persons are frequently intoxicated, cocaine users commonly develop the symptoms of cocaine intoxication during the course of a single binge. The euphoria may be accompanied by increasing suspiciousness, hypervigilance, anxiety, hyperactivity, talkativeness, and grandiosity. Users may engage in stereotyped and repetitive behaviors (e.g., disassembling and reassembling the same object). Typically other signs and symptoms of central stimulation occur, such as tachycardia, cardiac arrhythmias, blood pressure changes, pupillary dilation, perspiration, or chills. Hallucinations may occur, including tactile hallucinations. Judgment is impaired, and confusion may occur, but insight into the drug-induced nature of the hallucinations is retained. Any of these symptoms following the recent use of cocaine should invoke consideration of cocaine intoxication, provided they are not better accounted for by some other medical or mental disorder and there are at least two of a number of physiological signs commonly seen with cocaine use (e.g., tachycardia and elevated blood pressure). The DSM-IV diagnostic criteria for cocaine intoxication ( Table 11.6-2) are identical to the criteria for amphetamine intoxication except for the substitution of the word “cocaine” for the words “amphetamine or a related substance.” Any perceptual disturbances should be specified. In one study of cocaine abusers in the community, just over half reported experiencing paranoia or hallucinations at some time; among those who sought treatment, 63 percent reported those symptoms. Cocaine intoxication may occur in occasional users who do not meet the criteria for abuse or dependence.

Table 11.6-2 DSM-IV Diagnostic Criteria for Cocaine Intoxication

The development of paranoia does not seem to be closely related to cocaine dose. Some cocaine users develop the syndrome at far lower doses than are used by others who do not develop it. Furthermore, a person who has experienced cocaine-induced paranoia is more likely to have it recur with subsequent cocaine use. It is postulated that a change in threshold represents a form of sensitization. Cocaine use has also been linked to development of a panic disorder that outlasts the cocaine use; here too sensitization has been postulated. Cocaine Intoxication Delirium and Cocaine-Induced Psychotic Disorder Whereas some paranoia or hypervigilance is typical of cocaine intoxication and tactile and other hallucinations may also occur, cocaine use can also induce a toxic delirium and a more persistent toxic psychotic disorder characterized by suspiciousness, paranoia, visual and tactile hallucinations, and loss of insight. The hallucination of bugs (cocaine bugs) or vermin crawling under the skin (formication) is sometimes reported and is often associated with excoriation of the skin. A paranoid syndrome can develop within 24 hours after the beginning of a cocaine binge. When the syndrome develops in the presence of a clear sensorium and the person retains insight into the drug-induced nature of the symptoms, it is called cocaine intoxication,

even when there are hallucinations. When insight is lost but the sensorium is clear, the syndrome is called cocaine-induced psychotic disorder with delusions or with hallucinations. If consciousness is disturbed (i.e., the ability to focus, sustain, or shift attention is reduced) and deficits in memory and orientation exist, the diagnosis is cocaine intoxication delirium. Cocaine Withdrawal Cocaine withdrawal phenomena have not been as thoroughly studied as those associated with opioids or alcohol. No experimental studies have been conducted in which patients with known baseline characteristics have been stabilized solely on large doses of cocaine and then abruptly withdrawn. Consequently, most data have been derived from interviews and patients' recollections or from observations of hospitalized patients whose level of drug ingestion and prior baseline characteristics can only be estimated. Emil Erlenmeyer reported in 1886 that depression was likely to be seen when cocaine was stopped, and in Der Kokainismus Hans Maier noted depression and apathy upon cessation of cocaine. During the cocaine epidemic of the 1980s about 50 percent of cocaine users reported experiencing some type of withdrawal when drug use was interrupted. An early description of withdrawal, based on interviews of outpatients, described a three-phase syndrome in which the first phase, the crash, was characterized by agitation, depression, anorexia, and high cocaine craving. This cluster of symptoms was followed by a decrease in cocaine craving, fatigue, depression, and a desire for sleep; followed in turn by exhaustion and hypersomnia, with intermittent awakening, and hyperphagia. The second phase was reported to be heralded by normalized sleep, improved mood, and low levels of craving, but that relatively benign phase was succeeded by a return of anergia, anhedonia, anxiety, and increased cocaine craving, especially in response to stimuli previously associated with cocaine use. A third phase—extinction (which appears to represent a period of extended vulnerability to relapse rather than a phase of an extended withdrawal syndrome)—was also described. A complex phasic withdrawal has not been reported by others who observed cocaine-dependent patients admitted to clinical and research units. Instead, symptoms of depression and craving for cocaine declined steadily over several weeks. After 3 weeks, sleep, weight, and appetite were mostly comparable to those of normal controls on the same unit. Hypersomnia, disturbed sleep, hyperphagia, and excessive weight gain were not seen, nor was a severe crash observed. The phases and fluctuations in craving previously reported might have been related to environmental stimuli. Some of the inconsistencies in the findings and symptoms associated with cocaine cessation are probably attributable to differences in the dose and duration of use and to vulnerability factors. In interviews with almost 400 cocaine abusers, including about 100 who were not seeking treatment, some 83 percent reported tolerance to cocaine effects (needing more to get same effect), and 52 percent reported having undergone some type of withdrawal. Those seeking treatment were more likely to report experiencing withdrawal. Available data show no convincing evidence that a protracted cocaine withdrawal syndrome follows resolution of the signs and symptoms associated with abrupt cessation. However, abnormalities of brain function appear to persist for at least 12 weeks, and possibly, subtle withdrawal phenomena increase vulnerability to relapse. Drug craving, often part of cocaine withdrawal, is not included among DSM-IV diagnostic criteria. While not commonly observed during recent clinical studies, severe depression, sometimes associated with suicidal ideation, is reported in the older literature on cocaine withdrawal and in occasional contemporary clinical reports. To what degree the more severe depressive features are a part of withdrawal or represent the emergence of primary mood disorder is unclear. The DSM-IV diagnostic criteria for cocaine withdrawal Table 11.6-3 specify that the syndrome follows the cessation (or reduction) of heavy, prolonged cocaine use. Further, the dysphoric mood and other symptoms (e.g., fatigue and sleep disturbances) must be intense enough to cause significant distress or impairment. Thus, the criteria are structured so that the brief dysphoria and fatigue (crash) that follow a single short binge by an occasional user do not lead to a diagnosis of withdrawal.

Table 11.6-3 DSM-IV Diagnostic Criteria for Cocaine Withdrawal

Animal Models of Withdrawal Although there is no easily observable animal model of cocaine withdrawal comparable to that for the syndromes seen with alcohol or opioid withdrawal, animal analogues of the postuse dysphoria and anhedonia often seen in humans have been proposed. In rats cocaine typically lowers the threshold for intracranial electrical self-stimulation. After 24 hours of cocaine self-administration, the thresholds for such self-stimulation are elevated above baseline for several days, which suggests a relative dopaminergic deficiency or insensitivity. Rats administered cocaine in a binge pattern had elevated dopamine concentrations in the nucleus accumbens during cocaine administration and below-normal concentrations during withdrawal; after 14 days of drug administration, recovery to pretreatment levels was prolonged. Other Cocaine-Induced Disorders Other psychiatric syndromes that may develop in the course of cocaine use include cocaine-induced mood disorder, cocaine-induced anxiety disorder, and cocaine-induced sleep disorder. With each of those disorders the clinician should specify whether the onset occurred during intoxication or during withdrawal. DSM-IV also describes cocaine-induced sexual dysfunction and a category of cocaine-related disorder not otherwise specified (Table 11.6-4).

Table 11.6-4 DSM-IV Diagnostic Criteria for Cocaine-Related Disorder Not Otherwise Specified

Cocaine-induced mood disorder can occur during use, intoxication, or withdrawal. During use and intoxication, the disorder is more likely to simulate a manic, hypomanic, or mixed episode; during withdrawal, it is more likely to involve a depressed mood. Such diagnoses are difficult to make during periods of active drug use or during the first week or two of withdrawal. Because sexual dysfunction, anxiety, and disturbed sleep are seen so commonly during cocaine use and withdrawal, the diagnoses should be made only when the disturbances or dysfunctions are judged to be in excess of that usually associated with intoxication and withdrawal and only when severe enough to require independent treatment or attention. Panic episodes that develop during cocaine use may persist for many months following cessation.

Lasting vulnerability to panic attacks may be linked to sensitization phenomena. Comorbidity The frequent co-occurrence of other psychiatric disorders and cocaine dependence was noted during the cocaine epidemic in the early part of the twentieth century. The presence of other psychiatric disorders sharply increases the odds of substance dependence, and substance-dependent persons are more likely than the general population to meet the diagnostic criteria for additional psychiatric disorders. Among cocaine users seeking treatment, the rates of additional current and lifetime diagnoses are regularly found to be elevated. In one study, about 300 patients (69 percent men, average age 28, mostly lower socioeconomic class) were interviewed using the Schedule for Affective Disorders and Schizophrenia (SADS). Symptoms occurring within 10 days after the last drug use were not used in making any diagnoses. The additional psychiatric diagnoses are shown in Table 11.6-5. The most common additional lifetime diagnoses were alcoholism (62 percent), antisocial personality (33 percent), and major depression (30 percent). In this sample, depression preceded the onset of drug abuse in about one-third of the patients, whereas alcoholism preceded the onset of drug abuse in 21 percent.

Table 11.6-5 Additional Psychiatric Diagnoses Among Cocaine Users Seeking Treatment (New Haven Cocaine Diagnostic Study Results, Percentages)

Some studies have found that cocaine users who seek treatment have higher rates of depression and adverse consequences of drug use than those who do not. Another study found that those not seeking treatment had comparably severe cocaine use and lifetime and current psychiatric disorders, and higher rates of polysubstance use and involvement with the law, but they also tended to minimize the adverse consequence of substance use and lacked pressure to seek treatment. The prevalence of schizophrenia has generally been reported to be low among patients admitted to cocaine treatment programs, probably largely because people with schizophrenia are excluded from such programs. In fact, persons with schizophrenia commonly use cocaine or amphetamine and develop both dependence and toxic syndromes, although the diagnosis is not routinely made. Depending on the geographical area, an estimated 12 to 30 percent of persons with schizophrenia also abuse cocaine. It has been suggested that they use cocaine and stimulants to alleviate negative symptoms, postpsychotic depressive disorder of schizophrenia, and the side effects of antipsychotics. One nonblinded study did find fewer negative signs and more anxiety and depression among cocaine users with acute schizophrenia who had used cocaine prior to admission. A substantial proportion of schizophrenic patients admit having used cocaine during the months before hospitalization, but many are less candid about recent drug use, and urine tests frequently reveal recent cocaine use unsuspected by clinicians. Patients with schizophrenia who use cocaine tend to be younger and are more likely to be homeless and unemployed than psychotic patients who are not abusing drugs. Special programs involving peer-based support groups seem to be effective in linking substance-using schizophrenic patients to outpatient treatment programs. Toxicity and Complications High doses of cocaine can cause a wide variety of toxic effects, including cardiac arrhythmias, coronary artery spasms, myocardial infarction, and myocarditis. Other reported cardiovascular toxicities include headache, ischemic cerebral or spinal infarction, and subarachnoid or cranial hemorrhage. Toxic effects on the CNS may include seizures, hyperpyrexia, respiratory depression, and death. Cocaine-related seizures and loss of consciousness are often reported on questionnaires given to heavy users (up to 27 percent); most episodes do not lead to emergency room visits. Rhabdomyolysis, not uncommon after large doses of cocaine, may contribute to renal complications, although vasoconstriction alone may suffice to account for renal damage. Sniffing cocaine can cause ulcers of the mucosa in the nose and perforation of the nasal septum from persistent vasoconstriction. Inhaled cocaine freebase is thought to induce lung damage. Gastrointestinal necrosis, caused by vasoconstriction, has been associated with the rupture of swallowed condoms containing large amounts of cocaine. By producing placental vasoconstriction, cocaine may contribute to fetal anoxia. A list of medical complications associated with cocaine intoxication and abuse is shown in Table 11.6-6.

Table 11.6-6 Medical Complications of Cocaine Intoxication and Abuse

Seizures and respiratory depression may be related to cocaine's actions as a local anesthetic, and although the cardiovascular complications are primarily due to its effects on the reuptake of catecholamines in the peripheral nervous system, local anesthetic effects may contribute to myocardial depression. Animal studies reveal significant genetic vulnerability to various kinds of cocaine toxicities, suggesting that some of the observed toxicity in humans may not be predominantly dose dependent and predictable. Furthermore, cocaine elimination is nonlinear at high doses. Probably as a consequence of altered sensitivity of dopaminergic systems in the brain, chronic cocaine users may exhibit abnormal movements such as tics, choreoathetoid movements, and dystonic reactions. They may be particularly sensitive to neuroleptic-induced dystonias. Cocaine use is frequently associated with increased sexual activity, and sometimes the exchange of sex for cocaine. Such behaviors put cocaine users at elevated risk for venereal diseases, including infection with the human immunodeficiency virus (HIV). Treatment of Toxicity The treatment of acute cardiac emergencies is aimed at blocking the sympathomimetic effects of the drug and correcting arrhythmias. Some clinicians have recommended using combined a- and b-adrenergic receptor antagonists; however, others have advised against using adrenergic or dopaminergic blockers. Also suggested for myocardial ischemia are calcium channel blockers and nitroglycerine. Grand mal seizures may respond to diazepam (Valium). µ-Agonist opioids reduce cocaine lethality in animals. The fatal hyperpyrexia seen with cocaine shares some features with neuroleptic malignant syndrome and might respond to similar therapy (e.g., dantrolene [Dantrium]). Some researchers advise using ambient cooling. Pathology and Laboratory Examinations Cocaine metabolites can be detected for varying lengths of time in urine, depending on the dose of cocaine and sensitivity of the assay. They can also be detected in blood, saliva, sweat, and hair. Blood and saliva provide a better index of current concentrations, whereas urine provides a longer window of opportunity for detecting use over the previous few days. Hair analysis can reveal drug use over weeks to months but has little applicability in clinical situations.

Some of the insults to the CNS (e.g., cerebral infarction) are detectable by computed tomography (CT) scans or magnetic resonance imaging (MRI), but most chronic cocaine abusers who do not also abuse alcohol show no evidence of CNS structural damage when examined by these methods. However, studies using PET or SPECT have revealed a variety of functional abnormalities in the brains of recently abstinent cocaine users. Compared with controls, heavy cocaine users showed perfusion defects in the cortex. Considerable improvement in cortical perfusion occurs after several weeks of abstinence, although blood flow in many instances still does not match that of normal controls. Carefully controlled studies have found that brain volumes of cocaine users are slightly smaller (show atrophy) than those of controls who do not use drugs, but do not differ from those of other drug abusers. Compared with normal controls and patients withdrawn from alcohol, patients withdrawn from cocaine exhibited persistent resting tremor (4 to 6 Hz, similar to that of Parkinson's disease) lasting at least 12 weeks. The tremor is subtle and would not ordinarily be detected by clinical testing; no other cerebellar signs are present. They also exhibit slower reaction times in divided attention tasks that also persisted. Compared with age-matched and education-matched controls, chronic cocaine users are more likely to score in the impaired range on a neuropsychological screening battery. Impairment seems most obvious in concentration and memory, with less impairment in users who had been abstinent longer. To what extent the abnormalities in brain function are causally related to the signs and symptoms associated with cocaine cessation is uncertain. A few early studies of cocaine addicts reported that almost all patients exhibited hyperprolactinemia lasting several weeks, which seemed consistent with a dopaminergic deficiency. However, several subsequent studies found either no evidence of hyperprolactinemia or a much lower incidence of that effect, and no apparent correlation between high prolactin levels and either cocaine craving or the extent of cocaine use.

DIFFERENTIAL DIAGNOSIS The disorders associated with the use of cocaine need to be distinguished from both primary mental disorders and disorders induced by other classes of substances. A history of substance ingestion is important in making those distinctions. However, given the unreliability of self-reports about substance use and the likelihood that many users will deny any substance use at all, laboratory testing for drugs in body fluids and histories from collaterals are important. Disorders associated with cocaine use cannot be distinguished from those associated with amphetamines and related substances except by reliable history or laboratory tests. Users of cocaine (and amphetamine and related substances) may exhibit inappropriate optimism, euphoria, expansiveness, excessive talkativeness, and a decreased need for sleep sometimes associated with irritability in the context of a clear sensorium, a pattern also observed in manic and hypomanic episodes of bipolar disorder. However, these symptoms may not be obvious enough to suggest their relation to substance use, and the first indication of substance dependence may be financial difficulties, an arrest for drug sale or possession, or substance-induced toxicity. Intoxication Cocaine intoxication is diagnosed when the effects of cocaine exceed the mood-elevating effects its users typically seek. The diagnosis of intoxication is appropriate when the effects are problematic enough to require differentiation from hypomanic or manic behavior. Cocaine intoxication can also be confused with amphetamine intoxication and phencyclidine (PCP) intoxication, although the last is usually associated with nystagmus, motor incoordination, and some cognitive impairment. Endocrine disorders (such as Cushing's disease) and excessive use of steroids should also be considered. Toxic Psychosis Cocaine-induced toxic psychosis can be exceedingly difficult to differentiate from schizophrenia or other psychotic disorders characterized by hallucinations or delusions. The presence of vivid visual or tactile hallucinations should raise suspicion of substance-induced disorder. In areas and populations where cocaine use is common it may be necessary to provide only a provisional diagnosis until the patient can be observed and substance test results are obtained. Even then there may be difficulties because in some urban areas a high percentage of persons with established diagnoses of schizophrenia also use cocaine. Cocaine-Induced Anxiety Disorder Cocaine-induced anxiety disorder must also be distinguished from generalized anxiety disorder and panic disorder. Panic disorder that has its onset associated with the use of cocaine may persist well beyond the period of cocaine use. Other Symptoms The symptoms that may emerge during withdrawal—depression, dysphoria, anhedonia, disturbed sleep—need to be distinguished from those of primary mood disorders and primary sleep disorders. Unless the symptoms are more intense or more prolonged than is typical of cocaine withdrawal and so require independent treatment, the diagnosis should be limited to withdrawal, rather than cocaine-induced mood disorder. When a diagnosis of cocaine-induced mood disorder is made, it is important to specify whether the onset was during intoxication or withdrawal. One can also specify the subtype of mood disorder (i.e., with depressive, manic, or mixed features). In differentiating cocaine-induced mood disorder from the primary mood disorders the critical factor is the clinician's judgment that the mood disorder was caused by the cocaine. Generally, a cocaine-induced mood disorder, with onset during intoxication or withdrawal, remits in a week or two. It is appropriate, therefore, to withhold judgment about the diagnosis during the early phase of withdrawal. If depressed mood and related symptoms persist beyond a few weeks, alternative causes should be entertained. In reviewing diagnostic possibilities the clinician should consider the age at which symptoms began and a history of mood episodes that developed before the onset of cocaine use or during any long intervals without significant drug abuse.

COURSE AND PROGNOSIS Not all cocaine users develop cocaine-related disorders. However, even occasional users can experience cocaine toxicity. Among those who do develop dependence, the time from first use to problematic use ranges from a few months to 6 or more years. The course of cocaine use is often marked by shifts from intranasal to intravenous use and inhalation of freebase forms. In the United States, since most persons who tried cocaine did not become dependent, the decreased cocaine use in the general population in the early 1990s following peak rates of self-reported use in the 1980s does not shed much light on the natural history of cocaine dependence. Presently little information exists on untreated cocaine dependence, but there are findings on the course of cocaine use among those seeking treatment. A number of short-term (6-month to 2-year) follow-up studies seem to indicate that the course of dependence is more favorable for persons using cocaine who seek treatment than for heroin addicts who seek treatment. Among veterans on the East Coast randomly assigned to either an inpatient program or a day-hospital program lasting 28 days, 60 percent reported abstinence at 4 months, which was largely maintained at 7 months. About 56 percent of urine specimens were negative for each group at 7 months. In a 1-year follow-up of almost 300 cocaine users, half treated as outpatients and half treated initially as inpatients, both groups showed reductions in self-reported cocaine use during the 30 days before the interview: from an average 17 days per month at admission to 1.1 days for inpatients; from 10 days per month to 5 days for outpatients. Although the data do not give the percentage of those who were entirely abstinent, the improvement levels were substantial and differed from those typically found among heroin-dependent patients seeking treatment. The prognosis appears to be even better for persons with social support. DRUG ABUSE TREATMENT OUTCOME STUDY (DATOS) In DATOS, the largest recent study of drug users seeking treatment, about 3000 patients from 81 programs were interviewed at entry and 1 year after completion of index treatment. Cocaine dependence was the most frequent primary drug problem, but cocaine was also used by some whose major drug problem involved heroin or alcohol. Among the entire sample of clients 39 percent met criteria for antisocial personality disorder, and 14 percent met criteria for some other DSM-III-R Axis I disorder. At follow-up, weekly or more frequent cocaine use was reported by 35 percent of clients who stayed in long-term residential treatment for less than 3 months and 14 percent of those who stayed longer. For outpatient drug-free programs, the rates were 25 percent for those who stayed less than 3 months and 13.6 percent for those who stayed longer. Weekly or more frequent cocaine use decreased to about 20 percent for short-term inpatient treatment, but the drop was similar for those who stayed more than 2 weeks and those who stayed for a shorter time. Since baseline levels of cocaine use differed, the results across program types are easier to compare when expressed as percentage reduction from pretreatment levels. Reduction in weekly or more frequent cocaine use for the long-term residential clients was 54 percent for those who stayed less than 3 months and 82 percent for who stayed longer than 3 months; for outpatient drug-free clients, it was 57 percent (less than 3 months) and 87 percent (longer than 3 months); for short-term inpatient clients, 79 percent (less than 2 weeks), and 74 percent (longer than 2 weeks). A substantial proportion of patients were referred for additional social support and treatment after discharge, and many participated in self-help programs. The investigators concluded that there was little difference among program types, but that very different types of patients self-select different treatments. COCAINE-RETRO This retrospective study identified about 1000 charts of patients treated primarily for cocaine dependence at three types of programs—short-term inpatient, long-term residential, and drug-free outpatient. Some 772 of those patients were interviewed after discharge. Patients in all three types of programs reported substantial reductions not only in cocaine use but also in the use of other drugs. While the self-reports were generally confirmed by drug tests, cocaine use was underreported. About 37 percent of the drug tests were positive for cocaine metabolites (32 percent of the long-term residential patients, 33 percent of the drug-free

outpatients, and 46.4 percent of the short-term inpatients.) The researchers concluded that no significant differences in outcome existed across these three approaches. By self-report, weekly or daily cocaine or crack use was about one third of pretreatment levels for each of the modalities. However, different programs serve different groups. Patients entering these three modalities of treatment differed significantly in terms of gender, age, criminal justice pressure to enter treatment, and the extent and types of support and treatment received after discharge. VARIETIES OF REMISSIONS Treatment of cocaine dependence may have various outcomes, including, at the extremes, complete relapse to cocaine dependence or total abstinence from cocaine and related drugs for a prolonged period—more than 12 months (sustained full remission). However, sustained partial remissions occur in which, after at least 1 month when no criteria of dependence have been present, one or more criteria of abuse or dependence are again met, but over the course of 12 months fewer cocaine-dependence criteria have been met than the three required for full relapse. There are also situations in which these patterns are observed, but the period of observation is not a full year (early full remission and early partial remission). Any pattern of remission may be observed while the person is in a controlled environment, and that fact should be specified. DSM-IV criteria for both abuse and dependence require maladaptive use associated with distress or impairment. Technically, a person can be in sustained full remission from cocaine dependence despite occasional use, provided the drug use causes no problems or distress and does not escalate. How often such a return to occasional nonproblematic use takes place is unknown. Cocaine and Crime The typical interactive relation between the use of opioid drugs and crime generally holds true for cocaine users, but some significant differences exist. As with opioid users, considerable heterogeneity exists among cocaine users. Although a history of delinquency or antisocial behavior is often an antecedent to cocaine use, not everyone who uses cocaine or develops cocaine dependence engages in crime, even though the cost of using the drug may create serious financial problems for them. Sometimes, however, a person with no previous criminal behavior will engage in a variety of illegal activities ranging from fraud and white-collar crime to drug selling, prostitution, and predatory crime just to get enough money to buy cocaine. Among persons seeking treatment for any variety of substance abuse, use of cocaine is most highly correlated with income-generating crime. In a nationwide sample of adolescents 40 percent of serious crimes committed by the entire sample were committed by the 1.3 percent who reported using cocaine. In the late 1980s, when cocaine use declined in the general population in the United States, it rose or merely stabilized among those arrested for a variety of serious offenses. In the late 1990s, however, cocaine use began to decline, especially among younger arrestees. COCAINE, AGGRESSION, AND VIOLENCE One conceptual framework for thinking about the links between violence and substance (cocaine) use involves three major causal categories: psychopharmacological effects (effects of the substances), economic compulsion (violent crimes committed to obtain money for drugs), and systemic violence (associated with the business methods and lifestyle of drug dealers). Cocaine can induce states of paranoia and aggressive behavior, a common reason why cocaine users are brought to emergency rooms. However, pharmacologically induced aggression is not the major reason why cocaine and crime, and more specifically, cocaine and violence, are linked. Among those arrested for violent crime, the primary predictors of such crime are past arrests for violent crime, poor education, and poor intellectual ability. Past arrest for violence is also associated with antisocial personality disorder. Studies of violent predatory offenders indicate that most had histories of heavy involvement with multiple substance use and with serious crime as juveniles. Among predatory offenders high-frequency substance users were likely to use many substances, particularly heroin and cocaine, and to engage in a variety of crimes, including violent crimes, at high rates. Cocaine also has a nonpharmacologically based link to violent crime; many drug dealers who may not use cocaine routinely themselves resort to violence to protect or expand their customer base.

TREATMENT Selection of Treatment Setting The general principles of treatment for cocaine dependence do not differ much from those for other varieties of drug dependence. Patient heterogeneity requires careful assessment of the patient and thoughtful selection among alternative treatment approaches. Cocaine dependence severe enough to require formal treatment is often associated with other psychiatric diagnoses. Not all cocaine users require extensive treatment; some who are not severely dependent respond to external pressures, as when employers insist on carefully monitoring substance use. Among the factors influencing selection are the severity of dependence, other drugs being used concurrently, comorbid medical and psychiatric disorders, as well as the preferences of the patient and the alternatives available. Availability, in turn, is often influenced by the policies of managed care companies, the patient's resources, and the types of therapy provided locally. In general, treatment can be initiated in intensive outpatient settings, although often third party payers do not authorize, and public sector programs cannot provide, the duration of treatment or the intensity shown to be most effective. Some early studies found that inpatient treatment is associated with better outcomes at 1 year than outpatient treatment, even though patients initially treated as inpatients had more-severe cocaine problems. A study using random assignment found that at 4 months, working class veterans treated in a day-hospital program were about as successful in reducing their cocaine use and improving social functioning as those treated in a 28-day inpatient program. However, a somewhat higher proportion of those assigned to the inpatient setting completed the 28-day program. Currently, severe depression with suicidal ideation, psychosis, or substance use that has repeatedly failed to respond to outpatient efforts are the indications for hospitalization. A retrospective study of individuals treated for cocaine dependence in various settings found no advantage in outcome for inpatient treatment lasting longer than 2 weeks. In many instances, the selection of the setting and type of treatment is made by neither the patient nor the clinician. Patients are often referred (mandated) to treatment by the criminal justice system, which often prefers long-term residential programs (therapeutic communities). The intensity and specificity of services for particular problems (i.e., medical, psychiatric, and vocational) are now considered important determinants of outcome in the specific problem areas. Detoxification The cocaine withdrawal syndrome is distinct from that of opioids, alcohol, or sedative-hypnotics, since there are no physiological disturbances that necessitate inpatient or residential drug withdrawal. Thus it is generally possible to engage in a therapeutic trial of outpatient withdrawal before deciding whether a more intensive or controlled setting is required for patients unable to stop without help in limiting their access to cocaine. Patients withdrawing from cocaine typically experience fatigue, dysphoria, disturbed sleep, and some craving; some may experience depression. No pharmacological agents reliably reduce the intensity of withdrawal, but recovery over a week or two is generally uneventful. It may take longer, however, for sleep, mood, and cognitive function to recover fully. Treatment Methods A number of psychological and pharmacological approaches to the treatment of cocaine dependence have been explored. More than 20 different pharmacological agents have been tested in the search for drugs to facilitate withdrawal, reduce postwithdrawal craving, or prevent relapse. In general, no drug with robust therapeutic efficacy has emerged. Psychosocial approaches have included various forms of individual and group psychotherapies, drug counseling, and self-help groups. It is generally held that total and permanent abstinence from cocaine must be the goal of treatment for those who have developed symptoms of dependence; any use at all is seen as a prodrome to relapse. However, this perspective may underestimate the benefits that accrue from treatment that results in a substantial and prolonged reduction in drug use but falls short of total abstinence. In most studies of treatment effectiveness a significant proportion of patients report substantial reductions in use, even though they are not completely abstinent. Psychotherapy and Behavior Modification Psychological treatment approaches have used cognitive-behavioral, psychodynamic, and general supportive techniques. One cognitive-behavioral method uses contingency contracting in which it is agreed in advance that for a specified period of time (e.g., 3 months), if the patient uses cocaine (as detected by supervised urine testing) the therapist will initiate actions that will result in serious adverse consequences for the patient, such as informing an employer or a professional credentials board. In one such study 48 percent of potential patients accepted such a contractual arrangement, and 80 percent of those patients successfully abstained from cocaine during the period covered by the contract; many of the successful patients relapsed when the contract expired. Although the technique is not widely used by individual therapists, the general principle of linking drug use and aversive contingencies is central to many employment-based programs and criminal justice programs that use drug (urine) testing. No adequate studies exist comparing such adverse contingency contracts with alternatives. In contrast, several studies have compared relapse prevention and contingency contracts using positive rewards with 12-step type programs. In these studies, ambulatory cocaine abusers (mostly white, male, white-collar workers) were randomly assigned to either experienced therapists who used 12-step principles or therapists who used behavioral approaches that emphasized contingency management, community reinforcement, and positive rewards (such as vouchers) for cocaine-free urine samples. Retention rates were higher and cocaine use was significantly lower with contingency management and positive rewards. The same researchers found that positive reinforcement was more effective in terms of retention and abstinence than were otherwise identical behavioral treatment methods without positive reinforcement. Another research group randomly assigned cocaine users (typically white men with more than 12 years of education) to relapse prevention or to a 12-step treatment

that used group techniques. Relapse prevention involved teaching the patient how to recognize high-risk situations and ways of dealing with negative emotions, but it did not offer positive material reinforcement such as vouchers or lottery tickets for cocaine-free urine samples. The 12-step treatment group was led by a man and woman cotherapy team using 3 of the first 12 steps, but it was not Alcoholics Anonymous (AA) or Narcotics Anonymous (NA). The groups did not differ at 6-month follow-up or at end of treatment in retention in treatment or reduction in cocaine use. In another study, relapse prevention using cognitive-behavioral coping skills training was compared with clinical management in the context of a pharmacotherapy trial comparing desipramine (Norpramin) with placebo. Clinical management was intended to foster a supportive doctor-patient relationship, retention in the protocol, and compliance with medication. Unlike the other two studies, there were more women (27 percent), more minorities (54 percent), fewer high school graduates (24 percent), and fewer patients who were gainfully employed (53 percent). About 40 percent of patients completed the proposed 12-week protocol (mean of 7.2 weekly sessions). Overall, about 70 percent of patients improved, but cognitive-behavioral treatment did not appear better than clinical management. Although there was a trend for more patients receiving relapse prevention or desipramine to complete treatment, the differences were not significant. Relapse prevention appeared to be more helpful with those with more severe cocaine dependence. Desipramine seemed useful primarily for those with less-severe dependence and only early in the course of treatment. There were no differences between the response to drug and placebo at 12 weeks. Supportive Therapy The specific methods of supportive therapy overlap the techniques used by behaviorists. Patients are helped to separate themselves from drug-using friends and from situations where cocaine is available and which increase drug craving. They are urged to abstain from other substances, such as alcohol and cannabis, because those substances have been reported to increase cocaine craving and the probability of relapse. Patients are also helped to repair the areas of their lives that once provided satisfaction and may have been damaged by the behaviors associated with cocaine use. In addition, patients may be encouraged to participate in Cocaine Anonymous (CA), AA, or NA as a means of gaining control over other substance use. Psychodynamic, Interpersonal, and Combined Approaches Psychodynamically oriented clinicians emphasize the patient's unconscious motives for using cocaine (e.g., to relieve an inner sense of emptiness or depression). However, experienced clinicians with a wide range of skills believe that a combination of psychological approaches, with the emphasis tailored to the needs of the individual patient, is more effective than treatments that emphasize the principles of only one approach. Group Psychotherapy Techniques Several distinct approaches to group psychotherapy with cocaine users have been described. Interpersonal group therapy focuses on relationships and uses the group interactions to illustrate the interpersonal causes of individual distress and to offer alternative behaviors. Modified dynamic group therapy is described as emphasizing character, as it manifests itself individually and intrapsychically, and in the context of interpersonal relationships with a focus on affect, self-esteem, and self-care. Both approaches share the view that the group should serve as an interpersonal anchor that leads first to more-stable emotional status and enables members to face unresolved life issues. Both approaches recognize the vulnerability of the patients to narcissistic injury and the need for a supportive, empathetic environment. Some psychotherapists emphasize that the focus in the early months of treatment must be exclusively on the disease and on achieving sobriety and recovery, but modified dynamic group therapy asserts that even early in the process, those goals are not incompatible with attention to characterological problems. Dynamic group psychotherapy assumes that substances are used as self-medication and that the persons most likely to use cocaine include those whose depression, anergia, or boredom is alleviated by it. However, those who place exaggerated value on assertiveness and self-sufficiency may also find cocaine alluring. Since patients must sometimes be abstinent for at least 2 weeks before participating in this type of group therapy, the technique may be more accurately described as relapse prevention rather than treatment to induce initial cessation. Few studies bear on the effectiveness of such group therapy. Group Counseling Perhaps the most widely used form of psychosocial treatment for cocaine dependence is group counseling, in which the group is open ended with rolling admissions, the group leaders are drug counselors, many of whom are recovering from addiction, and the emphasis is on providing a supportive atmosphere discussing problems in recovery and encouraging participation in 12-step programs. It is unclear if this treatment is properly considered group therapy since the group is continually changing. Intensive and Eclectic Treatment Most private practitioners who typically work with employed patients of middle and upper socioeconomic class probably use approaches best described as intensive and eclectic and consider the patient's motivation for treatment (stage of change). The goals of treatment and the techniques shift over time, with the initial work focused on forging an alliance with the patient and increasing the motivation to achieve abstinence. Treatment may initially involve several group and individual sessions per week focused on interrupting the substance-use cycle and on developing detailed plans for avoiding exposure to the substances and high-risk situations. Experienced clinicians advise taking supervised urine samples at least weekly, so that patients know that they are accountable for their actions. Results are generally considered measures of progress, not tests designed to catch the patient in lies. Emphasizing shared goals and instilling hope, trust, and confidence may foster the engagement of even resistant patients. While arguing about whether or not the patient is an addict may drive a patient from treatment, since some may not be ready to give up cocaine entirely, clinicians need to be able to work with such patients despite their own doubts that they may be enabling substance-using behavior. Once abstinence is achieved, the goals of treatment shift to relapse prevention. Slips (occasional use of cocaine), especially during the first 60 days of treatment, should be used as learning experiences, with the focus on how to prevent reoccurrence. In the later stages of treatment a balance must be struck between enabling (tolerating continued use) and being so rigid about use that the patient leaves treatment. Sometimes a temporary suspension from the group, with continued individual sessions, is a therapeutically useful. Generally, the longer the retention in treatment, the better the long-term outcome. Self-help groups can fill the void in the patient's life once occupied by cocaine, but other drug-free alternatives exist. Cocaine use is often linked to compulsive sexual activity. Some practitioners believe that it is important to ascertain what kinds of sexual behaviors and fantasies are associated with being high on cocaine, since sexual feelings can trigger a craving for cocaine. It may sometimes be appropriate to ask patients to refrain from sex for the first weeks of treatment. Comparison of Psychotherapy Methods and Programs A large-scale collaborative multisite cocaine treatment study sponsored by the National Institute on Drug Abuse (NIDA) compared different psychosocial treatments. Following a brief period of stabilization, 487 cocaine-dependent patients were randomly assigned to one of four groups: weekly group drug counseling, group counseling plus individual drug counseling based on 12-step principles, group counseling plus individual cognitive therapy, or group counseling plus individual supportive expressive therapy. Group drug counseling was provided for 6 months; individual therapies were provided twice weekly for 3 months, then once weekly for 3 months. Therapy was manual guided, and cognitive therapy and supportive expressive therapists were fully trained professionals. Drug counselors had extensive experience with drug dependence treatment; about one third were in recovery from drug dependence. All patients reported substantial reduced cocaine use, whether measured by Addiction Severity Index composite, days of cocaine use in the past month, or number of months abstinent. Follow-up occurred 1 year after treatment entry (which for some patients was only 6 months after completion). Patients assigned to group drug counseling plus individual drug counseling reported significantly better outcomes; patients assigned to either cognitive therapy or supportive expressive therapy stayed in treatment longer, but outcomes in terms of cocaine use or dependence were not significantly better than those for group drug counseling alone. Among patients assigned to individual counseling, 73 percent achieved 1 month of complete abstinence, and 36 percent achieved 3 consecutive months of abstinence. In the other groups, 17 to 25 percent achieved 3 months of abstinence. By 6 months posttreatment, no delayed benefits of psychotherapy had emerged. Psychiatric severity and the presence of antisocial personality disorder did not significantly affect treatment outcome. Patients assigned to once-weekly group counseling reported substantially reduced cocaine use starting from the first month of treatment. Although only 23 percent of patients continued for the 6 months of treatment available, the reported improvement in drug use was sustained through the 1 year follow-up. Adding individual sessions of either cognitive therapy or supportive expressive therapy twice weekly (provided by professionally trained therapists) to the weekly group counseling session increased retention in treatment but did not increase the proportion of patients who reported being abstinent or using substantially less cocaine. In evaluating these outcomes one must know that all patients participated in a stabilization phase lasting 1 to 2 weeks during which they were required to attend one group session and two case-management visits before being assigned to a specific treatment. During that time there was attrition of less motivated patients. The therapists were highly qualified, carefully trained, used a manual to guide therapy, and were supervised. The study population was 77 percent male, 58 percent white and 60 percent employed, with a mean age of 34 and generally low psychiatric severity. Patients taking psychotropic medication, and those with schizophrenia, bipolar disorder, polysubstance dependence, or opioid dependence were excluded. However, 33 percent met criteria for alcohol dependence, 28 percent those for cocaine-induced mood disorder, 14 percent met full criteria for antisocial personality disorder, and 32 percent for adult antisocial personality disorder with history of conduct disorder. Pharmacological Adjuncts Presently no pharmacological treatments produce decreases in cocaine use that compare with the decreases in opioid use seen when heroin users are treated with methadone, levomethadyl acetate (ORLAAM) (commonly called L-a-acetylmethadol [LAAM]) or buprenorphine. However, a variety of pharmacological agents, most of which are approved for other uses, have been and are being tested clinically for the treatment of cocaine dependence and relapse. Some of these agents are being used routinely by clinicians although little solid evidence exists for their efficacy. The most common premises on which

pharmacological interventions are based are as follows: (1) chronic cocaine use alters dopaminergic systems, so that giving up the drug is associated with a hypodopaminergic state characterized by dysphoria or anhedonia; (2) some cocaine users are using the drug to ameliorate a preexisting psychiatric disorder, such as major depressive disorder, dysthymic disorder, attention-deficit disorder, or cyclothymic disorder; (3) cocaine produces a sensitization, or kindling, effect that somehow predisposes to continued use; and (4) relapse is related to memories of the reinforcing and euphoric effects of cocaine, craving for which can be elicited by stress, other drugs, or environmental stimuli. Cocaine users presumed to have preexisting attention-deficit/hyperactivity disorder or mood disorders have been treated with methylphenidate (Ritalin) and lithium (Eskalith), respectively. Those drugs are of little or no benefit in patients without the disorders, and clinicians should adhere strictly to maximal diagnostic criteria before using either of them in the treatment of cocaine dependence. In patients with attention-deficit/hyperactivity disorder, slow-release forms of methylphenidate may be less likely to trigger cocaine craving, but the impact of such pharmacotherapy on cocaine use remains to be demonstrated. Many pharmacological agents have been explored on the premise that chronic cocaine use alters the function of multiple neurotransmitter systems, especially the dopaminergic and serotonergic transmitters regulating hedonic tone, and that cocaine induces a state of relative dopaminergic deficiency. Although the evidence for such alterations in dopaminergic function has been growing, it has been difficult to demonstrate that agents theoretically capable of modifying dopamine function can alter the course of treatment. This has been so even when studies in animal models and open-label studies suggested that they would be successful. In well-designed, controlled trials that obtained objective evidence of drug use, the following agents are among those that have not been found to reduce cocaine use: neurotransmitter precursors, (e.g., dopa; tyrosine); dopaminergic agonists, (bromocriptine [Parlodel]; lisuride; pergolide [Permax]); and antiparkinson drugs that may also affect the dopaminergic system (amantadine [Symmetrel]). Tricyclic antidepressant drugs such as desipramine and imipramine (Tofranil) have also been tried. Although some double-blind studies that relied heavily on self-reports of drug use yielded some positive results, other studies have not found them significantly beneficial in inducing abstinence or preventing relapse. There is no consensus that the effects of desipramine are robust or reliable enough to justify routine use, but used early in treatment, it may have some transient benefit for patients who are less severely dependent. Also tried in pilot or open-label studies but not confirmed effective in controlled studies, are other antidepressants, such as bupropion (Wellbutrin), monoamine oxidase (MAO) inhibitors (selegiline [Eldepryl]); selective serotonin uptake inhibitors (SSRIs) (e.g., fluoxetine [Prozac]); mazindol (Sanorex); pemoline (Cylert); antipsychotics (e.g., flupenthixol); lithium; several different calcium channel inhibitors, anticonvulsants (e.g., carbamazepine [Tegretol] and valproic acid [Depakene]). One double-blind study not yet replicated found that 300 mg a day of phenytoin (Dilantin) reduced cocaine use. Several agents are being developed but have not been tried in human studies. These include agents that would selectively block or stimulate dopamine receptor subtypes (e.g., selective D 1 agonists) and drugs that can selectively block the access of cocaine to the dopamine transporters but still permit the transporters to remove cocaine from the synapse. Another approach is aimed at preventing cocaine from reaching the brain by using antibodies to bind cocaine in the bloodstream (a so-called cocaine vaccine). Such cocaine-binding antibodies do reduce the reinforcing effects of cocaine in animal models. Also under study are catalytic antibodies that accelerate the hydrolysis of cocaine; and butyrylcholinesterase (pseudocholinesterase), which appears to hydrolyze cocaine selectively and is normally present in the body. Acupuncture Use of auricular acupuncture to treat cocaine and other varieties of dependence behavior has become popular among some groups, including some drug courts and prison-based programs. Controlled studies of its efficacy for treating cocaine dependence (using sham acupuncture) have been conducted but are subject to varying interpretations; large differences in cocaine use (as measured by urine tests) have not been shown. In programs offering treatment in a drop-in outpatient setting, clients typically are instructed to stay as clean and sober as they can and to come in daily for treatment; clinic rules are minimal; treatment usually takes place in groups, with patients sitting in comfortable chairs for about 45 minutes. Dropout rates are generally high. Herbal teas are often consumed as part of the treatment. Also used for treatment of cocaine dependence are several forms of transcranial electrical stimulation (neuroelectric therapy [NET]). A comparison of NET with sham NET revealed no differences in successful detoxification over a 12-day hospitalization. Special Populations and Special Considerations Mixed Addictions PATIENTS MAINTAINED ON METHADONE Behavioral techniques and pharmacological agents have been used to help patients maintained on methadone reduce their use of cocaine (as measured by urine tests). Some methadone programs use progressive sanctions, such as decreased take-home privileges, a decreased methadone dosage, and finally in some cases, discharge from the program. However, in one comparison study, decreasing the methadone dosage proved far less effective than giving small (5 mg) increases (up to 120 mg a day in some cases) for each cocaine-positive urine test. However, an analysis of the relation between cocaine use and methadone dose at another clinic did not find less cocaine use among patients maintained on higher doses of methadone. Providing small rewards (such as vouchers for goods and services) contingent on submitting a urine specimen negative for cocaine does reduce the frequency of cocaine use. Other pharmacological agents that have been tried for methadone-maintenance patients who also use cocaine include bromocriptine, amantadine, desipramine, bupropion, carbamazepine, and buprenorphine. In a controlled comparison of amantadine, desipramine, and placebo, self-reports of cocaine use were lower for both medication groups at 4 weeks, but there were no significant differences in cocaine-positive urine tests, and there were no significant group differences at 8 or 12 weeks. Early animal studies and open-label clinical studies suggested that buprenorphine might help decrease cocaine use among patients dependent on both opioids and cocaine. In three double-blind controlled studies comparing buprenorphine and methadone (one of which was not specifically designed to test effects on cocaine use), cocaine use was not affected, although both buprenorphine and methadone significantly decreased heroin use. In animal models buprenorphine appears to antagonize some of the lethal effects of cocaine and to increase its reinforcing effects. Carbamazepine, which substantially stimulates the metabolism of methadone, has not shown any specific effects on cocaine use in controlled studies. In summary, no pharmacological agent has been shown to have reliably robust effects on cocaine use among patients maintained on methadone. COCAINE AND ALCOHOL In patients dependent on both cocaine and alcohol, the opioid antagonist naltrexone (Revia) had no effect on cocaine use. In an open-label trial, disulfiram (Antabuse) seemed useful for reducing cocaine use, perhaps because it discouraged the use of alcohol which is often used with cocaine. Women, Pregnant Women, and Their Children Data suggest that although women who seek treatment tend to be more severely drug dependent, they respond as well to treatment as do men. Women dependent on cocaine have a number of special needs, especially with respect to their physical health. Cocaine use by pregnant women represents a hazard to the fetus. At the peak of the cocaine epidemic, 10 to 45 percent of women who received obstetrical care in some urban hospitals reported using cocaine at some time during pregnancy. There is some controversy about the frequency and permanence of any damage sustained by the fetus, but there is little question that maternal cocaine use can be associated with some perinatal morbidity and mortality. Separating cocaine effects from the effects of other substances and of other maternal behavior is exceedingly difficult but some toxicity may be due to cocaine-induced hypertension, tachycardia, and vasoconstriction, which lead to impaired placental blood flow and decreased transfer of nutrients and oxygen to the fetus. Some toxicity also results from direct effects of cocaine on the fetus. Depending on the severity of the placental and fetal effects and when they occur during gestation, the result may be teratogenic, with destruction of developing tissues or overall retardation of fetal growth. Commonly reported abnormalities in fetuses exposed to cocaine are microcephaly and structural abnormalities in brain and urinary tract development. Ischemic and hemorrhagic lesions in the newborn brain have also been reported. Spontaneous abortions, premature birth, placenta previa, and abruptio placenta are complications of pregnancy that are more common among women who use cocaine than among nonusers; low-birth-weight babies are also common. Despite the risks, only a small percentage of the infants exhibit what might be called a neonatal cocaine exposure syndrome, which consists of poor feeding, irritability, tremor, and abnormal sleep patterns. Those abnormalities are most evident on the second day after birth and last for less than a week or two. Sudden infant death syndrome (SIDS) is reported to be more common among infants exposed to cocaine in utero, but since there are no controls, the evidence for this is not

conclusive. The long-term neurological, cognitive, and developmental consequences of intrauterine cocaine exposure are still not clear, but after the first few months, most of these children appear to be developmentally within normal limits. A follow-up study tested children ages 6 to 9 who were exposed prenatally to cocaine and then compared them with unexposed controls matched for gender, birth weight, ethnicity, and socioeconomic status. Intelligence quotient (I.Q.) scores did not differ and were unchanged when adjusted for caregiver I.Q. and home environment. There appears to be no contraindication to discontinuing cocaine abruptly during pregnancy (unlike opioids), and prompt abstinence from cocaine should be the goal of treatment. Patients With Other Psychiatric Disorders Persons with cocaine-dependence who also have mood or anxiety disorders are generally managed in programs that focus on the substance-use problem. Several clinical reports indicate that cocaine users with bipolar disorders generally are not compliant with prescribed lithium. Patients with a history of attention-deficit/hyperactivity disorder are also likely to have antisocial personality disorder. Although some studies found that patients with antisocial personality disorder and cocaine abuse responded relatively poorly to treatment, more recent studies found that in terms of their cocaine use, improvement was comparable to that of patients who did not have antisocial personality disorder. Up to 10 percent of persons meeting criteria for cocaine abuse also met DSM-IV criteria for adult attention-deficit/hyperactivity disorder. Clinical trials using methylphenidate on the assumption that cocaine use was an attempt to self-medicate attention-deficit/hyperactivity disorder have led to the caution that in most cases, the patient's demand for methylphenidate escalates and craving for cocaine is stimulated. A slow-release form of methylphenidate may be less likely to elicit craving, but its efficacy in reducing cocaine use has not been demonstrated. PATIENTS WITH DEPRESSION Symptoms of depression are common among patients seeking treatment for cocaine dependence. In studies of tricyclic drugs and SSRIs in patients who were using cocaine, outcomes of those who initially had depressive symptoms and patients who were initially without such symptoms did not differ. In a large-scale study of psychosocial treatment, cocaine-dependent patients who met criteria for any Axis I disorder were less likely to drop out once they became engaged in treatment. The relation of symptoms of depression and of concurrent major depression to treatment outcome needs further clarification. The most sensible course is to treat significant depression with antidepressants only if they persist after cessation of drug use. PATIENTS WITH SCHIZOPHRENIA Persons with schizophrenia and other psychotic disorders who use cocaine have been managed within either primary drug treatment or psychiatric facilities. In all settings, concurrent use of alcohol and cocaine further complicates treatment. There is a growing consensus that parallel treatment (two separate programs, one treating substance dependence/abuse and the other treating schizophrenia) is less effective than a comprehensive integrated program that deals with both disorders concurrently. Intensive case management that gives patients access to social services makes it possible to treat patients with schizophrenia who abuse cocaine in the same day-hospital setting as non-substance-abusing patients. However, requiring abstinence for admission or retention may be unrealistic for such patients, and some of the traditional rules concerning substance abuse and poor attendance may need to be relaxed. Most patients are not initially motivated to participate in abstinence-oriented programs, but when attention is paid to a patient's level of motivation, most can be engaged and moved toward active treatment. The use of cocaine, amphetamines, and cannabis exacerbates schizophreniform disorder, and such use is not an uncommon problem. Among patients receiving public assistance or disability payments, such use seems to increase substantially shortly after they receive monthly checks. Some cocaine (or stimulant) use may represent an attempt to alleviate negative symptoms, depression, or the side effects of antipsychotic agents. The last problem might be dealt with by using newer antipsychotic agents that have fewer extrapyramidal adverse effects.

SUGGESTED CROSS-REFERENCES See Chapter 1 for discussion of the neural sciences and Chapter 2 for a presentation of neuropsychiatry and behavioral neurology. A classification of mental disorders appears in Chapter 9. An introduction and overview of substance-related disorders is presented in Section 11.1, and amphetamine-related disorders in Section 11.3. Various drugs are discussed in the chapter on biological therapies ( Chapter 31), particularly sympathomimetics in Section 31.21. Schizophrenia is discussed in Chapter 12, and other psychotic disorders in Chapter 13. Animal research and its relevance to psychiatry is discussed in Section 5.4. Cognitive-behavioral therapy is discussed in Section 48.3 SECTION REFERENCES Alterman AI, McLellan AT: Inpatient and day hospital treatment services for cocaine and alcohol dependence. J Subst Abuse Treatment 10:269, 1993. Anthony JC, Warner LA, Kessler RC: Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 2:244, 1994. Benowitz NL: How toxic is cocaine? In Cocaine: Scientific and Social Dimensions, Ciba Foundation Symposium 166, GR Bock, J Whelan, editors. Wiley, New York, 1992. Brown RA, Monti PM, Myers MG, Martin RA, Rivinus T, Dubreuil ME, Rohsenow DJ: Depression among cocaine abusers in treatment: Relation to cocaine and alcohol use and treatment outcome. Am J Psychiatry 155:220, 1998. *Bullock ML, Kiresuk TJ, Pheley AM, Culliton PD, Lenz SK: Auricular acupuncture in the treatment of cocaine abuse: A study of efficacy and dosing. J Subst Abuse Treatment 16:31, 1999. Carroll KM, Rounsaville BJ: Contrast of treatment-seeking and untreated cocaine abusers. Arch Gen Psychiatry 49:464, 1992. Carroll KM, Rounsaville BJ, Gordon LT, Nich C, Jatlow P, Bisighini RM, Gawin FH: Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry 51:177, 1994. *Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP: Limbic activation during cue-induced cocaine craving. Am J Psychiatry

156:1, 1999.

Daras M: Neurologic complications of cocaine. NIDA Research Monogr 163:43, 1996. Drake RE, Mueser KT, Clark RE, Wallach MA: The course, treatment and outcome of substance disorder in persons with severe mental illness. Am J Orthopsychiatry 66:42, 1996. Fletcher BW, Tims FM, Brown BS: Drug Abuse Treatment Outcome Study (DATOS): Treatment evaluation research in the United States. Psychol Addict Behav 11:216, 1997. Foltin RW, Fischman MW: Effects of “binge” use of intravenous cocaine in methadone-maintained individuals. Addiction

93:825, 1998.

Gatley SJ, Volkow ND: Addiction and imaging of the living human brain. Drug Alcohol Depend 51:97, 1998. Gawin FH, Ellinwood EH: Cocaine and other stimulants. N Engl J Med 318:1173, 1988. Gold MS, Miller NS: Cocaine (and crack): Neurobiology. In Substance Abuse: A Comprehensive Textbook, ed 3, JH Lowinson, P Ruiz, RB Millman, JG Langrod, editors. Williams & Wilkins, Baltimore, 1997. *Gorelick DA: Pharmacologic therapies for cocaine and other stimulant addiction. In Principles of Addiction Medicine, ed 2, AW Graham, TK Schultz, editors. American Society of Addiction Medicine, Chevy Chase, MD, 1998. Higgins ST, Budney AJ, Bickel WK, Foeng FE, Donham R, Badger GJ: Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch Gen Psychiatry

51:568, 1994.

Hubbard RL, Craddock SG, Glynn PM, Anderson J, Etheridge RM: Overview of 1-year-follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychol Addict Behav 11:261, 1997. Hyman SE, Nestler EJ: Initiation and adaptation: A paradigm for understanding psychotropic drug action. Am J Psychiatry 153:151, 1996. Jaffe JH, Cascella NG, Kumor KM, Sherer MA: Cocaine-induced cocaine craving. Psychopharmacology 97:59, 1989. *Kreek MJ, Koob GF: Drug dependence: Stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23, 1998. Levin FR, Evans SM, Kleber HD: Prevalence of adult attention-deficit hyperactivity disorder among cocaine abusers seeking treatment. Drug Alcohol Depend 52:15, 1998.

Little KY, McLaughlin DP, Zhang L, McFinton PR, Dalack GW, Cook EH Jr, Cassin GJ, Watson SJ: Brain dopamine transporter messenger RNA and binding sites in cocaine users. Arch Gen Psychiatry 55:793, 1998. McLellan AT, Grossman DS, Blaine JD, Haverkos HW: Acupuncture treatment for drug abuse: A technical review. J Substance Abuse Treatment 10:569, 1993. Mendelson JH, Sholar M, Mello NK, Teoh SK, Sholar JW: Cocaine tolerance: Behavioral, cardiovascular, and neuroendocrine function in men. Neuropsychopharmacology 18:263, 1998. *Mulvaney FD, Alterman AI, Boardman CR, Kampman K: Cocaine abstinence symptomatology and treatment attrition. J Subst Abuse Treatment 16:129, 1999. Musto D: Opium, cocaine and marijuana in American history. Sci Am 265:40, 1991. *Ness RB, Grisso JA, Hirschinger N, Markovic N, Shaw LM, Day NL, Kline J: Cocaine and tobacco use and the riskof spontaneous abortion. N Engl J Med 340:333, 1999. *Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LJ, Goodwin FK: Comorbidity of mental disorders with alcohol and other drug abuse. JAMA 264:2511, 1990. Rounsaville BJ, Anton SI, Carroll K, Budde D, Prusoff BA, Gawin F: Psychiatric diagnoses of treatment-seeking cocaine abusers. Arch Gen Psychiatry 48:43, 1991. Rounsaville BJ, Bryant K: Tolerance and withdrawal in the DSM-III-R diagnosis of substance dependence. Am J Addictions 1:50, 1992. Rounsaville BJ, Bryant K, Babor T, Kranzler H, Kadden R: Cross system agreement for substance use disorders: DSM-III-R, DSM-IV, and ICD-10. Addiction 88:337, 1993. Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR: Buprenorphine versus methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psychiatry 54:713, 1997. Self DW, Nestler EJ: Relapse to drug-seeking: Neural and molecular mechanisms. Drug Alcohol Depend 51:49, 1998. Shaner A, Khalsa E, Roberts L, Wilkins J, Anglin D, Hsieh S-C: Unrecognized cocaine use among schizophrenic patients. Am J Psychiatry 150:758, 1993. Silverman K, Higgins ST, Brooner RK, Montoya ID, Cone EJ, Schuster CR, Preston KL: Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy. Arch Gen Psychiatry 53:409, 1996. Siqueland L, Crits-Christoph P, Frank A, Daley D, Weiss R, Chittams J, Blaine J, Luborsky L: Predictors of dropout from psychosocial treatment of cocaine dependence. Drug Alcohol Depend 52:1, 1998. Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J, True W, Lin N, Toomey R, Eaves L: Co-occurrence of abuse of different drugs in men. Arch Gen sychiatry

55:967, 1998.

van den Bree MB, Svikis DS, Pickens RW: Genetic influences in antisocial personality and drug use disorders. Drug Alcohol Depend 49:177, 1998. *van Gorp WG, Wilkins JN, Hinkin CH, Moore LH, Hull J, Horner MD, Plotkin D: Declarative and procedural memory functioning in abstinent cocaine abusers. Arch Gen Psychiatry

56:85, 1999.

Wasserman GA, Kline JK, Bateman DA, Chiriboga C, Lumey LH, Friedlander H, Melton L, Heagarty MC: Prenatal cocaine exposure and school-age intelligence. Drug Alcohol Depend 50:203, 1998. Weddington WW, Brown BS, Haertzen CA, Cone EJ, Dax EM, Herning RI, Michaelson MA: Changes in mood, craving and sleep during short-term abstinence reported by male cocaine addicts. Arch Gen Psychiatry 47:861, 1990.

Textbook of Psychiatry

11.7 HALLUCINOGEN-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.7 HALLUCINOGEN-RELATED DISORDERS HENRY DAVID ABRAHAM, M.D. Definition History Comparative Nosology Epidemiology Pharmacology Psychopharmacology Etiology Psychiatric Disorders Suggested Cross-References

The discovery of lysergic acid diethylamide (LSD) by Albert Hofmann in 1943 proved to be a double-edged sword that simultaneously widened the understanding of central mechanisms of neural regulation and led to the widespread abuse of hallucinogenic drugs. The emergence of this semisynthetic hallucinogen raised important questions about synaptic transmission, the mechanisms of hallucinations, and the phenomenology of the functional psychoses. However, the possibilities of the use and misuse of such hallucinogens was greater than that of botanical hallucinogens such as psilocybin mushrooms and peyote cacti because synthetic hallucinogens are readily made, easily distributed, cheaply sold, and thousands of times more potent than botanical preparations. These factors, among others, led to the abuse of synthetic hallucinogens and to the development of several disorders now seen in psychiatric practice.

DEFINITION An hallucinogenic drug has been defined by the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as “any agent which has alterations in perception, cognition and mood as its primary psychobiological actions in the presence of an otherwise clear sensorium. Most commonly this includes indoleakylamines and phenethylamines, and excludes, inter alia, the anticholinergics, the arylcyclohexylamine dissociative anesthestics such as phencyclidine, stimulants such as amphetamine and cocaine, bromism and heavy metal intoxication.” Excluded from this class are agents that produce hallucinations in the context of a delirium. The term hallucinogen emphasizes perceptual effects, but the literature supports ample evidence of the effects of hallucinogens on mood and cognition as well. Table 11.7-1 illustrates the representative hallucinogens.

Table 11.7-1 Overview of Representative Hallucinogens

By definition these drugs are intoxicants. Clinically the use of hallucinogenic drugs is associated with panic attacks, hallucinogen persisting perception disorder (flashbacks), psychosis, delirium, and mood and anxiety disorders. Empirical evidence more strongly supports the first three as discussed below. Although DSM-IV defines hallucinogen abuse and dependence with criteria applicable to other agents of abuse, hallucinogens differ from addictive drugs in that cessation after long-term use is not associated with a distinct withdrawal syndrome.

HISTORY The omnivorous diet of primeval man no doubt led to the discovery of certain plants which, while meager in nutrition, possessed extraordinary abilities to alter consciousness. Thus was introduced to history a class of plants that assumed importance in ritual, religion, and recreation. One of the earliest plants used for its mind-altering properties is the fly agaric mushroom, Amanita muscaria, which is thought to have been discovered by aboriginal Siberian hunters who observed intoxicated reindeer. The same plant is believed to have been described as soma in the 3500 year old Sanskrit text, the Rigveda. The Eleusian Mysteries of ancient Greece were thought to have used ergot alkaloids in the holy potion, kykeon, to induce mystical states. In the Middle Ages women used brooms as medicinal applicators for the vaginal insertion of hallucinogenic ointments, a probable origin of the contemporary association of brooms with witches. In 944 AD the ingestion of ergot-laden rye, produced by the ergot fungus Claviceps purpurea, is said to have killed 40,000 people in Europe. In the nineteenth century the mycologist Mordecai Cubit Cooke discriminated opiates from hallucinogens, a distinction that was more precisely drawn by Ernest Bosc DeVeze and Louis Lewin decades later. A Texas physician, John Briggs, described his self-experimentation with muscale buttons in 1887, the alkaloids of which Lewin described in the following year. Field work began in earnest in the 1920s, leading to the identification of 120 plants possessing hallucinatory properties, 80 percent of which are found in the western hemisphere. In 1928 Heinrich Klüver used mescaline to analyze the formal structure of hallucinations. The ethnobotanical work of Richard Schultes and others documented the use of hallucinogens among contemporary cultures such as the Waiká of Brazil and the Huichol of Mexico. Psychoactive agents were described in the bark of Banisteriopsis (b-carbolines), seeds of the common Morning Glory (lysergic acid), and skin glands of toad Bufo bufo (bufotenine). In 1943 Albert Hofmann discovered LSD by tracking down its identity after he accidentally ingested the drug and suffered a transient psychosis. Over the next 20 years psychiatrists in England and the United States attempted to use LSD as a therapeutic agent for a variety of illnesses, with unconvincing results. By the 1950s the drug was used by academicians, theologians, and the military for a variety of purposes. In the 1960s fascination with the drug, fueled by the American media, exploded in an epidemic of hallucinogen use involving much of Europe and the United States. The residuum of this epidemic continues today as an endemic among the young.

COMPARATIVE NOSOLOGY DSM-IV lists a number of hallucinogen-related disorders ( Table 11.7-2), but contains specific diagnostic criteria only for hallucinogen intoxication and hallucinogen persisting perception disorder (flashbacks). The diagnostic criteria for the other hallucinogen-related disorders are contained in the DSM-IV sections that are specific to each symptom. For example, hallucinogen-induced mood disorder is discussed with other mood disorders. Table 11.7-2 compares several diagnostic systems.

Table 11.7-2 DSM-IV Hallucinogen-Related Disorders

Differences between the revised third edition of DSM-III-R and DSM-IV are as follows: (1) psychoactive substance abuse was a residual category in DSM-III-R; DSM-IV provides specific diagnostic criteria for substance abuse; (2) the DSM-IV criteria for substance dependence are also modified from those of DSM-III-R; (3) DSM-IV generally permits subtyping of dependence with (or without) physiological dependence, but because hallucinogens produce no withdrawal, that option does not apply here; DSM-IV expands the list of hallucinogen mental disorders to include (4) hallucinogen intoxication delirium and (5) hallucinogen-induced anxiety disorder. Hallucinogen-induced psychotic disorder in DSM-IV is coded as a substance-induced psychotic disorder, developed concurrently with drug use, and is characterized by a longer-than-expected period of psychotic symptoms; as a rule of thumb for hallucinogens this means beyond 48 hours. Hallucinogen persisting perception disorder in DSM-IV applies to intermittent flashbacks, recurring days to years after the last hallucinogen use. This disorder now appears in certain subjects to be both permanent and constant. The 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) makes provision for flashbacks, but confuses the issue by considering them a psychotic disorder, which most authorities do not. DSM-IV provides no diagnosis for persisting hallucinogen-induced psychosis, although the literature now supports the existence of this disorder. In general, ICD-10 does not draw helpful distinctions between hallucinogen-related disorders. ICD-9 provides for seven hallucinogen-induced diagnoses, but summarily lumps four of them under “nondependent abuse.” The International Classification of the Diseases, 9th Revision, Clinical Modification (ICD-9-CM), a U.S. government classification for Medicare and Medicaid billing, calls intoxication “abuse” and provides no separate diagnosis of hallucinogen-induced anxiety disorder or flashbacks. ICD-10 names abuse “harmful use,” and has neither hallucinogen-induced mood disorder nor hallucinogen-induced anxiety disorder diagnoses; in part, these omissions reflect the lack of systematic research of these entities.

EPIDEMIOLOGY Surveys in the United States and Europe report that the use of hallucinogenic drugs among the young exceeds that of cocaine and heroin use. In the United Kingdom from 1989 to 1993 use of LSD rose from 7 to 11 percent. A survey of 781 German adolescent drug abusers found that 14.1 percent used LSD. A survey of 458 Danish students found that 7.2 percent experimented with a European hallucinogenic mushroom, P. semilanceata. Survey data in the United States show higher trends. In an analysis of data from two large universities, 13.7 percent of the students surveyed reported using hallucinogenic mushrooms. Trend data, gathered annually from approximately 15,000 U.S. high school seniors, reveal a precipitous rise in hallucinogen use from 10.3 to 15.1 percent in the decade from 1987 to 1997, beginning in 1991 (Fig. 11.7-1). Demographic data from 18,054 American householders in 1990 shows that LSD use is most likely to occur between the ages of 18 and 25. Use is more common among males, whites, and Hispanics and is more likely to occur in the American Northeast and West. Use is associated with lower levels of employment and education, although the parents of LSD users are more often of a white-collar socioeconomic status. Among American undergraduates the prevalence of the use of 3, 4-methylenedioxy-N-methylamphetamine (MDMA, “ecstasy”) has ranged widely from 2.3 to 24 percent in the first half of the 1990s.

FIGURE 11.7-1 Percentage change in lifetime use of hallucinogen use in U.S. high school seniors since 1987.

PHARMACOLOGY Several hundred known plants possess hallucinogenic properties. They vary widely in potency, but are orders of magnitude less potent than synthetic agents. Alexander Shulgin has synthesized and screened 179 phenethylamines for these effects in humans. The commonly used hallucinogens are the peyote cactus, containing mescaline, which is indigenous to the American Southwest and northern Mexico; mushrooms producing psilocybin and its active metabolites; and chemically substituted tryptamines such as dimethyltryptamine (DMT) and LSD. Hallucinogens have been classified according to their course of action assuming their usual clinical route of administration. By this schema, parenteral DMT is ultra–short-acting, with an onset when given parenterally of 1 to 5 minutes. Diethyltryptamine is short-acting (15–30 minutes), oral psilocybin is intermediate (30–60 minutes orally), LSD is long-acting (4–10 hours), and oral 2, 5-dimethoxy-4-methyl-amphetamine (DOM) and ibogaine are considered ultra–long-acting, lasting as long as 24 hours. Of the hallucinogens the pharmacology of LSD has been studied most extensively. The drug is active orally in doses of 50 to 100 µg. It is readily absorbed through the mucous membranes and exerts its psychological effects within 20 minutes. The drug is marketed illicitly as single crystals, drops deposited on blotter paper, or in sugar cubes. A drop of LSD when placed on a piece of blotter paper is for all practical purposes invisible. To mark its location, the spot is often stamped with an image of a cartoon character or New Age design. The drug's potency is underscored by the report of a drug dealer who was apprehended after he accidentally became psychotic from sitting on a wet surface with a sheet of “blotter acid” in his back pocket. Because of such potency the drug is seldom injected. Although it can cause a toxic psychosis lasting 6 to 12 or more hours, only 1 percent of the ingested drug reaches the central nervous system. Hallucinogenic drugs bind to multiple synaptic receptors in the brain. It has been shown that hallucinogenic potency is associated with binding affinities at the serotonin type 2 (5-hydroxytryptamine [5-HT 2]) receptor where these drugs act as partial agonists. Repeated administration of LSD in rats downregulates the density of 5-HT 2 binding sites, further implicating this receptor in the drug's mechanism of action. In monkey brain LSD is anatomically distributed maximally in the pituitary, pineal, the visual and auditory cortex, the hypothalamus, and the limbic cortex. This parallels the finding of high concentrations of 5-HT 2 receptors in human cerebral cortex. Studies in animals have produced mixed results on toxicity. Animals as a rule do not self-administer hallucinogens as they do reinforcing agents such as heroin and cocaine, possibly reflecting the drugs' predilection for affecting higher cortical centers that are less developed in nonhuman mammals. The LD 50 of LSD in mice is 150,000 µg/kg, whereas an elephant was killed by an LSD injection of 100 µg/kg. Accidental ingestion of between 10,000 and 100,000 µg LSD by eight persons resulted in confusion, hallucinations, and hemorrhage, but no deaths. However, fatalities have been documented with MDMA and 3,4-methylenedioxy-N-ethylamphetamine (MDEA, “Eve”). These drugs are ring-substituted isopropylamines. Drug discrimination studies in rats suggest that MDMA is “amphetamine-like.” Although MDMA was first synthesized in 1914, the drug achieved prominence in 1986 when clinicians claimed that the drug enhanced psychotherapy and improved social function. The following year widespread use was reported on

college campuses. In the following decade serotonergic neurotoxicity was described in numerous animal models for both MDMA and 3,4-methylenedioxy-N-amphetamine (MDA). MDMA deaths have been associated with drug-induced compulsive dancing, hyponatremia, and hyperthermia. Autopsy studies reveal massive hepatic necrosis and changes of heat stroke. Serotonergic cells appear particularly sensitive to MDMA; for these cells the drug is cytotoxic in rodents and monkeys, with effects lasting as long as 18 months. The coadministration of either selective serotonin uptake inhibitors or 5-HT 2 antagonists in animals appear to attenuate MDMA neurotoxicity. LSD is readily metabolized by the liver through hydroxylation and conjugation. Although tolerance occurs after 2 to 3 days of serial use, there is no withdrawal syndrome from hallucinogens, and no physiological dependence. Psychological dependence has been clinically observed. Cross-tolerance occurs between LSD, mescaline, and psilocybin, but not between these agents and amphetamines or marijuana. Phenylalkylamines, however, may elicit both hallucinogenic and amphetamine properties in varying ratios depending on the nature of the substituted moieties.

PSYCHOPHARMACOLOGY The classic description of the psychological effects of LSD remains that by Albert Hofmann, recalled in retrospect after an attempt to record his experiences ended with the entry into his journal, “Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh—” In addition to these symptoms, there are signs of sympathetic arousal, including mydriasis, hypertension, hyperreflexia, tachycardia, and tremor. Following this period of arousal, visual illusions and hallucinations may occur. They can be in any sensory modality, but visual events predominate. Synesthesia, in which one sensory modality stimulates a second one, (seeing sounds or hearing colors) is clinically rare, and probably reflects heightened connectivity between adjacent cerebral regions. Mood changes, by comparison, can be profound or can or reflect preexisting emotional conflicts. Feelings of terror, depression, and panic, described by Hofmann, may present to the clinician as a psychiatric emergency. As these perceptual and affective components of the trip subside, the user may be left with cognitive states of transcendence or paranoia. The entirety of the trip seldom lasts more than 12 hours ( Table 11.7-3).

Table 11.7-3 Hallucinogen Diagnoses, DSM and ICD

Initial studies compared the above hallucinogen-induced psychotic disorder to schizophrenia, but clinical and single photon emission tomography (SPECT) studies now clearly differentiate hallucinogen-induced psychotic states from schizophrenic states. The type of hallucinogenic experience is strongly influenced by the personality of the user, the instructional set, the setting in which the drug is used, and the chemical structure of the drug. More severe reactions occur when the patient is given the drug surreptitiously.

ETIOLOGY The rising trend of hallucinogen use among high school students in the United States since the late 1980s attests to the interplay of several factors in their use. Longitudinal studies show that hallucinogenic drugs like LSD occupy a midrange position in the progression of many drug use careers, in that many adolescents experiment first with legal drugs (alcohol and tobacco), fewer progress to misdemeanor drugs (marijuana and hallucinogens), and fewer still to felony drugs (cocaine and heroin). Accessibility is a key factor in drug use, and is high for LSD. A student can purchase a single dose of LSD for a few dollars, a fraction of the cost of a first-run Hollywood movie. The ease with which the synthetic hallucinogens can be manufactured in illegal laboratories keeps the price down. Facilitating the distribution of hallucinogens is their efficacy in microgram quantities, permitting them to be smuggled at will into any quarter of society, including schools, hospitals, and prisons, and almost as a routine, into rock concerts. The drugs are also attractive because of their prolonged effects and the absence of withdrawal symptoms and other stigmata of addiction.

PSYCHIATRIC DISORDERS With the excitement that accompanied the discovery of LSD in 1943 came a spate of experiments attempting to glean therapeutic benefits from this new agent. A review of all human studies published from 1960 to 1994 listed in Index Medicus revealed that favorable reports of LSD's effects in humans predominated from 1960 to 1965. But beginning in 1968, the Summer of Love in the United States that arguably was the modal peak in the LSD epidemic of the 1960s, adverse reports began to outnumber positive ones, initiating a legal, psychiatric, and social reaction against the use of this class of drugs; this reaction has persisted into the present ( Fig. 11.7-2). The figure describes a curve that can be applied not only to the trends found in the literature of LSD, but to any number of enthusiasms that mark the history of ideas, each characterized by initial excitement followed by sober reassessment. DSM-IV lists ten disorders associated with hallucinogenic drugs. ( Table 11.7-2). Of these, the commonest adverse reactions to hallucinogens are intoxication, hallucinogen-induced anxiety disorder, hallucinogen persisting perception disorder, and hallucinogen-induced psychotic disorders. Clinical reports also support the diagnosis of hallucinogen-induced mood disorder.

FIGURE 11.7-2 A comparison of the total number of clinically favorable and adverse reports on LSD appearing in the scientific literature between 1960 and 1995.

Hallucinogen Abuse and Dependence Diagnosis and Clinical Features The diagnosis of an abuse of hallucinogens is determined by DSM-IV criteria used for other forms of substance abuse, namely, the recurrent use of an hallucinogen in a maladaptive pattern associated with physical risks or adverse impact on psychosocial function. Dependence is diagnosed when three or more of the following are present: tolerance, increasing drug consumption, unsuccessful efforts to cut down, drug-seeking behaviors, reduction in psychosocial function, and continued use despite knowledge of adverse consequences. The latter diagnosis is uncommon, given the time-limited course of

hallucinogen use in most patients. Differential Diagnosis The patient presenting with a clinical picture of the sudden onset of inappropriate affect, visual hallucinations, and paranoid ideation suggests hallucinogen toxicity. Confusing this picture may be toxicity arising from other agents, including phencyclidine, anticholinergics, inhalants, and numerous other drugs. Laboratory tests screening for amphetamines, tetrahydrocannabinol, opiates, cocaine, benzodiazepines, and barbiturates are widely available. The presence of visual hallucinations or pseudohallucinations almost invariably points to a toxic, metabolic, vascular, epileptic, or neoplastic etiology in the central nervous system, rather than to schizophrenia. Hallucinations may also arise from within the eye as entoptic phenomena, but the patient with cataracts or retinal disease is likely to be older than the hallucinogen-abusing person. Course, Prognosis, and Treatment The lifetime character of hallucinogen abuse is commonly described as a bell curve characterized by initial experimentation with the drug in adolescence, followed by a rising frequency of use, and finally a decline and end to use because of disinterest or the onset of chronic psychopathology. Of note is that few persons appear for treatment of hallucinogen abuse or dependence, but do present with the comorbid symptoms of anxiety, depression, psychosis, and suicidal ideation following the use of hallucinogens. Although clinical observation relates the onset of these disorders to the use of hallucinogens, the etiological role of hallucinogen abuse in mood and psychotic disorders has not been established by controlled studies. However, data suggest that substance use in general and hallucinogen use in particular is associated with adolescent suicide. The risk of suicide in the patient with psychosis following hallucinogen use is not inconsiderable. A clinical rule of thumb is that any patient suffering a chronic illness following hallucinogenic drugs, such as a perceptual, mood, or psychotic disorder, should be considered at higher than general risk for suicide for the duration of time that the disorder is present. Hallucinogen Intoxication Diagnosis and Clinical Features The characteristic feature of hallucinogen intoxication is the rapid onset of alterations in mood, cognition, and perception in the presence of a clear sensorium and following the ingestion of a drug in a commonly distributable form. Because memory is preserved, the details of the trip may be retained. This has led to a number of extraordinary personal descriptions of drug-altered states of consciousness, including those by William James, Aldous Huxley, and others. Psychological distress is more likely the hallmark of the hallucinogen user who presents for psychiatric help. Such cases may present with a variety of perceptual and conceptual phenomena leading to anxiety and panic. The DSM-IV diagnostic criteria for hallucinogen intoxication are listed in Table 11.7-4.

Table 11.7-4 DSM-IV Diagnostic Criteria for Hallucinogen Intoxication

Differential Diagnosis The patient presenting to an emergency service with a possible adverse reaction to hallucinogens should routinely be screened for other toxic agents capable of presenting with psychosis or delirium. These include the abuse of substituted amphetamines, cocaine, and PCP, as well as withdrawal from alcohol and benzodiazepines. Screens of urine can eventually rule out abuse of other drugs, which may present with psychosis, but depend on cooperation from the patient. Although drug detection technology can identify LSD in such cases, tools including gas chromatography and mass spectroscopy are not universally available to clinicians. The single best diagnostic tool remains a careful history and physical examination. Often, the history must be obtained from a less disturbed friend. A nettlesome issue in the differential diagnosis of hallucinogen intoxication is the possibility of PCP intoxication. Discriminating LSD from PCP effects is important because the treatment for one disorder may exacerbate the other disorder. One useful technique is the palm test. The examiner holds up his or her own hand and asks the patient to name all the colors visible in the palm. If the patient is using LSD, the response will be a stream of improbable colors and occasional images; if the user has taken PCP, he or she will remain mute or attack the examiner's hand. Examiner agility is helpful in the latter case. Other features in the differential diagnosis include historical evidence of ingestion of an hallucinogen in an epidemiologically common form, the time of onset of toxic symptoms, and consensual validation of the drug history from companions. A physical examination will reveal marked mydriasis and other signs of autonomic arousal consistent with the acute drug state, in contrast to the miosis observed in PCP intoxication. Cases may be complicated by adulteration of the hallucinogen, mistaken attribution, or supplementation of the hallucinogen with marijuana, alcohol, cocaine, or other drugs. Course and Prognosis The natural history of the “bad trip” is benign, tending to end, depending on the nature of the hallucinogen used, with a resolution of psychotic symptoms 6 to 12 hours following the time of ingestion. Treatment Persons have historically been treated for hallucinogen intoxication by psychological support for the remainder of the trip. This is a time-consuming and potentially hazardous undertaking given the lability of a patient with hallucinogen-related delusions. Accordingly, treatment of hallucinogen intoxication is the oral administration of 20 mg of diazepam (Valium). This medication brings the LSD experience and any associated panic to a halt within 20 minutes, and is to be considered superior to “talking down” the patient over a period of hours, or to administering antipsychotic agents. The marketing of lower doses of LSD and a more sophisticated approach to treatment of casualties by drug users themselves have combined to reduce the appearance of this once-common disorder in psychiatric treatment facilities. Hallucinogen-Induced Mood Disorder DSM-IV provides a diagnostic category for hallucinogen-induced mood disorder (see Table 14.6-18). Unlike cocaine-induced mood disorder and amphetamine-induced mood disorder, in which the symptoms are somewhat predictable, mood disorder symptoms accompanying hallucinogen abuse can be variable. Abusers may experience manic-like symptoms with grandiose delusions or depression-like feelings and ideas or mixed symptoms. As with the hallucinogen-induced psychotic disorder symptoms, the symptoms of hallucinogen-induced mood disorder usually resolve once the drug has been eliminated from the person's body. However, depression, and suicide have been reported following the use of MDMA. Weekend use of MDMA has been shown to be followed by depression midweek, similar to the crashing syndrome of amphetamines and cocaine. The suggestion that hallucinogens may induce a chronic mood disorder is controversial, because patients may use mood-altering drugs to self-medicate a preexisting depressive disorder. Hallucinogen-Induced Anxiety Disorder One feature of this class of drugs that invites use is the unmasking and amplification of pleasurable affect. Feeling states appear unbidden, but are seldom under the user's control. When the affects are frightening, they may cause the user to fly into a drug-induced panic. Such patients are likely to be found terrified on the fringes of the rock concert or in the waiting rooms of psychiatric emergency centers. A 20-year-old man had a 7-year history of polysubstance abuse, including having used LSD an estimated 400 times. While driving with his girlfriend he ingested an unknown quantity of LSD and became intoxicated; he reported using no other drugs at this time. Within minutes after ingestion, he began to experience visual hallucinations that intensified as he drove. When he attempted to speak to his girlfriend, he saw that she had become a giant lizard. He became terrified and attempted to kill her by crashing the car, injuring himself and his passenger. By the time of discharge from the hospital 3 days later, his panic had resolved. Treatment is the use of oral benzodiazepines as described for hallucinogen intoxication. Hallucinogen Persisting Perception Disorder Prolonged visual disturbances following LSD have been described for over 40 years. They may occur contiguously

with the trip or spontaneously recur days to weeks following cessation of drug use. Visual symptoms that occur sporadically after drug use and last for a second or two are usually designated “flashbacks.” Those that linger continuously, with minor fluctuations in intensity, are more properly considered to be hallucinogen persisting perception disorder (Table 11.7-5).

Table 11.7-5 DSM-IV Diagnostic Criteria for Hallucinogen Persisting Perception Disorder (Flashbacks)

Such recurrences may involve somatic and emotional symptoms, but perceptual ones predominate. These may include geometric hallucinations, false fleeting perceptions of movement in the peripheral fields, flashes of color, and afterimagery. Common complaints are the persistence of trailing images as an object moves through the patient's visual field. Brighter objects such as auto tail lights induce trails more easily, although these may be induced simply by moving the examiner's hand across the patient's visual field, a maneuver with high sensitivity and specificity for hallucinogen persisting perception disorder. The entire visual field in many cases may be described as reticulated, grainy, or filled with numerous vibrating pinpoint-sized dots, to the extent that patients complain that they can see the air. This phenomenon of “aeropsia” also appears to be highly specific for hallucinogen persisting perception disorder. Comorbidly occurring secondary conditions include depressive and anxiety disorders; alcohol dependence may occur secondarily. Less frequently, psychosis may be present although the vast majority of patients with flashbacks have preserved reality testing, and understand that their new perceptual burden is “not real” and is more properly considered a form of pseudohallucinations. A 16-year-old girl presented with a complaint of “never being happy.” She had used LSD for the first time at the age of 13, and used the drug a total of 30 times until 3 months prior to her consultation. Occasional LSD trips had been notable for panic attacks, but she denied spontaneous panic. At the age of 14 she noted the onset of depression, which coincided insidiously with the onset of continuous visual symptoms. These included images of faces on the floor and walls (pareidolias), dots too numerous to count hovering in the air, flashes of color and white light, trails of moving objects, positive afterimages, boxes on walls, and occasionally, a face or its outline floating in space. At 15 she attempted suicide; major depression was diagnosed. A sleep electroencephalography (EEG) with sphenoidal leads was unremarkable although a year later a quantitative EEG showed abnormal sensory evoked potentials. A 19-year-old college student presented with a complaint of “feeling high all of the time.” His past history was positive for daily marijuana use from ages 15 to 17. In that period he also used LSD 13 times. He was asymptomatic for 3 years until he experienced an attack of anxiety, visual disturbances, and hyperacusis. The initial spell lasted several hours, and was characterized by the experience of continuous visual trails and auditory reverberations in passing stimuli. He felt distant from his body, and had a sense of impending doom. The anxiety attack subsided, but the visual disturbances continued without abatement. Among them was a complaint of seeing “millions” of clear dots in the air, “like I can see the molecules.” A computerized tomogram of the cerebrum and an EEG were negative. A brief trial of thioridazine (Mellaril) made the visual symptoms worse, but chlordiazepoxide (Librium) was effective in reducing but not obliterating his visual symptoms. The visual symptom of “seeing” the air was intensified on gazing at the sky, but seemed to remit spontaneously in the following 2 years. Visual and auditory trailing persisted, however, as have occasional episodes of panic attacks. A 26-year-old male was referred for an evaluation of possible LSD-related disorder. His past medical history was negative for preexisting disorders of the central nervous system. His family history was negative for psychiatric illness. The patient's first use of LSD occurred at age 14 with an alleged dose of 100 micrograms. In the next year he used the drug on approximately 30 occasions, and used marijuana frequently as well. Drug use coincided with family conflict, truancy, and running away from home. At the age of 15 on the day following a dysphoric LSD experience, he awoke with a sense that “something snapped” on the left side of his head. He suffered progressive dysphoria, depression, and withdrawal. Peering into a friend's eyes generated LSD-like feelings and panic. He hallucinated yellow geometric forms and the trails of passing objects. He became irrationally afraid of people, was unable to attend school, and 2 months later was hospitalized in a psychotic state. He was treated with chlorpromazine (Thorazine) with partial relief from paranoid delusions. Over the next 9 years his major symptom was depression in a context of constant visual pseudohallucinations. He saw trails of objects and auras around people. When listening to music he generated internal geometric imagery. He was able to visualize “the air,” which he described as yellow dots hovering in space. These images persisted daily for 12 years. Course and Prognosis Roughly half the patients with hallucinogen persisting perception disorder recover completely in 5 years, but others may irreversibly continue to have symptoms. The appearance of this disorder is not dose dependent; it may arise from a single LSD ingestion. The disorder is exacerbated by autonomic arousal, including psychostimulants such as amphetamines, cocaine, cold tablets containing pseudoephedrine, and caffeine; also by marijuana use, including passive inhalation; excessive fatigue, overexercise, and intercurrent infections. Symptoms are commonly precipitated by entering a dark environment. The disorder is associated with vivid visual hallucinations during alcohol withdrawal. Psychophysical evidence is consistent with the hypothesis that this disorder is associated with disinhibition of visual information processing; that is, once stimulated, the visual system is slow to return to a resting baseline. Quantitative electroencephalography also reveals evidence of visual disinhibition in these patients. Auditory responses are delayed ( Fig. 11.7-3). It is noteworthy that these findings closely parallel those EEG findings described during the acute administration of LSD to a variety of species, including humans. Thus, the patient's claim that he is “still tripping” is borne out neurophysiologically.

FIGURE 11.7-3 Illustrative cases of quantitative EEG abnormalities in hallucinogen persisting perreotion disorder (flashback). Patient 1: A 26-year-old computer programmer used LSD at the age of 18 on 15 occasions; 31 months later the patient experienced the abrupt onset of intense, LSD-like set of visual and affective disturbances lasting all night. At 25 he suffered the spontaneous onset of hourly flashing white lights centrally and black dots in his peripheral fields, which have continued for the past 10 years. Topographic brain maps are shown during the 380-420 msec epoch of the visually evoked potential in row A. The upper left map represents the subject's data. The upper middle map shows control subjects for the same poststimulus latency epoch. The right upper image is a significance probability map (SPM) showing Z-scores resulting from a comparison of the data from the left and middle upper maps. The patient shows an enhancement in the visually evoked signal involving both temporal regions of the cerebrum. Patient 2: A 23-year-old musician used LSD on 16 occasions over a 4-month period at the age of 20. Within 2 months he began to notice a progressive, continuous visual disorder characterized by flashes of color, persisting afterimages, haloes around objects, a grainy texture to the sky, and the lingering trails of objects as they passed through his visual field. The graininess in the visual field interfered with night vision. Topographic brain mapping is illustrated during the 260-300 msec epoch of auditory evoked potentials in row B. Note the region of reduced electrical activity in

the left posterior temporal region in the lower right map. (Reprinted with permission from Abraham HD, Duffy FH: Stable quantitative EEG difference in post-LSD visual disorder by split-half analysis: Evidence for disinhibition. Psychiatry Res 67:173, 1996.) (See Color Plate 6.)

Treatment Treatment for hallucinogen persisting perception disorder is palliative. The first step in the process is correct identification of the disorder; it is not uncommon for the patient to consult a number of specialists before the diagnosis is made. Pharmacological approaches include long-lasting benzodiazepines such as clonazepam (Klonopin), and to a lesser extent anticonvulsants including valproic acid (Depakene) and carbamazepine (Tegretol). No drug is yet completely effective in ablating symptoms. Antipsychotic agents should only be employed in the treatment of hallucinogen-induced psychoses. It is not uncommon for these agents to exacerbate the disorder within the first 72 hours of administration. Case reports suggest sertralin and naltremene may be beneficial. Serotonin type 2 antagonists such as risperidone (Risperdal) have also been shown to exacerbate the intensity of visual symptoms. A second dimension of treatment is behavioral. The patient must be instructed to avoid gratuitous stimulation in the form of over-the-counter drugs, caffeine, alcohol, and avoidable physical and emotional stressors. Marijuana smoke is a particularly strong intensifier of the disorder, even when passively inhaled. Finally, three comorbid conditions are associated with hallucinogen persisting perception disorder—panic disorder, major depression, and alcohol dependence. All these conditions require primary prevention and early intervention. Hallucinogen-Induced Psychotic Disorders Diagnosis and Clinical Features If psychotic symptoms are present in the absence of retained reality testing, a diagnosis of hallucinogen-induced psychotic disorder may be warranted (see Table 13.3-4). DSM-IV also allows clinicians to specify whether hallucinations or delusions are the prominent symptoms. Because the ingestion of an hallucinogen induces a toxic mental state analogous to a psychosis, it is useful operationally to define a posthallucinogen psychotic disorder as one that continues for more than 48 hours following ingestion. Attack rates of such disorders among those using hallucinogens are reported to occur in a range of 0.08 to 4.6 percent, with a trend of higher rates occurring in psychiatric patients and lower ones in healthy volunteers. Patients may suffer the onset of a psychosis immediately on ingestion of the drug, or may have a lucid interval of days to months before the onset. In the former case the hallucinogen is linked more convincingly as the cause of the psychosis than in the latter situation. The patient presenting with a prolonged psychosis following the verified ingestion of LSD or other hallucinogen should raise a strong suspicion of a substance induced disorder. Differential Diagnosis Prior to diagnosis the clinician must consider preexisting psychotic disorders like schizophrenia; mistaken attribution in samples of LSD that are in fact amphetamines, phencyclidine, or other drugs with psychotic potential; or sources of delirium such as alcohol withdrawal. Posthallucinogen psychotic symptoms include mood swings with euphoria and grandiosity, multimodal hallucinations, and hyperreligiosity. When compared to non–drug–using schizophrenia patients, patients with posthallucinogen psychosis have earlier ages of onset, more visual hallucinations, more depression, and a higher prevalence of families with mood disorder. Clinically they are more likely to suffer the positive symptoms of psychosis in the context of schizoaffective disorder. Finally, individuals claiming to have developed a lifelong psychosis following a single dose of LSD without being able to describe the symptoms of a typical trip are more likely to be suffering from a paranoid rather than a postdrug disorder. A 19-year-old musician used LSD on three occasions. Following the third trip, he failed to regain his pre-drug mental state. Instead, he experienced auditory and visual hallucinations, rapid and incoherent speech, sleeplessness, zoophilic delusions, and suicidal ideation. He acted out his psychotic fears aggressively, showering with his clothes on, ripping towel racks from the wall, and requiring four-point restraints. This disorder continued for 2 months during which time he was unsuccessfully treated with lithium carbonate (Eskalith), lorazepam (Ativan), propranolol (Inderal), haloperidol (Haldol), benztropine (Cogentin), and diphenhydramine (Benadryl). His symptoms slowly abated with a combination of lithium and perphenazine (Trilafon). A 22-year-old female photography student presented to the hospital with inappropriate mood and bizarre thinking. She had no prior psychiatric history. Nine days prior to admission she ingested one or two psilocybin mushrooms. Following the immediate ingestion, the patient began to giggle. She then described euphoria, which progressed to auditory hallucinations and belief in the ability to broadcast her thoughts on the media. Two days later she repeated the ingestion, and continued to exhibit psychotic symptoms to the day of admission. When examined she heard voices telling her she could be president, and reported the sounds of “lambs crying.” She continued to giggle inappropriately, bizarrely turning her head from side to side ritualistically. She continued to describe euphoria, but with an intermittent sense of hopelessness in a context of thought blocking. Her self-description was “feeling lucky.” Haloperidol was begun, 10 mg twice a day, along with benztropine 1 mg three times a day and lithium carbonate 300 mg twice a day. On this regimen her psychosis abated after 5 days. Another variety of posthallucinogen psychosis presents with catatonia, confusion, and multimodal hallucinations, supporting the concept of hallucinogenic delirium. A 23-year-old undergraduate was premorbidly a sociable, outgoing individual with no prior history of drug use. Over a 3-day period he used LSD on three occasions, and continued to act in a bizarre manner. He described auditory and visual hallucinations, including images of his estranged father on the ceiling, which fixated his gaze upwardly for long periods. He was disoriented and his gait was reduced to 3-inch steps. Speech was reduced to rare one- and two-word sentences. He could not follow simple commands. Generalized apraxia was present. Pauses of 30 to 60 seconds were noted between an examiner's question and his verbal response. A screen of his urine was negative for toxins. An awake EEG showed generalized slowing in the theta range. The catatonia, delusions, and hallucinations were partially reduced with antipsychotic medications, fluoxetine (Prozac), and electroconvulsive therapy, but the patient continued to exhibit psychotic symptoms chronically. This uncommon case shares features of hallucinogen-induced psychotic disorder, hallucinogen intoxication delirium, and schizophrenia. The continuity of a drug state with an enduring psychotic disorder suggests the first, though whether this class of drugs activates a pre-existing schizophrenogenic trigger remains to be shown. Treatment Treatment of hallucinogen-induced psychosis does not differ from conventional treatment for other psychoses. However, in addition to antipsychotic medications, a number of agents have been reported to be effective including lithium carbonate, carbamazepine, and electroconvulsive therapy. Antidepressant drugs, benzodiazepines, and anticonvulsant agents may each have a role in treatment as well. One hallmark of this disorder is that, as opposed to schizophrenia, in which negative symptoms and poor interpersonal relatedness may commonly be found, patients with hallucinogen-induced psychosis exhibit the positive symptoms of hallucinations and delusions while retaining the ability to relate to the psychiatrist. Medical therapies are best applied in a context of supportive, educational, and family therapies. The goals of treatment are the control of symptoms, a minimal use of hospitals, daily work, the development and preservation of social relationships, and the management of comorbid illnesses including alcohol dependence, depression, and suicide. The preservation of insight in these patients permits a painful comparison of their lives to those of their healthy contemporaries as the latter reach milestones of the life cycle while the former do not. Optimizing psychological and social development of the patient with psychosis is the central strategy for treatment. Hallucinogen Intoxication Delirium DSM-IV allows for the diagnosis of hallucinogen intoxication delirium (see Table 10-22 ), a relatively rare disorder beginning during intoxication in those who have ingested pure hallucinogens. Hallucinogens are often mixed with other substances, however, and the other components or their interactions with the hallucinogens can produce a clinical delirium. Hallucinogen-Related Disorder Not Otherwise Specified Chronic users of hallucinogenic drugs may present a number of symptoms and behaviors that do not easily conform to the preceding classification. Cerebral edema, has been reported following the use of MDMA. Not uncommonly, patients who have used LSD in the past may describe a constellation of symptoms suggestive of a disorder of the temporal lobes, including hyperreligiosity, sexual dysfunction, and occasionally hallucinations (Table 11.7-6).

Table 11.7-6 DSM-IV Diagnostic Criteria for Hallucinogen-Related Disorder Not Otherwise Specified

This syndrome must be differentiated from schizophrenia because the global, social, and occupational dysfunction of schizophrenia is absent in this patient. Not uncommonly hyperreligiosity may be coupled with organizational abilities so that the patient may present as a minister of a church of his own creation, a benign enough species of psychological diversity. On rare occasions, however, persons such as Charles Manson, combining drug use with quasireligious dogma, may form cults with lethal outcomes.

SUGGESTED CROSS-REFERENCES A general discussion of substance use disorders (intoxication, withdrawal, abuse, dependence, and persisting disorders) is found in Section 11.1. Section 12.7 on schizophrenia highlights differences in the clinical presentation and course between schizophrenia and hallucinogen abuse and hallucinogen, dependence, and Section 11.10 on phencyclidine (and related substances) clarifies differences from disorders involving those compounds. SECTION REFERENCES *Abraham H: Visual phenomenology of the LSD flashback. Arch Gen Psychiatry 40:884, 1983. *Abraham HD, Fava M: Order of onset of substance abuse and depression in a sample of depressed outpatients. Comprehensive Psychiatry 40:44, 1999. Abraham H, Wolf E: Visual function in past users of LSD: Psychophysical findings. J Abnorm Psychol 97:443, 1988. *Abraham HD, Aldridge A, Gogia P: Psychopharmacology of the hallucinogens. Neuropsychopharmacology 14:285, 1996. Abraham HD, Duffy FH: Stable qEEG differences in post-LSD visual disorder by split half analyses: Evidence for disinhibition. Psychiatry Res Neuroimag 67:173, 1996. Abramson H, Jarvik M, Kaufman M, Kronetsky C, Levine A, Wagner M: Lysergic acid diethylamide (LSD-25): Physiological and perceptual responses. J Physiol 39:3, 1955. Bowers M: Acute psychosis induced by psychotomimetic drug abuse, I: Clinical findings. Arch Gen Psychiatry 27:437, 1972a. Bowers M: Acute psychosis induced by psychotomimetic drug abuse, II: Neurochemical findings. Arch Gen Psychiatry 27:440, 1972b. *Bowers M: Psychoses precipitated by psychotomimetic drugs. Arch Gen Psychiatry 34:832, 1977. Brawley P, Duffield J: The pharmacology of hallucinogens. Pharm Rev 24:31, 1972. Breakey W, Goodell H, Lorenz P, McHugh P: Halluconigenic drugs as precipitants of schizophrenia. Psychol Med 4:225, 1974. Cohen S, Ditman K: Prolonged adverse reactions to lysergic acid diethylamide. Arch Gen Psychiatry 8:475, 1963. Dewhurst H: Differential diagnosis and treatment of lysergic acid diethylamide induced psychosis. The Practitioner 209:327, 1972. Elkes C, Elkes J, Mayer-Gross W: Hallucinogenic drugs. Lancet 268:719, 1955. Favazza A, Domino E: Recurrent LSD experience (flashbacks) triggered by marijuana. University of Michigan Medical Center J 35:214, 1969. Fink M, Simeon J, Haque W, Itil T: Prolonged adverse reactions to LSD in psychotic subjects. Arch Gen Psychiatry 15:450, 1966. Freedman D: On the use and abuse of LSD. Arch Gen Psychiatry 18:330, 1968. Glennon R, Teitler M, McKenney J: Evidence of 5-HT2 involvement in the mechanism of hallucinogenic agents. Life Sci

35:2505, 1984.

Halpern JH, Pope HG Jr: Do hallucinogens cause residual neuropsychological toxicity? Drug Alcohol Depend 53:247, 1999. Hatrick J, Dewhurst K: Delayed psychosis due to LSD. Lancet 2:742, 1970. Hermle L, Spitzer M, Gouzoulis E: Arylalkamine-induced effects in normal volunteers: On the significance of research in hallucinogenic agents for psychiatry. In Fifty Years of LSD: Current Status and Perspectives of Hallucinogens, A Pletscher, D Ladewig, editors. Parthenon Publishing Group, Parthenon, NY, 1994. *Hofmann A: LSD: My Problem Child. McGraw Hill, New York, 1980. Hollister L: Drug-induced psychoses and schizophrenic reactions: A critical comparison. Ann NY Sci 96:80, 1962. Horowitz M: Flashbacks: Recurrent intrusive images after LSD. Am J Psychiatry 126:556, 1969. Isbell H: Tolerance to LSD. Fed Proc 14:354, 1955. Klüver H: Mescal and the Mechanisms of Hallucinations. University of Chicago Press, Chicago, 1966. Krystal JH, Price LH, Opsahl C, Ricaurte GA, Heninger GR: Chronic 3,4-methylenedioxymethamphetamine (MDMA) use: Effects on mood and neuropsychological function? Am J Drug Alcohol Abuse 18:331, 1992. Lake R, Stirba A, Kinneman R, Carlson B, Holloway H: Mania associated with LSD ingestion. Am J Psychiatry 138:1508, 1981. Lang R, Barr H: Lysergic acid diethylamide (LSD-25) and schizophrenic reactions. J Nerv Ment Dis 147:163, 1968. Lerner AG, Oyefe I, Isaacs G, Sigal M: Naltrexone treatment of hallucinogen persisting perception disorder. Am J Psychiatry 154:437, 1997. Lewin L: Phantastica. Die Betaubenden und Erregenden Genussmittel. Verlag von Georg Stike, Berlin, 1924. Muller D: ECT in LSD psychosis: A report of three cases. Am J Psychiatry 128:351, 1971. Ricaurte GA, LS Forno, Wilson MA, De Lanney LE, Irwin I, Molliver M, Langston JW: (+/–)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA 260(1):51, 1988. Sankar D: LSD, A Total Study . PJD Publications, Westbury, NY, 1975.

Schultes R, Hofmann A: The Botany and Chemistry of Hallucinogens. Charles C. Thomas, Springfield, IL, 1980. Shulgin A: Pihkal, A Chemical Love Story. Transform Press, Berkeley, CA, 1991. *Siegel R: The natural history of hallucinogens. In Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives, B Jacobs, editor. Raven, New York, 1984. Strassman R, Qualls C, Uhlenhuth E, Kellner R: Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry 51:98, 1994. Teitler M, Leonhardt S, Appel NM, Defouza EB, Glennon RA: Receptor pharmacology of MDMA and related hallucinogens. Ann NY Acad Sci 600:626, 1990. Young CR: Sertraline treatment of hallucinogen persisting perception disorder. J Clin Psychiatry 58:85, 1997.

Textbook of Psychiatry

11.8 INHALANT-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.8 INHALANT-RELATED DISORDERS THOMAS J. CROWLEY, M.D. Definition Comparative Nosology Epidemiology Pharmacology and Toxicology Etiology Inhalant Dependence and Inhalant Abuse Inhalant Intoxication Inhalant Intoxication Delirium Inhalant-Induced Persisting Dementia Inhalant-Induced Psychotic Disorder Inhalant-Induced Mood Disorder Inhalant-Induced Anxiety Disorder Inhalant-Related Disorder Not Otherwise Specified Nitrous Oxide–Related Disorders Amyl and Butyl Nitrite–Related Disorders Suggested Cross-References

Inhalant drugs (sometimes called “volatile substances”) are widely available and frequently misused, especially by adolescents. About 20 percent of American eighth-grade students report that they have used these substances for psychoactive effects, more than the number who have tried marijuana. Most adolescents who try inhalants apparently discontinue them after one or a few times. However, for a smaller group of adolescents, especially those with comorbid conduct disorder, inhalant use may foreshadow many years of polysubstance abuse or dependence, including drug injections. Most of these persons eventually shift to other drugs, although some continue daily use of inhalants themselves for many years, suffering major behavioral and organ pathology from the drugs' chronic toxicity. A still smaller number of adolescents die from acute inhalant toxicity, often during their first use of the drugs. Indeed, in Great Britain where detailed records are available, inhalants have become a leading cause of adolescent death because, although such deaths are infrequent, adolescent deaths generally are uncommon. Inhalants are volatile hydrocarbons, such as toluene, n-hexane, methylbutyl ketone, trichloroethylene, trichloroethane, dichloromethane, gasoline, and butane. They make up four commercial classes: (1) solvents for glues and adhesives; (2) propellants for aerosol paint sprays, hair sprays, frying pan sprays, and shaving cream; (3) thinners (e.g., for paint products and typing correction fluids); and (4) fuels.

DEFINITION The section on inhalant-related disorders in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) “includes disorders induced by inhaling the aliphatic and aromatic hydrocarbons... Less commonly used are halogenated hydrocarbons... and other volatile compounds containing esters, ketones, and glycols.” DSM-IV provides two broad categories of inhalant-related disorders ( Table 11.8-1). The first category is inhalant use disorders (inhalant abuse and inhalant dependence), which are characterized by maladaptive patterns of inhalant use (e.g., frequency, dose, danger). The second category, inhalant-induced disorders (such as inhalant intoxication), result from the toxic effects of inhaled substances. Because of epidemiological and pharmacological differences, DMS-IV excludes from the inhalant-related disorders conditions related either to anesthetic gases or to amyl and butyl nitrites, classifying these as other (or unknown) substance-related disorders; some disorders associated with those compounds are briefly discussed at the end of this chapter. Although fumes of such combustible drugs as crack cocaine and tobacco also are inhaled, DSM-IV similarly places disorders related to those drugs in separate categories.

Table 11.8-1 DSM-IV Inhalant-Related Disorders

COMPARATIVE NOSOLOGY The section on inhalant-related disorders in DSM-IV lists three major categories: inhalant abuse, inhalant dependence, and inhalant intoxication. The other inhalant-related disorders have their diagnostic criteria specified in the DSM-IV sections that specifically address the major symptoms. For example, inhalant-induced psychotic disorder is included with other psychotic disorders. The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) refers to inhalants as “volatile substances.” ICD-10 does not use the term “abuse,” which is in DSM-IV, offering instead the term “harmful use.” DSM-IV provides no diagnosis of inhalant withdrawal (which clinicians describe, but which probably is rare), whereas ICD-10 includes that diagnosis, but gives no diagnostic criteria.

EPIDEMIOLOGY The 1995 United States National Household Survey estimated that 5.7 percent of Americans had used an inhalant at some time in their lives. The prevalence was 8.0 percent among males and 3.5 percent among females. The figures were highest for males 18 to 34 years of age; almost 15 percent of them reported using an inhalant at some time. The overall prevalence rates for use of inhalants at any time in one's life were 6.7 percent among whites, 3.5 percent among Hispanics, and 1.8 percent among blacks. A large annual survey has examined trends in drug use among American high school students. It shows that many adolescents have used inhalants. Among eighth-grade students inhalants are the most commonly used drug (except for alcohol and tobacco); about 20 percent of eighth-graders report having used an inhalant, while only about 17 percent report having used marijuana. Native-American students on reservations may be especially vulnerable to inhalant use; one large survey found that 34 percent of reservation-dwelling Native-American eighth-grade students had used an inhalant. In 1976 about 10 percent of interviewed high school seniors reported some use of inhalants. The figure peaked at 18 percent in 1990, and remained at about 17 percent in 1996. The number of students using inhalants more frequently is reflected in the proportion of high school seniors who report using an inhalant in the last 30 days. That figure gradually rose from about 1 percent of students in 1976 to 2.5 percent in 1996. In relation to other abused drugs inhalants are not a major cause of morbidity or mortality in the United States. Inhalants accounted for only 0.3 to 0.4 percent of drug-related episodes in federally monitored emergency rooms between 1991 and 1994. Similarly, inhalants contributed to only about 1.4 percent of federally

reviewed medical-examiner death reports for 1994. For inhalant males and whites (in comparison to females and blacks) were overrepresented in both medical-examiner reports and emergency-room visits. However, age distributions differed between patients in emergency rooms and those deceased. In 1994 the peak prevalence for inhalant-related emergency-room episodes was among patients 12 to 17 years of age (40 percent of all inhalant-related episodes), whereas the peak prevalence of deaths occurred in the age range 35 to 44 years (35 percent of inhalant-related death reports). Medical examiners considered over 40 percent of inhalant-related deaths to be suicides. Similarly, a suicide attempt was part of the presentation in 38 percent of inhalant-related emergency visits. Thus, it appears that inhalant intoxication often is associated with suicidality. In Great Britain inhalants are among the leading causes of death in adolescents and are the single most common cause in those 15 years old. First-time users there are the most likely to die, perhaps because they are inexperienced at this dangerous pastime. Comparable data are not available for the United States. In several developing countries heavy use of inhalants is common in groups of street kids, who live with no ties to adults. American data show widespread experimentation with inhalants, relatively few current users, and still fewer inhalant emergencies or deaths, suggesting that most users try the drugs a few times and stop without mishap. Most of these users probably will not develop further drug problems, but nevertheless the odds of such problems are much greater among them. For example, inhalant use is associated with increased odds of later injection-drug use, a risk factor for infection with the human immunodeficiency virus (HIV). In a general population survey, persons reporting any use of inhalants were 45 times more likely, and those who had used both inhalants and cannabis were 89 times more likely, than others to have injected drugs. Similarly, a prospective study of inner-city youths found that those who had used inhalants in adolescence were nine times more likely to use heroin later. The available data suggest that most adolescents who survive a brief experimentation with inhalants and who do not have conduct disorder soon abstain from inhalants and avoid pathological outcomes. However, among adolescents with conduct disorder, perhaps half will develop adult antisocial personality disorder. Inhalant problems in these youths often herald serious alcohol and polysubstance use in adulthood, and a few of these youths will become chronic, deteriorated, inhalant-dependent adults.

PHARMACOLOGY AND TOXICOLOGY Data on inhalant choice in the United States are limited, but of some 20 abused compounds, toluene and gasoline may be the most popular. Various authorities recommend industrial exposure limits for toluene of 50 to 100 parts per million (ppm), although a recent study showed that a 6-hour exposure to 100 ppm produced a temporary neuropsychological performance decrement of about 10 percent. By comparison, inhaled concentrations from a glue-containing bag may reach 10,000 ppm, and vapors from several tubes of glue may be inhaled each day. About 15 to 20 breaths of 1 percent gasoline vapor produce several hours of intoxication. Sniffing vapor through the nose or huffing (taking deep breaths) through the mouth leads to transpulmonary absorption with very rapid drug access to the brain. Breathing through a solvent-soaked cloth, inhaling fumes from a glue-containing bag, huffing vapor sprayed into a plastic bag, or breathing vapor from a gasoline can are common. Toluene concentrations in blood in hospitalized intoxicated persons reportedly range from 0.8 to 8 µg/g. Exposure at the industrial maximum of 100 ppm produces blood levels around 0.5 µg/g, although moderate exercise may triple these levels through increased respiration. Brain and fat achieve higher concentrations than blood because lipophilic compounds preferentially distribute there. The coadministration of alcohol dramatically raises toluene concentration in blood, increasing toxicity, probably through competition for hepatic metabolizing enzymes. About 20 percent of a toluene dose is excreted unchanged in the breath, but most is metabolized in the liver to hippuric acid before urinary excretion. Breath concentrations of toluene fall by half within a few minutes after the end of a prolonged exposure. Blood concentrations fall more slowly, becoming undetectable 4 to 10 hours after exposure. Urinary hippuric acid remains measurable somewhat longer; hippurate-creatinine ratios above 1 gram per gram suggest toluene use, but benzoic acid food preservatives may generate false-positive hippuric acid concentrations. The cellular mechanisms of inhalant action are unclear. Hypotheses include cell membrane fluidization or interactions at g-aminobutyric acid (GABA)-gated chloride channels, but data are very sparse. Behavioral actions in animals suggest that inhalants act like alcohol, barbiturates, and other depressants of the central nervous system (CNS). Like depressants they produce motor stimulation at lower doses and motor suppression at higher doses, as well as ataxia and loss of righting reflex. Inhalants also have anticonvulsant actions and show depressant-like effects in certain behavioral paradigms. Animals will work to self-administer inhalants, and animals trained to press one lever when injected with alcohol or pentobarbital and another when injected with saline will press the depressant-appropriate lever after exposure to toluene vapor, suggesting that the subjective experience after toluene or a depressant is similar. Moreover, alcohol and benzodiazepines potentiate inhalant effects. Rodents develop withdrawal seizures after several days' exposure to trichloroethane, a frequently abused inhalant. The seizures are blocked by toluene, ethanol, pentobarbital, and midazolam (Versed), a benzodiazepine. Thus, inhalants can produce physical dependence, and they show cross-dependence with familiar CNS depressants. In human subjects low-dose (0, 75, or 150 ppm) toluene exposures for several hours produce dose-related decrements in tests of perception, memory, and manual dexterity, with increased headaches, mucosal irritation, thirst, and sleepiness. Organ Pathology Inhalants are associated with many potentially serious adverse effects. The most serious of these is death, which can result from respiratory depression, cardiac arrhythmias, asphyxiation, aspiration of vomitus, or accident or injury (e.g., driving while intoxicated with inhalants). Placing an inhalant-soaked rag and one's head into a plastic bag, a common procedure, may cause coma and suffocation. Chronic inhalant users may have numerous neurological problems. Computed tomography and magnetic resonance imaging reveal diffuse cerebral, cerebellar, and brainstem atrophy with white-matter disease, a leukoencephalopathy. Several studies of house painters and factory workers who have been exposed to solvents for long periods also have found evidence of brain atrophy on computed tomography scans, with decreased cerebral blood flow. Neurological signs and symptoms may include hearing loss, peripheral neuritis, headache, paresthesias, cerebellar signs, persisting motor impairment, parkinsonism, and lead encephalopathy. The combination of organic solvents with high concentrations of copper, zinc, and heavy metals has been associated with the development of brain atrophy, temporal lobe epilepsy, decreased intelligence quotient (I.Q.), and a variety of electroencephalographic (EEG) changes. Other serious adverse effects associated with long-term inhalant use include irreversible hepatic disease or renal damage (tubular acidosis) and permanent muscle damage associated with rhabdomyolysis. Additional adverse effects include cardiovascular and pulmonary symptoms (e.g., chest pain and bronchospasm) as well as gastrointestinal symptoms (e.g., pain, nausea, vomiting, and hematemesis). Several reports suggest that in utero exposure to toluene may produce an embryopathy similar to fetal alcohol syndrome. Fortunately, there is no convincing evidence that toluene, the best-studied inhalant, produces genetic damage in somatic cells.

ETIOLOGY Multiple factors contribute to the etiology of inhalant-related disorders. First, availability is important in determining the prevalence of abuse or dependence on a drug. Inhalants are cheap, available in several forms in most households, easily concealed, legal to possess, and simple to take. Second, inhalant use apparently is rewarding, both through direct pharmacological action and through the drugs' social effects. As mentioned, under certain circumstances animals repeatedly self-administer inhalants, showing that these substances have innate reinforcing properties. In addition adolescents usually gather in small groups to use inhalants and being a user gains entry to the group, socially reinforcing the use. Third, inhalant users often can evade detection or punishment by parents or school authorities, since the drugs quickly produce a high that passes within a few hours. Fourth, inexpensive inhalants may be one of the few exciting and novel experiences available to youths in impoverished communities providing few other reinforcers. This may help to explain the high prevalence of inhalant use on some Indian reservations. In addition to those extrinsic factors at least one intrinsic factor contributes to inhalant problems. A risk-taking propensity may lead some persons to the at-the-brink excitement and danger of inhalant intoxication. Persons with adolescent conduct disorder or adult antisocial personality disorder are prone to taking extreme risks, and many inhalant users have those disorders. Several studies suggest an association of inhalant use and conduct problems. Among youths in grades 7 through 12, inhalant users (compared with others who used no drugs or who used only cannabis or alcohol) had many characteristics suggesting conduct disorder. They accepted

cheating more readily, admitted to more stealing, perceived less objection to drug use from their families, liked school less, and reported more sadness, tension, anger, and a feeling of being blamed by others. In addition, school surveys showed that solvent users were more likely to be involved with other drugs. Similarly, among youths referred to court-mandated education for minor alcohol offenses, those who also had used inhalants reported fewer school honors and more expulsions, truancy, academic failures, criminal offenses, running away, and associations with troubled peers, as well as many more drug and alcohol problems. More of them also had mothers or siblings with alcohol- or drug-related problems. Some families are burdened by antisocial personality disorder and substance dependence in the adults and by conduct disorder and substance use disorders (often including inhalant abuse or dependence) in the adolescent children, and there is growing evidence that genetics plays a role in these familial disorders. A group home referred a 16-year-old single Hispanic female to a university substance-treatment program for evaluation and recommendations regarding inhalant problems. The patient had been ordered to the group home for auto theft, menacing with a weapon, and being out of control by her family. By age 15 she had regularly been using inhalants and drinking alcohol heavily. She had tried typewriter erasing fluid, bleach, tile cleaner, hairspray, nail polish, glue, and gasoline, but preferred spray paint. She had huffed paint many times each day for about 6 months at age 15, using a maximum of eight paint cans per day. The patient said, “It blacks out everything.” Sometimes she had lost consciousness, and she believed that the paint had impaired her memory and made her “dumb.” The patient reported sexual abuse by an older, nonparental male relative beginning at age 3 and continuing for many years. By fifth grade she had begun showing extensive conduct problems, eventually including fighting, truancy, multiple runaways, gang involvement, and bringing weapons to school. Her family reportedly permitted gang meetings in their home. The patient reported stabbing one person with a screwdriver, another with a knife, and beating another unconscious with a bat. She said that her violence was greatest when she was intoxicated. The patient listed as her strengths and abilities as drawing, cooking, staying clean, fighting, and giving good tattoos. In formal testing her thinking seemed slow, and she had some difficulty understanding questions. Her I.Q. scores were Verbal, 72; Performance, 87; and Full Scale, 77. She met diagnostic criteria for inhalant dependence, alcohol abuse, and conduct disorder. The evaluating program recommended (1) individual and group substance treatment, emphasizing the adverse cognitive and health effects of huffing; (2) urine monitoring; (3) further neurological and neuropsychological assessment; (4) family evaluation and treatment addressing the patient's anger about sexual abuse and her rebelliousness; (5) specific attention in treatment to the patient's anger and aggression; (6) psychoeducation concerning contraception and protection from sexually transmitted diseases; and (7) active support for continued schooling, with consideration of placement in special education. The patient returned to the group home for several months, and it is unclear which of these recommendations were implemented. She then rejoined her parents in a distant community. One year after the evaluation the patient and two others died when their speeding car hit a tree. An investigating officer said, “It appears that all of them had been sniffing or huffing paint.”

INHALANT DEPENDENCE AND INHALANT ABUSE Diagnosis and Clinical Features A diagnosis of inhalant abuse or inhalant dependence should be considered in persons showing intermittent changes compatible with substance intoxication, together with an odor of organic solvents, inhalation paraphernalia, or the occasionally present perioral or perinasal papular glue-sniffers' rash. The cardinal feature of inhalant abuse is repeated use of inhalants in ways that produce a physical hazard or adverse social consequences for the user (see Table 11.1-8). Inhalant dependence is characterized by repeated use resulting in some combination of adverse consequences, loss of control of the drug use, and tolerance or withdrawal (see Table 11.1-3). Although DSM-IV provides no diagnosis for inhalant withdrawal, 17 percent of inhalant users in DSM-IV's substance field trial complained of withdrawal symptoms after inhalant use. Thus, despite the absence of a separate inhalant withdrawal diagnosis, patients' complaints of withdrawal symptoms probably should be counted toward a diagnosis of inhalant dependence. ICD-10 uses the category of volatile substance dependence syndrome for inhalant dependence. ICD-10 does not include the diagnostic category of inhalant abuse, offering instead the category of harmful use of volatile substances, which is defined as a pattern of use causing damage to health. Differential Diagnosis Three conditions should be considered. First, most adolescents who experiment with inhalants stop spontaneously after one or a few episodes of use, never meeting criteria for diagnoses of inhalant abuse or inhalant dependence. Although such use is dangerous and occasionally fatal (most often on the first try), the many spontaneous resolutions support recommendations of minimalist, nonalarmist interventions for adolescent users who do not meet criteria for diagnoses of inhalant use disorders; parents also should be involved. Second, polysubstance use is common in adolescent patients, and abuse or dependence on drugs other than inhalants is established through history, physical findings, and toxicological screens. Such disorders may exist in addition to, or instead of, inhalant abuse or dependence. Third, uncontrolled and impulsive behavior during repeated inhalant intoxications may mimic aspects of, or be comorbid with, conduct disorder or antisocial personality disorder. Antisocial behavior before the onset of inhalant abuse or dependence, or in periods of abstinence, suggests the presence of these disorders. Course and Prognosis The relatively high prevalence of inhalant use in high school surveys, and its relatively low prevalence in adulthood, led one expert to state that inhalant use “should be regarded as a passing phase or fad.” However, although most inhalant users probably do not progress to serious adult disorders, the risk of such progression is much greater for those who have used inhalants than for those who have not. Studies indicate that inhalant use is associated with increased risk for future diagnoses of antisocial personality disorder and other substance use disorders. Among adult substance-dependent patients, a history of inhalant use indicated a significantly enhanced risk for antisocial personality disorder, social phobia, polysubstance use, and injection drug use. Among a group of adult heroin addicts, those who had been inhalant users appeared to be a “marginal group with particularly unfavorable developmental conditions and a specific course of addition.” Most adolescents who progress from inhalant use to inhalant abuse or dependence eventually shift to other drugs, but some continue active inhalant dependence into adulthood. Such chronic patients may use the drugs for extended periods each day for many years; they demonstrate moderate criminal activity, weight loss, medical disease, slow and slurred speech, impaired attention and memory, and often are both dirty and louse-ridden. Tolerance occurs and, less commonly, mild withdrawal involving sleep disturbance, irritability, shakiness, sweating, fleeting illusions, and nausea. One observer reported tachycardia, delusions, and hallucinations during withdrawal. Medical problems in chronic users may include (1) muscle weakness, sometimes with myoglobinuria and rhabdomyolysis; (2) gastrointestinal problems, such as pain, nausea, vomiting, or hematemesis; (3) renal dysfunction, often with severe electrolyte imbalance; (4) cardiomyopathy; (5) hepatotoxicity; (6) pulmonary disorders (pulmonary hypertension, increased airway resistance, and acute respiratory distress); and (7) hematopoietic disorders (including elevated carboxyhemoglobin levels, methemoglobinemia, hemolytic anemia, aplastic anemia, and even acute myelocytic leukemia). Neurological problems include (1) headache, (2) paresthesias with peripheral neuropathy, (3) reversible cerebellar signs or cerebellar degeneration, (4) radiological abnormalities of widened sulci and basal cisterns, and (5) dementia (e.g., lead encephalopathy from leaded gasoline or white matter dementia from toluene). Researchers have examined individual patients or small series of mothers who regularly used toluene during pregnancy. The studies, although they need large-scale replication, strongly suggest that such inhalant use, often with accompanying distal renal tubular acidosis in the mother, has devastating effects. Mothers may experience nausea, vomiting, abdominal pain, elevated blood pressure, and early contractions. Preterm delivery is common, and even after correction for gestational age, the infants show intrauterine growth retardation. Growth retardation continues postnatally. Dysmorphic facies, similar to those of the fetal alcohol syndrome, may occur. Perinatal infant deaths are not infrequent. The management of pregnancy in women with inhalant abuse or inhalant dependence should aim at abstinence with attention to the early detection of renal tubular acidosis, preterm labor, and fetal growth retardation. Treatment No controlled studies guide the treatment of adults or adolescents who meet criteria for inhalant abuse or inhalant dependence. Obviously, appropriate medical care is required for the disorders' medical sequelae. In addition vigorous treatment is needed for adolescent patients who progress from experimentation to inhalant abuse or dependence. Most of these youths have comorbid conduct disorder and are at serious risk for adverse outcomes. One authority recommends that a comprehensive treatment plan include eight aspects: detoxification; a peer advocate system; assessment of physical, cognitive, and neurological deficits; building on existing strengths; developing new strengths; therapists trained in solvent abuse; attention to personal and family issues; and assistance in returning back to the community. The author and his colleagues provide day-treatment and nonhospital residential programs for adolescents 13 to 19 years of age with combined substance dependence and conduct disorder. About 20 percent of males and 6 percent of females admitted have diagnoses of inhalant abuse or dependence. However,

treatment for these polysubstance-dependent, delinquent youths is not specific by drug category (e.g., inhalants), but instead targets substance use and conduct problems generally. Most referrals are from social-service and juvenile-justice agencies, which pay for the treatment. Currently suicidal youths and those with recent fire-setting are excluded, although many patients have past histories of these problems, together with considerable violence and gang involvement. Treatment in these programs begins with detailed interviews addressing use and establishing diagnoses of abuse or dependence for each drug category in DSM-IV. Most patients meet criteria for dependence on several substances. Interviews also address diagnoses of disorders commonly comorbid in this group: conduct disorder attention-deficit/hyperactivity disorder, major depressive disorder, dysthymic disorder, and posttraumatic stress disorder. Interviews also address experiences of abuse or neglect, which are very common in these patients. Group and individual therapy is behaviorally oriented, with immediate rewards for progress in treatment and punishments for lapses to previous behaviors. Patients attend onsite schools with special education teachers, together with planned recreational activities. The programs provide birth control consultations with Planned Parenthood as well as a nursery for the babies of adolescent female patients. The patients' parental families, often very chaotic, are engaged in a modification of structural family therapy. Participation in 12-step programs is required. Treatment interventions are coordinated closely with interventions by community social workers and probation officers. No medications are prescribed for inhalant abuse or dependence per se, but a child-and-adolescent psychiatrist often prescribes antidepressants for depression, disulfiram (Antabuse) for comorbid alcohol dependence, or pemoline (Cylert) for attention-deficit/hyperactivity disorder. Progress is monitored with urine and breath samples at intake and frequently during treatment. Patients who fail to abstain in day treatment may transfer to residential care. Treatment usually lasts 3 to 12 months. Termination is considered successful if the youth has practiced a plan to stay abstinent in a supportive, drug-free environment; to interact with the family in a more productive way; to work or attend school; and to associate with drug-free, nondelinquent peers. In many cases, of course, these goals are only partially accomplished. As with all other treatments for inhalant abuse or dependence, controlled studies of long-term outcomes are lacking. Laboratory Examinations Therapy for substance use disorders often uses repeated tests of biological samples to validate patients' reports of abstinence or use. However, with inhalants such tests may be difficult to interpret. First, these volatile compounds have a relatively brief sojourn in the body and may be detected in urine for only a few hours after use. Second, even if the compounds occur in urine, they may volatilize out of samples during transfer or storage. Third, although hippuric acid, a toluene metabolite, can be detected longer than toluene, hippuric acid also may be produced from foods, raising a question of false-positive findings. Fourth, inhalants may bind to, or pass through, the plastic of urine cups or breath collection bags, reducing concentrations and making the compounds undetectable. Thus, the most careful monitoring of inhalant use would involve frequent urine samples (e.g., two or three per week) at random times, collected in tightly sealed glass containers with little or no air space, and carefully refrigerated until analysis. Analyses would be both for inhalants themselves and for the ratio of hippuric acid to creatinine. However, even under these ideal conditions, the short half-life of inhalants makes inhalant monitoring much less valuable clinically than monitoring for many other substances. Similarly, breath samples may be collected in specially designed glass traps or in Tedlar (not Mylar) bags. However, the half-life of inhalants in alveolar air apparently is a matter of minutes, and so breath samples may be useless for monitoring treatment progress in patients who show no current signs of intoxication.

INHALANT INTOXICATION Diagnosis and Clinical Features Inhalant intoxication should be considered in persons showing an acute onset of behavioral disturbance, coupled with the characteristic odor of organic solvents or the presence of inhalation paraphernalia. Inhalant intoxication is an inhalant-related, clinically significant maladaptive behavioral disorder that develops during or immediately after inhalant use and (assuming survival) clears a few hours later. Intoxication signs initially may include vomiting and motor stimulation, followed by slowing, ataxia, depressed reflexes, slurred speech, disorientation, impaired judgment, lethargy, or coma. Bronchospasm, chest pain, cardiac arrhythmias or arrest, trauma, accidental burns, seizures, aspiration of vomitus, or suffocation in a plastic bag may result. Users often show slowed speech, elated mood, fearfulness, illusions, auditory and visual hallucinations, delusions, and perceptions of altered body size. The DSM-IV diagnostic criteria are listed in Table 11.8-2. ICD-10 provides a comparable diagnostic category of acute intoxication due to use of volatile substances.

Table 11.8-2 DSM-IV Diagnostic Criteria for Inhalant Intoxication

Laboratory Examinations As noted above, random, intermittent monitoring of biological samples has modest value for confirming self-reported abstinence in nonintoxicated patients with inhalant abuse or dependence, because inhalants are so briefly detectable in the body. However, patients showing behavioral signs of inhalant intoxication do, in most cases, have detectable concentrations of inhalants in urine and breath. Confirming their presence may have later clinical or forensic value. Urine samples should be collected in glass vessels with little or no air space, sealed tightly, and refrigerated until analysis for inhalants themselves and for the ratio of hippuric acid (a toluene metabolite) to creatinine. Alternatively, breath samples may be collected in specially-designed glass traps or in Tedlar (not Mylar) bags, and they should be analyzed for inhalants within a few hours. Differential Diagnosis Differentiation from other intoxications is aided by a history of inhalant use, the presence of inhalant odor and residues on the skin or clothing, a characteristic perioral rash from contact with organic solvents, and toxicological examination of body fluids. Polysubstance use is common among solvent users, and concurrent intoxications with other drugs may be assessed by history and toxicological examinations. Despite evidence of inhalant intoxication, in comatose patients other explanations (e.g., closed head injury) must be sought. Dextrose 50 percent for injection (50 grams) and naloxone (Narcan) 2 mg intravenously help rule out coma of diabetic or narcotic origin. If delirium develops in the course of an intoxication with inhalants, the diagnosis is inhalant intoxication delirium, rather than inhalant intoxication. If a mood disturbance, anxiety, or psychosis appear very prominently during an intoxication and if those symptoms are severe enough to warrant independent clinical attention, the diagnosis should be inhalant-induced mood disorder, inhalant-induced psychotic disorder, or inhalant-induced anxiety disorder, respectively. Course and Prognosis The onset of intoxication is almost instantaneous after the inhalation of volatile hydrocarbons, given the rapid absorption of those inhalants across pulmonary membranes and their quick distribution into the brain and other lipids. Inhalant drugs are rapidly metabolized and excreted, and inhalant intoxication usually lasts a few hours or less. Unless trauma, hypoxia, cardiac arrest, burns, or other problems ensue, there probably are no lasting effects from one or a few intoxications, except that each use of these reinforcing drugs increases the probability of further use. Prolonged, repeated use causes persisting effects. Treatment Inhalant intoxication, like alcohol intoxication, usually receives no medical attention and resolves spontaneously. However, effects of the intoxication, such as coma, bronchospasm, laryngospasm, cardiac arrhythmias, trauma, or burns, need treatment. Otherwise, care primarily involves reassurance, quiet support, and attention to vital signs and level of consciousness. Some evidence suggests that physical agitation during inhalant intoxication may precipitate cardiac arrhythmias or cardiac arrest, so the environment should be calming and reassuring. However, sedative drugs, including benzodiazepines, are contraindicated, since they may potentiate inhalant effects. Because of the short half-life of inhalants, inhalant intoxication usually improves considerably after about 30 minutes of abstinence, unless other drugs were also consumed. Following resolution of the intoxication a careful evaluation is needed with appropriate intervention or referral for inhalant abuse or dependence, other substance use disorders, conduct disorder, or antisocial personality disorder.

INHALANT INTOXICATION DELIRIUM DSM-IV provides a diagnostic category for inhalant intoxication delirium (see Table 10-22). Inhalant intoxication delirium is a disturbance of consciousness and a

change in cognition that results from intoxication with inhalants and is not better explained by dementia. The course and treatment are like those of inhalant intoxication but the additional confusion requires special attention to patient safety. If the delirium results in severe behavioral disturbances, short-term treatment with a dopamine receptor antagonist—for example, haloperidol (Haldol)—may be necessary. Benzodiazepines should be avoided because of the possibility of adding to the patient's respiratory depression. ICD-10 provides a comparable diagnostic category, “acute intoxication due to use of volatile substances, with delirium.”

INHALANT-INDUCED PERSISTING DEMENTIA Diagnosis and Clinical Features Studies of inhalant-caused cognitive impairment have been equivocal and have been beset by numerous methodological problems, including a focus on adolescent users with briefer lifetime exposures. But clinical and some research evidence suggests that some inhalant-using adults develop inhalant-induced persisting dementia. For example, among toluene users (average age, 29 years) studied with magnetic resonance imaging, the neuropsychological deficits correlated strongly with the severity of cerebral white matter abnormalities. The cardinal feature of the disorder is dementia resulting from the use of inhalants (see Table 10-31). Nearly all of these persons also meet the criteria for inhalant dependence. Patients with inhalant-induced persisting dementia have memory impairment and at least one of the following: aphasia (language disturbance), apraxia (impaired ability to carry out motor activities despite intact motor function), agnosia (failure to recognize or identify objects despite intact sensory function), and disturbed executive functioning (planning, organizing, sequencing, abstracting). The symptoms must significantly impair social or occupational functioning, represent a decrement from earlier functioning, not occur exclusively in the course of a delirium, and persist beyond the usual duration of inhalant intoxication. The ICD-10 category of dementia in other specified diseases classified elsewhere includes inhalant-induced persisting dementia. Differential Diagnosis Nearly all of these patients have inhalant dependence and many are dependent on alcohol, which also produces dementia. Moreover, histories of head injury are very common among such patients. Thus, despite clear evidence of prolonged inhalant use, this disorder requires a full evaluation for the multiple causes of dementia. Course and Prognosis Few of these patients have been studied prospectively. Despite some reports of improvement when patients abstained from inhalants, it seems likely that most neuropsychological deficits that persist for days or weeks after intoxication will continue or worsen. Moreover, as dementia progresses, patients become more difficult to treat, and each relapse adds to their cerebral toxicity. Treatment There is no established treatment for the cognitive and memory problems of inhalant-induced persisting dementia. Low-key street outreach and extensive social service support have been offered to severely deteriorated inhalant-dependent homeless adults. Patients may require extensive support within their families or in foster or domiciliary care.

INHALANT-INDUCED PSYCHOTIC DISORDER The essential features of inhalant-induced psychotic disorder are prominent hallucinations or delusions judged to be due to the direct physiological effect of inhalant substances. Such psychotic symptoms sometimes develop during intoxication with inhalants, so this diagnosis applies to patients who meet criteria for inhalant intoxication but who also have psychotic symptoms in excess of those usually associated with inhalant intoxication. The psychotic symptoms must be severe enough to warrant independent clinical attention. This diagnosis is not made in the presence of inhalant intoxication delirium. The clinician can specify whether hallucinations or delusions predominate (Table 13.3-4). The course and treatment of inhalant-induced psychotic disorder are like those of inhalant intoxication. The disorder is brief, lasting a few hours to (at most) a very few weeks beyond the intoxication. Vigorous treatment of such life-threatening complications as respiratory or cardiac arrest, together with conservative management of the intoxication itself, is appropriate. Confusion, panic, and psychosis mandate special attention to patient safety. Severe agitation may require cautious control with haloperidol (5 mg per 70 kg intramuscularly, repeated once in 20 minutes if needed). Sedative drugs, including benzodiazepines, may potentiate and worsen inhalant intoxications. Despite similarities in name, DSM-IV's inhalant-induced psychotic disorder differs from ICD-10's residual and late-onset psychotic disorder due to volatile substance use. The former is a variant of inhalant intoxication, while the later is conceptualized as persisting long after direct psychoactive substance effects abate. Controversy continues as to whether inhalants produce persisting psychotic states. In ICD-10, acute intoxication due to use of volatile substances includes patients with marked psychotic symptoms arising in the course of the intoxication.

INHALANT-INDUCED MOOD DISORDER The essential feature of inhalant-induced mood disorder (see Table 14.6-18) is a prominent disturbance of mood judged to be due to the direct physiological effect of inhalant substances. Such mood symptoms sometimes develop during intoxication with inhalants, so this diagnosis applies to patients who meet criteria for inhalant intoxication but who also have mood symptoms in excess of those usually associated with inhalant intoxication. The mood symptoms must be severe enough to warrant independent clinical attention. The clinician can specify one of the following subtypes: with depressive features (probably the more common subtype), with manic features, or with mixed features. This diagnosis is not made in the presence of inhalant intoxication delirium. In ICD-10, acute intoxication due to use of volatile substances includes patients with marked affective symptoms arising in the course of the intoxication. The course and treatment of inhalant-induced mood disorder are like those of inhalant intoxication. Inhalant-induced mood disorder is brief, lasting a few hours to (at most) a very few weeks beyond the intoxication. Although antidepressant or antimanic drugs are seldom appropriate for these relatively brief disorders, a history and psychosocial attention to suicide are important. Suicide has been implicated in 40 percent of inhalant-related medical examiners' death reports and in 38 percent of inhalant-related visits to hospital emergency departments.

INHALANT-INDUCED ANXIETY DISORDER The essential features of inhalant-induced anxiety disorder (see Table 15.6-18) are prominent anxiety symptoms judged to be due to the direct physiological effect of inhalant substances. Such anxiety symptoms sometimes develop during intoxication with inhalants, so this diagnosis applies to patients who meet criteria for inhalant intoxication but who also have anxiety symptoms in excess of those usually associated with inhalant intoxication. The anxiety symptoms must be severe enough to warrant independent clinical attention. This diagnosis is not made in the presence of inhalant intoxication delirium. The clinician can specify one of the following subtypes: with generalized anxiety, with panic attacks, with obsessive-compulsive symptoms, or with phobic symptoms; generalized anxiety and panic attacks are probably most common. In ICD-10, acute intoxication due to use of volatile substances includes patients with marked anxiety symptoms arising in the course of the intoxication. The course and treatment of inhalant-induced anxiety disorder are like those of inhalant intoxication. Sedative and antianxiety drugs are contraindicated, since they worsen inhalant intoxication, which precipitates inhalant-induced anxiety disorder.

INHALANT-RELATED DISORDER NOT OTHERWISE SPECIFIED The diagnosis of inhalant-related disorder not otherwise specified is reserved for inhalant-related disorders that do not fit into one of the above diagnostic categories (Table 11.8-3).

Table 11.8-3 DSM-IV Diagnostic Criteria for Inhalant-Related Disorder Not Otherwise Specified

NITROUS OXIDE–RELATED DISORDERS DSM-IV includes nitrous oxide–related disorders among other substance-related disorders because of differences in modes of action and associated problems. Nitrous oxide was introduced for clinical practice in 1844 and is still a widely used inorganic gas anesthetic. It also is a propellant in whipped-cream dispensers. Not surprisingly, nitrous oxide misuse seems to appear most commonly among the health-care and food-service workers who use these preparations, although there is little scientific information on its epidemiology. The drug has a rapid onset and offset of action. It is mostly excreted in the breath with little or no biotransformation. Some users experience euphoria and a pleasant dreamlike state with nitrous oxide, but several studies show that it is not a reinforcer for most research subjects who have been exposed only a few times. Chronic use may produce diffuse polyneuropathy and myelinopathy with extensive, although sometimes reversible, neurological symptoms mimicking those of vitamin B12–related pernicious anemia. Active vitamin B 12 requires reduced cobalt, but nitrous oxide irreversibly oxidizes cobalt, suppressing the activity of an important enzyme, methionine synthase. A 35-year-old male dentist with no history of other substance problems complained of problems with nitrous abuse for 10 years. This had begun as experimentation with what he had considered a harmless substance. However, his rate of use increased over several years, eventually becoming almost daily for months at a time. He felt a craving before sessions of use. Then, using the gas while alone in his office, he immediately felt numbness, a change in his temperature and heart rate, and an alleviation of depressed feelings. “Things would go through my mind. Time was erased.” He sometimes fell asleep. Sessions might last a few minutes, or up to 8 hours; they ended when the craving and euphoria ended. He had often tried to stop or cut down, sometimes consulting professionals about the problem. Cases in the literature strongly suggest that nitrous oxide intoxication, dependence, and abuse do occur. Considering the drug's brief duration of action and users' intermittent inhalation patterns, nitrous oxide appears unlikely to produce clinically significant withdrawal. It is not clear, however, whether nitrous oxide produces other substance-related disorders. There are no clinically practical urine or breath tests for the presence of nitrous oxide. Misusers of the drug who develop neurological symptoms may have low serum concentrations of vitamin B 12, and remission of neurological symptoms has followed combined administration of B 12 and folate, together with abstinence from nitrous oxide. In the absence of controlled studies of treatment for nitrous oxide use disorders, general principles for treating other substance use disorders should guide the treatment of these patients.

AMYL AND BUTYL NITRITE–RELATED DISORDERS DSM-IV includes amyl and butyl nitrite–related disorders among other substance-related disorders. The vapors of amyl nitrite, a volatile liquid, produce vasodilation and smooth muscle relaxation. Supplied in easily “popped” glass vials, amyl nitrite found wide use as acute inhalation therapy for angina pectoris between 1867 and about 1980. Sublingual nitroglycerin tablets now have superseded that use. Amyl nitrite and its close relative, butyl nitrite, enjoyed a flurry of use as recreational drugs during the 1970s and 1980s. Reports from that time suggest that the use mainly was among adolescents, users of other drugs, and homosexual men. The latter group especially reported using the drugs to enhance orgasm, and these nitrites also were considered to produce a high, a feeling of wild abandon, or an altered state of consciousness. Nonmedical users called amyl nitrite vials “poppers.” Those vials' availability declined with their declining medical use. Butyl nitrite was then increasingly sold as a “room odorizer” (but really for inhalation) under suggestive names such as Rush or Locker Room. In one study of patients who had misused these drugs, most experienced dizziness, lightheadedness, cardiac palpitations, blurred vision, and a feeling of warmth immediately after the inhalation. Others complained of immediate headache, nasal burning, nausea, cough, dyspnea, or syncope. Nearly half found the experience not at all pleasant, and the others rated it only as “fair to good.” A few case reports document severe, but nonfatal methemoglobinemia after nitrite inhalation by persons genetically deficient in methemoglobin reductase. There also are reports of rapidly fatal methemoglobinemia after oral ingestion (not inhalation) of these compounds by genetically normal persons. Some epidemiological studies further suggested that among homosexual men nitrite use might increase the risk of HIV infection or of developing Kaposi's sarcoma after HIV infection. However, those observations were heavily confounded, since nitrite users tended to have more partners and to pursue unsafe sexual practices more frequently. Considered together, the lack of a compelling instantaneous high, the immediate unpleasant feelings, and the longer-term risks from amyl and butyl nitrite seem to have reduced the prevalence of their use. In 1979 an annual national survey of high school seniors found that 6.5 percent reported using these drugs in the previous year, but that percentage fell to 1.2 percent by 1997. Similarly, among Americans over 12 years of age living in households, only 2 percent said in 1996 that they ever had used amyl nitrite “for kicks or to get high.” No studies have examined users of amyl or butyl nitrite with modern diagnostic procedures, and it is unknown how many (if any) meet criteria for intoxication, abuse, or dependence. Some persons with sustained industrial exposures to nitrites experience withdrawal headaches on weekends or vacations, but it seems unlikely that intermittent, brief exposures to these short-acting drugs would produce clinically significant withdrawal in recreational misusers of nitrites. There are no studies of the treatment of amyl or butyl nitrite–related disorders, and so such treatment should follow general principles for the treatment of other substance-related disorders.

SUGGESTED CROSS-REFERENCES An overview of substance-related disorders is given in Section 11.1, hallucinogen-related disorders are discussed in Section 11.7, and phencyclidine-related disorders are discussed in Section 11.11. Mood disorders are discussed in Chapter 14. Chapter 15 reviews anxiety disorders, and Chapter 13 covers psychotic disorders. SECTION REFERENCES Altenkirch H, Kindermann W: Inhalant abuse and heroin addiction: A comparative study on 574 opiate addicts with and without a history of sniffing. Addict Behav 11:93, 1986. Boutros NN, Bowers MB: Chronic substance-induced psychotic disorders: State of the literature. J Neuropsychiatry Clin Neurosci 8:262, 1996. Chang AP, England JD, Garcia CA, Sumner AJ: Focal conduction block in n-hexane polyneuropathy. Muscle Nerve 21:964, 1998. Compton WM, Cottler LB, Dinwiddie SH, Spitznagel EL, Mager DE, Asmus G: Inhalant use: Characteristics and predictors. Am J Addict 3:263, 1994. Cottler LB, Schuckit MA, Helzer JE, Crowley T, Woody G, Nathan P, Hughes J: The DSM-IV field trial for substance use disorders: Major results. Drug Alcohol Dependend 38:59, 1995. *Dinwiddie SH: Abuse of inhalants: A review. Addiction 89:925, 1994. Dinwiddie SH, Reich T, Cloninger CR: The relationship of solvent use to other substance use. Am J Drug Alcohol Abuse 17:173, 1991.

Dinwiddie SH, Reich T, Cloninger CR: Solvent use as a precursor to intravenous drug abuse. Compr Psychiatry 32:133, 1991. Echeverria D, Fine L, Langolf G, Schork A, Sampaio C: Acute neurobehavioral effects of toluene. Br J Ind Med 46:483, 1989. Esmail A, Meyer L, Pottier A, Wright S: Deaths from volatile substance abuse in those under 18 years: Results from a national epidemiological study. Arch Dis Child 69:356, 1993. *Evans EB, Balster RL: CNS depressant effects of volatile organic solvents. Neurosci Biobehav Rev 15:233, 1991. Evans EB, Balster RL: Inhaled 1,1,1-trichloroethane-produced physical dependence in mice: Effects of drugs and vapors on withdrawal. J Pharmacol Exp Ther 264:726, 1993. Filley CM, Heaton RK, Rosenberg NL: White matter dementia in chronic toluene abuse. Neurology 40:532, 1990. *Flanagan RJ, Ives RJ: Volatile substance abuse. Bull Narc 46:49, 1994. Johns A: Volatile substance abuse and 963 deaths. Br J Addict 86:1053, 1991. *Johnson EO, Schutz CG, Anthony JC, Ensminger ME: Inhalants to heroin: A prospective analysis from adolescence to adulthood. Drug Alcohol Depend 40:159, 1995. Johnston LD, O'Malley PM, Bachman JG: National Survey Results on Drug Use from the Monitoring the Future Study, 1975–1994, vol 1. National Institute on Drug Abuse, Rockville, MD, NIH publ no. 95-4026, 1995. Kozel N, Sloboda Z, De La Rosa M: Epidemiology of Inhalant Abuse: An International Perspective. National Institute on Drug Abuse research monogr 148, Rockville, MD. NIH publ no. 95-3831, 1995. *Levinthal CF: Drugs, behavior and modern society. Allyn & Bacon, Boston, 1999. Morton HG: Occurrence and treatment of solvent abuse in children and adolescents. Pharmacol Ther 33:449, 1987. Pearson MA, Hoyme E, Seaver LH, Rimsza ME: Toluene embryopathy: Delineation of the phenotype and comparison with fetal alcohol syndrome. Pediatrics 93:211, 1994. Ramsey J, Anderson HR, Bloor K, Flanagan RJ: An introduction to the practice, prevalence and chemical toxicology of volatile substance abuse. Hum Toxicol 8:261, 1989. Rosenberg NL, Kleinschmidt-DeMasters, Davis KA, Dreisbach JN, Hormes JT, Filley CM: Toluene abuse causes diffuse central nervous system white matter changes. Ann Neurol 23:611, 1988. *Schutz CG, Chilcoat HD, Anthony JC: The association between sniffing inhalants and injecting drugs. Compr Psychiatry 35:99, 1994. Sharp CW, Rosenberg NL: Volatile substances. In Substance Abuse: A Comprehensive Textbook, ed 2, JH Lowinson, P Ruiz, RB Millman, JG Langrod, editors. Williams & Wilkins, Baltimore, 1992. Spiller HA, Krenzelok EP: Epidemiology of inhalant abuse reported to two regional poison centers. Clin Toxicol 35:167, 1997. Substance Abuse and Mental Health Services Administration: Annual Medical Examiner Data 1994. Rockville, MD, DHHS publ no. (SMA) 96-3078, 1996. Substance Abuse and Mental Health Services Administration: Annual Emergency Department Data 1994. Rockville, MD, DHHS publ no. (SMA) 96-3104, 1996. Substance Abuse and Mental Health Services Administration: National Household Survey on Drug Abuse: Population Estimates 1995. Rockville, MD, DHHS publ no. (SMA) 96-3095, 1996. Westermeyer J: The psychiatrist and solvent-inhalant abuse: Recognition, assessment, and treatment. Am J Psychiatry 144:903, 1987. Wilkins-Haug L, Gabow PA: Toluene abuse during pregnancy: Obstetric complications and perinatal outcomes. Obstet Gynecol 77:504, 1991. Young SE, Mikulich SK, Goodwin MB, Hardy J, Martin CL, Zoccolillo MS, Crowley TJ: Treated delinquent boys' substance use: Onset, pattern, relationship to conduct and mood disorders. Drug Alcohol Depend 37:149, 1995.

Textbook of Psychiatry

11.9 NICOTINE-RELATED DISORDERS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 11. SUBSTANCE-RELATED DISORDERS

11.9 NICOTINE-RELATED DISORDERS JOHN R. HUGHES, M.D. Definition History and Comparative Nosology Epidemiology Etiology Diagnosis and Clinical Features Differential Diagnosis Course and Prognosis Treatment Suggested Cross-References

Nicotine dependence is the most prevalent, most deadly, most costly, yet most treatable of the substance dependencies. In the past psychiatrists have often not participated in the diagnosis and treatment of nicotine dependence, perhaps because of the incorrect notion that most smokers do not need treatment or that psychiatric patients are unlikely to respond to smoking cessation treatment because most health insurers or organizations do not reimburse for treatment of smoking. There is increasing recognition that smoking is usually a form of substance dependence and that treatment for smoking is highly cost effective. In addition, persons who continue to smoke despite significant social pressure appear to be those who are severely nicotine dependent or who have significant psychiatric problems that interfere with cessation. These two trends—increasing legitimization of treatment and a selection bias toward highly dependent smokers with comorbid mental disorders—suggest that psychiatrists will play a larger role in treating smoking cessation.

DEFINITION Nicotine dependence and withdrawal are the two defined nicotine-related disorders in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The essential feature of any substance dependence disorder in DSM-IV is that “the individual continues use of the substance despite significant substance-related problems.” Because 50 percent of smokers die of a smoking-related illness, this definition clearly is applicable to nicotine use. The essential feature of withdrawal is “a substance-specific maladaptive behavioral change... that is due to the cessation of, or reduction in, heavy and prolonged substance use.” Because nicotine withdrawal produces an observable, well-defined, time-limited syndrome in over half of smokers, this definition also appears appropriate. Nicotine abuse is not included in DSM-IV because abuse is confined to significant psychosocial but not physical problems and the former is rare with nicotine use. The 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) includes harmful use, a category similar to abuse but that includes continued use that causes physical problems; thus, harmful use from the nicotine-containing products often occurs. Nicotine intoxication is very rare; it is included in ICD-10 but not DSM-IV.

HISTORY AND COMPARATIVE NOSOLOGY Tobacco use in the New World dates back to at least 600 AD and was introduced into European culture in the sixteenth century. Early on, most tobacco use was via pipes, smokeless tobacco, or cigars. The cigarette became popular beginning in the early 1900s with the invention of the cigarette-making machine and the use of acidifying agents to permit nicotine to enter the lower respiratory tract where it could be rapidly absorbed into the arterial circulation. Cigarette use grew dramatically in the first half of the twentieth century. The first reports of the association of smoking and disease began in the 1950s and culminated with the 1964 Surgeon General's Report on Smoking and Health. Use in the United States fell slightly after this but then began to decline dramatically in the 1970s but has plateaued recently. However, in the 1990s use has stabilized plus noncigarette products such as cigars and smokeless tobacco use have increased. Although tobacco use in other Western nations has declined somewhat, use in developing countries is actually increasing. Nicotine dependence was widely accepted but not codified until the 1980 third edition of DSM and (DSM-III) and the ninth revision of the International Statistical Classification of Diseases (ICD-9) included tobacco dependence and withdrawal as disorders. The revised third edition of DSM (DSM-III-R) and the 1988 U.S. Surgeon General's The Health Consequences of Smoking—Nicotine Addiction concluded that smoking was a form of substance dependence.

EPIDEMIOLOGY In 1998 25 percent of Americans smoked, 25 percent are former smokers, and 50 percent have never smoked cigarettes. The prevalence of pipe, cigar, and smokeless tobacco use is less than 2 percent. The prevalence of smoking in the United States was decreasing about 1 percent a year but it has not changed in the last 4 years because of increased initiation and decreased cessation. The mean age of onset of smoking is 16 and few persons start after 20. Dependence features appear to develop quickly. Classroom and other programs to prevent initiation are only mildly effective and increased taxation does decrease initiation. Over 75 percent of smokers have tried to quit, about 40 percent try to quit each year. On a given quit attempt only 30 percent remain abstinent for even 2 days and only 5 to 10 percent stop permanently. However, most smokers make 5 to 10 attempts such that eventually 50 percent of eversmokers quit. In the past, 90 percent of successful quit attempts involved no treatment. However, with the advent of over-the-counter (OTC) and nonnicotine medications in 1998, about one third of all quits were due to use of medication. In terms of the diagnosis of nicotine dependence per se, about 20 percent of the population develops nicotine dependence at some point, making it the most prevalent psychiatric disorder. Approximately 85 percent of current daily smokers are nicotine dependent. Nicotine withdrawal occurs in about 50 percent of smokers who try to quit. Smoking is now as common in women as in men. Smoking is more prevalent in those with lower education and income, in most ethnic groups, and is especially high in psychiatric patients (50 percent), including those with other substance use disorders (80 percent).

ETIOLOGY Both nicotine and acetylcholine interact with nicotinic-cholinergic receptors. Originally these receptors were thought to be confined to the ganglia and neuromuscular junction but have now been found in several areas of the central nervous system (CNS). These receptors are unusual in that they quickly desensitize. This phenomena plus the fact that repeated use of nicotine increases, not decreases, the number of receptors suggests that nicotine may actually act much as an antagonist as an agonist at this receptor. The dependence-producing effects of nicotine appear to be modulated by dopamine (e.g., nicotinic-cholinergic receptors lie on dopamine neurons, nicotine increases dopamine, and dopamine blockers attenuate nicotine self-administration). Nicotine also increases norepinephrine, epinephrine, and serotonin and these increases may modulate some of the reinforcing effects from cigarettes. Nicotine via cigarettes is rapidly absorbed directly into the arterial circulation and reaches the CNS in less than 15 seconds. Peak behavioral and cardiovascular effects occur within a few minutes. Nicotine is metabolized via the liver and has a half-life of about 2 hours. Nicotine levels from smoking typically rise in the morning, plateau in the evening, and fall to near zero in the night. This pattern causes an acute tolerance such that the first cigarettes of the day are more potent than later cigarettes. Nicotine improves performance on long, fatiguing, boring tasks. It decreases anger and stabilizes mood. It decreases hunger and food intake and increases metabolic

rate. When a smoker experiences these effects, it is often not clear how much of them result from nicotine combating withdrawal and bringing the smoker back to normal and how much is actual improvement above the norm. Some of nicotine's effects (e.g., performance enhancement) appear to occur independent of withdrawal relief. Nicotine use, like most substance use, begins because of social reinforcement. However, with repeated exposure, many young users find the pharmacological effects of nicotine well suited to help them with the demands of adolescence. In addition, a physical dependence on nicotine begins so that periods of nonuse become uncomfortable. Children more likely to start smoking are those who have a high need to conform, low academic performance, rebelliousness, depressive symptoms, and poor self-esteem. Both peer and family influences are paramount. Attention deficit, conduct, and alcohol or drug use disorders increase the risk of initiation and maintenance of smoking. Although not widely known, initiation and cessation of tobacco use are as heritable as alcoholism (alcohol dependence or abuse). Some of the genetic effects are shared with alcohol and some are specific to tobacco ( Table 11.9-1). The biological and behavioral mechanisms for genetic effects on tobacco use are not known.

Table 11.9-1 Percent of Variation in Cigarette Smoking and Alcohol Consumption, Attributable to Genetic Sources

DIAGNOSIS AND CLINICAL FEATURES Table 11.9-2 lists the DSM-IV nicotine-related disorders. Most of the generic criteria for substance dependence readily apply to nicotine (e.g., tolerance, a withdrawal syndrome, use to avoid withdrawal, inability to stop despite repeated attempts, and continued use despite knowing that use is harmful) ( Table 11.9-3). Because nicotine is legal and easily available, spending a great deal of time to procure the drug and giving up activities to use the drug are rare.

Table 11.9-2 DSM-IV Nicotine-Related Disorders

Table 11.9-3 Examples of DSM-IV Nicotine Dependence Criteria

There are several reasons smoking can produce such a severe dependence: (1) nicotine produces many different effects that can be used in many different situations (2) with pulmonary; absorption, nicotine reaches the brain in a few seconds producing a rapid effect; (3) smoking allows the user to titrate the dose; (4) smoking is an intense habit >200 puffs/day × 20 years); (5) there are many environmental cues eliciting smoking (e.g., others smoking and advertisements); and (6) nicotine use almost never impairs the user via intoxication. Nicotine withdrawal (Table 11.9-4) is manifested by changes in mood, insomnia, difficulty concentrating, restlessness, decreased heart rate (average decline is 8 beats per minute [bpm]), and weight gain (average is 2 to 3 kg). The insomnia appears to be specific to increased awakenings and intense dreaming. Postcessation weight gain is due both to increased eating and the loss of nicotine stimulation of metabolism. Craving is common and increased coughing and poor performance on vigilance tasks can occur. The syndrome is typically worse in cigarette smokers, intermediate in users of smokeless tobacco, and mild in users of nicotine replacement products. Most withdrawal symptoms peak at 1 to 3 days and last 3 to 4 weeks; however, 40 percent of smokers have withdrawal that lasts for more than 4 weeks. In addition, craving and weight gain often persist for 6 months or more.

Table 11.9-4 DSM-IV Diagnostic Criteria for Nicotine Withdrawal

Abstinence can also have pharmacokinetic effects. Nonnicotine chemicals in tobacco smoke activate cytochrome P450 enzymes, thereby decreasing the levels of several medications. As a result, smoking cessation increases the concentrations of these medications. Many of these medications are psychiatric medications and often the increase can be clinically significant (e.g., haloperidol [Haldol], clozapine [Clozaril], and fluvoxamine [Luvox] concentration increase 30 to 40 percent with abstinence) (Table 11.9-5).

Table 11.9-5 Effect of Abstinence From Smoking on Blood Concentrations of Psychiatric Medicines

Smoking (and particularly nicotine dependence) is two to three times more prevalent among patients with mood, substance use, and other psychiatric disorders. Conversely, these psychiatric disorders are two to three times more common among current smokers than among never or exsmokers. There are several possible reasons for this association—for example, shared genetic influences on smoking and psychiatric disorders, modeling other psychiatric patients, and boredom. Among adolescents the number of depressive symptoms predicts both the likelihood of starting to smoke and the probability of becoming dependent. Recent work suggests that more than nicotine may be responsible for this association. Tobacco smoke and extracts of smokeless tobacco contain substances other than nicotine that inhibit monoamine oxidase type A (MAOA) and MAOB, and recent work using positron emission technology has shown less MAO B activity in the brains of cigarette smokers. The nature of the chemical entity is not known but in in vitro models, this inhibition, like that of most clinically available MAO inhibitors, is irreversible. This suggests that MAO inhibition would persist until the body synthesizes new enzymes, a process that usually takes several weeks. Psychiatric patients may have a special need for the anxiolytic, anorexic, antiaggression, antidepressant, and improved concentration effects of nicotine. Nicotine also increases the self-administration of alcohol, which may predispose smokers to alcoholism. Finally, smokers with a current or past history of a depressive disorder have more withdrawal upon cessation and a lower rate of smoking cessation. DSM-IV also includes a residual category of nicotine-related disorders not otherwise specified ( Table 11.9-6).

Table 11.9-6 DSM-IV Diagnostic Criteria for Nicotine-Related Disorder Not Otherwise Specified

DIFFERENTIAL DIAGNOSIS Many of the symptoms of nicotine withdrawal can mimic, exacerbate, or mask the symptoms of psychiatric disorders or the adverse effects of psychiatric medications (e.g., akathesia, anxiety, depression, irritability, insomnia, and weight gain). Some recent data suggests that cessation of smoking can reinitiate a psychiatric (including substance use) disorder in a subgroup of smokers; however, other data refute this.

COURSE AND PROGNOSIS About half of smokers finally stop smoking; however, half do not and many of those who stopped had unfortunately done so having already developed smoking-related diseases. Twenty percent of all mortality in the United States is due to smoking. About 45 percent of smokers will die of a smoking-related disease resulting in over 410,000 deaths a year in the United States. Smoking is a huge risk for lung cancer, accounting for over 90 percent of all deaths from lung cancer. Smoking doubles the risk for cardiovascular disease deaths, but because this disease is more prevalent, it accounts for more smoking deaths than lung cancer. Other common smoking-related diseases include chronic obstructive pulmonary disease, low–birth-weight, perinatal complications, other cancers (e.g., throat, breast, and pancreas) and ulcers. Second-hand smoke increases the risk of cancer and heart disease in spouses and the incidence of respiratory and ear problems in children. The tar in cigarette smoke is responsible for the cancers. Irritants and ciliotoxins appear to be responsible for lung diseases. Carbon monoxide and clotting factors appear to be the most likely causes of cardiovascular disease. The role of nicotine in cardiovascular disease is actually not well defined and how many perinatal problems are caused by carbon monoxide or by nicotine is debatable. Cessation of smoking almost eliminates the risk of heart disease in 5 years and of lung cancer in 20 years. Although cross-sectional epidemiological data suggest that switching to low-tar cigarettes should decrease cancer, this is still not firmly established. Whether decreasing the number of cigarettes decreases risk has also not been directly tested. Nicotine intoxication causes abdominal pain, dizziness, headaches, nausea, pallor, palpitations, sweating, vomiting, and weakness. Intoxication is rare although mild

symptoms can occur with nicotine replacement; treatment is supportive. Epidemiological, biochemical, and clinical trial data suggest that nicotine may be beneficial for dementia of the Alzheimer's type, Parkinson's disease, Tourette's disorder, and ulcerative colitis disorders.

TREATMENT Psychiatrists are urged to read the two guidelines for the treatment of smoking published in 1996 by the Agency for Health Care Policy Research and by the American Psychiatric Association. All patients should be assessed for smoking status, motivation to quit, and motivators for and barriers to quitting. Smoking status includes current, exsmoker, or neversmoker; type of tobacco used; and frequency of use. Motivation to quit can be classified as precontemplation (no plans to quit), contemplation (thinking about quitting but no plans), and preparations (plans to quit in near future). Common motivators to quit are health concerns, effects of smoking on others, and social pressure. Common barriers to cessation are withdrawal, fear of failure, and fear of weight gain. Psychiatrists should advise all patients who are not in crisis to quit smoking. Many psychiatric patients are precontemplators and thus the psychiatrist's role is often to use the patient's concerns as motivators for cessation and to suggest ways to decrease barriers to cessation. The psychiatrist should also reintroduce cessation at later visits. Among patients who are ready to stop smoking, it is best to set a quit date. Most clinicians and smokers prefer abrupt cessation but because there is no good data that abrupt cessation is better than gradual cessation, patient preference for gradual cessation should be respected. Brief advice should focus on the need for medication or group therapy, weight gain concerns, high-risk situations, making cigarettes unavailable, and so forth. Because relapse is often rapid, the first follow-up phone call or visit should be 2 to 3 days after the quit date. These strategies have been shown to double self-initiated quit rates ( Table 11.9-7). The psychiatrist should also inform the patient about existing therapies ( Table 11.9-8), which can be done by giving the patient the APA booklet Treatment Works.

Table 11.9-7 Typical Quit Rates of Common Therapies

Table 11.9-8 Scientifically-Proven Treatments for Smoking

Ms. H. was a 55-year-old patient with schizophrenia who smoked 35 cigarettes a day and smoked each cigarette very intensely. She began her cigarette use at around the age of 20 during the prodromal stages of her first psychotic break. Over the next 35 years she had several psychotic breaks and was treated with conventional antipsychotic agents. During the first 30 years of treatment, no psychiatrist or physician advised her to stop smoking, largely because they believed she could not stop. At age 53 she was diagnosed with diabetes and early ischemic heart disease. At that time her primary care physician recommended smoking cessation. The patient attempted to stop on her own but lasted only 48 hours, partly because her housemates and friends smoked. After a second failure on her own, she became discouraged and concluded that she could not stop smoking. During a routine medication check, her psychiatrist recommended that she stop smoking and the patient described her prior attempts. The psychiatrist and the patient discussed ways to avoid smokers and had the patient announce her intent to quit and request her friends to try not to smoke around her and to offer encouragement for her attempt to quit. The psychiatrist also noted that she became irritable, slightly depressed, restless, and insomniacal during prior cessation attempts, and thus recommended medications and used the APA brochure Treatment Works to help the patient decide which medication was best for her. The patient chose a nicotine patch. The psychiatrist had the patient call 2 days after her quit attempt. At this point the patient stated that the patch and gum were helping but she still felt “left out” when her friends smoked and talked. One week later the patient returned after having relapsed back to smoking. The psychiatrist praised the patient for not smoking for 4 days. He suggested that the patient contact him again if she wished to try to stop again. Seven months later during another medication check the psychiatrist again asked the patient to consider cessation but she was reluctant. Two months later the patient called and said she wished to try again. She met with the psychiatrist and this time the psychiatrist and patient listed several activities the patient could do to avoid being around friends who smoked, phoned the patient's boyfriend to ask him to assist the patient in stopping, asked the nurses on the inpatient ward to call the patient to encourage her, plus decided to enrol the patient in a support group for the next 4 weeks. The nicotine patch was used again but this time, the nonnicotine medication buproprion (Zyban) was added. The patient was followed with 15-minute visits for each of the first 3 weeks and two phone calls thereafter. She had two “slips” when she became angry with her boyfriend but did not go back to smoking and remained an exsmoker. An unexpected result of her successful cessation was an improvement in the therapeutic alliance between the patient and her psychiatrist. Discussion Most psychiatrists fail to diagnose and treat nicotine dependence. Unfortunately, sometimes psychiatrists find that although they have adequately treated the disorder that brought the patient into treatment, the patient has such morbidity or mortality from smoking that he or she cannot reap the benefits of psychiatric treatment. Ms. H.'s psychiatrist was correct in using pragmatic plans to help the patient overcome specific problems, in following the patient with short visits or phone calls, and in recommending nicotine replacement. The total amount of time spent with the patient on smoking was about 3 hours. Although this was not reimbursed, the psychiatrist knew that his intervention was an important contribution to the patient's health and was unlikely to be given by other care providers. Psychosocial Therapies Behavior therapy is the most widely accepted and well-proven psychological therapy for smoking. Behavior therapy consists of several techniques, three of which are supported by good evidence to support them. Skills training and relapse prevention identifies high-risk situations and plans and practices behavioral or cognitive coping skills for these situations. Stimulus control refers to eliminating cues for smoking in the environment. Rapid smoking has smokers repeatedly smoke to the point of nausea, etc. in sessions to associate smoking with unpleasant rather than pleasant sensations. This last therapy appears

effective but requires a good therapeutic alliance and patient compliance. Often behavior therapy is conducted in group settings to promote social support and save on costs. Typically, several sessions are conducted prior to the quit date and several are scheduled for early after the quit date. Although group therapy for alcohol dependence is widely accepted, most smokers believe that they should be able to quit without help. Even those who seek treatment find that smoking cessation treatments are generally not reimbursable, only voluntary agencies and wellness programs offer treatment and, in most locales, treatment is offered only a few times a year. In addition, these programs are only in larger cities and require patient payment. As a result of these barriers, less than 5 percent of smokers enrol in behavior therapies. Although written materials are the most common self-help format, telephone systems that tailor treatment to patient concerns have recently been found to be more effective and more acceptable. These systems are available free of charge from pharmaceutical firms and some state health departments and industries. Psychopharmacological Therapies Pharmacotherapy The AHCPR and the APA guidelines recommends that all smokers be offered medication to aid in smoking cessation. All the medications approved by the Food and Drug Administration (FDA) for smoking cessation appear equally effective, and they all double the quit rate (similar to results obtained with behavior therapy) ( Table 11.9-7). With all these medications few produce side-effects; less than 5 percent of patients stop medication due to adverse effects. Although there are many theories, there are no empirically-verified methods to match smokers to specific therapies. Most clinicians believe that patients should be informed of the various therapies and allowed to choose the therapy they believe will be most helpful. In other substance use disorders, psychosocial therapy is thought to be essential and pharmacotherapy is used as an aid to psychosocial therapy. In nicotine dependence the opposite is true: pharmacotherapy is the treatment to be offered to all, and psychosocial therapy should be added when desirable and feasible. Nicotine Replacement Therapies All nicotine replacement therapies double cessation rates, presumably because they reduce nicotine withdrawal. These therapies can also be used to reduce withdrawal in patients on smoke-free wards. Replacement therapies use a short period of maintenance (6 to 12 weeks) often followed a gradual reduction period (6 to 12 weeks). Nicotine gum (Nicorette) is an over-the-counter product that releases nicotine via chewing and buccal absorption. A 2-mg (for 3.09, P < 0.001, by reference to the unit normal distribution) are displayed in color, superimposed upon a single structural T1-weighted magnetic resonance imaging (MRI) scan that has been transformed into the Talairach space for anatomical reference. Section numbers refer to the distance from the anterior commissure-posterior commissure line, with positive numbers being superior to the line. The areas of activation extend into the amygdala bilaterally, and into the right orbitofrontal cortex. Although these regions of extension are consistent with the limbic paralimbic component of activity during hallucinations, and may contribute to drive and affect in this context, definitive statements cannot be made in the absence of discrete maxima. (Reprinted with permission from Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, et al: A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:1769, 1995.)(See Color Plate 7.)

FIGURE 12.1-2 There is a significant difference in O 15 activity in the prefrontal and parietal cortex during the performance of an auditory discrimination task in deficit and nondeficit patients, with deficit patients having decreased activity in these regions. (Courtesy of A. Lahti, Maryland Psychiatric Research Center, Baltimore, MD.)

(See Color Plate 7.)

Present-day knowledge of the pathophysiology of schizophrenia is acquired from the study of living subjects by using structural and functional imaging, and anatomically relevant symptom assessment and neuropsychological techniques. These technologies are supplemented by advances in postmortem biochemical, molecular, and structural evaluations to test increasingly sophisticated neuroanatomical and biochemical theories of schizophrenia. Major Neuroanatomical Theories Over the last 20 years there has been a gradual evolution from conceptualizing schizophrenia as a disorder that involves discrete areas of the brain to a perspective that views schizophrenia as a disorder of brain neural circuits. These neural circuit models of the pathophysiology of schizophrenia posit that either a structural or a functional lesion disrupts the functional integrity of the entire circuit. There are several factors that have contributed to this change in perspective. First, the delineation of the neuroanatomy of the different neurotransmitter pathways has led to an increased appreciation of how different brain regions are connected with each other and how cortical and subcortical structures are able to reciprocally regulate the function of each other. For example, the identification of the mesolimbic and mesocortical dopaminergic pathways contributed to the development of neuroanatomical hypotheses implicating the prefrontal cortex and limbic system in the pathophysiology of schizophrenia. The further delineation of the reciprocal regulatory pathways between the prefrontal cortex and the limbic system, particularly the hippocampus, led to more recent formulations of these hypotheses, in which limbic and prefrontal neuroanatomical models of schizophrenia have been integrated into a single unifying neurodevelopmental theory of schizophrenia. These hypotheses propose that an early developmental lesion of the dopaminergic tracts to the prefrontal cortex results in the disturbance of both prefrontal and limbic system function, and leads to the positive and negative symptoms and cognitive impairments observed in patients with schizophrenia. Prefrontal cortex and limbic system hypotheses are the predominant neuroanatomical hypotheses of schizophrenia. The demonstration of decreased volumes of prefrontal gray or white matter, prefrontal cortical interneuron abnormalities, disturbed prefrontal metabolism and blood flow, decreased volumes of hippocampal and entorhinal cortex, and disarray or abnormal migration of hippocampal and entorhinal neurons provide strong support for the involvement of these brain regions in the pathophysiology of schizophrenia. In the context of neural circuit hypotheses linking the prefrontal cortex and limbic system, studies demonstrating a relation between hippocampal morphological abnormalities and disturbances in prefrontal cortex metabolism or function are particularly interesting. A second contributing factor to the adoption of a neural circuit conceptual framework has been the increased understanding of how the brain is organized into local microcircuits, which consist of the connections among afferent and efferent neurons and interneurons, and macrocircuits. An example of the latter are the segregated parallel basal ganglia-thalamocortical neural circuits, which connect the cerebral cortex with the thalamus through the basal ganglia. Each of these circuits is hypothesized to subserve a discrete range of functions. Several investigators have used these circuits as a starting point for their hypotheses of schizophrenic pathophysiology. These hypotheses differ from each other primarily on their point of emphasis. For example, integrating data from animal studies, and neurobehavioral, functional, and structural imaging studies in humans, it has been hypothesized that dysfunction of the anterior cingulate basal ganglia-thalamocortical circuit underlies the production of psychotic symptoms ( Fig. 12.1-1) and dysfunction of the dorsolateral prefrontal circuit underlies the production of primary enduring negative or deficit symptoms ( Fig. 12.1-2). Dysfunction in one of these circuits may be independent from dysfunction in the other. P>A third factor has been the elucidation of the neural basis of cognitive functions observed to be impaired in patients with schizophrenia. The observation of the relationship among impaired Wisconsin Card Sort Test (WCST) performance and diminished prefrontal cortex blood flow and diminished hippocampal volume provides strong support for the validity of prefrontal cortex or limbic system neuroanatomical models. Similarly, the delineation of the neural circuits for language and attention or information processing have influenced the conceptualization of schizophrenia pathophysiology. The classic language circuit, which includes Wernicke's and Broca's areas and associated cortical and subcortical structures, has been hypothesized to be involved in the production of hallucinations, delusions, and positive formal thought disorder. This hypothesis is the most important alternative to the anterior cingulate hypothesis for positive symptoms. The involvement of this circuit, at least for auditory hallucinations, has been documented in a number of functional imaging studies contrasting hallucinating versus nonhallucinating patients. Attention and information processing abnormalities are routinely observed in patients with schizophrenia. The type of abnormalities range from disturbances in sensory gating to disturbances in visual information processing. The latter impairments have been argued to be selectively related to negative symptoms. The overlap between brain regions that have been implicated in the production of negative symptoms and the visual information processing neural circuit, which includes inferior and superior parietal and prefrontal cortices, caudate and thalamic nuclei, and the reticular activating system, provides a neuroanatomical rationale for the relationship between these two dimensions of schizophrenia and a conceptual framework for future studies of the neuroanatomy of negative symptoms. The development of neural circuit hypotheses offers tremendous advantages to the investigation of the neuroanatomy of schizophrenia. First, these hypotheses more accurately reflect the actual organization of the brain. Second, models of neural circuit hypotheses can be developed to investigate how perturbations of circuit function can lead to schizophrenia signs and symptoms. Neural circuit models have been created for both the cognitive and symptom manifestations of schizophrenia. Third, neural circuit hypotheses provide a conceptual framework for hypothesis-testing studies and optimize the interpretation of information derived from current brain imaging and postmortem studies. Finally, the use of neural circuit models implicates brain regions, such as the thalamus and the cerebellum, that are not typically conceptualized as being central to the neuroanatomy of schizophrenia. Major Biochemical Theories Information is processed in neuronal networks through the transmission of an electrical signal from a nerve cell through its axon and across synapses to postsynaptic receptors on other nerve cell components. Nerve cells generally receive, process, and send signals to and from thousands of other cells. The transmission of the signal across the synapse and the processing of the signal within a cell involve a complex series of biochemical events that require large amounts of energy and include gene expression and the synthesis and degradation of protein. It is evident that physiological function in any brain system involves the chemistry of that system, and that dysfunction can emanate from these biochemical processes. It is therefore natural to assume that the biochemistry of the brain plays a fundamental role in the disruptions of brain function involved in schizophrenia. The move from a general concept of the biochemistry of schizophrenia to specific theories is based on two principal sources of knowledge. The first is an ever-increasing understanding of intracellular communication from the cell membrane to the nucleus and the cell's genetic material and of intercellular communication through the various neurotransmitter systems of the brain. The second source is knowledge of the mechanism of action of drugs that can induce schizophrenia-like behaviors or that alter symptom expression in patients with schizophrenia. Our knowledge of cellular communication and the pharmacological actions of antipsychotic drugs have led to biochemical hypotheses involving dopamine, noradrenalin, serotonin, acetylcholine, glutamate, and several neuromodulatory peptides and their receptors. Because there are many possibilities, it is important to understand the general development of a biochemical hypothesis of schizophrenia, of which the dopamine hypothesis is the most prominent and enduring. Dopamine and Schizophrenia The hyperdopamineric hypothesis of schizophrenia arose from two sets of observations of drug action relating to the dopaminergic system. Drugs that increase dopamine system activity, such as d-amphetamine, cocaine, levodopa (Larodopa), and methylphenidate (Ritalin), can induce a paranoid psychosis that is similar to some aspects of schizophrenia. When administered to schizophrenic patients, these compounds may produce a transitory worsening of symptoms, especially in the area of hallucinations, delusions, and thought disturbance. In contrast, drugs that share the capacity to block postsynaptic dopamine receptors reduce the symptoms of schizophrenia. Substantial evidence supports the role of postsynaptic dopamine blockade as an initiating factor in a cascade of events responsible for the mode of therapeutic action of antipsychotic drugs. Other mechanisms, such as depolarization blockade, have been implicated as plausible explanations for long-term antipsychotic effects. That these actions are actually corrective for the pathophysiological disturbance in schizophrenia is suggested by the fact that dopamine-stimulating drugs can worsen schizophrenic symptoms or induce psychosis. This rationale for the role of dopamine excess, particularly for the cognitive and positive symptom aspects of schizophrenia, is compelling. However, despite the compelling evidence for the role of dopamine in schizophrenia, testing the hypothesis has proven problematic. Clinical studies across a broad range of indices of dopamine metabolism have been characterized by marked variability in results. The most decisive clinical testing of the hypothesis has been at the level of observed drug action and symptom manipulation. Studies aimed at measuring abnormal concentrations of dopamine or its metabolites in blood, urine, and spinal fluid are confronted by problems that are almost insurmountable. In large fluid compartments, alterations in dopamine metabolism associated with schizophrenia will represent only a minor contribution to the particular index of dopamine metabolism; spinal fluid necessarily provides a summation of total brain activity, most of which is not considered germane to schizophrenia, and blood and urine provide even more indirect indices. Functional imaging studies provide indirect evidence of dopamine involvement through the examination of metabolic rates in brain regions where dopamine is an important neurotransmitter. For example, data confirming metabolic alterations in limbic anatomy are consistent with a disturbance in dopamine metabolism, but it is not possible to determine the extent to which this reflects an alteration of dopamine biochemistry versus an alteration of any one of a number of interacting neurotransmitter and neuromodulatory systems. A more informative approach for assessing abnormal dopamine metabolism in patients with schizophrenia is to infuse

subjects with an indirect dopamine agonist and then determine the extent to which radioligand occupancy of postsynaptic dopamine receptors is reduced by competition with the increased endogenous dopamine. The comparison of preinfusion and postinfusion radioligand occupancy provides an index of dopamine release and reuptake rates. PET studies of dopamine receptor distribution and the density of receptor expression may offer an alternative approach for documenting the dopamine hypothesis. The observation of an increased quantity of dopamine type 2 (D 2) receptors in the caudate nucleus of drug-free schizophrenic patients is an example of this approach, but replication has been difficult. The extension of this approach to other dopamine receptor types is an important new direction of research. Finally, there is the potential for the relatively precise biochemical study of dopamine in postmortem tissue, but here, as with the use of body fluids, sources of artifact and imprecision have been difficult to manage. The concentration of a neurotransmitter in any tissue will be altered as cellular components break down following death and as small differences in dissection from brain to brain take place. The administration of neuroleptic drugs during life almost always confounds the biochemistry of postmortem tissue, and one can rarely be sure of the extent to which any biochemical finding is secondary, rather than primary, to the schizophrenic disease process. In addition, there are a large number of candidate areas for brain dysfunction, so that one may easily examine the wrong location. It is also quite possible that areas of biochemical dysfunction earlier in life are no longer dysfunctional at the time of death or that the biochemistry of death may obscure the biochemistry of life. Despite these methodological limitations, postmortem studies have reported differences between schizophrenic and control brains. For example, increased concentration of dopamine has been found in the left amygdala (a limbic system structure) in the postmortem brains of patients with schizophrenia. This finding has been replicated and, since it is lateralized, is not likely to be an artifact. There has also been a report of an increase in D 2 postsynaptic receptors in postmortem tissue of schizophrenic patients whose medical records provided a diagnosis of schizophrenia but did not reveal neuroleptic drug use. These results suggest that the increase in binding (receptor) number is not secondary to neuroleptic drugs. The investigation of receptor abnormalities has been extended to other dopamine receptor types, and an increase of D 4 receptors in entorhinal cortex, independent of antipsychotic use, has been reported. Although conclusive evidence for the dopamine excess theory has been elusive, the hypothesis remains a viable explanation for the positive symptoms of schizophrenia. It is a particularly robust proposition for explaining the antipsychotic effect of neuroleptic drugs. Interestingly, recent studies have suggested the possibility that a dopamine deficiency may also occur in schizophrenic patients. For example, an inverse correlation between cerebrospinal fluid (CSF) and homovanillic acid (HVA) concentrations and negative symptoms has been reported. Also, patients with influenza encephalitis, who were mistaken for being schizophrenic, tended to have emotional dullness and low drive. Similarities in these cases with aspects of Parkinson's disease (which is known to involve loss of dopamine neurons) and the fact that some of these postencephalitic patients developed Parkinson's disease, lends support to a dopamine deficiency hypothesis for the negative symptom aspect of schizophrenia. In addition, neuroleptic drugs, which are dopamine-blocking agents, produce behaviors suggestive of the negative symptoms of schizophrenia in animals and humans free of mental illness. A modification of the dopamine hypothesis, incorporating the possibility of concomitant dopamine excess and deficiency, would restrict dopamine excess to the dopaminergic pathways projecting to the basal ganglia and limbic system and dopamine deficiency to the mesocortical pathways. Hypofunction of the mesocortical neurons would account for the negative symptoms of schizophrenia. Glutamate and Schizophrenia Glutamate is the major excitatory neurotransmitter in the brain. Interest in the possible role of glutamate in the pathophysiology of schizophrenia has emerged from an increased understanding of the N-methyl- D-aspartate (NMDA) receptor complex, a major glutamate system receptor; an increased understanding of the interactions between glutamatergic and dopaminergic and GABAergic systems; and observations of the acute and chronic effects of phencyclidine (PCP). The consequences of PCP use provide a compelling model of schizophrenia symptomatology. Short-term administration of PCP produces symptoms that have been argued to mimic both the positive and negative symptoms of schizophrenia. Chronic administration produces a hypodopaminergic state in the prefrontal cortex, a state that has been argued to result in negative symptoms. PCP occupies receptors within the open calcium channels of the NMDA receptor complex, thereby blocking ion flow. PCP and the analogue ketamine (Ketalar) interfere with glutamatergic transmission. In addition to the observation of schizophrenia-like symptomatology in humans abusing PCP or ketamine has been used in the laboratory and has been observed to produce transitory mild manifestations of positive and negative symptoms in normal volunteers and a transitory and mild worsening of positive symptoms in patients with schizophrenia. Activation of dopamine receptors inhibiting glutamatergic neurons or decreased NMDA-mediated inhibition of dopamine neurons, either directly or through the actions of GABAergic interneurons, could be associated with a dopamine-excess psychosis ( Fig. 12.1-3). These considerations support a hypoglutamatergic hypothesis for schizophrenia pathophysiology and predict a therapeutic effect for compounds activating the NMDA receptor complex. This is a difficult strategy to implement because excessive glutamatergic activity is neurotoxic; however, activation of the NMDA receptor complex via the glycine site with either glycine or d-cycloserine has been reported to alleviate negative symptoms in patients with schizophrenia.

FIGURE 12.1-3 A tentative scheme of interactions between glutamate and dopamine in the basal ganglia. The cholinergic interneurone in the striatum is a large, aspiny cell with a rich collateral network that can be assumed to make synaptic contacts with a large number of other striatal cells. The cholinergic interneurone receives a cortical glutamatergic input on its soma, while its axon terminals are in synaptic contact with medium-sized, spiny GABAergic output neurones. Only two such GABA neurons are shown but in reality it is reasonable to assume that one cholinergic neurone innervates many GABAergic neurones. The cholinergic interneurone also makes contact (although maybe not forming a real synapse) with dopaminergic nerve terminals. From the way the synapses are drawn here, the cortex would be able to control the activity in the GABAergic output neurones projecting to the thalamus via the medial segment of the globus pallidus (partly via the subthalamic nucleus and substantia nigra pars reticulata. In this manner the cortex can selectively suppress impulse flow in one subpopulation of GABAergic projection neurones while facilitating impulse flow in another, thus presumably enabling a meaningful behavior by suppressing irrelevant locomotor programs. The importance of glutamatergic pathways for maintaining a purposeful behavior is revealed by the primitive locomotor pattern that results from treatment with the NMDA antagonist MK-801. For the sake of simplification, the different thalamic nuclei are not shown. Conceivably, striatopallido-thalamic neurones can influence the entire thalamus via, for example, the reticular nucleus, which communicates with all other thalamic nuclei. Apart from the corticostriatal glutamatergic pathway, there are at least three other corticifugal systems that the cortex can use to protect itself from overstimulation: (1) the corticonigral projection; (2) the corticothalamic projection, which terminates in the thalamic intralaminar nuclei, from which a thalamostriatal projection originates; and (3) the corticosubthalamic projection. Abbreviations: DA, dopamine; Glu, glutamate; Snc, Substantia nigra pars compacta; Snr, substantia nigra pars reticulata; STN, subthalamic nucleus; VTA, ventral tegmental area. (Reprinted with permission from Carlsson M, Carlsson A: Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson's disease. Trends Neurosci 13:896, 1990.)

The glutamatergic hypothesis exemplifies a major transition that has occurred recently in the biochemistry of schizophrenia. Prior to this transition, observations of drug actions in schizophrenia first led to clinical treatment and then to the advancement of the pathophysiological theory of schizophrenia. With the ever-increasing knowledge of the neural organization of the brain and of the various properties and receptor sites of neurotransmitters, it is now possible to postulate pathophysiological theory first and then attempt to derive new clinical treatment from theory. New treatment approaches will be developed more rapidly in the future, based on a broader range of pathophysiological hypotheses and the availability of animal models for aspects of the illness that are not therapeutically responsive to dopamine blockade-based medications. Other Neurotransmitters and Neuromodulators Any neurotransmitter involved in neural systems subserving behaviors whose disruption could result in symptoms

of schizophrenia is naturally of interest in schizophrenia theory and research. The rich innervation of the frontal cortex and limbic system with serotonergic neurons, the modulatory effect of these neurons on dopaminergic neurons, and the involvement of these pathways in the regulation of a broad range of complex functions has led several investigators to posit a pathophysiological role for serotonin in schizophrenia. These hypotheses have taken various forms over the course of the last four decades. In the early 1950s a serotonergic deficiency hypothesis was proposed for schizophrenia. Observations of hallucinations in subjects who had ingested lysergic acid diethylamide (LSD), a compound that is chemically similar to serotonin and blocks serotonin receptor sites, furthered the hyposerotonin hypothesis. However, drugs that decrease serotonin activity tend to reduce schizophrenic symptoms (e.g., reserpine [Serpasil], some antipsychotics, clozapine [Clozaril]), and have diminished interest in the deficiency hypothesis. Of greater current interest are hypotheses positing that a serotonin excess causes positive and negative symptomatology. The robust serotonergic antagonist activity of clozapine and other new-generation antipsychotics, coupled with clozapine's demonstrated effectiveness for positive symptoms in chronic, treatment-resistant patients have contributed to the current emphasis on this proposition. However, several studies have raised questions about the efficacy of serotonin antagonists for either negative symptoms broadly defined or deficit symptoms. Moreover, pharmacological modification of serotonin systems with specific serotonergic agents has not produced impressive clinical results. As with the dopamine hypothesis, the strength of the support for the serotonin hypothesis is derived from reasoning based on knowledge of brain and behavior relationships, the anatomy of neural transmitter systems, and drug mechanism of actions, and the same weaknesses in the clinical and postmortem studies on dopamine apply to serotonin also. A similar rationale can be applied to construct hypotheses implicating norepinephrine in the psychopathology of schizophrenia. Anhedonia, (i.e., the impaired capacity for emotional gratification and the decreased ability to experience pleasure), has long been noted to be a prominent feature of schizophrenia. A selective neuronal degeneration within the norepinephrine reward neural system could account for this symptom. However, biochemical and pharmacological data bearing on this proposal are inconclusive. As with dopamine and serotonin, there have been both noradrenergic excess and deficiency pathophysiological hypotheses. Neuromodulatory hypotheses focus on the fact that neuropeptides, such as substance P and neurotensin, are co-localized with the catecholamine and indolamine neurotransmitters, and influence the action of these neurotransmitters. Alterations in neuromodulatory mechanisms could facilitate, inhibit, or otherwise alter the pattern of firing in these neuronal systems. Explorations of neuromodulator hypotheses are preliminary and inconclusive at this time. Integrative Hypotheses The natural evolution of pathophysiological hypotheses of schizophrenia is the development of comprehensive models that integrate both neuroanatomical and biochemical hypotheses. The superimposition of the neurotransmitters involved in the connections among cortical, basal ganglia, and thalamic structures that comprise the basal ganglia-thalamocortical neural circuits is a prime example of this approach. Through glutamate projections from the cortex to the basal ganglia, the cerebral cortex facilitates the performance of selected behaviors while inhibiting others. The excitatory glutamatergic neurons terminate on GABAergic and cholinergic neurons, which in turn suppress or excite dopaminergic and other neurons. This regulatory activity can enable the cortex to protect itself from overstimulation from thalamocortical neurons. The elucidation of the neuroanatomy and biochemistry of cortical microcircuits has also served as a starting point for the articulation of pathophysiological hypotheses of schizophrenia. These integrative models provide a framework for identifying potential neurotransmitter targets for drug development, as well as providing explanatory models for the observed effects of pharmacological agents in patients with schizophrenia (e.g., PCP-induced psychotic symptoms mediated through the interactions of glutamate and other neurotransmitter systems in the neocortex, basal ganglia, or limbic system structures).

DIAGNOSIS The history of the diagnosis of schizophrenia is often misunderstood, which has led to erroneous conclusions about the validity of the diagnostic process. Throughout most of the twentienth century there has been substantial agreement among diagnosticians throughout the world, using seemingly divergent diagnostic approaches, in the recognition of typical cases of schizophrenia. There has also been no difficulty in distinguishing schizophrenia from normality. Although useful refinements have evolved, diagnostic systems in place when effective drug treatment was introduced in 1952 were capable of identifying suitable subjects for therapy. The major areas of disagreement among diagnostic approaches were how broad the definition of schizophrenia should be; whether positive symptoms, including hallucinations, delusions, and positive formal thought disorder, were required; and whether positive symptoms in the absence of known organic causes always signified schizophrenia. In general, the broader the definition the greater the likelihood that more subtle cases would be included and the greater the likelihood that disagreement would arise regarding the diagnosis of such cases. Even in such cases, there was little disagreement regarding the presence of psychopathology; rather, when present, the disagreement focused on whether the psychopathology observed was part of schizophrenia. This difference in viewpoint did create problems, which became important as different types of drugs were found to be effective for different classes of illness. The success of the scientific search for more effective drugs for specific disease classes created the urgency to establish an agreed-upon diagnostic approach to schizophrenia and the major affective disorders in order to maximize appropriateness of treatment. The need for such agreement was also highlighted by the results of an influential study comparing diagnostic approaches in the United Kingdom with those in New York City, in which it was convincingly demonstrated that American diagnosticians employed a much broader and less defined construct of schizophrenia than their British counterparts. For a time in North America, especially in the northeastern United States, a broad definition of schizophrenia tended to include two categories of patients ill suited for the standard pharmacological treatment of schizophrenia. The first category was patients with bipolar or major depressive disorders with psychotic features, who, if erroneously considered to have schizophrenia, were administered antipsychotic medication rather than the more specific and effective treatments available for patients with these disorders (i.e., antidepressants, lithium, and electroconvulsive therapy). The second category included patients with schizophrenia spectrum personality disorders, (i.e., schizoid, schizotypal, and borderline personality disorders). These patients were sometimes misdiagnosed as having schizophrenia and were thus likely to be administered drugs designed for the positive symptoms of schizophrenia, which provided them little benefit and subjected them to substantial risk. A considerable body of research during the 1960s and 1970s clarified many diagnostic issues and set the stage for the development of a diagnostic system implemented in the third edition of the American Psychiatric Association's Diagnostic and Statistical Manual of the Mental Disorders (DSM-III). The DSM-III approach, with specified symptom-based diagnostic criteria and demonstrated reliability, is now the accepted diagnostic system in North America and throughout the international research community. The use of this approach has led to the reliable and consistent differential diagnosis of schizophrenia, which has enhanced scientific and clinical communication and substantially increased the likelihood of the effective use of diagnostically specific treatments. The DSM-III approach has been retained in the revised third edition of DSM (DSM-III-R) and the fourth edition of DSM (DSM-IV) and has been incorporated in the International Classification of Diseases (ICD) diagnostic system. The ultimate goal is to standardize the diagnosis of schizophrenia across all diagnostic systems. Substantial progress has been made in this area, with extensive integration between DSM-IV and the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10). Beyond Diagnosis A valid diagnostic system for schizophrenia has considerable utility for clinical and epidemiological purposes. It is now possible to estimate the occurrence of schizophrenia accurately, to identify individuals suffering from the illness process, to guide treatment and rehabilitation considerations, and to differentiate schizophrenia from other illnesses with similar manifestations but with importantly different treatment requirements. However, diagnosis at the syndrome level has not been an adequate guide to the scientific study of either the etiology or pathophysiology of schizophrenia nor to the development of treatments for all key features of the illness. The traditional approach to reducing the heterogeneity of the schizophrenia syndrome has been to delineate subtypes and attempt to confirm or disprove their validity. The classic subtypes, disorganized (DSM-IV) or hebephrenic (ICD-10), paranoid (DSM-IV and ICD-10), catatonic (DSM-IV and ICD-10) and simple schizophrenia (ICD-10) or simple deteriorative disorder (DSM-IV) represent the most frequently used subtype approach for reducing heterogeneity. Although important differences such as age of onset and pattern of symptom development validate these subtypes, the classical subtypes have not provided a strong heuristic framework for the study of differential etiology and pathophysiology. In light of the limitations of the classic subtypes, alternative approaches have been sought to reduce syndromal heterogeneity. One approach that has received considerable attention is the proposition that specific symptom complexes define pathological entities that differ from one another in neuroanatomical pathophysiology, in course and onset, in treatment requirements, and possibly in etiology. Interest in the proposition that symptom complexes, or domains of psychopathology, represent unique disease processes has emerged from the extensive study of the longitudinal patterns of symptom manifestations in patients with schizophrenia. A large number of studies have documented that the symptoms of schizophrenia usually segregate into three semi-independent symptom complexes: (1) hallucinations and delusions; (2) disorganized behavior, including positive formal thought disorder, bizarre behavior, and inappropriate affect; and (3) primary, enduring negative or deficit symptoms, including restricted affective experience and expression, diminished drive, and poverty of thought. Longitudinal studies provide

support for the long-term independence and stability of these domains. These results suggest a modification of the central paradigm for the study of the etiopathophysiology and neuroanatomy of schizophrenia: the study of the etiopathophysiology and neuroanatomy of schizophrenia becomes the study of the etiopathophysiology and neuroanatomy of hallucinations and delusions, of disorganized behavior, and of negative symptoms. This approach is also germane for treatment and rehabilitation studies. The domains approach has been extensively applied to the investigation of deficit symptoms. These symptoms differ from the other symptom complexes in their familial heritability, neuroanatomy as evidenced in both structural and functional neuroimaging studies, and response to antipsychotic treatment. Long-term outcome, season of birth, and age of onset are also distinctive. These results provide strong support for the heuristic value of this approach and raise the hope that this approach to heterogeneity reduction will yield more decisive data in studies of etiopathophysiology and neuroanatomy and will provide explicit information regarding the efficacy profile of pharmacological treatments. Cognitive Impairment In addition to the three symptom complexes, patients with schizophrenia also manifest a broad array of cognitive impairments, including impaired performance on measures reflecting attention, information processing, executive function, memory, and language capabilities. These manifestations are not used in the diagnosis of schizophrenia, but are a critical component of the disorder. On a theoretical level, attentional and verbal memory impairments are conceptualized as vulnerability markers, which may be useful in defining schizophrenia phenotypes, may be applicable to early detection, and may provide a basis for creating new models for treatment development. Cognitive impairments are also hypothesized to meaningfully determine many aspects of quality of life and functional capacity and adjustment. Moreover, the neuropsychological assessment of cognitive impairments permits probablistic anatomical inferences, and the use of cognitive tasks that assess these impairments has become increasingly important in guiding functional neuroimaging studies. The relations among cognitive impairments and the symptoms of schizophrenia are unclear. For many years, cognitive impairments were conceptualized as the psychological foundations of symptom manifestations. However, there is a large body of evidence that has documented the relative independence of cognitive impairments and symptoms. For example, clinical trials have repeatedly demonstrated that large changes in symptom status can occur without a corresponding improvement in cognitive function as reflected in cognitive or neuropsychological test performance. Parenthetically, these trials have also revealed the lack of effective pharmacological treatment for these fundamental manifestations of the illness. The use of the three-symptom complex model and less complex cognitive paradigms may lead to the elucidation of possible relationships between the various cognitive impairments and the symptom complexes. In summary, the manifestations of schizophrenia have been consistently described since the turn of the century. The conceptualization of schizophrenia as a clinical syndrome, importantly distinguished from manic-depressive and other psychoses, has been validated. Research on diagnostic systems has produced modest modifications in classification and has demonstrated the adequacy of the reliability and validity of current approaches. It has also produced a reasonable degree of uniformity in international usage that serves both clinical and scientific purposes. Because the clinical syndrome of schizophrenia probably represents more than one pathological process, specifically addressing the etiology, pathophysiology, and treatment of specific symptom complexes offers important new power to research designs.

COURSE, PROGNOSIS, AND OUTCOME In his pioneering description of schizophrenia Emil Kraepelin argued that schizophrenia was characterized by an early onset, which was followed by a chronic deteriorating course. Eugen Bleueler suggested that a chronic deteriorating course was a frequent but not a necessary outcome. However, neither of these early workers took into account the extent to which their observations were based on chronic, institutionalized populations. Extensive longitudinal-outcome data on patients who were treated prior to and after the introduction of antipsychotics support a more optimistic prognostic picture. Whereas schizophrenia is always a serious disease, it is now clear that patients suffering from it may follow a variety of courses over the long term, including some that are relatively benign. It remains true that although schizophrenia does not always progress to a deteriorated end state, there are substantial and enduring adverse consequences for most patients. The course of the illness can be divided into four major epochs: premorbid adjustment, onset of illness, middle course, and late course. Premorbid Adjustment Premorbid adjustment refers to symptoms that appear prior to the onset of positive symptoms. Twenty-five to fifty percent of patients with schizophrenia have abnormal premorbid adjustment, which may be manifested as poor social and scholastic adjustment or diminished social drive; decreased emotional responsivity; withdrawn, introverted, suspicious, or impulsive behavior; idiosyncratic responses to ordinary events or circumstances; short attention span; and delayed developmental milestones or poor motor and sensorimotor coordination. Childhood asociality, a trait that has been referred to in the past as a poor prognostic indicator, is probably more appropriately conceptualized as the early morbid manifestation of deficit symptomatology. Disturbances in social behavior have been picked up as early as infancy by workers who have noticed a lack of responsiveness and emotional expression in infants who later developed schizophrenia. It is also evident, however, that deficit symptoms may have their onset following psychosis and become part of the progression of the illness during the initial years of psychosis. Subtle forms of positive formal thought disorder may also be manifest before overt hallucinations and delusions occur. Studies that have evaluated the development of the offspring of mothers with schizophrenia have observed cognitive difficulties during the pre-teen and teenage years in these high-risk children. Onset of Illness The second epoch, onset of illness, typically refers to the onset of positive symptoms (i.e., hallucinations, delusions, and positive formal thought disorder). The onset of positive symptoms is insidious in about half of the patients, with the earliest signs of involvement occurring many years before the appearance of the more blatant manifestations of psychosis. In other cases, onset is relatively sudden or acute, with the onset of positive symptoms marking a sharp deviation in development. Patients with the insidious type of onset are very likely to have a poor intermediate course and a poor long-term outcome. In contrast, patients with normal development and ordinary personality attributes who experience a relatively sudden appearance of hallucinations, delusions, and disorganized thought vary widely in their intermediate and long-term outcomes. Although the rate of schizophrenia is relatively similar in women and men, there are gender differences in age of onset. In males, the peak age of onset ranges from 17 to 27, whereas females tend to have a wider and flatter window of vulnerability, with age of onset generally between ages 17 and 37. Middle Course The middle epoch or course of illness may be subdivided into two subepochs. The first 5 to 10 years of illness are frequently characterized by multiple exacerbations of positive symptoms, during which a patient may return to an asymptomatic baseline between episodes, or remain actively psychotic without achieving full recovery. This subepoch is followed by a plateau phase, in which patients experience a stabilization of their symptoms and a decrease in the number of exacerbations. Recent studies have made it evident that the underlying deterioration associated with schizophrenia principally occurs during the onset of illness and the first half of the middle phase, rather than over the remaining course of illness. However, complications caused by the illness lead to ever-increasing impediments to normal existence, so that secondary effects may be progressive even though the primary pathology has plateaued. For example, patients who live in understimulating environments will lose social skills and work capabilities even if their symptoms improve. Effective treatment late in the course of a chronic disease will diminish morbidity, but it will not restore lost experience and opportunity—nor will it overcome stigma. A history of disabling schizophrenia is a serious social and occupational burden regardless of the degree of recovery. Late Course In the late epoch there is a tendency for the intensity of positive symptoms to diminish, and many patients with long-term impairments regain some degree of social and occupational competence. Although the illness becomes less disruptive and easier to manage, the effects of years of dysfunction are rarely overcome. It would be highly unusual for an individual with a chronic form of the illness to gain the niche in society and the quality of personal life that would have been possible had the illness not been present. More typically, patients continue to manifest direct signs of the illness process throughout their lives. Twenty- to forty-year follow-up studies provide a basis for estimating that approximately 55 percent of patients with schizophrenia have moderately good outcomes and 45 percent have more severe outcomes. These figures are more optimistic than earlier views for at least two reasons. First, sample selection was broader and more representative. Second, effective treatments, which make a considerable difference in the short-term course, also have a modest impact on the long-term course of the illness. Although no present treatment approach can prevent or cure schizophrenia, some approaches have had remarkable remedial effects on course. Despite not being scientifically verified, there is considerable evidence from a large body of clinical experience that a form of schizophrenia referred to as devastating schizophrenia, which represented about 15 percent of the cases before the introduction of antipsychotic medication, now represents only about 5 percent of the cases. This form of the illness had an acute rather than insidious onset, but, paradoxically, had an unrelenting deteriorating course. Another line of evidence suggests that outcome may be related to the time interval between the initial detection of schizophrenia and the initiation of antipsychotic treatment. The more rapidly patients are treated, the more benign is the course of illness. This observation has led to an increased interest in establishing a methodology for early detection and the development of intensive therapeutic interventions, which combine pharmacological and psychosocial treatments, in order to ascertain whether future course can be substantially affected by treatment. There is also considerable evidence suggesting that the prophylactic use of antipsychotic medication reduces the relapse rate by more than

one-half. This fact is largely responsible for making it possible to substantially reduce inpatient care in favor of brief hospital stay, crisis intervention, and community-based treatment. The level of success associated with this major shift in primary treatment setting as well as the serious shortcomings associated with shifting care to unprepared communities are noted in the discussion on treatment and rehabilitation. Predictors of outcome have been principally found to be related to the already-established pattern of illness, the early developmental pattern, and the emotional qualities of the patient. Patients with limited emotional expression, who demonstrate a lack of social drive and social affiliation during childhood, and who display poor social and occupational functioning in recent years, are quite likely to run a chronic course of the illness. On the other hand, patients who have a normal developmental history with an abrupt onset of psychosis, and who have not established a pattern of social and occupational failure, have a much better prognosis. There is also evidence that prognosis is better in females than males. However, some patients in the good prognosis group will progress to a devastating form of the illness. In general, there are more reliable predictors of poor than good prognosis, with prognosis uncertain until the pattern of illness has been established. There are interesting results from the World Health Organization study of the social determinants of outcome in different cultures. This work has documented that the course of schizophrenia tends to be more benign in developing countries than in developed countries. This difference in course is generally understood as representing a psychosocial influence on course rather than cultural differences in the causes of schizophrenia. The incidence and lifetime prevalence of the disease appear to be relatively comparable across cultures and societies. One compelling explanation for the observed difference is that the sociocentric structures of developing countries place less demand on individual performance and provide a more broadly supportive interpersonal environment than do the egocentric cultures of more developed nations. With their marked emphasis on individual accomplishment and productivity, the latter nations are more demanding and stressful for those with impaired drive or impaired mental functioning. Rather than finding an appropriate, usually reduced level of functioning, the patient with schizophrenia in Western industrialized societies tends to be isolated, with greatly reduced opportunities for work and meaningful social contacts. Indicative of this lack of involvement, unemployment rates for patients with schizophrenia are over 70 percent in the United States.

TREATMENT AND REHABILITATION The history of the care and treatment of patients with schizophrenia is replete with instances of both humane and inhumane approaches. From a practical and moral standpoint, the value of humane care is intrinsic and does not rest on scientific evaluation of efficacy. There is a large body of literature and scientific data regarding the pharmacological and psychosocial interventions and the rehabilitation of patients with schizophrenia. The general conclusions of this accumulated information are presented below. Pharmacological Interventions Prior to 1952, there were no generally applicable, effective pharmacological treatments of schizophrenia. Reserpine had been used with some limited success, and electroconvulsive treatment (ECT) was important in reducing symptoms in the most acutely disturbed cases. This situation changed abruptly with the introduction of chlorpromazine (Thorazine) in France in 1952 and in North America in 1954, which ushered in the modern era of effective pharmacological therapy for schizophrenia. The antipsychotic drugs used to treat schizophrenia have a wide variety of mechanisms of action, but all share the capacity to occupy postsynaptic dopamine receptors in the brain. Conventional antipsychotics or dopamine-receptor antagonists are often referred to as neuroleptics because of their neurological adverse effects. The new antipsychotics are less likely to exhibit these effects and have been referred to as atypical antipsychotics or serotonin-dopamine antagonists. The generally recognized clinical effect of antipsychotic drugs is to diminish symptom expression and reduce relapse rates. Although sedation may be a side effect and diminished anxiety a clinical effect, the primary value of these drugs is their remedial effect on positive symptoms, and not their sedating or tranquilizing properties. In contrast to positive symptoms, conventional antipsychotics have not been shown to be effective for either primary, enduring negative or deficit symptoms or the cognitive impairments observed in patients with schizophrenia. Antipsychotic drugs are used throughout the world for four primary clinical purposes: (1) to manage acute positive symptomatic disturbances; (2) to induce remission from positive symptom exacerbations; (3) to maintain the achieved clinical effect over prolonged periods of time (maintenance therapy); and (4) to prevent relapses or new episodes of positive symptom expression (prophylactic therapy). A recent emphasis with regard to the use of conventional antipsychotic drugs has been on dose reduction, in the hope of diminishing adverse effects without losing clinical benefit. The intent is to administer the drugs in a manner that will increase patient compliance and avoid illness exacerbations caused by patients' discontinuing their medication. The first atypical antipsychotic to be available for clinical use was clozapine. Clozapine has a unique mechanism of action, and was shown in the 1970s to have a superior effect on patients resistant to the therapeutic effects of conventional antipsychotics. However, patients on clozapine run an approximately 1 percent risk of agranulocytosis. This potentially lethal cessation in the production of white blood cells was associated with a series of deaths in Finland during the mid-1970s and led to a decreased use of clozapine in Europe and a failure to market the drug in the United States. Interest in clozapine in the United States was rekindled by the results of a large-scale multicenter study in chronic, treatment-resistant patients with schizophrenia. The study yielded convincing evidence of clozapine's effectiveness in ameliorating positive symptoms in approximately one-third of these patients. In addition, the study also showed that clozapine could be used with relative safety within the context of careful monitoring for agranulocytosis. Clozapine represents the first incremental gain in the effectiveness of the pharmacological agents used to treat schizophrenia since the original introduction of chlorpromazine. The demonstration of clozapine's efficacy for treatment-resistant patients has spawned considerable interest in the development of new pharmacological treatments for schizophrenia. Risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Serlect), ziprasidone and other compounds have quickly followed. Since the specific mode of clozapine's superior therapeutic efficacy is not known, it is not possible to design new compounds with confidence that they will have superior efficacy. However, each of the new medications appears to be as effective an antipsychotic drug as the conventional antipsychotics, but with a substantially decreased adverse effect burden. This decreased adverse effect burden may result in greater effectiveness based on better patient compliance, and may reduce the incidence of long-lasting adverse effects (e.g., tardive dyskinesia). As each new drug is introduced, it will be important to examine whether the drug shares with clozapine a superior efficacy for positive symptoms. In addition, it will be important to examine if there are any meaningful advantages to using atypical antipsychotic medications in first-episode patients. Finally, future drug development must also recognize the absence of significant therapeutic efficacy of currently available medications for the primary avolitional component of the disease and the fundamental cognitive impairments detected by various psychological performance tasks. The rapidly advancing knowledge of brain biochemistry and brain-behavior relationships has set the stage for the development of new models for psychopathological processes other than positive symptoms. These new models may prove useful for screening potential novel treatments, which would enable a more comprehensive treatment of the varied manifestations of schizophrenia. Lithium and antiepileptic, antidepressant, and antianxiety drugs have also been used to treat the positive symptoms of schizophrenia. However, these drugs have not proved to be effective alternatives to antipsychotic therapy, nor has there been a consistent demonstration of substantially enhanced benefits when they are used in combination with antipsychotics. A small subgroup of patients may be differentially responsive to a class of drugs other than antipsychotics, but in the absence of the capacity to identify in advance which patients will respond favorably, it is difficult to prove or disprove this proposition. In contrast, these drugs and a series of medications that counteract the side effects of conventional antipsychotics have been effective for co-occurring anxiety and depressive, manic, and aggressive symptoms. Augmentation strategies have also been used for persistent negative symptoms, including deficit symptoms. These strategies have included the use of dopamine and serotonergic and noradrenergic agents. Perhaps the most promising development is the attempt to treat these symptoms by activating the NMDA receptor at the glycine site. Glycine and d-cycloserine have produced encouraging results in preliminary controlled clinical trials. ECT was frequently used to treat patients with schizophrenia prior to the introduction of antipsychotic drugs. ECT is particularly effective in the treatment of catatonic stupor and excitement, but generally produces results similar to those obtained with antipsychotics, (i.e., a reduction of positive symptoms rather than a reversal of long-term functional impairments). Although ECT is safe and painless, its use is restricted, in part by litigation and societal attitudes, but also because any therapeutic advantage gained in an initial series of treatments is not easily maintained. Also, there is no indication that ECT is effective in patients who are resistant to conventional antipsychotics. For all of these reasons, drug treatment approaches are generally preferred. Psychosocial Interventions The debate over whether patients should be administered pharmacological agents or psychosocial treatments has given way to the search for how these treatments should be optimally integrated. Controlled clinical trials have conclusively demonstrated that intensive psychotherapy is less effective than drug treatment; that it is not superior to less expensive, less ambitious psychosocial forms of psychotherapy; and that it should no longer be considered an alternative to the use of antipsychotic drugs. In addition, studies have repeatedly demonstrated that supportive forms of psychosocial treatment are entirely compatible with drug treatment and can increase the effectiveness of overall treatment, reduce the amount of medication necessary, enhance patient participation in

the full range of treatment, and optimize social and occupational functioning. Especially impressive are studies documenting the considerable additional benefit achieved in reducing relapse and hospitalization rates when family therapy and education programs are added to maintenance pharmacological treatment. These studies make it clear that psychosocial and rehabilitative interventions have become essential components of the comprehensive treatment of patients with schizophrenia. Psychosocial and rehabilitation interventions include supportive, problem-solving, educationally oriented psychotherapy; family therapy and education programs aimed at helping patients and their families understand the patient's illness, reduce stress, and enhance coping capabilities; social and living skills training; vocational training, including job coaching; and the provision of supervised residential living arrangements. The development and increased utilization of psychosocial services have been complemented by the evolution of services designed to decrease the utilization of inpatient hospital services and to maintain the patient in the community. Assertive community treatment teams are designed to provide intensive outreach services to patients who are unable to be maintained in the community with traditional outpatient clinical treatment. Crisis management services, including 24-hour crisis beds and partial hospitalization programs, represent alternatives to hospitalization during periods of symptom exacerbation. The development of these services reflects the ongoing shift in the treatment of the patient with schizophrenia from a hospital-based to a community-based system of care. When optimal treatment with these services is provided, the rewards of therapeutic accomplishment, reduction in morbidity, and economic cost benefits are profound and rival therapeutic accomplishments found anywhere in medicine. The demonstrated benefits of these services challenge the field to establish an adequate community-based treatment approach prepared to meet the challenge and demands of broad-based integrated treatment.

FUTURE DIRECTIONS The care and study of the person afflicted with schizophrenia are extraordinarily interesting and promising. Basic brain science has matured, and technological advances permit increasingly sophisticated questions to be addressed regarding the anatomy, ultrastructure, and function of the brain. The field is closer to understanding risk factors at the level of causal mechanism, and new treatments are being developed at an increasing rate. The cadre of schizophrenologists capable of integrating basic and clinical sciences has grown substantially, and new paradigms providing heuristic advantage in the classification of psychopathological phenomena provide and address the problem of heterogeneity, which has undermined so much of the investigative work in schizophrenia. Physiological markers have been validated, and investigators are able to articulate, with ever-increasing specificity, the what and where of brain dysfunction in patients with schizophrenia. The twenty-first century promises to be a time of fundamental discovery regarding the etiology and pathophysiology of what may be the world's most vexing public health problem. These developments have emerged at a time of decreasing stigma, increasing partnership in clinical care and research with citizen advocacy groups, and the initiation of nationwide private fundraising for research on this disease.

SUGGESTED CROSS-REFERENCES More detailed discussions of etiology, brain structure and function, clinical features, and somatic and psychosocial treatments are presented in the other sections of Chapter 12. A detailed introduction to areas of neuroscience and cognitive science relevant to schizophrenia is provided in Section 1.2 on functional neuroanatomy, Section 1.3 on neuronal development and plasticity, Section 1.15 and Section 1.16 on brain imaging, and Section 3.1 on perception and cognition. SECTION REFERENCES Andreasen NC, Arndt S, Swayze V II, Cizadlo T, Flaum M, O'Leary D, Ehrhardt JC, Yuh WTC: Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 266:294, 1994. *Andreasen NC, O'Leary DS, Cizadlo T, Arndt S, Rezai K, Boles Ponto LL, Watkins G ll, Hichwa RD: Schizophrenia and cognitive dysmetria: A positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad Sci 93:9985, 1996. Braff DL: Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 19:233, 1993. Breier A, Su T-P, Saunders R, Carson RE, Kolachana BS, De Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WD, Pickar D: Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a noval positron emission tomography method. Proc Natl Acad Sci 94:2569, 1997. Buchanan RW, Brandes M, Breier A: Treating negative symptoms: Pharmacological strategies. In The New Pharmacotherapy of Schizophrenia, vol 36, A Breier, editor. American Psychiatric Press, Washington, DC, 1996. Carlsson A: Neurocircuitries and neurotransmitter interactions in schizophrenia. Int Clin Psychopharmacol 3:21, 1995. Carpenter WT, Buchanan RW: Schizophrenia. N Engl J Med 330:681, 1994. *Carpenter WT, Buchanan RW, Kirkpatrick B, Tamminga C, Wood F: Strong inference, theory testing, and the neuroanatomy of schizophrenia. Arch Gen Psychiatry 50:825, 1993. Cohen JD, Servan-Schreiber D: A theory of dopamine function and its role in cognitive deficits in schizophrenia. Schizophr Bull 19:85, 1993. Conley RR, Buchanan RW: Evaluation of treatment-resistant schizophrenia. Schizophr Bull 23:663, 1997. *Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W: Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci 94:587, 1997. *Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, McCarley R, Coyle JT: A placebo-controlled trial of schizophrenia. Arch Gen Psychiatry 56:21, 1999.

D-cycloserine

added to conventional neuroleptics in patients with

*Goff DC, Wine L. Glutamate in schizophrenia: Clinical and research implications. Schizophr Res 27:157, 1997. *Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichenstein M: Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999.

56:29,

Howells JG, editor: The Concept of Schizophrenia: Historical Perspectives. American Psychiatric Press, Washington, DC, 1991. Kane JM: Drug therapy: Schizophrenia. N Engl J Med 334:34, 1996. Kendler KS, Straub RE, MacLean CJ, Walsh D: Reflections on the evidence for a vulnerability locus for schizophrenia on chromosome 6p24-22. Am J Med Genet (Neuropsychiatr Genet) 67:124, 1996. Lawrie SM, Abukmeil SS: Brain abnormality in schizophrenia. Br J Psychiatry 172:110, 1998. *Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, Mors O, Andersen PK, Melbye M: Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med 340:603, 1999. Olney JW, Farber NB: Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998, 1995. Schooler NR, Keith SJ, Severe JB, Matthews SM, Bellack AS, Glick ID, Hargreaves WA, Kane JM, Ninan PT, Frances A, Jacobs M, Lieberman JA, Mance R, Simpson GM, Woerner MG: Relapse and rehospitalization during maintenance treatment of schizophrenia. Arch Gen Psychiatry 54:453, 1997. *Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnoor L, Jones T, Frackowiak RSJ: A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176, 1995. Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, Gorman JM: Schizophrenia after prenatal famine: Further evidence. Arch Gen Psychiatry 53:25, 1996. Weinberger DR: From neuropathology to neurodevelopment. Lancet 346:552, 1995.

Textbook of Psychiatry

12.2 SCHIZOPHRENIA: EPIDEMIOLOGY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.2 SCHIZOPHRENIA: EPIDEMIOLOGY GRAYSON S. NORQUIST, M.D., M.S.P.H., AND WILLIAM E. NARROW, M.D., M.P.H. Evolution of Nomenclature and Diagnostic Criteria Diagnostic Assessment Instruments Community Surveys Prevalence Incidence Use of Services Risk Factors Future Directions Suggested Cross-References

An etiologically puzzling and clinically severe disorder, schizophrenia has long held the attention of psychiatric epidemiologists. Until fairly recently, however, efforts to elucidate the epidemiology of schizophrenia were hindered by two critical deficiencies: the lack of reliable case definition and limited generalizability of findings because of reliance on treated samples. Two lines of scientific development have converged since the late 1970s to help resolve these issues and advance epidemiological studies of schizophrenia. First was the development of Diagnostic and Statistical Manual of Mental Disorders (DSM), culminating in the publication of operationalized criteria for schizophrenia in the third edition of DSM (DSM-III). Second, modern epidemiological methods, particularly those of chronic disease and genetic epidemiology, have been applied to the study of schizophrenia. These methods have increased the robustness of epidemiological research findings because of their emphasis on precise study designs, representative sampling, and sophisticated techniques of data analysis. Psychiatric epidemiology is traditionally concerned with patterns of psychopathology in human population groups and the factors that influence these patterns. It examines the occurrence of pathology in terms of time, place, and individual characteristics, in order to elucidate the etiology of illness and its population burden. In terms of schizophrenia, such research includes studies of prevalence and incidence, natural history of illness including risk and protective factors for onset, remission, and relapse; longitudinal followup of populations at high risk for schizophrenia, including children of parents with schizophrenia or relatives of a proband with schizophrenia; and genetic epidemiology, including twin, family, association, and linkage studies in samples that are representative of the persons with schizophrenia, an associated marker of interest, or a population isolate with a high prevalence of the disorder. In epidemiology, a population is a collection of individuals defined by time, place, and characteristics such as age, sex, and race. Although general community populations are often studied, epidemiological study populations may be defined in other ways, including treatment status or exposure to a risk factor. For rare disorders such as schizophrenia, it is often easier to sample study cases from treated populations. However, by excluding untreated cases, the findings are not generalizable to all individuals with schizophrenia. Point prevalence is defined as the number of persons in a population who are affected with a disorder at a given point in time. Incidence is defined as the number of persons without a disorder at the beginning of a given time period who subsequently develop the disorder in that time period. A “first” or “true” incident case has never had a previous episode of disorder; a recurrent case has had a previous episode. Period prevalence includes existing cases at the beginning of a given time period (point prevalence), plus all incident cases developing in the time period, both first incidence and recurrence. An important concept in epidemiology is that prevalence is proportional to incidence and duration (P~I × d). Thus, in a chronic condition such as schizophrenia, a steady prevalence is maintained by a long duration of illness despite a relatively low incidence rate; cutting short the duration of illness would decrease the prevalence of the condition if incidence remained unchanged.

EVOLUTION OF NOMENCLATURE AND DIAGNOSTIC CRITERIA The value of operationalized diagnostic criteria as a commonly accepted language for clinicians and researchers cannot be overemphasized. In the United States the DSM system of classification has become the diagnostic standard for both clinical and research purposes. DSM In 1952 the first edition of DSM (DSM-I) was published by the Mental Hospital Service of the American Psychiatric Association. DSM-I was derived largely from the section on mental disorders in the Standard Classified Nomenclature of Disease developed by the National Conference on Nomenclature of Disease in 1933. In DSM-I, “Schizophrenic Reactions” were classified under “Disorders of Psychogenic Origin or without Clearly Defined Physical Cause or Structural Change in the Brain.” and were described as “synonymous with formerly used term dementia praecox.” It represents a group of psychotic reactions characterized by fundamental disturbances in reality relationships and concept formations, with affective, behavioral, and intellectual disturbances in varying degrees and mixtures. The disorders are marked by strong tendency to retreat from reality, by emotional disharmony, unpredictable disturbances in stream of thought, regressive behavior, and in some, by a tendency to “deterioration.” The predominant symptomatology will be the determining factor in classifying such patients into types. The types of schizophrenic reactions were simple, hebephrenic, catatonic, paranoid, acute undifferentiated, chronic undifferentiated, schizo-affective, childhood, and residual. DSM-II The second edition of DSM (DSM-II) was published in 1968 and was an attempt to achieve uniformity of diagnostic classification at an international level. The nomenclature used in DSM-II was based, with a few exceptions, on the terms used in the eighth revision of the World Health Organization's (WHO's) International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-8). DSM-II had initial attempts to remove from the diagnostic nomenclature implications about the nature or cause of a disorder. Thus, the “schizophrenic reaction” of DSM-I became “schizophrenia” in DSM-II. Attempts were also made to distinguish schizophrenia from the psychotic mood disorders. The term schizophrenia was defined as: . . . a group of disorders manifested by characteristic disturbances in thinking, mood, and behavior. Disturbances in thinking are marked by alterations of concept formation which may lead to misinterpretation of reality and sometimes to delusions and hallucinations, which frequently appear psychologically self-protective. Corollary mood changes include ambivalent, constricted, and inappropriate emotional responsiveness and loss of empathy with others. Behavior may be withdrawn, regressive and bizarre. The schizophrenias, in which the mental status is attributable primarily to a thought disorder, are to be distinguished from the Major affective illnesses which are dominated by a mood disorder. The paranoid states are distinguished from schizophrenia by the narrowness of their distortions of reality and by the absence of other psychotic symptoms. Several subtypes remained unchanged in DSM-II: simple, hebephrenic, paranoid, childhood, and residual. Catatonic type was divided into excited and withdrawn subtypes, and schizoaffective type was divided into excited and depressed subtypes. Acute undifferentiated type was renamed acute schizophrenic episode. Latent type was distinguished from the DSM-I chronic undifferentiated type in order to cover patients unofficially diagnosed as having incipient, prepsychotic, pseudoneurotic, pseudopsychopathic, or borderline schizophrenia. DSM-III and DSM-III-R The publication of the third edition of DSM (DSM-III) in 1980 represented a revolutionary advance in the development of a common diagnostic language for clinicians and researchers. It offered explicit criteria for diagnosing disorders based on observable signs and symptoms, rather than the earlier prose definitions that had a rather wide latitude of clinical interpretation. Beginning with DSM-III and continuing through the revised third edition of DSM (DSM-III-R) and the fourth edition (DSM-IV), the criteria for schizophrenia have followed a general pattern. These are: (1) a listing of the psychotic symptoms, of which one or two are required to be present; (2) a requirement for decline in social functioning and self-care; (3) “exclusion criteria” in which other disorders must be ruled out before assigning a diagnosis of schizophrenia; and (4) a duration and course criterion. Thus, in DSM-III, schizophrenic disorder was defined by the presence of six criteria: Criterion A required the presence of one of a list of six psychotic symptoms: three having to do with delusions; two with auditory hallucinations; and one with thought disorder associated with affective disturbance, delusions, hallucinations, or catatonic or grossly disorganized behavior. Criterion B required a deterioration in functioning from a previous level. Criterion C required a 6-month duration of illness with an active phase that included criterion A, and additional prodromal and residual symptoms, which were listed. Criterion D excluded persons for whom psychotic symptoms were preceded by a manic or depressive syndrome or for whom the mood syndrome was not “brief” in relation to the duration of the psychotic syndrome. Criterion E restricted age of onset to under 45 years. Criterion F ruled out syndromes that were “due to” any organic mental disorder or mental retardation. In DSM-III, catatonic, paranoid, and residual types were maintained. Hebephrenic

type was renamed disorganized type. The term chronic was removed from chronic undifferentiated type. Schizoaffective type was removed from the schizophrenic disorders, renamed schizoaffective disorder and placed in the “Psychotic Disorders not Elsewhere Classified” category; unlike schizophrenia, no criteria were provided for the diagnosis of schizoaffective disorder in DSM-III. Another innovation in DSM-III was its classification of course of illness into categories of subchronic, chronic, subchronic with acute exacerbation, chronic with acute exacerbation, and in remission. DSM-III-R, published in 1987, contained several changes in criteria for schizophrenia (no longer “schizophrenic disorder”). The various types of delusions specified in DSM-III criterion A were simplified—DSM-III-R distinguished only bizarre and nonbizarre delusions. In addition criterion A symptoms were expanded to allow nonauditory hallucinations. A minimum duration requirement of 1 week for criterion A symptoms was set. Criterion B was clarified, with a comparison point of the person's highest-ever level of functioning. Criterion C in DSM-III became criterion D in DSM-III-R; little was changed in this criterion except for the addition of “marked lack of initiative, interests, or energy” as a prodromal or residual symptom. Criterion D, the mood disorder exclusion, became criterion C in DSM-III-R; now if a mood syndrome was ever present during an active phase of the illness, schizophrenia was not diagnosed. Significantly, criterion E, the age requirement, was dropped in DSM-III-R. The organic mental disorder exclusion remained in DSM-III-R, and a new criterion was added that dealt with the comorbidity of autistic disorder and schizophrenia. DSM-IV Few changes were made to the diagnosis of schizophrenia in DSM-IV. Most significantly for case identification, the duration requirement for criterion A symptoms was increased to 1 month. In Criterion A, the concept of negative symptoms was added and the concept of loosening of associations was dropped and replaced with “disorganized speech.” Specific criteria for prodromal and residual phases were dropped. Modifications were made to the organic disorder exclusion to include direct physiological effects of a substance, and the autistic disorder relationship was expanded to include all pervasive developmental disorders. No additional schizophrenia types were added in DSM-IV.

DIAGNOSTIC ASSESSMENT INSTRUMENTS Identification of persons with mental disorders in the community, regardless of treatment status or severity of disorder, is the ultimate test of a diagnostic classification system. In order to be useful for service planning and research needs, a credible diagnostic classification system must be able to detect and correctly classify untreated cases and cases on the threshold of diagnosis. Unfortunately, for many years the lack of reliably operationalized diagnostic criteria hindered the ability of epidemiologists to identify cases in the community, and prevalence rates were usually based on treated cases only. Diagnostic Interview Schedule In the 1970s several psychiatric interviews were developed: the Schedule for Affective Disorders and Schizophrenia (SADS), a clinical interview based on Research Diagnostic Criteria (RDC); the Present State Examination (PSE), a nondiagnostic clinical interview that covered present symptoms only; the Psychiatric Epidemiological Research Interview (PERI), another nondiagnostic interview; and the Renard Diagnostic Interview, a diagnostic interview based on Feighner diagnostic criteria. The development of DSM-III in 1980 spurred renewed interest in gathering community epidemiological data based on the new criteria, but none of these interviews were entirely suitable for the purpose. To respond to this need, the Diagnostic Interview Schedule (DIS) was developed for use in the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area (ECA) Program. The DIS covered DSM-III criteria for schizophrenia and schizophreniform disorder; Research Diagnostic Criteria for schizophrenia and schizoaffective disorder, manic and depressed types; and Feighner criteria for schizophrenia. It was a highly structured interview, based on respondent self-report only, which did not allow interviewer discretion in the administration of questions or recording of responses and did not rely on other clinical information to make diagnoses. Diagnoses were generated by computer algorithm, not by the interviewer. Because of these factors, the DIS was suitable for administration by nonclinician interviewers and could be administered in large surveys for relatively low cost. The DIS has undergone subsequent revisions to incorporate DSM-III-R and DSM-IV diagnostic criteria and it has been translated into over twenty other languages. Various reliability and validity studies performed on the DIS have demonstrated inconsistent results for schizophrenia; in such studies, results are often within an acceptable range if corrected for the low prevalence of schizophrenia in the population. CIDI With the evolution of the DSM and the International Classification of Diseases (ICD) diagnostic systems, the need for a comprehensive diagnostic instrument for use in cross-cultural and comparative studies worldwide became apparent. To address this need, the Composite International Diagnostic Instrument (CIDI) was developed as a joint venture of WHO and the U.S. Alcohol, Drug Abuse, and Mental Health Administration. The structured question-and-probe structure of the DIS served as the template for the construction of the CIDI. Questions from the PSE, an interview widely used in epidemiological studies outside the United States were then added. Updates of the CIDI added criteria from the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10), and then DSM-III-R and DSM-IV criteria. The CIDI, like the DIS, remains a highly structured diagnostic interview with diagnoses made via computer algorithm. Throughout its development, efforts were made to ensure its cross-cultural appropriateness.

COMMUNITY SURVEYS Three community surveys are most frequently cited for data on the prevalence and incidence of schizophrenia. ECA NIMH Epidemiologic Catchment Area Program The ECA NIMH Program is the largest community survey of mental disorders ever undertaken in the United States. A total of 18,571 household residents and 2290 institutional residents (of nursing homes, jails, psychiatric hospitals) age 18 and over were sampled and interviewed in five areas: New Haven, Baltimore, Durham, St. Louis, and Los Angeles. Two face-to-face interviews were done 12 months apart (Wave I and Wave II). A telephone interview (face-to-face in New Haven) of the household respondents was conducted 6 months after Wave I. The institutional residents were interviewed in Waves I and II only; no telephone interview was conducted for these respondents. DSM-III diagnostic data were obtained at Waves I and II using the DIS. Respondents were asked about their use of health services at each wave. Questions to ECA respondents pertaining to use of mental health services covered use of ambulatory specialty mental and addictive, general medical, and human services, and admissions to hospitals and residential treatment centers for reasons related to mental health or addictions. National Comorbidity Survey Following the success of the ECA Program, the National Comorbidity Survey (NCS) was conducted in the early 1990s to obtain more detailed information about mental disorders in the community, particularly the relation between co-occurring mental disorders and co-occurring mental and substance use disorders. Conducted by the Institute for Social Research at the University of Michigan, the study used a nationally representative household sample of 15- to 54-year-olds. A modified version of the CIDI (the UM CIDI) for DSM-III-R was used in the NCS. For psychotic disorders, in addition to a CIDI computerized diagnosis, a clinical reinterview was conducted with individuals who screened positive for psychosis on the CIDI. Results pertaining to the schizophrenia and related disorders are usually presented in a summary category called nonaffective psychosis, which is made up of schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, and atypical psychosis. Comparisons of the results of the ECA to the NCS are not straightforward because of the differences in the diagnostic instrument, differences in age range of respondents, and temporal differences, among other factors. WHO Collaborative Study on the Determinants of Outcome of Severe Mental Disorders (DOS) This study was conducted at 12 field centers in 10 countries across the world. At each of the 12 centers, all persons in a catchment area making first contact with a psychiatric, medical, or other agency for symptoms of possible schizophrenia were identified, assessed, and followed for 2 years. Like the NCS, the study selected only individuals between the ages of 15 and 54. The assessment instrument was the PSE. The final cohort size was 1379. Incidence of schizophrenia was obtained in 7 sites and clinical information on diagnosis and course was obtained at all 12 sites.

PREVALENCE A 1987 review of over 70 prevalence studies of schizophrenia published since 1948 identified point prevalence in various population groups ranging from 0.06 percent to 1.7 percent, with lower rates in developing countries. It was suggested that this difference was not entirely caused by differences in diagnostic procedures and study methods. Rather, it was posited that higher recovery rates in developing countries and etiological heterogeneity, among other factors, could account for at least a tenfold difference in prevalence. The prevalence of schizophrenia in the ECA is presented in Table 12.2-1. According to convention in the presentation of ECA results, these figures represent the combined prevalence of schizophrenia and schizophreniform disorders. One-month prevalence is conventionally viewed as “current” prevalence, so based on the ECA results, 0.7 percent of the adult population currently has a diagnosis of schizophrenia. The 1-year prevalence is similar, whether measured retrospectively or prospectively. The prospective period prevalence illustrates the chronicity of schizophrenia: more than twice as many persons had the disorder at the start of the year (0.7 percent) as developed the disorder or had a relapse during the following year (0.3 percent).

Table 12.2-1 Prevalence of Schizophrenia Disorders in the NIMH Epidemiologic Catchment Area Program

Based on the UM CIDI DSM-III-R computer diagnosis, the lifetime prevalence of “narrowly defined psychotic illness” (schizophrenia or schizophreniform disorder) in the National Comorbidity Survey was 1.3 ± 0.2 percent, very close to the ECA lifetime prevalence. Based on clinician diagnoses, the lifetime prevalence of narrowly defined psychotic illness in the NCS dropped to 0.16 ± 0.06 percent. In examining the sociodemographic correlates in Table 12.2-2, it is helpful to keep in mind that an unadjusted prevalence represents the prevalence of schizophrenia as it actually appears in the community. The odds ratio tells us whether this rate is different when corrected for differences in age, sex, race, marital status, and socioeconomic status among the groups. For example, the prevalence of schizophrenia among blacks is 1.2 ± 0.2 percent, twice as high as for non-black, non-Hispanic persons. However, when correcting for differences in age, sex, race, and socioeconomic status between the ethnic groups, the odds of having schizophrenia among blacks (0.86) is actually no different than the odds for non-black, non-Hispanic persons (whose odds ratio as the comparison for this group is set at 1.00). It should also be noted that despite the size of the ECA survey, relatively few cases of schizophrenia were detected so there is limited power to detect significant differences in prevalence.

Table 12.2-2 Sociodemographic Correlates of 1-Month Prevalence of Schizophrenia in the NIMH ECA Program

Persons over age 65 were significantly less likely than persons between 18 to 24 years of age to have a diagnosis of schizophrenia. Persons aged 25 to 44 were twice as likely to have the diagnosis, although this difference did not reach statistical significance. The sex ratio was relatively even. Although blacks had twice the rate of schizophrenia in the community compared to other ethnic groups, when adjusted for socioeconomic status, age, and other factors, this difference disappeared. Being unmarried, particularly separated or divorced, was associated with a diagnosis of schizophrenia. There was an eightfold increase in odds of having schizophrenia in the lowest socioeconomic quartile compared to the highest quartile. Comorbidity of schizophrenic disorders with substance use disorders in the ECA Program is shown in Table 12.2-3. Both the ECA and the NCS have demonstrated extremely high lifetime comorbidity of the psychotic disorders and substance use disorders; 50 to 60 percent of persons with schizophrenia or nonaffective psychosis had a comorbid alcohol or drug use diagnosis. Comorbidity in the NCS was higher, which may be due to methodological differences as well as secular changes in drug and alcohol use in the United States.

Table 12.2-3 Comorbidity of Schizophrenia With Substance Use Disorders in the ECA Program

INCIDENCE In the WHO DOS, incidence (based on service contacts) ranged between 0.016 and 0.042 percent per year across the sites for broadly defined schizophrenia. For narrowly defined schizophrenia, incidence showed less variation, ranging from 0.007 to 0.014 percent, which was not a statistically significant difference. Age- and sex-specific incidence showed a tendency toward earlier onset in males, a consistent finding in both developing and developed countries. Overall disease expectancy was virtually the same for males and females across the overall age range of 15 to 54 years. Because the DOS minimized methods variance through standardized case ascertainment and assessment methods, the consistency in the incidence of narrowly defined schizophrenia across several international sites is a noteworthy finding. The study's investigators raised fundamental questions in the study of risk factors for schizophrenia such as the possibility of a widely distributed genetic liability, the roles of ubiquitous and culturally specific environmental factors in interacting with that liability, and alternatively, the possibility of multiple genetic liabilities with remarkably similar phenotypic expression in various population groups. Several studies report that the incidence of schizophrenia is on the decline. Interpretation of these findings is not easy, requiring as it does an accounting of the rapid changes in psychiatry that have occurred in the past 30 years, as well as in social policy and in population demographics. For example, incidence based on inpatient admissions, once widely accepted, is no longer a valid indicator of illness onset because of the shift of treatment away from institutionalization. Diagnostic systems have changed dramatically and these changes are likely to be reflected in different estimates. As the populations of developed countries continue to get older, fewer citizens will be at risk for developing schizophrenia. The issue of declining incidence has not yet been satisfactorily resolved and controversy remains as to what degree the findings represent a true decline in new cases versus a methodological artifact.

USE OF SERVICES In the ECA Program about 64 percent of persons with a current diagnosis of schizophrenia used some form of mental health service in a 1-year period, a relatively high treated percentage compared to the other disorders surveyed and similar to bipolar I and II disorder and somatization disorder. About 17 percent received inpatient treatment at some point in the year. Consistent with the clinical picture of schizophrenia, most treated individuals had contact in a specialty or general medical setting. Among all ECA disorders, individuals with schizophrenia had the highest proportion (46 percent) treated in the specialty sector, and the bulk of treatment visits were made to this sector as well. Despite the large number of people who had visited the general medical sector, relatively few visits were made there. About 14 percent of persons with schizophrenia were seen only in the general medical sector.

RISK FACTORS The term risk refers to the likelihood that a person who does not currently have schizophrenia will develop the disorder after exposure to certain factors. Thus, a risk factor for schizophrenia is an inherent or acquired characteristic or an external condition associated with an increased probability of developing schizophrenia. Epidemiological studies in schizophrenia seek to determine the most important risk factors for this disorder. The concept of risk can be expressed in several ways. The most common is a report of the absolute number of new schizophrenia cases detected in a population exposed to a postulated risk factor. The terms relative risk (risk ratio) and risk difference (attributable risk)—expressions of the relationship of the incidence in those exposed to the risk factor to that of those not exposed—are also often used. In case control studies, if the disorder is rare, the risk ratio is approximated by an odds ratio. Significant risk factors are identified through the use of several different study designs. One type, cross-sectional studies, reports descriptive data at a defined point in time, such as the increased presence of a particular factor in a population with a higher prevalence of schizophrenia. Case control studies compare schizophrenia cases with unaffected controls and determine whether those who express the disease were exposed to a given risk factor. The most informative (and expensive) study design is the prospective cohort study, which follows a group over time to determine whether those exposed to certain risk factors have a higher incidence of schizophrenia. Risk factors are categorized in several different ways: demographic and concomitant factors (such as age, sex, race, social class), precipitating factors that operate immediately before the onset of schizophrenia (such as life events, migration), and predisposing factors that act for a long period of time or during an earlier part of life (such as genes, perinatal complications, infections). Another schema describes risk factors as either familial influences or sociodemographic factors. The latter can be further subdivided into mutable factors (such as social class, marital status, immigration) and immutable ones (such as ethnic group, sex, birthplace); mutable sociodemographic factors could be a result and not a cause of the disease. This latter distinction is particularly difficult to disentangle in cross-sectional studies. Several cautions are necessary before reports from studies of risk factors for schizophrenia are evaluated. First, a high prevalence of schizophrenia in a particular area may be the result of protracted illness rather than an increased incidence of schizophrenia (i.e., prevalence is roughly equal to incidence × duration). Second, studies that report only the prevalence of schizophrenia may have failed to control other confounding factors, such as socioeconomic status, that might increase prevalence. Third, designating something as a risk factor does not imply that everyone exposed to it is at personal risk of developing schizophrenia. It means that the group of people exposed to the risk factor at some time are likely to show a higher incidence of schizophrenia than a similar group who were not exposed. Risk does not prove causation but rather an association between that risk factor and the development of schizophrenia. Fourth, schizophrenia may be an etiologically heterogeneous disorder involving many risk factors and many protective factors. Earlier studies or risk factors have many methodological problems, the most important being the failure to standardize diagnostic criteria for selection of schizophrenia cases. However, those studies have helped in the continued search to understand this complicated disorder. Genetic Factors Identification of a genetic influence is a major challenge in the understanding of schizophrenia. The search for a genetic risk factor has been examined through studies of twins, of families, and of adopted-away children of parents with schizophrenia. Twin studies have shown a concordance of 33 to 78 percent among monozygotic twins, but of only 8 to 28 percent in dizygotic twins. Those results may be affected by selection bias if monozygotic twins are more likely to come to the attention of researchers than are dizygotic twins. Also, monozygotic twins may have greater environmental similarity. Family studies reveal that first-degree relatives of a person with schizophrenia have approximately a fivefold to tenfold chance of developing schizophrenia than nonrelatives. Children have about a 35 percent greater chance of schizophrenia if both parents have schizophrenia compared with about a 1 percent lifetime risk if neither parent has schizophrenia. Although the results from family studies are thought to indicate genetic influences, similar environmental factors among relatives cannot be discounted. Adoption studies are conducted in an effort to control environmental influences. Those studies show that the adopted-away offspring of persons with schizophrenia are at increased risk for schizophrenia and schizophrenia-spectrum disorders. More recent studies using narrower, criterion-based definitions of schizophrenia have reported risk figures that are lower than those reported in earlier studies. Although there are methodological problems with all three study approaches, findings from them suggest some type of genetic influence in schizophrenia, the significance of which has yet to be delineated. Likewise, the mode of transmission has not been found. Recent efforts have focused on linkage analyses and attempts to locate specific genes. Genetic and environmental factors play a role in the development of schizophrenia, and further refinement in methodology should help to identify the environmental and genetic components of schizophrenia. Ethnicity and Racial Factors Several studies have discovered differences in the prevalence and number of new cases of schizophrenia among various ethnic and racial groups. The findings are not consistent and may result from failure to control for confounding factors such as social class, age, sex, and immigration status. Data from the NIMH ECA study confirm that if potential confounding factors such as socioeconomic status are controlled, the difference in prevalence across races disappears. Previous studies of different geographical areas have found a higher prevalence and a larger number of new cases in different countries (e.g., Ireland) and within countries (e.g., the Istrian peninsula of Yugoslavia). Most studies comparing geographical areas are usually flawed because they fail to validate diagnostic methods in different ethnic groups and localities. The WHO Determinants of Outcome study reported that the incidence of schizophrenia is similar in various cultures, especially when a restricted definition is used. If true differences in incidence can be shown, perhaps differences in environmental characteristics, genetic characteristics, or both, can be found in these areas. Age Early studies showed mean ages of onset for schizophrenia well below 45 in men and women. However, recent data indicate that onset after age 45 is not as rare as was previously assumed. Data from the ECA study reveal that schizophrenia may remain undiagnosed in the elderly because the disease has a different presentation in this age group. When compared with younger persons, most elderly people with delusions or hallucinations may not have the typical pattern of chronic progressive schizophrenia and are less likely to be significantly impaired or to be under the care of a mental health specialist. Sex Studies that do not separate groups by age of onset show a male-to-female ratio of close to 1, but this changes when various age cohorts are examined. Men are most likely to have the onset of symptoms between ages 15 and 25; women are at highest risk at ages 25 to 35; the reasons for this difference are not clear. The disease may manifest differently in the two sexes, hormonal factors may be involved or sociocultural factors may predispose men to earlier case findings. As data from the WHO DOS show, when different cultures are examined the findings (earlier date for first treatment and first hospitalizations for men) are the same. More asocial premorbid characteristics, birth complications, and cerebral structural changes (especially in the left or dominant hemisphere) have been reported in men than in women, and schizophrenia in men may have a more chronic and disabling course. The findings are not conclusive and are limited by methodological problems such as failure to control for sociocultural factors. Season and Birth Order Studies have shown that a disproportionate number of persons with schizophrenia are born during winter months (seasonal excess of approximately 10 percent); which, together with a birth pattern in their nonschizophrenic siblings that is similar to that seen in the general population, suggests the presence of a seasonal factor. Proposed explanations for this seasonal effect include deleterious environmental factors in the winter (such as temperature, nutritional deficiencies, infectious agents); a genetic factor in those with a propensity for schizophrenia that protects against infection and other insults and thus increases the likelihood of survival; and more frequent conception in the spring and summer by the parents of persons with schizophrenia. Although no experimental testing has been conducted, studies appear to favor the harmful-effects hypothesis that schizophrenia involves infectious agents, but the

other hypotheses have not been ruled out conclusively. Although some studies in the southern hemisphere confirm a higher birth rate for schizophrenic persons in winter than in other seasons, further study of that hypothesis is needed. There are a number of methodological problems with previous studies. If there are statistically significant increases of schizophrenic births during the southern hemisphere winter, environmental factors should be favored over sociocultural ones. Whether winterand summer-born persons with schizophrenia differ is not clear, but that would not necessarily be expected if the causative agent is active all year but more active in the colder months. Early studies also reported a characteristic birth order pattern for persons with schizophrenia, but the results have not been consistent and family size can affect the findings. For example, some have found schizophrenia to be unusually common in the youngest children of large families and in the first-born sons of small families. Again, methodological problems limit the value of the studies. Birth and Fetal Complications When compared with controls, persons with schizophrenia as a group, and especially male infants, experience a greater number of birth complications. Some studies have also reported a relationship between perinatal complications and early onset of disease, negative symptoms, and poorer prognosis. The crucial factor appears to be transient perinatal hypoxia, although not all infants so affected later develop a psychiatric disorder. There is, however, a general trend toward psychopathology in persons who have suffered obstetrical complications; such events appear to increase the vulnerability to development of schizophrenia and probably are not a specific cause. Some have proposed that complications at birth may be the result of preexisting fetal neurodevelopmental abnormalities or a vulnerability to such abnormalities. No prospective studies have been done, and retrospective case control studies may be biased if informants interviewed about a relative with schizophrenia try harder to remember birth complications than do informants reporting on healthy controls. Obstetrical records often refer only to severe complications. Social Class Social class can be specified in various ways using some combinations of income, occupation, education, and place of residence. In previous studies the prevalence and number of newly identified cases of schizophrenia have been reported to be higher among members of the lower than the upper social classes. Two different explanations have been proposed. One explanation is that socioenvironmental factors found at lower socioeconomic levels are a cause of schizophrenia (social causation theory). Those factors include more life event stressors, increased exposure to environmental and occupational hazards and infectious agents, poorer prenatal care, and fewer support resources if stress does occur. The other explanation is that lower socioeconomic status is a consequence of the disorder (social selection or drift theory). The insidious onset of inherited schizophrenia is believed to preclude elevating one's status or to cause a downward drift in status. Prospective studies have shown that persons with schizophrenia have less upward mobility from generation to generation than do the general population and that there is downward drift after the onset of symptoms. Many continue to argue this unsettled question, but a recent study strongly suggests that social drift processes are more important than social causation. Marital Status Reports based on first hospital admissions have shown higher rates of schizophrenia for unmarried than for married patients, and some have inferred that single status contributes to the development of schizophrenia. However, the phenomenon may be similar to that described under social class; that is, the disease lessens the chance of marriage and increases the chance of divorce. Studies have not shown marriage to have a protective effect against schizophrenia and have not shown an excess of schizophrenia in widowed persons. Previous research using subjects hospitalized for the first time may have been flawed because unmarried and married men appear to have different hospital utilization patterns. Immigration A higher risk for schizophrenia among recent immigrants than in native populations has been reported, but no study to date has confirmed that immigration stress leads to schizophrenia. Indeed, the ECA study found a low prevalence of schizophrenia among Mexican-Americans studied in Los Angeles, most of whom were immigrants. The generally reported increased prevalence of schizophrenia among immigrants could result from selection (i.e., persons with schizophrenia may be more likely to leave their families); from the failure to control for such other factors as social class, age, and sex; or from the failure to compare immigrant patients to nonimmigrant controls from the same homeland. These methodological issues limit any conclusions that can be drawn from existing reports. Urbanization and Industrialization The prevalence of schizophrenia has been reported to be higher in urban environments than in rural areas. This is consistent with widely held beliefs that cities are places of rapid change and social disorganization, whereas rural areas are more socially stable and the inhabitants more integrated. However, data from the ECA study show no difference in the prevalence of schizophrenia between urban and rural areas when such factors as race, sex, and age are controlled. The assertion that the prevalence and incidence of schizophrenia have increased in the twentieth century has been tested by comparing developing countries with industrialized nations, but such studies are fraught with methodological problems. For example, because infant mortality is lower in industrialized countries, those likely to develop schizophrenia may survive more frequently. Families are smaller and more insular, and ill members may be more obvious. The question of whether schizophrenia is more prevalent in modern times has also been studied by analyzing the reported number of new cases over time. However, it is difficult to control for probable diagnostic or recognition bias across centuries, especially for a disease that was first defined only in the late 1800s. Life Stressors The association between stressful life events (such as loss of job, divorce) and the etiology and course of schizophrenia has been much studied. Schizophrenia or relapse of a preexisting disorder often follows extraordinary stress, so it has been suggested that such stress might provoke acute schizophrenia in a healthy person. Others argue that stress plays only a marginal role in the pathogenesis of the disorder or simply triggers schizophrenia in vulnerable persons. The few studies that have considered the issue have suffered the usual methodological problems of retrospective case-control studies and have had difficulty in outlining predispositional factors in schizophrenia. The stressor might have triggered the onset of a disorder that would have occurred without the stressor. The issue is not settled and will require further studies, especially prospective ones in which the role and severity of stressors in individual cases can be considered. Infections Anatomical changes suggestive of viral infection of the central nervous system have been reported in some people with schizophrenia. A viral hypothesis is consistent with seasonal excesses and geographical differences. Viruses could also interact with a genetic predisposition, familial transmission, or both, in complex ways in the development of the disease. Recent studies have reported that exposure to viral infections during the second trimester may increase the risk for development of schizophrenia. As yet no study has conclusively shown an association between viral infection and the onset of schizophrenia. Further studies, especially those that can show evidence of viral transmission, are needed. Suicide Risk Suicide is a leading cause of mortality in people suffering from schizophrenia. Estimates vary, but as many as 10 percent of people with schizophrenia may die because of a suicide attempt. Although the risk for suicide is greater in people with schizophrenia than in the general population, some risk factors—such as being male, white, and socially isolated—are similar in both groups. Factors such as depressive illness, a history of suicide attempts, unemployment, and recent rejection also increase the risk for suicide in both populations. Previous studies have revealed other risk factors that are unique to this disorder. Among these are being young and male and having a chronic illness with numerous exacerbations. A postdischarge course involving high levels of psychopathology and functional impairment increases the risk for suicide. In addition, people who have a realistic awareness of the deteriorative effects of the illness and a nondelusional assessment of their future are at increased risk for suicide. Other factors such as fear of further mental deterioration, hopelessness, excessive dependence on treatment, or loss of faith in treatment increase the risk of suicide in people with schizophrenia. The risk of mortality is especially high in the young, during the early postdischarge period, and early in the course of illness, although the risk persists across the person's life span. Risk factors identified in previous studies may be helpful in assessing acute suicidal risk in a specific individual. Further research is needed to better understand what risk factors are most predictive of future suicide in people with schizophrenia and what interventions are most helpful in preventing suicide. Childhood Schizophrenia As with adult-onset schizophrenia, different diagnostic criteria can affect the interpretation of results from studies of childhood-onset schizophrenia. Early definitions of childhood-onset schizophrenia tended to be broad and often included patients with autistic disorder. Recent diagnostic systems have departed from these earlier definitions by using the more restrictive criteria applied to adults that emphasize hallucinations and formal thought disorder. This restrictive definition, however, fails to consider developmental issues, such as the nature of delusions in childhood, and how a formal thought disorder can be diagnosed in a child under 8 years of age whose formal cognitive processes are not fully developed. Others have considered developmental stages in diagnosing childhood-onset schizophrenia, but no consensus has been reached. The accuracy of any reported epidemiological data on childhood-onset schizophrenia is compromised by differences in diagnostic criteria. Therefore, the prevalence of childhood-onset schizophrenia is not clear, but it is probably less than that of early infantile autism and is estimated to be less than that of adult-onset schizophrenia. There does not appear to be a greater incidence in boys than girls, as there is in infantile autism. The risk factors of childhood-onset schizophrenia are not well known, and many investigators have simply extrapolated from adult findings. However, environmental stressors, perinatal complications, and central nervous system dysfunction have all been reported to occur more frequently in children who are diagnosed with

schizophrenia.

FUTURE DIRECTIONS Future epidemiological work in schizophrenia should use multisite, prospective, long-term studies. The WHO studies provide some of the foundations for such proposed efforts. However, longitudinal prospective studies of people at risk should be carried out, from near birth, and extending through the ages of major risk (early adult years). Such studies, with appropriate controls, should incorporate opportunities for genetic mapping of families at risk; chromosomal studies; and current laboratory measures of potential psychophysiological vulnerability such as continuous performance and sensory discrimination testing, neuroimaging, and other measures evolving with methodological advances. The expense of such studies would not be greater than that of comparable multisite, long-term studies of risk factors for cardiovascular and other diseases and would be small compared to the extraordinary direct and indirect costs of this most devastating of mental disorders.

SUGGESTED CROSS-REFERENCES Some of the methods and concepts applicable to this section are discussed in Section 5.2 on statistics and experimental design. The genetics of schizophrenia is discussed in Section 12.5. Other aspects of schizophrenia are presented throughout the other sections of Chapter 12. Other psychotic disorders are reviewed in Chapter 13. Section 11.3 discusses amphetamine-related disorders, Section 11.7 discusses hallucinogen-related disorders, and Section 11.11 discusses phencyclidine-related disorders. SECTION REFERENCES Caldwell CB, Gotesman II: Schizophrenics kill themselves too: A review of risk factors for suicide. Schizoph Bull 16:571, 1990. Cannon T, Mednick S, Parnas J, Schulsinger S, Praestholm J, Vestergaard A: Developmental brain abnormalities in the offspring of schizophrenic mothers. Arch Gen Psychiatry 50:551, 1993. Castle DJ, Murray M: The epidemiology of late-onset schizophrenia. Schizophr Bull 19:691, 1993. *Castrogiovanni P, Iapichino S, Pacchierotti C, Pieraccini F: Season of birth in psychiatry. A review. Neuropsychobiology 37:175, 1998. Cohen A: Prognosis for schizophrenia in the third world: A reevaluation of cross-cultural research. Cult Med Psychiatry 16:53, 1992. Crow TJ: Prenatal exposure to influenza as a cause of schizophrenia. There are inconsistencies and contradictions in the evidence. Br J Psychiatry 164:588, 1994. Day R, Nielsen JA, Korten A, Ernberg G, Dube KC, Gebhart J, Jablensky A, Leon C, Marsella A, Olatawura M, Sartorius N, Stromgren E, Takahashi R, Wig N, Wynne LC: Stressful life events preceding the acute onset of schizophrenia: A cross-national study from the World Health Organization. Cult Med Psychiatry 11:123, 1987. *Dohrenwend BP, Levov I, Shrout PE, Schwartz S, Noveh G, Link BG, Skodol AE, Stueve A: Socioeconomic status and psychiatric disorders: The causation-selection issue. Science 255:946, 1992. Eaton WW: The epidemiology of schizophrenia. In Handbook of Studies on Schizophrenia, GD Burrows, TR Norman, G Rubinstein, editors. Elsevier, New York, 1986. Edgerton RB, Cohen A: Culture and schizophrenia: The DOSMD challenge. Br J Psychiatry 164:222, 1994. *Gottesman I, Moldin S: Schizophrenia genetics at the millennium: Cautious optimism. Clin Genet 52:404, 1997. Haffner H: What is schizophrenia? Changing perspectives in epidemiology. Eur Arch Psychiatry Neurol Sci 238:63, 1988. Jablensky A: Schizophrenia: Recent epidemiologic issues. Epidemiol Rev 17:10, 1995. Jablensky A, Sartorius N, Ernberg G, Anger M, Korten A, Cooper JE, Day R, Bertelsen A: Schizophrenia: Manifestations, incidence, and course in different cultures. Psychol Med 20:38, 1992. Jablensky A: The 100-year epidemiology of schizophrenia. Schizophr Res 28:111, 1997. Jones P, Cannon M: The new epidemiology of schizophrenia. Psychiatr Clin North Am 23:1, 1998. Jones PB, Rantakallio P, Hartikainen A, Isohanni M, Sipila P: Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: A 28-year follow-up of the 1966 North Finland general population birth cohort. Am J Psychiatry 155:355, 1998. Karayiorgou M, Kasch L, Lasseter VK, Hwang J, Elango R, Bernardini DJ, Kimberland M, Babb R, Francomano A, Wolyniec PS, Lamacz M, Nestadt G, Meyers D, Ott J, Childs B, Antonarakis S, Kazazian HH, Housman DE, Pulver AE: Report from the Maryland Epidemiology Schizophrenia Linkage Study: No evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model. Am J Med Genetics (Neuropsychiatr Genet) 54:345, 1994. Keith SJ, Regier DA, Rae DS: Schizophrenic disorders. In Psychiatric Disorders in America, LN Robins, DA Regier, editors. Free Press, New York, 1991. Kendler KS, Diehl SR: The genetics of schizophrenia: A current, genetic-epidemiologic perspective. Schizophr Bull 19:261, 1993. *Kendler KS, Gallagher TJ, Abelson JM, Kessler RC: Lifetime prevalence, demographic risk factors, and diagnostic validity of nonaffective psychosis as assessed in a US community sample. Arch Gen Psychiatry 53:1022, 1996. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler K: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8, 1994. Kringlen E, Cramer G: Offspring of monozygotic twins discordant for schizophrenia. Arch Gen Psychiatry 46:873, 1989. Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A, Hayward NK, Crowe RR, Andreasen NC, Black DM, Silverman JM, Endicott J, Sharpe L, Mohs RC, Siever LJ, Walters MK, Lennon DP, Jones HL, Nertney DA, Daly MJ, Gladis M, Mowry BJ: Genome scan of schizophrenia. Am J Psychiatry 155:741, 1998. Lewis MS: Age incidence and schizophrenia: Part II. The season of birth controversy. Schizophr Bull 15:75, 1989. McGrath J, Castle D: Does influenza cause schizophrenia? A five-year review. Aust NZ J Psychiatry 29:23, 1995. Muller HG, Kleider W: A hypothesis on the abnormal seasonality of schizophrenic births. Eur Arch Psychiatry Neurol Sci 239:331, 1990. Narrow WE, Regier DA, Rae DS, Manderscheid RW, Locke BZ: Use of services by persons with mental and addictive disorders. Arch Gen Psychiatry 50:95, 1993. Norman RM, Malla AK: Stressful life events and schizophrenia. Br J Psychiatry 162:161, 1993. O'Callaghan E, Gibson T, Colohon HA, Walshe D, Backley P, Lorkin C, Waddington JL: Season of birth in schizophrenia. Br J Psychiatry 158:764, 1991. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK: Comorbidity of mental disorders with alcohol and other drug abuse. JAMA 264:2511, 1990. Regier DA, Farmer ME, Rae DS, Myers JK, Kramer M, Robins LN, George LK, Karno M, Locke BZ: One-month prevalence of mental disorders in the United States and sociodemographic characteristics: The epidemiologic catchment area study. Acta Psychiatr Scand 88:35, 1993. *Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK: The de facto U.S. mental and addictive disorders service system. Arch Gen Psychiatry 50:85, 1993. Torrey EF, Bowler AE: Geographical distribution of insanity in America: Evidence for an urban factor. Schizophr Bull 16:591, 1990. Torrey EF: Prevalence studies in schizophrenia. Br J Psychiatry 150:598, 1987. Torrey EF, Bowler AE, Rawlings R, Terrazas A: Seasonality of schizophrenia and stillbirths. Schizophr Bull 19:557, 1993. *Waldo MC: Schizophrenia in Kosrae, Micronesia: Prevalence, gender ratios, and clinical symptomatology. Schizophr Res 35:175, 1999.

Wing JK, Cooper JE, Sartorius N: Measurement and Classification of Psychiatric Symptoms: An Instruction Manual for the Present State Examination and CATEGO Program . Cambridge University Press, Cambridge, 1974.

Textbook of Psychiatry

12.3 SCHIZOPHRENIA: BRAIN STRUCTURE AND FUNCTION Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.3 SCHIZOPHRENIA: BRAIN STRUCTURE AND FUNCTION RAQUEL E. GUR, M.D., PH.D. AND RUBEN C. GUR, PH.D. Neuroanatomical Studies in Schizophrenia Functional Neuroimaging Cerebral Metabolism and Blood Flow Studies Neuroreceptor Studies Metabolite Studies: Magnetic Resonance Spectroscopy (MRS) Future Directions Suggested Cross-References

The past decade has seen a transformation in psychiatric thinking about schizophrenia. Its conception as a complex behavioral disorder that reflects an interplay between biological and psychosocial factors has been changing as developments in the neurosciences have yielded tools for probing neural substrates of behavior. In particular, advances in neuroimaging methods have enabled translational research in which schizophrenia can be studied from the molecular to the behavioral levels using complementary top-down and bottom-up strategies. Such work has identified some consistent aberration in brain structure and function that may help formulate our new conception of schizophrenia as a brain disorder. This is not to dismiss environmental stressors, but rather to put these in the perspective of a brain disorder in evolution. Two major aspects of brain integrity can be assessed through neuroimaging: structural anatomy and functional activity. In view of the complexity and course of schizophrenia, these measures need to be taken across the life span and longitudinally to document the association between brain changes and behavior. Furthermore, the disorder-related effects are superimposed on healthy individual differences—for example, sex differences and maturational changes—that have to be established in healthy people before we can understand pathological changes. However, despite the complexity of such an approach, its implementation can yield new opportunities for elucidating the neural substrate of schizophrenia in a way that will lead to improved diagnosis and treatment. Accordingly, the section first describes studies of structural imaging in schizophrenia, which have been linked to neuropathological findings in postmortem research. This is followed by findings obtained by functional imaging studies.

NEUROANATOMICAL STUDIES IN SCHIZOPHRENIA Neuroanatomical correlates of dysfunctional performance have provided the foundation for current thinking about brain regulation of behavior. The behavioral aberrations manifested in schizophrenia implicate a diffuse abnormality likely to involve several brain systems. Defining the neuroanatomical differences and possible changes associated with schizophrenia is arguably a prerequisite for understanding its neural substrates and for interpreting functional studies of brain physiology and neurochemistry. Structural studies have progressed from reliance on ratings to planimetric measures and, more recently, reliable computerized segmentation methods for obtaining volumetric measures. The improvement in precision of neuroanatomical parameters has yielded some consistency in effects and correlations with clinical and neurobehavioral measures. Structural Neuroimaging Earlier neuroimaging studies with computerized tomography (CT) applied nonvolumetric measures and suggested enlarged ventricles, implying reduced brain parenchyma. Magnetic resonance imaging (MRI) has advanced the study of the neuroanatomy of schizophrenia. It offers improved sensitivity for examining sulcal changes, better contrast resolution, direct multiplanar imaging, lack of bone artifacts, and no ionizing radiation. The field has progressed from initial studies of small samples, examining multiple regions with low-field scanners, using linear and area measurements, to the application of computerized image analysis in large samples. This has enabled linking neuroanatomical measures to two behavioral dimensions: clinical features of the disorder and neurocognitive deficits. Whole Brain and CSF Volumes Studies with MRI have replicated earlier findings with CT indicating smaller brain volume and more cerebrospinal fluid in patients with schizophrenia than in healthy people. As can be seen in Figure 12.3-1, a person with schizophrenia shows evidence for widening of CSF spaces in both the ventricles and the sulci. Image segmentation methods have permitted increasingly precise quantitation of brain and CSF volume, and although these studies generally support the notion of increased CSF relative to brain volume in schizophrenia, they also indicate considerable overlap with healthy people ( Fig. 12.3-2). This suggests that abnormalities at the level of whole brain may characterize only subtypes of patients with schizophrenia. Some patients exhibit a concomitant decrease in brain and increase in CSF volume, consistent with atrophy, whereas other patients show concomitant decreases in brain and CSF volume (hence cranial volume) which is more consistent with dystrophy. A third group shows neither abnormality.

FIGURE 12.3-1 MRI of a young healthy adult (A) and a same-aged adult with schizophrenia (B). Radiological examination showed evidence of the patient's increased cerebrospinal fluid in ventricles and sulci.

FIGURE 12.3-2 Scatterplot of brain volume of adults with schizophrenia relative to that of healthy adults matched sociodemographically.

These measures have been related to phenomenological and other clinical variables such as premorbid functioning, symptom severity, and outcome. The results

suggest that whole brain measures are related to clinical features. Abnormalities in these measures are likely to be more pronounced in patients with poorer premorbid functioning, more severe symptoms, and worse outcome. The concept of brain reserve that has been suggested in other disorders, such as Alzheimer's disease, may apply to schizophrenia as well. Thus, normal brain and CSF volumes are preliminary indicators of protective capacity. As our understanding of how brain systems regulate behavior in health and disease improves, we can take advantage of neuroimaging to examine specific brain regions implicated in the pathophysiology of schizophrenia. Regional Volumes Examination of brain regions implicated in schizophrenia has required methodological developments to enable testing specific hypotheses regarding the neuroanatomical basis of the aberrant behavior. Studies have evolved beyond comparing patients with controls, and current work linking regional measures to specific symptoms and subtypes requires large samples and systematic data acquisition. Furthermore, given the subtle changes evident in schizophrenia, findings must be evaluated relative to well-characterized healthy people. For example, the effects of normal aging appear to be sexually dimorphic. Cross-sectional studies reported age-related reduction in frontal and temporal lobe volumes in healthy men but not women ( Fig. 12.3-3).

FIGURE 12.3-3 Frontal and temporal lobe volume in younger and older healthy adult men and women. (Reprinted with permission from Cowell PE, Turetsky BT, Gur RC, Grossman RI, Shtasel DL, Gur RE: Sex differences in aging of the human frontal and temporal lobe. J Neurosci 14:4748, 1994.)

The main regions showing consistent abnormalities in schizophrenia have been frontal and temporal lobe structures. Lower frontal and temporal lobe volume has been observed in patients than in healthy controls matched demographically ( Fig. 12.3-4). Reduced temporal lobe volume correlated with both memory impairment and severity of negative symptoms. These findings were observed in first-episode patients, indicating that structural changes are evident at the first clinical presentation, which supports a neurodevelopmental origin. The differences are more pronounced in men than in women with schizophrenia.

FIGURE 12.3-4 Frontal and temporal lobe volume in adults with schizophrenia compared with that of healthy adults matched sociodemographically.

Reduced volume was reported in multiple regions including the superior temporal gyrus, hippocampus, and thalamus. These structures are critical for maintaining the integrity of the complex behaviors that are impaired in schizophrenia. Figure 12.3-5 illustrates some of the regions that show abnormal volume in schizophrenia, as well as an example of an image that has been segmented into gray and white matter and CSF. Most regions show volume decrease; the exception is basal ganglia regions reported to show increased volume in schizophrenia. This increase seems to be related to the effects of dopamine receptor antagonists.

FIGURE 12.3-5 Illustration of regions that have shown volume abnormalities in schizophrenia: A, frontal lobe; B, temporal lobe; C, basal ganglia.

Gray Matter and White Matter Segmentation MRI can yield detailed anatomical information apart from the demarcation of brain and CSF. With sequences that are T1-weighted it is possible to segment gray from white matter ( Fig. 12.3-5A, upper right image). Several lines of investigation have demonstrated advantages of applying such methods. Gray matter changes have been found during adolescence and in the course of the normal aging process. Gray-white segmentation is critical in developmental studies in which age-related decreases in gray matter may be obscured by simultaneous increases in total brain and cranial volumes. These improvements in image processing methodology have helped determine whether tissue loss and disorganization in schizophrenia is primarily a gray matter deficit or whether abnormalities in white matter are also involved. Reduced cortical gray matter was noted in a number of studies that evaluated chronic patients with schizophrenia. More recently, one study of first-episode patients also reported a gray matter deficit in individuals with a recent onset of illness. Longitudinal Studies Efforts to elucidate the pathophysiology of schizophrenia have focused on the role of the neurodevelopmental relative to progressive neurodegenerative processes. Documenting neuroanatomical aberrations with structural neuroimaging and evaluating their course in relation to clinical and neurobehavioral manifestations can help test such hypotheses. CT and MRI studies have been primarily cross-sectional, and a longitudinal design is necessary to examine the possibility of progressive deterioration suggested by the neurodegenerative hypothesis. The few longitudinal evaluations of structural abnormalities have not been integrated with clinical and neurobehavioral measures. Results from CT follow-up studies, with planimetric methods and ratings of sulcal enlargement, have varied. Some studies found no significant changes in

ventricle-brain ratio (VBR) in relatively small samples rescanned after a number of years, commonly ranging from 2 to 5. Other studies reported that some patients do show an increased VBR over similar time spans. The investigators noted that these initial studies have limitations related to sample size, patient characteristics, and scanning and measurement procedures. While most follow-up CT studies evaluated chronic patients with schizophrenia, MRI longitudinal studies have examined first-episode patients. This is an informative population because the design enables prospective follow-up starting early in the course of illness. One group of investigators found no ventricular changes in a follow-up (1–2 years) study of 13 patients and 8 controls. Lyn DeLisi and her colleagues initially evaluated 16 patients and 5 controls, studied 2 years after a first psychotic episode. Patients showed no consistent change in ventricular size with time, although there were individual increases or decreases. With a larger group of 24 patients and 6 controls no significant changes were observed in ventricular or temporal lobe volume at follow-up. Recently, a report on 20 of these patients and 5 controls rescanned over 4 years noted greater decreases in whole-brain volume and enlargement in left ventricular volume in patients and concluded that subtle cortical changes may occur after the onset of illness. These authors have described a reliable and validated method for obtaining MRI measures of brain volume. In healthy adults, these parameters have been related to sex differences and the effects of aging, and in schizophrenia, they were related to clinical features. This method was applied in a longitudinal study of 40 patients (20 first-episode, 20 previously treated) and 17 healthy controls, rescanned an average of 2.5 years later. Volumes of whole brain, CSF, and frontal and temporal lobes were measured. Severity of negative and positive symptoms was assessed, medications were monitored, and neurobehavioral functioning in eight domains was evaluated. First-episode and previously treated patients had smaller whole-brain and frontal and temporal lobe volumes than controls at intake. Longitudinally, reduced frontal lobe volume was found only in patients, whereas temporal lobe reduction was also seen in controls. The association between volume reduction and symptom change differed between patient groups, but in both first-episode and previously treated patients, volume reduction was associated with decline in some neurobehavioral functions. The existence of neuroanatomical and neurobehavioral abnormalities in first-episode patients indicates that brain dysfunction occurred before clinical presentation. However, the longitudinal studies suggest progression in which anatomical changes may affect some clinical and neurobehavioral features of the illness in some patients. The limited number of longitudinal MRI studies and small sample sizes leaves the question of progression unresolved and precludes confident distinction of disease-related changes from those associated with normal aging. Furthermore, standard therapeutic interventions need to be included in such longitudinal studies.

FUNCTIONAL NEUROIMAGING Application of Functional Brain Imaging Methods Evolving technology provides an increasing array of measures of brain function. Some of these measures overlap and others are complementary. For example, the functional integrity of the brain can be examined through measures related to energy metabolism, such as rates of glucose and oxygen utilization and cerebral blood flow. Neuroreceptor function can be assessed through methods for measuring receptor density and affinity at presynaptic and postsynaptic sites. Methods that have been applied in schizophrenia included the Xenon-133 ( 133Xe) clearance technique for measuring cortical cerebral blood flow; positron emission tomography (PET) for assessing glucose metabolism, cerebral blood flow, and neuroreceptor functioning; single photon emission computerized tomography (SPECT) for studying cerebral blood flow and neuroreceptors; and, more recently, functional MRI (fMRI) for measuring changes attributable to cerebral blood flow. Figure 12.3-6 illustrates the application of such methods in healthy people.

FIGURE 12.3-6 Illustration of functional imaging data obtained in healthy people: A, sex differences in local glucose metabolism; B, activation with verbal and spatial tasks as seen by functional MRI. Abbreviations: SF, superior frontal; DL, dorsal prefrontal-lateral; DM, dorsal prefrontal-medial; MF, midfrontal; IF, inferior frontal; SM, sensorimotor; SP, superior parietal; SG, supramarginal gyrus; OL, occipital cortex, lateral; OM, occipital cortex, medial; LI, lingual gyrus; FG, fusiform gyrus; OT, occipital temporal; ST, superior temporal; MT, midtemporal; IT, inferior temporal; TP, temporal pole; PH, parahippocampal gyrus; HI, hippocampus; AM, amygdala; IN, insula; OF, orbital frontal; RG, rectal gyrus; CA, cingulate gyrus-anterior; CG, cingulate gyrus; CP, cingulate gyrus-posterior; C1, corpus callosum-anterior; C2, corpus callosum-posterior; CN, caudate nucleus; LM, lenticular-medial (globus pallidus); LL, lenticular-lateral (putamen); MB, mammillary body; TH, thalamus; MI, midbrain; PO, pons; CE, cerebellum. Cortical regions are grouped by lobe in a rostral-caudal order, followed by corpus callosum and subcortical regions. This order heuristically also reflects ontogenic and evolutionary development. Top graph shows means + SEM of region to whole brain (R/WB) ratios, and bottom graph shows laterality differences in percentage, i.e., 100*(LR)/mean(L,R). (See Color Plate 7.)

Links between clinical features of schizophrenia and brain function have been guided by hypotheses relating behavior to specific brain regions and systems implicated in schizophrenia. These links are based on preclinical research and the emergence of symptoms commonly seen in schizophrenia that also occur following brain lesions. Persistent negative symptoms have been observed as a eurobehavioral sequela of frontal lobe damage. Other frontal lobe functions such as abstraction, attention, verbal fluency, mental flexibility, and concept formation are also impaired. Productive positive symptoms of hallucinations and delusions have been related to the temporolimbic system, and this region is also implicated by evidence of impaired learning and memory. The greater impairment in verbal functions, the similarity of some symptoms to those observed in patients with left temporal lobe epilepsy, and the increased frequency of left-handedness (or, rather, “left-sidedness” as measured by a combined index of strength of right-handedness, footedness, and sighting dominance) in schizophrenia have led to the laterality hypothesis stipulating left hemispheric dysfunction. Thus the laterality gradient has been examined in several studies. Subcortical regions have been studied with special emphasis on the basal ganglia (implicated by the dopamine hypothesis) and the thalamus (related to sensory gating). These early efforts, focusing on brain systems that are likely to modulate normal and pathological psychotic behavior, have generated hypotheses that can be examined with functional brain imaging. In addition to obtaining baseline measures of the resting topography of glucose metabolism and cerebral blood flow, functional imaging is an especially powerful methodology for the probe paradigm. There are two complementary approaches: neurobehavioral probes and neuropharmacological probes. The application of neurobehavioral probes has enhanced our ability to evaluate brain systems that regulate specific processes in healthy people and in those affected by schizophrenia, including attention, learning, memory, and executive functions. Neuropharmacological probe paradigms include examination of neuroreceptor function as well as the effects of pharmacological intervention on cerebral blood flow and metabolism.

CEREBRAL METABOLISM AND BLOOD FLOW STUDIES Semour Kety and his colleagues have pioneered the measurements of whole-brain metabolism and blood flow in healthy people and reported normal values for patients with schizophrenia. Subsequent studies of regional cerebral metabolism and blood flow can be divided into those that measure the physiological parameters at a resting state and those that introduce a perturbation, or challenge, in the form of a neurobehavioral probe or a pharmacological intervention. Initially, investigators have aimed at assessing whether resting cerebral blood flow and glucose metabolism differ between patients with schizophrenia and healthy controls. The topography of physiological activity was examined along the anterior-posterior, subcortical-cortical, and lateral dimensions. Resting Baseline The frontal lobes were implicated when early physiological studies of cerebral blood flow, reported that patients did not show the normal pattern of more anterior than posterior flow. This “hypofrontal” disturbance in the anterior-posterior gradient has been supported by some, but not all, studies of resting cerebral blood flow (by 133Xe and SPECT) and glucose metabolism (with PET). The relation between this pattern of metabolic activity and clinical variables has also been examined. Decreased frontal metabolic activity has been associated with duration of illness and negative symptoms. Longer duration of illness and more severe

negative symptoms are related to a relative decrease in frontal lobe metabolism. Differences in resting values between patients and controls were also found in laterality indexes, suggesting relatively higher left hemispheric values in more severely ill patients. Furthermore, improvement in clinical status correlated with a shift toward lower left hemispheric metabolism relative to that in the right hemisphere. This supports hypotheses derived from behavioral data concerning lateralized abnormalities in schizophrenia. After assessing global, anterior-posterior, and lateral dimensions, investigators have begun the study of functional changes in brain systems linked to other impaired behavior in schizophrenia. Dysfunction in temporolimbic structures, including the hippocampus as well as temporal cortex, is supported by neuroanatomical and neuropsychological studies. Lateralized abnormalities in these regions, with greater left than right hemispheric dysfunction, are implicated by characteristic clinical features of schizophrenia, such as thought disorder, auditory hallucinations, and language disturbances. PET studies of temporal lobe metabolism show both increased and decreased glucose utilization. Decreased metabolism was also noted in hippocampus and anterior cingulate cortex. Studies in this region have been limited in part by instrument resolution. Metabolism and flow pattern in temporolimbic regions have also been related to symptoms. An oxygen-15 ( 15O)-labeled water study with PET described abnormal cerebral blood flow in the parahippocampal gyrus, associated with positive symptoms. Hallucinations were associated with SPECT blood flow changes in the hippocampus, parahippocampus, and amygdala. There are conflicting reports of superior temporal gyrus functional changes in schizophrenia during active auditory hallucinations. While one study suggested that patients with hallucinations have lower relative metabolism in Wernicke's region, another study showed asymmetrical temporal lobe perfusion (lower in the left than the right) in patients with auditory hallucinations. In one PET study the rate of glucose metabolism was greater in the left anterior temporal lobe and was related to the severity of symptoms. This is consistent with another reported association between severity of symptoms and a relative increase in left hemispheric metabolism. These reports varied in the method used and definition of regional parameters. Most studies used ratios such as region to whole brain or anterior to posterior rather than absolute values of activity. Inconsistencies in findings could also be related to sample size, heterogeneity, analytical approaches, and individual techniques. Most studies included relatively small samples of patients, which varied in important clinical factors such as chronicity, symptom subtypes and severity, level of functioning, and history of treatment. Furthermore, inclusion criteria varied, and some laboratories applied more stringent criteria (e.g., related to history of comorbidity of substance abuse or head trauma with loss of consciousness). Another potential source of variability in results is the definition of resting state. Investigators have been reluctant to include an unstructured resting state because of concern that such measures will be uncontrolled and therefore produce unreliable results. Some studies used reduced sensory input, and others used sensory stimulation to standardize this condition. However, several studies examined the reproducibility of resting baseline measures with relatively unstructured conditions (i.e., eyes open and ears unoccluded, with ambient noise kept to a minimum). These studies found high reproducibility among healthy subjects and patients with schizophrenia. Given the demonstrated reliability of the standardized resting baseline condition, these authors believe such a condition should be included in physiological neuroimaging studies. This will serve three main purposes. First, it will permit comparison across studies within a center as technology evolves and patient characteristics change. Without a common resting baseline condition it would be impossible to interpret differences in results. Second, it will enable comparability across centers. Imagine the need to explain why two centers using the same or similar tasks find evidence for different regional abnormalities in schizophrenia. If resting baseline values are available and are comparable in the two samples, different task effects could be legitimately attributed to theoretically meaningful sources such as task condition or symptomatic variability. Third, a standardized resting baseline provides a reference point for determining whether a given task or condition has increased neural activity. In studies that have included such a condition, cognitive activation was consistently shown to increase cortical activity in both patients and controls. Using a resting baseline condition enables the investigator to make much stronger statements in interpreting regional effects. Rather than being restricted to statements that a given region has changed in its activation relative to the remainder of the brain, resting baseline data can be used to determine whether the task has induced increased neural activity. Functional changes in the basal ganglia have been examined with PET and SPECT. Several PET studies implicate basal ganglia dysfunction in schizophrenia. The withdrawal-retardation factor (emotional withdrawal, blunted affect, and motor retardation) of the Brief Psychiatric Rating Scale has been negatively correlated with PET basal ganglia metabolic activity. Neuroleptic-naive patients with schizophrenia were reported to have relatively increased blood flow in the left globus pallidus. Other PET studies report decreased basal ganglia metabolism in schizophrenia, while yet others found increased basal ganglia metabolic rates following administration of neuroleptic medication. Thus, while the contribution of PET metabolic and blood flow studies so far has been to add to the growing evidence implicating basal ganglia involvement in schizophrenia, the exact nature of the dysfunction remains unclear. In particular, the relation between basal ganglia and frontal lobe activity in schizophrenia needs further scrutiny. Emerging evidence from structural and functional imaging indicates a dynamic interrelationship between the various key regions. One study showed that patients with schizophrenia not only fail to activate dorsolateral prefrontal cortex in response to the Wisconsin Card Sorting Test, but they also fail to inhibit caudate activation. Hence, in schizophrenia, basal ganglia continue to show relatively increased flow in the caudate during performance of the task, while healthy controls seem to demonstrate a reciprocal relationship in which relative blood flow decrease in the basal ganglia is associated with increased perfusion to the frontal region. Activation Studies Regardless of the debate over the value of obtaining resting baseline measures, measures of cerebral blood flow and metabolism during the performance of cognitive tasks clearly tend to accentuate differences between patients and controls. Perhaps even more importantly, such measures are critical for establishing the link between behavioral deficits and the ability of brain regions to become activated in response to task demands. This expectation has been supported in studies that used neurobehavioral probes. The general approach in the field has been to work from hypotheses, derived from neurobehavioral data, which associate behavioral measures with regional brain function. Task selection can be made to include a target task (for which patients are expected to have a differential deficit) and control tasks. Patients are then compared with healthy controls in the pattern of task-induced changes in regional brain activity. This has now become the established research paradigm and significant progress has been made since the early studies with 133Xe. The authors, Daniel Weinberger, and their colleagues applied the 133Xe method during resting measures and while subjects were performing specific tasks. Both groups found no differences in overall or hemispheric cerebral blood flow between patients and controls at resting baseline. However, distinct abnormalities were seen when physiological activity was measured in response to cognitive probes. Pursuing the laterality hypothesis, the first author of this section and coworkers administered tasks with a demonstrated link to left (verbal analogies) and right (spatial line orientation) hemispheric functioning. Healthy controls showed the expected greater left hemispheric increase for the verbal task and greater right hemispheric increase for the spatial task. However, patients with schizophrenia had a bilaterally symmetrical activation for the verbal task and greater left hemispheric activation for the spatial task. Thus, patients failed to show the normal left hemispheric dominance for the verbal task and instead showed left hemispheric overactivation for the spatial task. Similarly, Weinberger and coworkers found no regional abnormalities in the resting cerebral blood flow of patients with schizophrenia. However, distinct abnormalities were reported in the dorsolateral prefrontal region during activation with the Wisconsin Card Sorting Test of abstraction and mental flexibility, which is sensitive to frontal lobe damage. Application of this paradigm to the study of monozygotic twins discordant for schizophrenia revealed that all affected twins had lower dorsolateral prefrontal cortex cerebral blood flow response than discordant cotwins. Furthermore, negative symptoms, which have been related to frontal lobe dysfunction, showed a negative correlation with frontal blood flow during performance of executive tasks but not control tasks. Probing brain systems with specific tasks has also been advanced in SPECT and in cerebral blood flow studies with PET. These methods have also indicated abnormalities in patients with schizophrenia with a range of tasks including memory, executive, and attentional measures. The consistent finding is a lack of normal regional activation in response to task, and activation in some regions not seen in healthy subjects. These results suggest that brain systems recruited for the performance of specific tasks in healthy people are not similarly engaged in patients with schizophrenia. What may account for such aberrations? Genetic liability, neurodevelopmental abnormalities in which brain systems fail to achieve maturity, or the impact of a psychotic process that interrupts normally developed structures and processes? Does therapeutic intervention ameliorate the abnormal signature? How specific are the results to schizophrenia? These are some of the questions yet to be answered that can certainly be addressed with neuroimaging. Functional MRI The introduction of MRI is an exciting, more recent development in functional imaging research. Functional MRI methods offer several potential advantages over PET for imaging brain function, including higher spatial resolution, higher temporal resolution, noninvasiveness, lack of ionizing radiation, direct correlation with anatomical imaging, greater reproducibility, and economy. Disadvantages include the loud background noise generated by the gradients, difficulties in

presenting stimuli and performing tasks in the magnet bore, claustrophobia, low signal-to-noise ratio for most methods, and lack of quantitation in physiological units for most methods. Many of these disadvantages can be overcome by using specialized equipment compatible with the MRI environment. These methods are described briefly because they are recent and hold potential for functional imaging in schizophrenia. Currently, three main techniques exist for MRI of the brain. Gadolinium bolus-tracking was the first technique to be applied to mapping task-specific regional brain function in animals and humans by use of MRI. In normal brain, gadolinium diethylenetriaminepentaacetic acid (DPTA) is an intravascular tracer, allowing semiquantitative transit time and blood volume images to be calculated with rapid imaging techniques. Because of the accumulation of the intravascular tracer, the number of determinations is limited to two to three per day. Because gadolinium DPTA is an intravascular tracer, dynamic measurements of its passage through brain yield measurements of cerebral blood volume and mean transit time rather than cerebral blood flow, but changes in cerebral blood flow are generally reflected by changes in these other indexes. Blood oxygenation–sensitive imaging has been most widely applied to fMRI, replicating previous PET studies. The technique relies on magnetic susceptibility effects of deoxyhemoglobin that cause regional signal decreases in imaging sequences that are sensitive to susceptibility (e.g., echoplanar or routine gradient echo sequences). With regional brain activation studies a net increase in signal intensity is observed in regions known to be activated by the task. The increase in image intensity corresponds to a local decrease in deoxyhemoglobin. This finding is attributed to a greater increase in regional blood flow than in regional oxygen consumption, a notion supported by PET measurements of blood flow and oxygen consumption with regional brain activation. A wide variety of pulse sequences can be used to obtain blood oxygenation–sensitive imaging measures. Many simple activation paradigms have been tested, and activation has been observed with both fast and slow imaging. A typical response is a 1 to 25 percent change in regional image intensity, which develops over 3 to 8 seconds following task initiation. Susceptibility effects of deoxyhemoglobin are field dependent. Thus, a scanner with 1.5 tesla field strength would typically record signal changes with functional activation of about 0.25 to 5 percent, while at 4 telsa changes up to 25 percent have been observed. The main advantage of ultrafast imaging is that the time course of signal change can be observed and multislice imaging can be carried out in a reasonable time period. The third technique, arterial spin tagging (quantitative perfusion imaging) uses magnetization tagging of endogenous arterial water to determine the perfusion of brain parenchyma by comparing images obtained with and without a labeled arterial supply. The method is analogous to steady-state techniques used in PET, since the regional signal intensity depends upon the arterial blood flow (which delivers labeled spins) and the T1 relaxation rate (which causes the labeling to decay). This technique has the important advantage of providing quantitative cerebral blood flow parameters. Furthermore, perfusion is measured in brain parenchyma directly and is thus better localized than measurements obtained by use of an intravascular tracer, which is most sensitive to venous outflow effects. There may also be less motion sensitivity than with blood oxygenation–sensitive imaging. Application of this technology to the study of schizophrenia is quite new. Perry Renshaw and colleagues measured the relative change in image signal intensity caused by photic stimulation in eight patients and nine controls. The mean signal intensity change in the primary visual cortex was significantly greater in patients than in controls. A subsequent study examined a sample of 12 subjects with schizophrenia and 11 healthy controls performing a word fluency task, associated with left frontal lobe function. Patients showed less left frontal activation and greater left temporal activation than controls. Sensorimotor cortex and supplementary motor area activation were examined in right-handed patients (8) and controls (9) during finger-to-thumb opposition. All subjects showed a significant activation of the supplementary motor area and both ipsilateral and contralateral sensorimotor cortices. Compared with controls, patients showed a decreased activation of both sensorimotor cortices and supplementary motor area as well as a reversed lateralization effect. Increased understanding of the technology and elucidation of neural systems involved in the processing of tasks in healthy people should enhance our ability to apply this methodology to schizophrenia. Effects of Medication The pharmacological status of patients undergoing metabolic and blood flow studies has varied. Research has ranged from investigations in which antipsychotic agents were considered a variable that needed to be controlled to those in which pharmacological intervention was introduced in a standardized fashion to examine treatment effects on the regional metabolic landscape. The washout period in studies that attempted to control the effects of antipsychotic drugs on cerebral blood flow and metabolism has commonly been short, ranging from 2 to 4 weeks. This period is a compromise between what is feasible and desirable. Monte Buchsbaum and colleagues examined cerebral glucose metabolism in cortical-striatal-thalamic circuits in a large sample of unmedicated men with schizophrenia. They found that patients had low metabolic activity in the medial frontal cortical regions and the basal ganglia, as well as an impaired lateralization pattern in the frontal and temporal regions. More recently in schizophrenia research, antipsychotic drug-naive first-episode patients have been studied. This population is particularly informative when the study is focused on the effects of pharmacological intervention. The study of neuroleptic-naive patients before pharmacological intervention separates the disease state from its treatment. The pattern of abnormalities summarized above is evident in first-episode patients across studies that examined differences between their first episode and episodes of previously treated patients. This suggests that disruption in normal brain processes is apparent at the presentation of illness and cannot be attributed to treatment or chronicity. While this is an informative approach, further progress can be made in metabolic studies using complementary methods to integrate pharmacological probes with metabolic studies. A repeated-measures longitudinal design has been applied in a limited number of PET studies. In addition to examining symptom severity over time, this paradigm is singularly useful when pharmacological intervention is standardized. One study compared the effects of thiothixene (Navane) and haloperidol (Haldol) in chronic patients who were scanned off medication and after 4 to 6 weeks on medication. A different pattern of global and regional glucose metabolism was seen in the two groups. In another study PET scans were obtained at weeks 5 and 10 of a double-blind crossover trial of haloperidol and placebo in 25 patients with schizophrenia. Low relative metabolism in the striatum on placebo was associated with improved symptomatology. Responders to treatment had increased metabolism in the striatum after treatment. Nonresponders failed to show such a change and had more marked hypofrontality on medication. In a subsequent study, 12 patients were scanned before and 4 to 6 weeks after treatment with clozapine (Clozaril) or thiothixene. The drugs had a differential effect, with clozapine increasing and thiothixene decreasing metabolism in the basal ganglia, right more than left. Henry Holcomb and coworkers used a repeated-measures design to study glucose metabolism in 12 patients on a fixed dose of haloperidol and 5 and 30 days after drug withdrawal. No differences were observed between metabolism on medication and after 5 days of discontinuation. However, at 30 days, metabolism decreased in the caudate, putamen, and anterior thalamus and increased in the frontal cortex and anterior cingulate. The authors concluded that the basal ganglia are the site of the primary antidopaminergic action of haloperidol and that other changes observed are mediated through the cortical-striatal-thalamic pathways. The integration of pharmacological and neurobehavioral probes is a potentially powerful approach. For example, patients exhibited enhanced activation of the anterior cingulate after administration of apomorphine, suggesting a modulating role for dopamine. Methodological Considerations and Potential Limitations Anxiety has complex effects on regional cerebral blood flow and metabolism, which investigators in a few laboratories have reported. It would seem desirable to measure anxiety carefully by use of complementary behavioral and psychophysiological procedures and to examine the relation of these measures to the regional metabolic and cerebral blood flow values and performance. Motivation is an important factor in cognitive studies of schizophrenia. Whether poor performance can be improved by providing instructions and monetary reinforcement has been addressed in studies with the Wisconsin Card Sorting Test. One approach to this issue is the calculation of “mental effort” scores by subtracting basal cognitive abilities (e.g., I.Q. measures) from current performance. This difference between current and basal performance provides a measure of how well subjects perform in relation to their inherent ability, which may provide a parameter of motivation that can be related to cognitive and physiological data. This approach has been taken in 133Xe and PET cerebral blood flow studies. Task selection and choice of stimuli raise several questions. There are reasons to prefer elemental tasks that have been used extensively in cognitive psychology and are applicable across physiological measurements. A continuous presentation format of the tasks provides flexibility and ensures that subjects receive continuous stimulation during the measurement epoch. The importance of examining the issue of epoch has been recently demonstrated in a study by the Iowa group. In many studies, self-paced task presentation was used with the hope of engaging the subject's utmost mental resources and efforts. This was considered essential for the 133Xe and the PET flurodeoxyglucose studies, which integrate data across long periods of clearance (15 and 40 minutes, respectively). The disadvantage of self-paced administration for the PET cerebral blood flow and functional MRI measurements may, however, outweigh their advantage because of the brief measurement epoch. For brief duration, there could be considerable variability in the number of stimuli processed by subjects, and because patients with schizophrenia have slower initiation and response times, the differences in cerebral blood flow activation between patients and controls could be hard to interpret. Central to the goal of relating regional cerebral blood flow change to task performance and clinical state variables is the problem of correlating behavioral data with physiologic data that are themselves intercorrelated. Innovative statistical approaches (e.g., Statistical Probability Mapping [SPM]) are used to address the global scaling factors inherent in this area of investigation.

NEURORECEPTOR STUDIES

Study of Neuroreceptors Another critical window for assessing brain function, the study of neuroreceptors, can give insight into the nature of neurochemical abnormalities in schizophrenia. Because advances in elucidating the pathophysiology of schizophrenia require understanding neurotransmitter function, the application of PET and SPECT to the study of receptor occupancy is likely to have an impact in the near future. These efforts are guided both by an extensive psychopharmacological literature and by advances in basic neuroscience on neuroreceptor subtyping. Functional neuroimaging is the meeting ground of preclinical and clinical neuropharmacology. Human neuroreceptor PET studies have built on progress with in vitro binding measurements of receptor density and affinity and neuroreceptor autoradiography. Psychotic symptoms seen in schizophrenia have been associated with dysfunction of dopamine, and the dopamine hypothesis has undergone revisions on the basis of these data. PET Studies of D 2 Ligands The development of radioligands for PET studies first focused on the dopamine type 2 (D 2) receptor because of its clinical significance in relation to treatment with a neuroleptic agent. The study of antipsychotic drug-naive patients could potentially differentiate effects of the psychotic state before antipsychotic-drug intervention. Two major methodologies for quantitative measurement were developed and applied in the study of schizophrenia. Investigators at Johns Hopkins University applied [ 11C]N-methylspiperone and reported that patients have higher D 2 Bmax values than controls. Studies at the Karolinska Institute, using [ 11C]raclopride, reported similar B max and Kd values in patients and controls. These apparent differences have been discussed and summarized extensively and are likely related to multiple factors including patient variables, ligand properties, and PET modeling methods. Because the ligands differ in binding properties and sensitivity to endogenous dopamine, studies permitting a more direct comparison will be particularly helpful. In such an effort, Anna-Lena Nordstrom and coworkers evaluated the reproducibility of the [ 11C]N-methylspiperone finding in a study of seven neuroleptic-naive patients and seven controls, before and after administration of 7.5 mg of haloperidol. Consistent with previous quantitative PET study of [11C]raclopride binding, there were no differences between patients and controls pretreatment, and after haloperidol the specific binding of [ 11C]N-methylspiperone was reduced by 80 to 90 percent. More recently, investigators at Johns Hopkins replicated the initial report in a new sample of drug-naive patients with schizophrenia. Other data reveal D2 receptor density increases in psychotic, but not in nonpsychotic, patients with bipolar I disorder. The increase is comparable to that reported in schizophrenia. This raises questions regarding the specificity of the dopamine hypothesis to schizophrenia versus other psychotic syndromes. Jean-Luc Martinot and coworkers measured D 2 striatal dopamine receptors using [ 76Br]-bromospiperone in a PET study of 12 untreated patients with schizophrenia and found no increase in receptors in patients relative to controls. In a subsequent study, [ 76Br]bromolisuride was applied to the measurement of striatal D 2 receptors in 19 untreated patients and 14 controls. Again, no differences in striatum-to-cerebellum ratios emerged, and no relation to symptoms or subtypes was evident in either study. Receptor Function and Clinical Response The study of neuroreceptors can also address issues related to the relationship between receptor function and signs such as akathisia, commonly seen in patients treated with neuroleptic agents. Farde and colleagues determined in four control subjects the activity of [ 11C]SCH 23390, a selective D 1 receptor antagonist. Two PET studies, at low and high doses of the radioligand, were conducted per subject. Transient akathisia occurred only when binding in the basal ganglia was at a high level with 45 to 59 percent occupancy. The D 2 receptor antagonist [ 11C]raclopride was measured in 20 controls and 13 patients. Akathisia was associated with maximal ligand binding in the basal ganglia in patients and controls. Adam Wolkin and colleagues found that neuroleptic-resistant patients with schizophrenia did not differ from neuroleptic responders in degree of D 2 receptor occupancy by the antipsychotic agents. The regional distribution and kinetics of haloperidol binding were studied with [ 18F]haloperidol in a PET study of five patients with schizophrenia examined while on haloperidol and after a drug washout and nine controls. Wide regional distribution of the ligand was evident in the cerebellum, basal ganglia, and thalamus, in contrast to the specific binding to the basal ganglia of [ 18F]N-methylspiroperidol. Thus, small structural differences among butyrophenones are associated with changes in kinetics and distribution. Typical and Atypical Antipsychotics PET neuroreceptor methods have also been applied in studies comparing atypical (serotonin–dopamine antagonists) and typical (dopamine receptor antagonists) antipsychotic drugs. The properties of clozapine binding to D 1 and D2 receptors were examined in an open study of 5 patients, relative to 22 patients treated with dopamine receptor antagonists. Clozapine induced lower D 2 occupancy (38 to 63 percent), whereas D 2 receptor occupancy with dopamine receptor antagonists at conventional doses was 70 to 89 percent. Neuroleptic-induced extrapyramidal syndromes were associated with higher D 2 occupancy. In a follow-up study, Nordstrom and coworkers examined the relation between D 2 receptor occupancy and antipsychotic drug effect in a double-blind PET study using [ 11C]raclopride. Seventeen patients with schizophrenia were randomly assigned to three groups treated with varied dosages of raclopride. A PET study was conducted at steady-state on 13 patients during the third to fourth week of treatment. A curvilinear relation between plasma concentration of raclopride and D 2 receptor occupancy was obtained. A significant relationship was noted between D 2 receptor occupancy and Brief Psychiatric Rating Scale percentage change as a measure of outcome. The D2 receptor occupancy in patients who had extrapyramidal adverse effects was higher than in patients without. Nordstrom and coworkers examined D1, D2, and 5-hydroxytryptamine type 2 (5-HT2) receptor occupancy in 17 patients treated with clozapine (125 to 600 mg a day) applying [ 11C]SCH23390, [11C]raclopride, and [ 11C]N-methylspiperone. D 2 receptor occupancy (20 to 67 percent) was lower than for dopamine receptor antagonists (70 to 90 percent); D 1 receptor occupancy (36 to 59 percent) was higher than that reported for dopamine receptor antagonists (0 to 44 percent); and 5-HT 2 receptor occupancy was high (84 to 94 percent). Thus clozapine shows a combination of relatively high D 1, low D2, and quite high 5-HT 2 receptor occupancy values, and serum concentrations are not predictive of receptor occupancy. In a PET study of [ 11C]raclopride, Shitis Kapur and coworkers determined D 2 receptor occupancy induced by 2 mg a day of haloperidol for 2 weeks in seven patients. High levels of D 2 occupancy (53 to 74 percent) were noted with substantial clinical improvement. A similar investigation in nine patients receiving 2 to 6 mg a day of risperidone (Risperdal) showed receptor occupancy (66 to 79 percent) similar to that of dopamine receptor antagonists and higher than that of clozapine. When 10 patients with psychoses treated with loxapine were evaluated for D 2 and 5-HT 2 receptor occupancy, the agent differed from serotonin-dopamine antagonists. It has high 5-HT 2 receptor occupancy, which is not higher than D 2 occupancy. These research paradigms illustrate the integration of functional neuroimaging with pharmacological research. Incorporation of these strategies to psychopharmacological studies of schizophrenia with available therapeutic agents can advance the field and guide treatment intervention. SPECT Studies The D2 receptor SPECT ligand iodine-benzamide 123I-iodobenzamide (IBZM) has been applied in studying dopamine D 2 receptors in patients with schizophrenia. Fifty-six patients were evaluated and a semiquantitative analysis of D 2 receptor binding was calculated (basal ganglia to frontal cortex ratio of activity). These ratios in patients taking typical neuroleptic agents were significantly lower than those in the neuroleptic-free subjects but not lower than those in the patients taking serotonin-dopamine antagonists (clozapine, remoxipride). No overall elevation of D 2 receptor binding was observed comparing 20 patients off medications and 20 controls, but a left lateralized asymmetry was found in male patients.

METABOLITE STUDIES: MAGNETIC RESONANCE SPECTROSCOPY (MRS) MRS provides analytical qualitative and quantitative data on cellular metabolism and molecular structure. It has been used to study metabolism in vitro and in vivo in animals and humans. Spectral localization methods permit the measurement of 1H and 31P nuclear magnetic resonance (NMR) spectra from precisely localized volumes of interest, and this provides the basis for applying these techniques to study brain diseases. Because the technology is fundamentally similar to that used in MRI, several groups have begun to develop an approach that integrates these two modalities into a single examination. There are few reports that use this approach to investigate the underlying metabolism of neuropsychiatric disorders. Jay Pettegrew and colleagues pioneered applying phosphorus-31 ( 31P) methods to the study of several neuropsychiatric diseases, including schizophrenia. They reported hypofunction in the dorsolateral prefrontal cortex in a sample of antipsychotic drug-naive patients with schizophrenia. The patients had significantly lower levels of phosphorus monoesters (PME) and higher levels of phosphorus diesters (PDE) than normal controls. Inorganic phosphate concentration was decreased and ATP concentration was increased in the patients. These latter results were interpreted as reflecting hypofunction of the dorsal prefrontal cortex in the patients. This interpretation is consistent with reports of decreased blood flow and decreased utilization of glucose in this region, as summarized above. A follow-up case report described a patient who exhibited in the 31P MRS spectra PME and PDE levels similar to those reported for schizophrenia, well before the onset of psychotic symptoms. This finding led the authors to suggest that MRS may be of value in examining high-risk subjects such as family members of patients with schizophrenia for the presence of spectral abnormalities. Another group reported 31P MRS results on patients with schizophrenia that support the findings of Jay Pettegrew and coworkers. Thus, a growing body of evidence from several laboratories shows converging findings. This suggests the possibility of dysfunction in the normal process of programed synaptic pruning. Abnormal pruning could result in neuronal loss as well as upregulation of the postsynaptic dopaminergic receptors. These changes observed with 31P clearly suggest that there should be alterations in the levels of the

compounds routinely detectable by localized proton MRS. Considerable interest exists in obtaining solvent-suppressed proton spectra in humans. As the technical issues involved in obtaining spectra are being solved, it is important to begin to relate MRS measurements to the underlying biochemistry in the tissue being sampled. The role of N-acetylaspartate was reviewed by D.L. Birken and W.H. Oldendorf. This compound was found by NMR in glia and neurons but not on astrocytes. For this reason N-acetylaspartate concentration has been proposed as an index of neuronal integrity. The roles of the amino acids present in the brain have been examined. There is about 12 mM glutamate present in the brain, making it by far the most abundant amino acid. The rates of glutamate synthesis and oxidation differ in astrocytes and neurons. Two important products of glutamate are glutamine which is formed from glutamate by glutamate synthetase located in astrocytes and g-aminobutyric acid (GABA), an inhibitory neurotransmitter. Aspects of the metabolism of these compounds and the influence of this metabolism on MRS spectral appearance has received increased attention. Glutamate is largely confined to the tissue in which it is formed by barriers in permeability. Glutamine can be converted to glutamate at the site of neurotransmitter activity by glutaminase, which is present in neurons. The combination of two enzymes, glutamine synthetase (which converts glutamate to glutamine) and glutaminase, acts as a sort of cycle to maintain the concentrations of glutamate and glutamine. GABA and glutamate concentrations were determined by MRS in cultured preparations of cortical neurons and cerebellar granule cells, and colleagues granule cells contained large amounts of glutamate, while the neuronal cells contained large amounts of GABA. Detection of these compounds in vivo in clinical studies showed increased glutamine concentrations in patients with chronic hepatic encephalopathy. Douglas Rothman and coworkers showed that it is possible to determine the glutamine concentration in human brain by spectral editing methods. The glutamine concentrations reported were in excellent agreement with literature values. These workers referenced their measurement of glutamate to the concentration of total creatine present (9.6 mM) in the brain. The key feature in their methodology was the use of short echo delays (12 milliseconds) to estimate the glutamate present. It seems therefore that MRS can be used to measure the concentrations of these amino acids, which may provide some insights into the activity of the excitatory glutamate and inhibitory (GABA) neurotransmitters present in the tissue being sampled. The studies so far are preliminary, since larger samples and a comprehensive and systematic approach to behavioral assessment are needed to link behavioral dimensions to both neuroanatomy and metabolism.

FUTURE DIRECTIONS Structural and functional neuroimaging research in schizophrenia has made progress in advancing the understanding of neuroanatomical and neurophysiological substrates of this disorder. Structural imaging studies have identified subtypes of patients with reduced brain volume, and lower regional volumes have also been reported in structures that are key to healthy processing of complex behavior. While it is too early to outline with any precision the network of regions most affected, some consistent evidence has emerged implicating frontotemporal and corticostriatal thalamic regions. By and large, these structural abnormalities are present early in the course of illness and are related to disease features. These research methods can be applied to informative populations such as high-risk individuals and in genetic paradigms. Furthermore, recent evidence for progressive changes in some patients encourages longitudinal studies. Two areas have been examined in functional imaging studies: energy metabolism and neuroreceptor studies. In a review of this field Goran Sedvall concluded that the major future contribution for understanding the pathophysiology of schizophrenia will be achieved through advanced resolution and development of new ligands for neurotransmitter systems. While the authors agree on the potential of these developments, they believe that metabolic studies can make unique contributions that will prove essential for finding the neural basis of schizophrenia and ultimately for improved treatment. In the context of the overall effort in neurobiological research in schizophrenia, functional neuroimaging studies have advanced the understanding of brain dysfunction related to neurobehavior and neuropharmacology. The field has reached some maturity in developing appropriate paradigms, and there is now a need for adequate sample size in patient and healthy populations, with attention to clinical heterogeneity and variability in brain function in relation to gender and age. One of the major challenges in this research is the integration of neuroimaging data across anatomical and functional measures with clinical and neurobehavioral variables. A potential strength of functional neuroimaging is the integration of data on neuroreceptor function, metabolites, and metabolic activity. Ultimately, dysfunctional neurotransmitter systems translate to aberrant metabolism. Since cerebral blood flow and metabolism reflect neuronal activity, relating these domains is prerequisite to understanding the neurobiology of schizophrenia. As new receptor subtypes are cloned and radioligands are developed and available for human studies, it will be necessary to know which neuroreceptor measures result in increased neuronal activity and in turn how regional activation relates to behavior. Thus, while new receptor ligands and improved resolution are welcome and exciting, as is the development of methods for MRS and flow measures, it is unlikely that the neural basis of schizophrenia will simply result from applying the right method with sufficient resolution. Rather, the harder and longer route of understanding the interaction among the brain's structural integrity, regional activity, and neuroreceptors as they affect the clinical and neurobehavioral manifestations of schizophrenia will probably be needed. On the positive side, this examination may yield partial answers of immediate benefit for treatment, and the evolution of this work will systematically improve our ability to articulate a neuropsychiatric perspective of this devastating disorder.

SUGGESTED CROSS-REFERENCES The neural basis of schizophrenia psychopathology is further discussed in Section 1.1 an introduction and overview of neural sciences, in Section 1.2 on functional neuroanatomy, in Section 1.4 on monoamine neurotransmitters, in Section 1.10 on basic molecular neurobiology, and in Section 3.5 on brain models of mind. Neuroimaging is presented in Section 1.15 and Section 1.16. Typical antipsychotics drugs are presented in Section 31.17 on dopamine receptor antagonists. Atypical antipsychotics are covered in Section 31.26 on serotonin-dopamine antagonists. Other aspects of schizophrenia are discussed throughout Chapter 12. SECTION REFERENCES Andreasen NC, Arndt S, Swayze V II, Cizadlo T, Flaum M, O'Leary D, Ehrhardt JC, Yuh WT: Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 266:294, 1994. Andreasen NC, Flashman L, Flaum M, Arndt ST, Swayze V II, O'Leary DS, Ehrhardt JC, Yuh WTC: Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA 272:1763, 1994. Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L, Canaran G, Rylett RJ, Neufeld RWJ: Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 54:959, 1997. Bertolino A, Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CTW, Frank JA, Tedeschi G, Weinberger DR: Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 153:1554, 1996. Buchsbaum MS, Someya T, Teng CY, Abel L, Chin S, Najafi A, Haier RJ, Wu J, Bunney WE Jr: PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 153:191, 1996. Cannon TD, van Erp TG, Huttunen M, Lonnqvist J, Salonen O, Poutanen VP, Standerstskjold-Nordenstam CG, Gur RE, Yan M: Regional gram matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their sibliings, and controls. Arch Gen Psychiatry 55:1084, 1998. DeLisi LE, Tew W, Xie S, Hoff AL, Sakuma M, Kushner M, Lee G, Shedlack K, Smith AM, Grimson R: A prospective follow-up study of brain morphology and cognition in 1st episode schizophrenic patients: Preliminary findings. Biol Psychiatry 38:349, 1995. Dolan RJ, Fletcher P, Frith CD, Friston KJ, Frackowiak RS, Grasby PM: Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature 1995.

378:180,

Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G: PET analysis of central D1 and D2 dopamine receptor occupancy in patients treated with chemical neuroleptics and clozapine: Relation to extra-pyramidal side effects. Arch Gen Psychiatry 49:538, 1992. Frith CD, Friston KJ, Herold S, Silbersweigh D, Fletcher P, Cahill C, Dolan RJ, Frackowiak RS, Liddle PF: Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 167:343, 1995. Gur RC, Erwin RJ, Gur RE: Neurobehavioral probes for physiologic neuroimaging studies. Arch Gen Psychiatry 49:409, 1992. Gur RE, Jaggi JL, Shtasel DL, Ragland JD, Gur RC: Cerebral blood flow in schizophrenia: Effects of memory processing on regional activation. Biol Psychiatry 35:3, 1994.

Gur RE, Maany V, Mozley D, Swanson C, Bilker W, Gur RC: Subcortical MRI volumes in neuroleptic-naive and treated patient with schizophrenia. Am J Psychistry 155:1711, 1998. Gur RE, Mozley PD, Resnick SM, Mozley LH, Shtasel DL, Gallacher F, Arnold SE, Karp JS, Alavi A, Reivich M, Gur RC: Resting cerebral glucose metabolism and clinical features of schizophrenia. Arch Gen Psychiatry 52:657, 1995. Gur RE, Mozley PD, Shtasel DL, Cannon TD, Gallacher F, Turetsky BI, Grossman RI, Gur RC: Clinical subtypes of schizophrenia differ in brain and cerebrospinal fluid volume. Am J Psychiatry 151:343, 1994. Gur RE, Pearlson GD: Neuroimaging in schizophrenia research. Schizophr Bull 19:337, 1993. Holcomb HH, Cascella NG, Thaker GK, Medoff DR, Dannals RF, Tamminga CA: Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol. Am J Psychiatry 153:41, 1996. Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, Zipursky R: High levels of dopamine D 153:948, 1996.

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receptor occupancy with low-dose haloperidol treatment: A PET study. Am J Psychiatry

Kapur S, Zipursky R, Remington G, Jones C, McKay G, Houle S. PET evidence that loxapine is an equipotent blocker of 5-HT Am J Psychiatry 154:1525, 1997.

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and D2 receptors: Implications for the therapeutics of schizophrenia.

Kotrla KJ, Weinberger DR: Brain imaging in schizophrenia. Ann Rev Med 46:113, 1995. Lim KO, Tew W, Kushner M, Chow K, Matsumoto B, DeLisi LE: Cortical gray matter volume deficit in patients with first-episode schizophrenia. Am J Psychiatry

153:1548, 1996.

Nopoulos P, Flaum M, Andreasen NC: Sex differences in brain morphology in schizophrenia. Am J Psychiatry 154:1648, 1997. Nordstrom AL, Farde L, Eriksson L, Halldin C: No elevated D 2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [ Psychiatry Res 61:67, 1995.

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C]N-methylspiperone.

Nyberg S, Farde L, Halldin D. Delayed normalization of central D 2 dopamine receptor availability after discontinuation of haloperidol decanoate. Arch Gen Psychiatry 54:953, 1997. O'Leary DS, Andreasen NC, Hurtig RR, Kesler ML, Rogers M, Arndt S, Cizadlo T, Watkins GL, Ponto LL, Kirchner PT, Hichwa RD: Auditory attentional deficits in patients with schizophrenia. A positron emission tomography study. Arch Gen Psychiatry 53:633, 1996. Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M: Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. Arch Gen Psychiatry 48:563, 1991. Petty RG, Barta PE, Pearlson GD, McGilchrist IK, Lewis RW, Tien AY, Pulver A, Vaughn DD, Casanova MF, Powers RE: Reversal of asymmetry of the planum temporale in schizophrenia. Am J Psychiatry 152:715, 1995. Rojas DC, Teale P, Sheeder J, Simon J, Reite M. Sex-specific expression of Heschle's gyrus functional and structural abnormalities in paranoid schizophrenia. Am J Psychiatry 154:1655, 1997. Sedvall G: The current status of PET-scanning with respect to schizophrenia. Neuropsychopharmacology 7:50, 1992. Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, Wible CG, Hokama H, Martin J, Metcalf D, Coleman M, McCarley RW: Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N Engl J Med 327:604, 1992. Siegel BV, Buchsbaum MS, Bunney WE Jr, Gottschalk LA, Haier RJ, Lohr JB, Lottenberg S, Najafi A, Nuechterlein KH, Potkin SG, Wu JC: Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients. Am J Psychiatry 150:1325, 1993. Suddath RL, Casanova MF, Goldberg TE, Daniel DG, Kelsoe JR Jr, Weinberger DR: Temporal lobe pathology in schizophrenia: A quantitative magnetic resonance imaging study. Am J Psychiatry 146:464, 1989. Turetsky BI, Cowell PE, Gur RC, Grossman RI, Shtasel DL, Gur RE: Frontal and temporal lobe brain volumes in schizophrenia: Relationship to symptomatology and clinical subtype. Arch Gen Psychiatry 52:1061, 1995. *Velakoulis D, Pantelis C, McGorry PD, Dudgeon P, Brewer W, Cook M, Desmond P, Bridle N, Tierney P, Murrie V, Singh B, Copolov D: Hippocampal volume in first-episode psychoses and chronic schizophrenia. Arch Gen Psychiatry 56:133, 1999. Weinberger DR, Berman KF, Suddath R, Torrey EF: Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: A magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry 149:890, 1992.

Textbook of Psychiatry

12.4 SCHIZOPHRENIA: NEUROBIOLOGY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.4 SCHIZOPHRENIA: NEUROBIOLOGY MICHAEL F. EGAN, M.D., AND THOMAS M. HYDE, M.D., PH.D. Role of Genes and Environment Structural and Functional Neuroimaging Neuropathology Neurochemistry Neural Circuits Neurobiological Models Suggested Cross-References

Schizophrenia is a chronic mental illness affecting approximately 1 percent of the population. Beginning in early adulthood, schizophrenia typically causes a dramatic, lifelong impairment in social and occupational functioning. From a public health standpoint, the costs of treatment and lost productivity make this illness one of the most expensive disorders in medicine. Despite the tremendous economic and emotional costs, research on schizophrenia lags far behind that on other major medical disorders. A primary impediment to developing more effective treatment is the limited understanding of the etiology and neurobiology of this disorder. New technologies, such as neuroimaging and molecular genetics, are removing the obstacles that once blocked major progress in the field. Although the stigma associated with the illness has not yet been eliminated, these new techniques have markedly altered the conception of the nature of schizophrenia. One of the most rapidly changing fields is genetics. Family, twin, and adoption studies have clearly shown that genes play a prominent role in the development of schizophrenia. Estimates of heritability typically range from 50 to 85 percent. Initial attempts to isolate major genes using linkage studies were unsuccessful, but more recent approaches using increasingly sophisticated methods have uncovered several chromosomal regions that may harbor genes of minor effect. It seems likely that schizophrenia is the result of the interaction of many genes, some of which also interact with environmental factors. Investigations of environmental factors have looked at the role of stress, viruses, obstetrical complications, and in utero insults, among others. None of these have been definitively shown to be causative. It is possible that different combinations of genetic and environmental factors affect specific neurobiological systems, leading to a final common pathway of neural dysfunction. Several neurobiological abnormalities have been found to have major implications for understanding the pathophysiology of schizophrenia. The first are structural brain abnormalities. Initially seen decades ago using pneumoencephalography, structural changes have been more clearly delineated using computerized tomography (CT) and magnetic resonance imaging (MRI). The most commonly reported alterations include enlarged lateral ventricles, enlarged third ventricle, and reduced volume of a number of structures, including hippocampus, amygdala, and frontal and temporal cortices. These abnormalities may predate the onset of illness. Second, functional cortical deficits have been seen with a variety of techniques, such as neuroimaging and neuropsychological testing. Prefrontal and temporal lobe dysfunction is most prominent, and is possibly related to structural abnormalities. Third, neuropathological studies have consistently failed to find any evidence of gliosis to account for the structural deficits. If anything, they tend to find subtle cytoarchitectural alterations. The recurring theme of this research suggests some type of failure in neuronal migration, orientation, or connectivity. Finally, several neurotransmitter systems appear to play a role, particularly in the expression of positive as well as negative psychotic symptoms. Evidence for alterations in the dopamine system is the most compelling. Other neurotransmitters have also been implicated, including glutamate, serotonin, and g-aminobutyric acid (GABA). Neurochemical, structural, and functional imaging abnormalities can be understood in the context of the neural circuits involved and models of the illness. Cortico-striato-thalamic, limbic, and dopamine systems all appear to play a role. These three interconnected pathways mediate different aspects of higher-level information processing, such as judgment, memory, planning, and motivation. Their involvement could arise in several ways. One model suggests that neurodevelopmental abnormalities occur in utero. The clinical manifestations of schizophrenia appear only after brain development is largely completed, in late adolescence. Although this hypothesis has come to dominate thinking about schizophrenia, the neurodevelopmental model has several weaknesses.

ROLE OF GENES AND ENVIRONMENT Genetic Factors Family, twin, and adoption studies indicate that there is a major heritable component to schizophrenia. Whereas the incidence in the normal population is approximately 0.5 to 1 percent, the lifetime risk in first-degree relatives is roughly 10 percent, indicating that the risk to first-degree relatives is 10 times that of the general population. This strongly implicates a familial factor in the etiology of the illness. Twin and adoption studies have shown that this is mostly, if not entirely, due to genetic factors. For example, the concordance rate in monozygotic twins is approximately 50 percent, as compared to 10 to 14 percent for dizygotic twins, suggesting that heritability may be as high as 80 percent. Of seven adoption studies, all found an increased incidence of schizophrenia in biological relatives, but not in adoptive relatives. This data convincingly demonstrates that genetic factors rather than shared, familial environmental factors are at work. Although such epidemiological data implicate a major heritable component, the genetic architecture appears complex. Early attempts at modeling genetic transmission in families (using segregation analysis) suggested that heritability could not be explained by a single, dominant gene. In the early 1990s, increasingly sophisticated modeling indicated that at least several genes were involved, each with incomplete penetrance. One very real possibility is that there are many genes of minor effect. Such genes are difficult to detect using traditional linkage approaches. A triggering role for the environment in those with a genetic predisposition has also been hypothesized. While genetic modeling has been heuristically useful, the lack of a clear genetic mechanism complicates attempts to find the causative genes. Early linkage studies were based on traditional assumptions that a single dominant gene produced the illness. These were, in general, unsuccessful. The first published study to use restriction fragment length polymorphisms (RFLP) reported linkage between two markers on the long arm of chromosome 5 (5q11-13) and schizophrenia. Subsequently, a number of other groups using separate cohorts were unable to replicate this, and several were able to clearly reject linkage to loci from 5q. While this failure dampened enthusiasm for genetic studies of schizophrenia, the relentless advances in statistical genetics and the molecular biology of the human genome have provided powerful new tools for detecting genes of minor effect. For example, some of the problems with specifying the unknown parameters needed for linkage analysis can be circumvented by using nonparametric approaches. These approaches use large collections of sibling pairs, both affected with the illness. As investigators have begun to use such tools, positive linkage reports for schizophrenia susceptibility genes of minor effect have been reported. Recent examples of putative schizophrenia susceptibility loci yielding some evidence of confirmation include loci on chromosomes 6, 8, and 22. Despite real advances, several statistical issues continue to complicate interpretation of linkage studies. First, ambiguities persist about what diagnoses should be included. Family and adoption studies have suggested that diagnoses such as schizoaffective disorder, schizotypal personality disorder, and atypical psychosis are genetically related. To hedge their bets, investigators looking for linkage typically test several definitions of “schizophrenia spectrum,” ranging from narrow to very broad inclusion criteria. This means that more family members are included in the analysis as diagnostic criteria broaden. Second, the issue of which genetic model to use continues to plague parametric approaches. Typically, linkage studies include dominant, recessive, and mixed models. Here again, investigators hedge their bets by testing three or four genetic models. Since both problems lead to multiple testing, correction for multiple comparisons is indicated. Unfortunately, it is not entirely clear how to correct for this multiple testing. Currently, the commonly accepted significance level ( p values) for initial linkage reports is ~10 –4 to 10–5 or a logarithm of the odds (LOD) score of 3.3 and 0.01 for confirmation. Several groups have published putative replications of linkage findings based on these statistical criteria. The first linkage study with some independent confirmation came from a study of a large Irish cohort. Using microsatellite markers and 186 multiplex schizophrenia families, evidence was found for linkage to the short arm of chromosome 6 (6p22). However, when adjusting for multiple comparisons, a genome-wide significance was estimated at .05 to .08 percent. When the original cohort was extended to 265 pedigrees, an LOD score of 3.51 was obtained, again using a moderately broad definition of illness. The LOD score was highest with a model of intermediate penetrance; of note, only 15 to 30 percent of pedigrees were linked. Supportive evidence for linkage to 6p22 was found in three independent studies. Interestingly, the three replications were different from the original in several ways; one used a recessive model and a narrow definition. In contrast to the original findings, a dominant model and broad disease definition yielded an LOD score of 0.06. A second replication study found suggestive linkage at a marker very close to the one in the original report. Not unexpectedly, a number of studies have failed to replicate the D6p22 linkage. These results illustrate some of the complexities of linkage studies of schizophrenia, but also provide some hope that these methods will uncover the genes involved in schizophrenia.

In addition to 6p22-24, at least two other regions have yielded evidence of linkage to schizophrenia. Ann Pulver and colleagues first described evidence for suggestive linkage to chromosome 8 at 8p22-p21 using 57 multiplex families. Soon after, another group, using a very broad definition of illness, reported confirmatory evidence for linkage using the Irish cohort; again, only 10 to 25 percent appeared to be affected by this putative susceptibility gene. A second attempt at replication by a multicenter collaborative group also found support for linkage. Suggestive evidence for a third potential vulnerability locus was reported for chromosome 22 at q12-q13.1. Although the evidence for susceptibility loci in these reports does not overlap completely, the differences in location are not large. In other heritable complex diseases, for example, susceptibility genes have been cloned that are 20 centimorgans (about 20 million base pairs) away from the sites initially linked to the illness. As with 6p22-24, the strength of evidence for linkage to both 8p22-p21 and 22q12-q13.1 depends in part on what is acceptable as a significant replication. This in turn is related to how multiple tests are corrected for using a variety of phenotypes and model parameters. It is possible that there are schizophrenia susceptibility genes in a roughly 10 to 20 cM area in these regions that may each affect a small percentage of families. Several other regions have received attention but the evidence is less compelling. These regions include, at present, 5q, 6q, 9p, 18p, and 22q. Using the candidate gene approach, weak support for involvement of the dopamine type 3 (D 3) receptor gene has emerged. In 1992, an excess of homozygosity was noted in schizophrenia patients compared to controls for a polymorphism in the first exon of the D 3 receptor gene. A few subsequent studies have supported a modest association between schizophrenia and homozygosity of the Ser-9-Gly polymorphism, but a large number of other studies failed to replicate this association. Linkage studies with D 3 receptor gene polymorphisms have not found significant LOD scores. As more functional variants in candidate genes are discovered, focused association studies of these genes will become increasingly common. It is crucial to determine exactly what is inherited. One possibility is that genes determine susceptibility to certain environmental factors. Another possibility is that specific neurobiological abnormalities are produced by specific genes. Family studies have shown that relatives have an increased incidence of several neurobiological traits associated with schizophrenia. These include structural brain abnormalities, changes in evoked potentials, eye-tracking dysfunction, negative symptoms, and subtle cognitive deficts. These parameters could be more basic phenotypes that are closer to the molecular manifestations of the genes that cause schizophrenia. If so, they may improve the ability to detect these genes. Environmental Factors Family-based epidemiological studies clearly demonstrate that environmental factors play a role in the pathophysiology of schizophrenia. The contributions of environmental factors have been estimated to be as much as 30 to 50 percent. Genetic modeling indicates that genes could set the threshold for liability to environmental factors. It is sobering to realize that environment can play a crucial role even in disorders that appear to be autosomal dominant. For example, phenylketonuria is an autosomal-dominant disorder that causes mental retardation. The illness is expressed, however, only if individuals with the abnormal gene ingest phenylalanine. Without this critical environmental exposure, the illness does not develop. Environmental factors hypothesized to play a role in schizophrenia range from problems with maternal bonding and early rearing to poverty, immigration status, stress, and viruses. The neurodevelopmental hypothesis has shifted the research focus somewhat from psychosocial variables to those that affect brain development. Several specific insults have been implicated, including pregnancy and birth complications, in utero viral infections (such as influenza), season of birth, and prenatal starvation. Research into pregnancy, obstetric, and neonatal complications has had a particularly significant impact on the field. These complications include events such as prolonged labor, prematurity, preeclampsia, toxemia, fetal distress, and hypoxia. The majority of studies examining the incidence of such complications find increases in patients with schizophrenia. Positive studies include those that compare patients with matched controls, with their own well siblings, and even with a monozygotic twin discordant for schizophrenia. On the other hand, several impressive negative reports, including prospective, epidemiological surveys have failed to find a significant increase in such complications. However, these studies have been criticized on methodological grounds, thereby leaving the issue in doubt. Some authors have suggested that perinatal complications may increase risk only in persons with a genetic predisposition whereas others assert just the opposite. Although these conflicting findings make definite conclusions tentative, the bulk of the data suggests that perinatal complications are increased somewhat in patients with schizophrenia. One possibility for how such complications lead to schizophrenia is that they produce some type of brain damage. The hippocampus, for example, is particularly susceptible to perinatal hypoxia and this limbic structure is thought to play an important role in schizophrenia. A number of studies have found that patients with a history of obstetric complications have increased likelihood of structural brain abnormalities, such as enlarged ventricles. A similar relationship has been seen in nonschizophrenic controls with a history of obstetric complications. However, many studies have failed to find any relationship between structural abnormalities and obstetric complications. Some authors have suggested that only nongenetic forms of the illness (sporadic cases) are more likely to have structural problems and obstetric complications, but data on this are very mixed. More problematic, obstetric complications are thought to mediate increased risk by transient hypoxia but hypoxia typically produces gliosis, a finding notably absent from the postmortem literature on schizophrenia. An alternative explanation is that obstetric complications are themselves secondary to abnormal fetal brain development. In any event, if obstetric complications increase the risk of schizophrenia, they are likely to be a minor factor; most persons with these complications do not develop schizophrenia and most patients with schizophrenia do not have an obvious history of obstetric complications. A second risk factor that has been extensively studied is season of birth. There appears to be an increased incidence of schizophrenia associated with winter and spring birth dates. This finding is controversial, and has been attributed by detractors to a statistical artifact. If there is such a relationship, it could implicate an infectious process, such as a virus; viral infections are more common during winter months. Viral hypotheses have taken several forms, and candidates include slow viruses, retroviruses, or virally activated autoimmune reactions. In a related vein, several large-scale epidemiological studies have reported that the frequency of schizophrenia is increased following exposure to influenza during the second trimester. The effect is slight, however, and some studies have not observed this relationship. Another intriguing risk factor is starvation or poor nutrition. In studies of the effects of starvation during World War II in Holland, researchers found that starvation at the time of conception and in the first trimester increased the risk of developing schizophrenia by a factor of 2. Other factors recently reported to increase the risk of schizophrenia include Rh incompatibility and low intelligence quotient (I.Q.). At this point, no single major factor has been unambiguously identified as an environmental cause of schizophrenia, and it is likely that none exists. As with genetic loci, environmental effects probably consist of a variety of factors, each having a minor effect at best. These will be difficult to detect, as will their hypothesized interaction with genes of minor effect, without large-scale studies.

STRUCTURAL AND FUNCTIONAL NEUROIMAGING Neuroimaging studies of schizophrenia have demonstrated alterations in both structural and functional measures. Structural abnormalities include increased volume of the third and lateral ventricles, sulcal widening, and reduced volume of gray matter regions. Functional abnormalities include alterations in blood flow and measures of chemical moieties using MRI spectroscopy. Neuroimaging has also been used to assay receptor density and dynamic parameters related to dopamine release. Neurochemical studies are discussed separately in sections on specific neurotransmitters. Neuroimaging has had a major impact on the conceptualization of schizophrenia. The notion that patients with schizophrenia have an actual deficit in the volume of brain tissue clearly established that this was a brain disease rather than a purely psychological or biochemical disorder. Functional neuroimaging has implicated the prefrontal and temporal lobes in particular, and has begun to relate activity in these regions to the clinical manifestation of schizophrenia. As critical as these findings have been, important controversies remain. Structural Abnormalities One of the most widely replicated neurobiological findings in schizophrenia research is that of altered volume of cerebral structures. Increased size of the cerebral ventricles and reduced brain volume were observed early in the twentieth century using pneumoencephalography and postmortem material. These early findings, however, had little enduring impact on the field. The advent of CT technology renewed interest in cerebral volumetric parameters. The earliest CT studies found enlargement of the lateral and third ventricles and cortical sulci. Although these findings were initially viewed with skepticism, over 100 subsequent studies have been published with lateral ventricular enlargement reported in 75 percent, third ventricular enlargement in 83 percent, and cortical changes in 67 percent. Concerns that ventricular enlargement could be secondary to factors such as antipsychotic medications, institutionalization, and diet have generally been ruled out. Furthermore, studies using MRI, with its markedly enhanced resolution, have confirmed the presence of lateral and third ventricular enlargement and provided estimates of tissue loss to be roughly 3 to 10 percent. The finding of ventricular enlargement dramatically shifted the focus of research on schizophrenia. Subsequently, several critical questions have dominated this landscape. First, is ventricular enlargement caused by focal areas of tissue loss or a more generalized process? Second, do the structural abnormalities predate the

onset of the illness, implicating a neurodevelopmental process, or do they arise concomitantly with the illness, suggesting a neurodegenerative process? Third, are all patients affected or only a subgroup? Finally, what are the functional implications of these abnormalities? To localize brain abnormalities, researchers have looked at a variety of measures, including cortical sulcal enlargement, ventricular enlargement, and quantitative measures of individual brain structures. Regarding cortical sulcal enlargement the data are split, with some reporting sulcal enlargement in the frontal and temporal lobes whereas others have found more diffuse enlargement. More specific measures of cortical volume typically show reductions of temporal and, less consistently, frontal lobe volume. These reductions involve gray rather than white matter, although some studies have found reductions in white matter as well. Regional volumetric studies of specific brain structures have generally focused on the temporal lobes. Bilateral volume reductions in amygdala-hippocampus, parahippocampal gyrus, entorhinal cortex, and superior temporal gyrus have been reported. In the ventricular system, increased volume in the temporal poles of the lateral ventricles has been found most often; increased volume of the frontal horns and third ventricle is also commonly found. In quantitative studies of subcortical regions, findings have been mixed. Some researchers find no changes in areas such as caudate, putamen, nucleus accumbens, and external segment of the globus pallidus; others have reported increased striatal volume and reduced globus pallidus (internal segment) volume. Increased striatal volume is thought to be an effect of treatment with antipsychotic medications. Reduced volume of the thalamus has also been observed. The notion that the temporal and frontal lobes may play a particularly important role in schizophrenia has been supported by findings from other areas. For example, neurological damage to the temporal lobes sometimes produces positive psychotic symptoms, such as hallucinations, while damage to the frontal lobes is associated with negative symptoms such as apathy, social withdrawal, and blunted affect. On neuropsychological testing, patients with schizophrenia typically show impaired frontal and temporal lobe function. More recently, magnetic resonance spectroscopy has been used to examine these regions. This new technology can measure in vivo concentrations of a variety of neurochemical moieties. These include N-acetyl aspartate (NAA), an intraneuronal amino acid sensitive to mitochondrial energy metabolism and to pathological processes affecting neuronal integrity, choline-containing compounds, creatine plus phosphocreatine, glutamate, glutamine, and high-energy phosphate-containing compounds. Several intriguing findings have emerged. First, specific reductions of NAA have been observed in the dorsolateral prefrontal cortex and hippocampal area, probably reflecting neuronal pathology in these locations. Other areas are, for the most part, unaffected. Second, an imbalance between phosphomonoesters and phosphodiesters has been described in the frontal cortex. These studies, combined with volumetric data, lend support to the theory that there may be selective deficits in frontal and temporal regions. Attempts to pinpoint when volumetric alterations occur have led to studies of patients at the onset of their illness. This issue is crucial to understanding what neurobiological processes could possibly account for structural abnormalities. In general, first-break studies have found the same alterations seen in prior studies of patients with chronic schizophrenia. These results are supported by the lack of relation between volumetric alterations and duration of illness or age of onset seen in studies of such patients. If an active process produced tissue loss, the loss would be correlated with illness duration, which it is not in most studies. On the other hand, cognitive deficits associated with schizophrenia do not progress but probably develop very early in the illness. Although portions of these deficits may be present even in childhood, a significant component probably develops sometime around the onset of the illness. It is not inconceivable that structural abnormalities could develop at the same time. Such changes would not necessarily be detected by first-break studies. Another approach has been to scan first-break patients when they initially present for treatment and then again several years later. The results have been mixed: some find no changes whereas others have suggested that a subgroup of patients do show slight, but progressive tissue loss. The latter approach has been criticized on methodological grounds and certainly more studies are needed. At present, it seems fairly certain that structural abnormalities are present from very early on in the illness. A third issue is whether structural alterations are present in all patients or only a subgroup. Several early studies had found associations between ventricular enlargement and a variety of clinical characteristics, including poor premorbid adjustment, age of onset, cognitive impairment, negative symptoms, poor response to antipsychotic medications, and greater incidence of tardive dyskinesia. Such observations have led to suggestions that there are two forms of schizophrenia, one involving a hyperdopaminergic state and the other involving structural abnormalities. Since then, many CT and MRI studies have examined this issue but have generally failed to confirm this schema. Structural abnormalities do appear to be correlated to some degree with cognitive impairment and negative symptoms, but these correlations are not particularly robust. Another approach to subtyping has been to look at the distribution of these deficits. In a meta-analysis of studies that have used CT scans to evaluate ventricular enlargement, the lack of a bimodal distribution in over 1000 patients suggests that a clear subgroup with these abnormalities does not exist. An elegant attempt to assess the frequency of structural abnormalities was provided by a study of discordant monozygotic twin pairs. Unaffected monozygotic twins serve as an ideal control for assessing illness-related changes. In an MRI study of 15 such pairs, the ill twin had more pronounced deficits for most structural measures in over 85 percent of cases. These findings are similar to those of a prior twin study using CT scans. The data suggest that volumetric abnormalities in schizophrenia are very common, if not ubiquitous; detecting the abnormality may depend on having a perfectly matched genetic control ( Fig. 12.4-1) because patients with normal ventricular volume were often seen to have significantly larger ventricles than their unaffected twin. However, when this MRI study of twins was expanded to 27 discordant pairs, lateral ventricular enlargement was only seen in about 63 percent of the affected twins relative to the unaffected twins. This is only somewhat higher than 50 percent, which is what would be expected by chance. In this expanded sample, it appears that ventricular enlargement may not be universal. In contrast, hippocampal measures continued to predict the affected twin in roughly 80 percent of cases, which is significantly higher than the 50 percent chance level; this suggests that hippocampal pathology is common. Although the exact percent of patients having structural abnormalities is not known, it is probably fairly high. An alternative view is that structural abnormalities represent a quantitative trait that is commonly associated with schizophrenia but neither necessary nor sufficient to produce the illness.

FIGURE 12.4-1 MRI scans (coronal sections) of two sets of discordant monozygotic twins ( A and B = set 1; C and D = set 2). For each pair, one has schizophrenia ( A and C) while the other does not (B and D). For both pairs, the affected twin has larger ventricles than the unaffected twin, even though ventricular size appears to be within the normal range for the affected twin (C). (Courtesy of D. Weinberger and E. F. Torrey.)

In summary, structural abnormalities, such as enlarged ventricles and reduced cortical volume, are a prominent feature of schizophrenia. It is unclear whether cortical involvement is multifocal or diffuse. Temporal and frontal lobe regions are certainly involved. These abnormalities are present very early in the illness. It is too early to say, however, whether they are present from birth or develop at a later stage. Structural abnormalities may be present in a majority of patients, although the exact percentage is unknown. The prevalence is most apparent when compared to ideally matched genetic controls. Structural abnormalities are correlated to some degree with clinical aspects of the illness, such as cognitive deficits. A key issue remains unresolved: what neurobiological processes account for these enigmatic changes? Functional Neuroimaging Functional neuroimaging refers to a group of methods that look at changes in regional neural activity by measuring regional cerebral blood flow (rCBF) or glucose utilization. These two parameters can be measured with several techniques, including positron emission tomography (PET),* (SPECT), and more recently functional MRI (fMRI), each having its own particular advantages and disadvantages. These techniques have been used to explore brain regions that may be dysfunctional in schizophrenia. Several designs have been employed: (1) patients and controls are compared at rest; (2) they are compared during cognitive testing that normally increases activity in a particular brain region; and (3) brain activity is correlated with psychiatric symptoms, either cross-sectionally among patients or within a patient over time. The most consistent finding is reduced activation of the prefrontal cortex (hypofrontality), but other regions, such as the temporal lobes, have also been implicated. Also, correlations have been found between specific symptom clusters and regional activity in both frontal and temporal areas ( Fig. 12.4-2).

FIGURE 12.4-2 PET scans using H 2O15 of two monozygotic twins, one with (right) and one without (left) schizophrenia. Top and bottom scans show two levels through the dorsolateral prefrontal cortex. At the time of scanning, subjects are performing a cognitive task that typically requires prefrontal cortical function. The affected twin blood flow to the dorsolateral prefrontal cortex is markedly reduced compared to the unaffected twin. (Courtesy of R. Berman and D. Weinberger.) (See Color Plate 8.)

Frontal lobe function has been studied most intensively. Initially reported in 1974, the finding of reduced frontal blood flow has been controversial. Many studies, particularly those looking at the resting state, have not found evidence of hypofrontality. Such studies have been criticized, however, because the resting state is an uncontrolled feature and may introduce unnecessary variability. Using cognitive tasks that appear to require prefrontal activation in controls, a number of studies have consistently found that patients with schizophrenia fail to increase blood flow to this region. Although many resting studies have reported hypofrontality, most, if not all, studies using activation tasks have found hypofrontality; this suggests that the use of activation tasks can increase the sensitivity of these procedures to detecting abnormalities by assessing function of regions involved in the illness ( Fig. 12.4-2). The finding of hypofrontality in schizophrenia has often been interpreted as an artifact of poor performance, motivation, clinical state, medications, or other factors. However, studies have not shown that these factors account for differences between patients and controls. For example, poor performance on working memory tasks is not necessarily associated with reduced prefrontal blood flow. Patients with Huntington's disease and groups with low I.Q. who do equally poorly on prefrontal cognitive tasks, are able to activate the dorsolateral prefrontal cortex. Interestingly, hypofrontality appears to be correlated with several structural and neurochemical indices. Prefrontal activation is highly correlated with homovanillic acid (HVA) concentrations in cerebrospinal fluid, possibly reflecting prefrontal dopamine activity. Hypofrontality has also been correlated with hippocampal volume in one study of discordant monozygotic twins, suggesting a dysfunctional circuit. Finally, preliminary reports suggest that reduced prefrontal NAA concentrations, markers of neuronal integrity, are correlated with reduced frontal activation. These data imply that hypofrontality could result from a process that affects neuronal viability in both frontal and hippocampal regions and that these have downstream effects on the regulation of prefrontal dopamine. The temporal lobe has also been examined with functional neuroimaging techniques. Both elevated and reduced blood flow has been reported. The most common finding is an association between resting blood flow and positive psychotic symptoms. For example, one report found a correlation between increased psychopathology and blood flow to the left parahippocampal gyrus; a second found a similar correlation between positive symptoms and left temporal lobe blood flow. More specific correlations have been seen for auditory hallucinations and activation of Broca's area and medial temporal regions. A potential criticism of this finding is that patients may have simply been responding to auditory hallucinations with their own vocalizations. Activation of Broca's area, in this case, would be expected and trivial. Research into the relation between symptom clusters and blood flow revealed that positive symptoms were associated with increased medial temporal flow, negative symptoms with decreased prefrontal (dorsolateral) blood flow, and disorganization with increased cingulate flow. This parcelation of symptoms with neuroanatomy suggests that separate but related neurophysiological processes may underlie specific types of symptoms. The few studies that examine several regions simultaneously tend to find changes in the coordinated activity between regions, particularly between prefrontal and temporal areas. Typically, increased activation in temporal areas is found in functional connectivity of the two regions. One report on other brain regions found increased left globus pallidus activity at rest; others have reported both decreased and increased glucose utilization in the striatum (Fig. 12.4-3). Antipsychotic medications appear to increase striatal metabolism, suggesting that medications are an important confound. Reduced cingulate activation has also been described. As newer techniques that do not depend on radioactivity, such as fMRI, are more commonly used, further characterization of these and other brain regions can be expected.

FIGURE 12.4-3 A, Schematic diagram of the mesial temporal lobe at the level of the body of the hippocampus and posterior entorhinal cortex, in coronal section. B, The illustrated connections of the coronal section are described in this table. (Drawn by Kyle Christensen.)

In summary, blood flow to several brain regions, including prefrontal and temporal areas, is altered in schizophrenia. These changes may be related to or may underlie positive and negative symptoms as well as some cognitive deficits. Regional abnormalities may also be related to each other, indicating a more global problem with the function of the larger systems or neural networks. Many questions remain. How closely are the changes in temporal and prefrontal activity associated with the clinical features of schizophrenia? Is the activation of other brain regions affected? Can functional brain imaging pinpoint which brain areas cause specific symptoms? What neurobiological processes account for differences in brain function? Correlations with structural abnormalities, dopamine metabolites, and regional NAA levels suggest that these variables could play a role.

NEUROPATHOLOGY The neuropathological basis of schizophrenia remains obscure despite an increased number of techniques applied to the investigation of this subject. The future appears bright, however, as more laboratories across the world become engaged in this research. Regions that have become the focus of postmortem studies include temporal and limbic structures (hippocampus, amygdala, hypothalamus, nucleus accumbens, and cingulate cortex), and prefrontal and orbitofrontal cortices. Other paralimbic structures recently have been added to the neural network thought to be dysfunctional in schizophrenia, including the ventral tegmental area, substantia nigra, anterior thalamic nuclei, and entorhinal cortex. With this focused approach a number of intriguing findings have emerged; almost all still need independent replication, and the confounds of antemortem exposure to antipsychotic drugs must be considered when reviewing these studies. Temporal Lobes Mesial Structures Perhaps the one region that has received the greatest attention in postmortem schizophrenia research is the mesial temporal lobe, which contains the entorhinal cortex, amygdala, and hippocampal formation ( Fig. 12.4-3). These structures have been examined in both morphological and neurochemical studies. The entorhinal cortex, which relays cortical input into the hippocampus and distributes output from the hippocampus to a diverse group of brain structures, has been carefully scrutinized. The laminar distribution of neurons in the superficial layers of the rostral entorhinal cortex has been reported to be abnormal and disorganized by

several independent groups of investigators. One study in particular has suggested that the subtle changes in neuronal aggregation may be restricted to layers II and III. Taken together, these data suggest a mild disruption of normal cytoarchitectural features. Although it may not be impossible for this to occur later in life, the findings would strongly support the notion that abnormal neuronal migration may occur during brain development in patients with schizophrenia. The finding that cytoarchitectural abnormalities are present in the entorhinal cortex have recently been contested by two carefully controlled, anatomically precise studies. Both studies failed to find the abnormal cytoarchitectural features described previously and suggested that earlier reports may have been confounded by incomplete matching of sections from normal controls and individuals with schizophrenia. The normal cytoarchitecture of the entorhinal cortex markedly changes along its rostrocaudal extent, making the issue of appropriate matching critical. However, the entorhinal cortex may not be entirely normal in schizophrenia; one study found a limited reduction in neuronal number and density. This is consistent with other reports of smaller volume, a reduction in the number of neurons, and volumetric measures using MRI. Neurochemical elements that subserve the anatomic integrity of a given brain region have also been measured, as an indirect assessment of the cytoarchitecture. Microtubule-associated proteins (MAPs) are important elements of the neuronal cytoskeleton. One recent study found a marked loss of MAPS immunoreactivity in the subiculum and the entorhinal cortex in schizophrenia. This finding was interpreted as support for and evidence of cytoarchitectural abnormalities in this mesial temporal lobe. However, given the qualitative nature of most immunostaining techniques, direct replication and additional investigations with more quantifiable strategies are needed. Synaptophysin is a synaptic vesicle protein, and as such is widely distributed throughout the central nervous system. Levels of synaptophysin or its mRNA on both can be used as indices of synaptic density. Decreased synapsin I, but not synapsin IIb or synaptophysin, has been found in the hippocampus of patients with schizophrenia. A more recent report noted a reduction in synaptophysin messenger ribonuclei acid (mRNA) in CA4, CA3, subiculum, and the parahippocampal gyrus. There were no changes in synaptophysin in these regions, however, suggesting that the loss of synapses may occur at extra-hippocampal sites. Alternatively, local circuits within the hippocampus may be compromised but the ability to detect these changes is limited by the volume of extra-hippocampal input to this brain region. In any event, this finding is another element in the emerging picture of structural alterations in the mesial temporal lobe. Hippocampus The hippocampus, the predominant structure within the mesial temporal lobe, also may have anatomic abnormalities. Postmortem studies of the hippocampus have proliferated since the mid-1980s. One group found a volume reduction in the whole hippocampal formation in schizophrenia. Others, however, have reported that decreased volume is restricted to the white matter of the left hippocampus, or in the volume of the CA4 subfield. A number of other postmortem studies have found subtle structural abnormalities in the hippocampal formation in schizophrenia, providing a relatively robust body of evidence implicating alterations of the hippocampal formation in schizophrenia. Within the pyramidal cell layer of the hippocampus, the most recognizable microscopic feature is the orientation of pyramidal cells. While cellular disarray in the CA1-prosubiculum and CA1-CA2 interface has been observed by one group, at least three other groups were unable to replicate this finding. Decreased numbers of pyramidal cells in hippocampal subfields and reduced neuronal size (in left CA1 and CA2, and right CA3) have also been found. These are both consistent with prior MRI findings. Alteration in the density of staining of the mossy fibers in the hilus of the dentate gyrus, and several hippocampal subfields have been seen as well. However, this finding is surprising because cell loss in the adjacent entorhinal complex should lead to an increase in the staining density of the mossy fibers. Finally, decreased polysialic acid-neural cell adhesion molecule (PSA-NCAM) immunoreactivity has been reported in the CA4 subfield of the hippocampus in schizophrenia. PSA-NCAM, a cell adhesion molecule, is thought to be important in synaptic rearrangements in adulthood. Although no clear consensus has emerged on the nature of pathological change within the hippocampus proper, there is abundant evidence of structural abnormalities. Amgydala The amygdala, located within the mesial temporal lobe, has major interconnections with the entorhinal cortex and hippocampus, as well as many other structures. The amygdala appears to have a smaller volume in schizophrenia patients; this finding is in accordance with postmortem reports. Prefrontal Cortex Postmortem studies of the prefrontal cortex have been stimulated by the deficits observed with in vivo neuroimaging. One recent study found increased neuronal density in prefrontal area 9; a change of similar magnitude was observed in occipital area 17 as well, suggesting a widespread pathological process. This finding was interpreted as representing a loss of neuropil throughout the cortex in schizophrenia without accompanying gliosis. Area 9 has also been shown to have a smaller average neuronal size and an increased density of smaller neurons, with unchanged glial size and density. The absence of gliosis again suggests that the pathological change in schizophrenia is probably not an active inflammatory process. Area 17, visual cortex, did not show any of these abnormalities, suggesting some anatomic specificity of this finding. In addition to smaller neuronal size, layer 3 pyramidal cells may have diminished dendritic spine density, which in part may explain the abnormalities in neuropil noted by others. Finally, area 46, prefrontal cortex adjacent to area 9, also has increased neuronal density in layers 2, 3, 4, and 6, and a thinning of layer 2. Taken together, these studies suggest a loss of neuropil in the prefrontal cortex, and abnormalities in the cellular constituency of this region. A somewhat murky picture has emerged from studies of the distribution of neurons in the subcortical white matter underlying the prefrontal cortex. Such neurons are thought to represent a vestige of neuronal migration during early brain development. One group found an increased density of nicotinamide-adenine dinucleotide phosphate diaphorase-positive neurons in the deep white matter and a lower density in the superficial white matter underlying the superior and middle frontal gyri. This is consistent with a developmental arrest in the migration of cortical neurons from deeper white matter areas to superficial cortical layers. A second, similar study looked at MAP2-immunoreactive neuron distribution in the subcortical white matter underlying area 46 and the transition zone between areas 46 and 9 in the prefrontal region. Patients with schizophrenia had a greater density of MAP2-immunoreactive neurons in the superficial white matter compared to controls. In contrast to the first study, no differences are seen in deeper white matter. This was interpreted as either abnormal expression of MAP2, a defect in neuronal migration, a failure of programmed cell death, or a decrease in white matter volume in schizophrenia patients. Although these two studies looked at different neuronal subpopulations, the different findings are contradictory and must be interpreted with caution. Orbitofrontal Cortex The orbitofrontal cortex has also come under scrutiny, at least in part because of interconnections with a variety of limbic system structures and the efficacy of leukotomy in the treatment of some clinical aspects of schizophrenia. In area 10, orbitofrontal cortex, a decrease in neuronal number, maximal in layers 4 and 5, and in cortical thickness has been observed in a small sample of schizophrenia subjects. A similar reduction in areas 4 (frontal), 24 (cingulate), and 17 (occipital), has also been seen, suggesting a pancortical process. A more recent study found a significant reduction in neuronal density in layer 6 of area 10, but also in layer 5 of area 24 (cingulate cortex) and layer 3 of area 4 (primary motor cortex). The meaning of changes in such disparate layers cannot be easily explained, especially in light of the findings in areas 9 and 17. Neurochemical analyses also have been performed on the prefrontal cortex as an index of structural integrity. One group examined the concentrations of synaptic vesicle associated protein-25 (SNAP-25) a synaptosomal associated protein involved in neurotransmitter release. Using quantitative Western blots, they found an elevation in SNAP-25 concentrations in area 9, reductions in areas 10 and 20 (temporal cortex), and no change in area 17. Such findings could be due to either a change in synaptic density or to an abnormality in neurotransmitter release; the former interpretation may account at least in part for the decreased neuropil in area 9. Cingulate Cortex The anterior cingulate cortex (area 24) is part of the neural network subserving the cortical regulation of emotion and attention, both of which appear to be deficient in schizophrenia. In a series of postmortem studies, one group demonstrated an increase in vertical axon number in the cingulate cortex of schizophrenia patients. These researchers have also reported abnormalities in neuronal aggregation in layer 2 of area 24 and a decrease in the number of interneurons in layers 2-6 of this region. Others have seen an abnormality in the usual asymmetry of weight and surface area for the anterior cingulate cortex; independent replication of these findings will be important. Other Regions Subcortical structures also may have an abnormal anatomy in schizophrenia. Consistent with MRI studies, the mediodorsal nucleus of the thalamus may have fewer neurons in schizophrenia patients in comparison to controls. Studies of the basal ganglia are somewhat limited. Whereas one study did not find any absolute volume differences in the striatum as a whole or individually in the caudate, putamen, or nucleus accumbens, a second group reported an increase in left striatal volume in schizophrenia patients. A third report on the ultrastructure of the caudate nucleus using electron microscopy ound abnormalities in synaptic morphology and dystrophic and reactive changes in astrocytes. Regarding midbrain dopaminergic nuclei, decreased volume of the lateral substantia nigra, and a decrease in the average volume of the nerve cell bodies in the medial segment have been observed. Several other studies have found no significant brainstem pathology or relatively nonspecific findings. Clearly, more research needs to be devoted to the brainstem, given the importance of ascending catecholamine and serotonin systems in regulating the activity of forebrain structures, and the clinical data implicating these neurochemical systems in schizophrenia. Gliosis Of all these subtle yet potentially important cytoarchitectural findings, one of the most critical observations is the apparent absence of gliosis. The importance of this stems from theoretical implication that reduced volume of brain regions and other abnormalities are not the result of an active pathological process: instead, they are likely to be secondary to very early developmental processes. The issue of whether gliosis is present has been addressed by many postmortem studies over

the past century. Of these, at least a dozen recent studies have used methodologically superior quantitative techniques. While several have noted increased gliosis, the large majority has found no differences between brains from patients with schizophrenia and those from normal controls. These include studies using several different techniques for counting glial cell number, such as the Holzer stain, Nissl stain, and immunoreactivity for glial fibrillary acidic protein. Some methodological questions about the ability of some techniques to detect the effects of chronic gliosis persist; it seems unlikely, however, that clinically relevant gliosis would be obscured. The wide variety of potentially important findings must be approached with a healthy skepticism. Several common problems plague almost all postmortem volumetric and cell counting studies in schizophrenia. First, standard stereological techniques, using serial sections at regular intervals through the rostrocaudal extent of the mesial temporal lobe, are infrequently applied. Fortunately, more recent studies are employing stereology with greater frequency. Moreover, rarely, if ever, is the time of fixation carefully controlled, so that there is a wide variation within and across studies. Tissue shrinkage, which affects tissue volume and cell density, and maybe quality of cell staining, varies with the duration of fixation. Nevertheless, postmortem studies point to subtle volume reductions in the hippocampal formation in schizophrenia. The precise neuropathological changes that underlie this volume reduction remain controversial.

NEUROCHEMISTRY Dopamine One of the most important observations in twentieth-century psychiatry is that dopamine antagonists ameliorate symptoms of schizophrenia. The implication that too much dopamine causes psychosis has dominated research for well over two generations and continues to exert a profound impact. In its most basic form, the dopamine hypothesis states that an excess of subcortical dopamine neurotransmission leads to psychotic symptoms. Observations that the prefrontal cortex modulates subcortical dopamine release have established a compelling link between cortical abnormalities and changes in the dopamine system. A current version of the dopamine hypothesis is that dopamine is dysregulated; levels may be reduced in the prefrontal cortex and altered in complex ways in subcortical and limbic regions. Reduced cortical dopamine could explain hypofrontality, impaired cognition, and negative symptoms (such as anhedonia and lack of motivation). Altered subcortical and limbic dopamine, on the other hand, could cause positive symptoms (such as hallucinations and delusions). Theories about the role of dopamine in schizophrenia have advanced in tandem with the increased understanding of the neurobiology of dopamine. Neurobiology of Dopamine Dopamine (Fig. 12.4-4) is synthesized from tyrosine through dopa. The first step, the conversion of tyrosine to dopa by tyrosine hydroxylase, is the rate-limiting step, and is subject to feedback regulation. The major metabolic product of dopamine catabolism in humans is homovanillic acid, and, to a lesser extent dihydroxyphenylacetic acid and 3-methoxytyramine. Concentrations of these metabolites have been examined in the brain, cerebral spinal fluid (CSF), plasma, and urine of patients with schizophrenia to look for evidence of increased or decreased dopamine neurotransmission.

FIGURE 12.4-4 Dopamine metabolism and synaptic structure. In this schematic synapse, dopamine is released into the synaptic cleft where it can act on D 1 or D2 postsynaptic receptors. Synaptic dopamine is inactivated by reuptake pumps or by catabolism via COMT and MAO. Presynaptic D 2 autoreceptors modulate dopamine synthesis and release in the striatum. (Drawn by Kyle Christensen.)

Dopamine cell bodies are primarily located in two midbrain nuclei: the ubstantia nigra (pars compacta) and ventral tegmental area. Projections from these nuclei have three primary target regions, and are named accordingly. The nigrostriatal tract carries nigral dopaminergic projections to subcortical motor control areas of the striatum (caudate and putamen in humans). The nigrostriatal projections come primarily from the substantia nigra but also, to a lesser extent, from the ventral tegmental area. Mesolimbic dopamine projections from this area target a number of limbic regions, such as the nucleus accumbens and temporal lobes. The mesocortical dopamine pathway projects primarily from the ventral tegmental area to the prefrontal cortex. A fourth dopamine tract is found entirely within the hypothalamus. In addition to different target regions, these separate projection systems function independently to some degree and are regulated by different mechanisms. Dopamine exerts its effects through at least five receptor types, D 1 through D5, identified on the basis of their deoxyribonucleic acid (DNA) sequence. Most pharmacological functions of dopamine receptors characterized so far are attributed to D 1 and D2 receptors. Much less is known about the actions of D 3, D4, and D 5 receptors. The D 1 family includes D 1 and D5, while the D2 family includes D 2, D3, and D4 receptors. Genes for the D 2 family have a number of introns, leading to alternative splicing and several isoforms. For example, the D 2 receptor has two common splice variants, a long and short form, usually both expressed in the same cell. The D 4 receptor has numerous polymorphisms, including longer and shorter forms, although these do not arise through alternative splicing. Different isoforms of the D2 family may have different affinities for second messenger systems, presumably leading to variations in biological effects. Introns or alternative splicing variants for the D1 family of receptors have not yet been identified. D 1 and D2 receptors are found predominantly on the primary efferent neurons of the striatum, and limbic system (e.g., the nucleus accumbens), prefrontal cortex, and other cortical regions. D 2 receptors are also located on the presynaptic dopamine terminals in target regions and dopamine cell bodies in the midbrain. These autoreceptors regulate dopamine synthesis, neuronal firing, and release. The latter two autoreceptors are not on mesocortical nerve terminals in the prefrontal cortex. D 3 receptors are expressed predominantly in subcortical limbic regions, such as the islands of Calleja and nucleus accumbens in the rodent, but are also seen in the hippocampus. D 4 receptors are thought to be presynaptic regulators of glutamate release on projections from cortical areas to the striatum and some limbic regions. D 5 receptors are found in limited distribution in the thalamus, hippocampus, and hypothalamus. The role of the dopamine system in the overall economy of the brain is not well understood. The relation between dopamine cell loss and Parkinson's disease established its role in regulating motor activity. The link between dopamine and drugs of abuse suggest a critical role in motivation and reward. Increasingly sophisticated electrophysiological studies have shown that activation of subcortical dopamine pathways alert the organism to changes associated with the prediction of future salient and rewarding events. This function is essential for predicting future events, which allows an organism the ability to plan and control interactions with the environment. Furthermore, prefrontal cortical dopamine is critically involved with working memory, a key component for higher-level information processing tasks. Thus, dopamine is involved in motor behavior, motivation, reward, and a variety of higher cognitive tasks, all of which have been implicated in schizophrenia. Clearly, the dopamine system has a complex molecular, cellular, and physiological neurobiology, and this underlies an equally complex functional role in normal brain and behavioral function. Dopamine and Schizophrenia Evidence for the dopamine hypothesis of schizophrenia comes from a variety of sources. One approach has been to examine the effects of different medications on schizophrenic symptoms. Drugs that block D 2 receptors reduce psychotic symptoms; dopamine agonists worsen symptoms. These observations form the cornerstone of the dopamine hypothesis. A second approach has been to look at various indices of dopaminergic neurotransmission in patients with schizophrenia. Such indices include measures of presynaptic activity, such as the major dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, as well as postsynaptic markers, primarily dopamine receptors. Metabolite studies have examined homovanillic acid in urine, plasma, CSF, and autopsied brain. Receptor studies have been performed on postmortem brain tissue and in living patients using PET and SPECT. More recent methods have been used to assess in vivo presynaptic dopamine levels and dopamine release using both PET and SPECT. Dopamine neurotransmission could be altered by changes in any one of a number of neuronal functions, including synthesis, degradation, release, uptake, receptor binding, or effects on second and third messenger systems. Although several decades of research have not provided definitive affirmation of the dopamine hypothesis, increasingly sophisticated methods to assess in vivo dopamine

activity are beginning to yield important clues. The notion that dopamine neurotransmission is increased in schizophrenia derives its most compelling support from clinical observations on the effects of drugs that impact psychotic symptoms. The introduction of antipsychotic medications in 1954 was a dramatic breakthrough in psychiatry and initiated an intense search for their mechanism of action. In 1963 antipsychotic medications were found to increase the concentrations of dopamine metabolites. It was suggested that increased metabolite concentrations were a compensatory response to the blockade of dopamine receptors by antipsychotic agents and a subsequent reduction in dopamine neurotransmission. The idea that these drugs reduced dopamine neurotransmission was further supported by the observation that they also induced parkinsonian adverse effects, symptoms that had recently been linked to the loss of midbrain dopamine neurons. In 1977, following pharmacological characterization of the D 2 receptor, a striking correlation was reported between the relative clinical potencies of all clinically available antipsychotic medications and their ability to block D 2 receptors. This landmark finding convincingly demonstrated that antipsychotic effects were mediated by D 2 receptor blockade. While the correlation between clinical potency and D 2 blockade for antipsychotic medications was compelling, several problems emerged. D 2 blockade occurs within hours of administration, but the antipsychotic effects can take days or weeks to develop; this suggests that a secondary process is required. Studies of the chronic effects of neuroleptics then led to the observation that, after several weeks, dopamine neurons themselves stopped firing. After short-term administration of antipsychotic medications there is an initial increase in dopamine neuronal firing as neurons attempt to overcome D 2 blockade; eventually this overexcitation leads to the phenomenon of depolarization block, where depolarized neurons simply stop firing. Reduced neuronal firing was thought to markedly reduce dopamine release, leading to reduced dopamine neurotransmission. For some time, the depolarization block theory was crucial in supporting the view that antipsychotic drugs exert their therapeutic effects by reducing dopamine neurotransmission. Subsequently, a number of studies have not found reduced dopamine release after long-term treatment with antipsychotic medication. While methodological issues are still debated, this suggests that some process other than a simple reduction in dopamine release may underlie the therapeutic effects of these medications. Other observations have been difficult to reconcile with the dopamine hypothesis. For example, many symptoms such as cognitive deficits, anhedonia, and alogia typically fail to respond to treatment with antipsychotic medications, suggesting that other processes are involved. A second problem relates to the unique clinical effects of clozapine (Clozaril). Clozapine has been shown to benefit patients who do not respond to dopamine receptor antagonists. The dopamine hypothesis, on the other hand, implies that D 2 blockers should be equally efficacious. The unique clinical effects of clozapine suggest that it may have a different mechanism of action. Clozapine's effects have been attributed to several properties, such as its antagonism of serotonin receptors or its combination of D 1, D2, and D 4 blockade. Drugs developed to mimic different aspects of clozapine's receptor-binding profile, such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel), share some of clozapine's “atypical” characteristics. A second line of evidence supporting the dopamine hypothesis comes from observing the effects of dopamine agonists. Chronic amphetamine abuse, for example, increases dopamine release and can lead to a psychosis similar to paranoid schizophrenia. Amphetamine-induced psychotic disorder, however, lacks other features associated with schizophrenia, such as negative symptoms and cognitive impairment. Furthermore, psychotic symptoms only develop after prolonged use (and typically at high doses), whereas dopamine neurotransmission is increased shortly after a single dose of amphetamine. This suggests that repeated increases in dopamine release produce secondary changes that are more directly responsible for the psychosis. METABOLITE STUDIES The search for more direct evidence of altered dopamine release in schizophrenia led to investigations of dopamine and its metabolites in urine, plasma, CSF, and postmortem brain tissue. Consistent with the basic dopamine hypothesis, several studies of plasma homovanillic acid have found increases in unmedicated schizophrenia patients compared with controls. These studies sometimes report correlations between concentrations of homovanillic acid and severity of psychosis. Furthermore, antipsychotic medications appear to reduce plasma homovanillic acid over time, correlating with patients' improvement. Methodological problems, however, cloud the interpretation of studies using plasma homovanillic acid. It is unclear whether plasma homovanillic acid correlates with its concentrations in limbic brain regions, areas most likely to underlie the production of psychotic symptoms. Investigators have also looked at dopamine metabolite levels in CSF. While most studies have failed to find significant changes, several have reported a correlation between concentration of homovanillic acid and severity of psychotic symptoms. Studies of medication-free patients have tended to show a reduction in dopamine metabolites. Negative correlations have been found between concentrations of homovanillic acid in CSF and ventricular enlargement and severity of negative symptoms (e.g., anhedonia and flat affect). Prefrontal cognitive deficits have also been associated with reduced CSF homovanillic acid, perhaps consistent with a model of subcortical dopaminergic overactivity and prefrontal cortical hypoactivity; methodological issues make the interpretation of CSF studies problematic. First, dopamine and metabolite concentrations in the CSF are affected by a number of variables that are not commonly controlled. These include diet, time of day, height, and motor activity. Second, increased ventricular volume itself could affect the concentration of homovanillic acid. Third, CSF monoamine concentrations appear to have little relation to either regional brain levels of dopamine or, more importantly, to more direct measures of dopamine neurotransmission. Certainly if dopamine transmission in the prefrontal cortex is reduced and subcortical transmission is increased, it is difficult to predict what would happen to CSF concentration. Nevertheless, CSF data is often interpreted as supporting the notion that too much dopamine is related to positive symptoms whereas too little underlies negative symptoms. More direct assessments of dopamine neurotransmission have come from postmortem studies of dopamine metabolites. Increased dopamine or homovanillic acid or both have been reported in a number of brain regions, although reports are often inconsistent. For example, one study found increased dopamine in the left amygdala, a second reported increases in the nucleus accumbens, and a third found increases in the caudate but not the accumbens. Increased homovanillic acid has been found in the cortex, accumbens, and caudate. The latter finding has been attributed to the effects of previous treatment with antipsychotic medications. At this point no clear consensus can be derived from studies of dopamine metabolites. DOPAMINE RECEPTOR STUDIES A number of studies using postmortem brain tissue have shown increased numbers of D 2 dopamine binding sites in the brains of schizophrenia patients. A major confounding issue is whether this increase is a primary alteration in schizophrenia or secondary to long-term treatment with antipsychotic agents, known to cause rapid D 2 upregulation in animals. Studies in nonmedicated and medication-naive patients are conflicting. A number of studies of patients off medication for at least 1 month have found increased D 2 receptors, although several have not. It has been suggested that treatment with antipsychotic medications cannot account for the marked increase and bimodal distribution of D 2 receptors seen in patients who had been treated. Imbalances between D 1 and D2 receptors have also been reported. Recent studies of D 3 receptors have suggested that D 3 mRNA may be processed abnormally in cortical neurons of patients with schizophrenia, resulting in reductions in the normal D 3 mRNA transcript. On the other hand, a postmortem study of striatal D 3 receptor binding found a significant increase in patients who were medication free for 1 month. D 4 receptors have been harder to assay because of the lack of specific ligands. While two reports using an indirect method have found evidence of increased D 4 receptor density, assays of mRNA for D 4 using highly specific antisense probes have not found increased levels. Neuroimaging techniques have been used to measure indices of dopamine neurotransmission in living human patients. Striatal D 2 receptors have been assayed in medication-free patients by several groups using PET; the results, however, have been conflicting. One study found increased receptor numbers while two others did not. These studies used different PET ligands to measure D 2 receptor density, perhaps accounting for the conflicting results. One of the PET ligands binds only to D 2 and D3 receptors; the second also binds to D 4 receptors. The discrepant PET findings have been attributed to an increase in D 4 receptors, consistent with postmortem studies. More recently, in vivo neuroimaging methods have been refined to assay presynaptic indices of dopamine storage and release. In this paradigm, radioactive D 2 ligand binding is examined at baseline and following a pharmacological challenge with amphetamine. The dramatic increase in dopamine release caused by amphetamine displaces the postsynaptic binding of the D 2 ligand. The washoff of the D 2 ligand can thus be used as an index of dopamine release. Unmedicated patients with schizophrenia show reduced ligand binding after amphetamine, but not at baseline. This suggests that patients with schizophrenia have increased synaptic dopamine following amphetamine. One explanation for this is that presynaptic stores may be increased; another possibility is that synaptic reuptake is reduced. Although methodological issues continue to be refined, this promising lead implies that subtle aspects of dopamine neurotransmission may be altered. ANIMAL MODELS Animal studies have been invaluable in efforts to understand normal and abnormal function of the dopamine system. Of particular relevance for schizophrenia research are studies that attempt to model dysfunctional dopamine systems in a way that may shed light on the neurobiology of psychosis. Initial attempts to develop relevant animal models began with repeated, high doses of stimulants (such as amphetamine), based on the association between stimulant abuse and psychosis in humans. Repeated stimulant treatment was also thought to model repeated stress, an apparent trigger of psychotic relapse. Remarkably, stimulants increase the sensitivity of the mesolimbic dopamine system to stress, a process referred to as sensitization. Furthermore, in some paradigms stimulants can reduce presynaptic indices of dopamine activity, which has led to speculations that repeated increases in dopaminergic transmission (e.g., from stress) could lead to sensitization in limbic regions and long-term dopamine depletion in prefrontal regions. Thus, long-term administration of stimulant may provide a model to explore the

interactions between known triggers of psychosis and dysfunctional dopamine systems. Another promising line of animal research suggests that alterations in dopamine neurotransmission in one region may be secondary to primary deficits in another. For example, depletion of dopamine from prefrontal regions can increase dopamine metabolism in the striatum of rats. This suggests that a primary reduction of prefrontal dopamine in humans could theoretically lead to secondary alterations in subcortical dopamine. Reduced prefrontal dopamine could certainly explain the hypofrontality and negative symptoms that characterize schizophrenia. Although no direct evidence has shown that there are dopamine abnormalities in these regions, the indirect evidence reviewed above is suggestive. In a related line of research, structural damage to cortical and limbic regions has been shown to change subcortical dopamine neurotransmission. For example, within the limbic system lesions of the hippocampus or amygdala alter dopamine neurotransmission in the nucleus accumbens and prefrontal cortex. Such observations have been critical in attempts to relate structural and functional changes in frontal, temporal, and hippocampal regions with abnormalities in the dopamine system. They suggest that information-processing deficits in frontal and limbic regions have marked effects on subcortical processes, including dopamine neurotransmission. The dopamine hypothesis continues to exert a profound effect on research in schizophrenia. The discovery of new subtypes of dopamine receptors along with new neuroimaging approaches offer improved methods to study the function and pathophysiology of this system in humans. Particularly important for schizophrenia research is the finding that dopamine subsystems are interconnected and that damage to different brain regions previously implicated in schizophrenia can have marked effects of dopamine neurotransmission. At present, a variety of indirect data suggest that prefrontal dopamine neurotransmission may be reduced whereas subcortical dopamine is dysregulated in schizophrenia. Whether these changes are real and whether they are secondary to cortical or limbic dysfunction remains to be seen. Glutamate Interest in glutamate's role in the pathophysiology of schizophrenia has developed relatively recently. This interest was spurred primarily by two observations. First, acute ingestion of phencyclidine (PCP), a glutamate antagonist, produces a syndrome similar to schizophrenia. Second, glutamate is an essential neurotransmitter in those neural networks that may be involved in schizophrenia. Subsequently, a variety of postmortem and clinical data have been garnered in support of a glutamatergic abnormality. Neurobiology of Glutamate Glutamate is one of the most prevalent neurotransmitters in the brain. Virtually all neurons in the brain are affected when glutamate is applied. A nonessential amino acid that does not cross the blood-brain barrier, it can be synthesized in the brain from glutamine. The dominant mode of inactivation of synaptic glutamate is via reuptake by specific, high-affinity uptake sites. The four classes of glutamate receptors have been identified and named after their affinity for specific ligands: N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainic acid (KA), and L-aminophosphono-butyric acid (AP4). The first three are ionotropic receptors; their effects are mediated by changes in ionic conductance through neuronal membranes, including sodium, potassium, and calcium. The ionotopic receptors have been implicated in neurotoxicity following ischemia, mediated in part by increased intracellular calcium influx and apoptosis. The NMDA receptor is functionally different from the others and has been implicated in long-term potentiation (a process related to memory) in the hippocampus. Paradoxically, NMDA blockade can also result in neurotoxicity, apparently modulated by interneurons and activation of non-NMDA glutamate receptors. The last type of glutamate receptor, labeled by AP4, is a metabotropic receptor, a member of the family of G-protein–linked receptors. The metabotropic receptors modulate activation of second messengers, such as phospoinositide and cyclic adenosine monophosphate (cAMP), which can produce long-term, modulatory effects. Major advances in understanding the molecular biology of these receptors is increasing the understanding of their function. The NMDA receptor is a complex protein that has particular relevance for schizophrenia research. Blockade of the NMDA receptor by phencyclidine (PCP), a noncompetitive antagonist, produces symptoms similar to those seen in schizophrenia. NMDA receptor activation is excitatory, reducing postsynaptic membrane potential. PCP binds to a site within the open NMDA ion channel, thus blocking ionic flux. The mechanism by which NMDA antagonism produces psychotic symptoms is unclear; one theory is that NMDA antagonists exert their psychotomimetic effects via NMDA receptors' role in regulating striatal and limbic dopamine neurotransmission. Of note, NMDA receptor density is highest in the hippocampus and prefrontal cortex, two areas already implicated in the pathophysiology of schizophrenia. Altered neurotransmission in these regions could also play a role in PCP's effects. The NMDA receptor has a number of modulatory sites that regulate ionic conductance. Endogenous modulators include glycine, zinc, magnesium, and the polyamine spermidine. The glycine modulatory site has become a target for drug development. Increasing NMDA neurotransmission by increased glycine binding has been hypothesized to reduce symptoms of schizophrenia. Several studies have attempted to do so using glycine agonists such as milacemide or cylcoserine, and the results have been mixed. Another potential pharmacological target is the high-affinity glycine uptake pump. Antagonists of this site should increase synaptic glycine concentrations, enhancing NMDA neurotransmission. Similarly, antagonists of the glutamate reuptake pump could boost NMDA receptor activation. It is unclear whether ongoing efforts to develop antagonists at these sites will lead to therapeutic agents for patients with schizophrenia. A major difficulty with increasing NMDA neurotransmission is its narrow range of physiological responsivity. If NMDA stimulation is too high, seizures or neurotoxicity can result. Glutamate is relevant to the neurochemistry of schizophrenia because of its role in key neural networks. Projections to and from cortical and hippocampal pyramidal neurons use glutamate as a primary neurotransmitter. These include projections to subcortical structures such as the striatum, nucleus accumbens, and ventral tegmental area; output from these areas is strongly modulated by glutamate. Thalamic projections to the cortex also employ glutamate as the major neurotransmitter. Glutamate neurotransmission is important not only for rapid synaptic transmission between these regions, but also for experience-dependent cortical plasticity and memory. This is particularly true for the voltage-sensitive NMDA receptor, a likely candidate for modulating memory traces at Hebbian synapses. Glutamate's essential role in key neural networks, memory and cortical plasticity, thus make it a likely candidate for involvement in altered information processing in schizophrenia. Glutamate in Schizophrenia Acute intoxication with the NMDA antagonist, PCP, produces hallucinations, thought disorder, negative symptoms, and cognitive deficits. In comparison, dopamine agonists, such as amphetamine, primarily induce paranoid delusions, and only after long-term use. The differences in these drug-induced psychoses suggest that glutamatergic neurotransmission could be more proximal to the pathological processes mediating psychosis. The search for more direct evidence has focused on CSF and postmortem studies of brain tissue. Studies of glutamate levels in CSF and brain have been mixed. An initial, pioneering study of CSF found low levels of glutamate in patients compared with controls. Possible methodological problems make this data difficult to interpret, however, and three subsequent studies have been unable to replicate the finding. Two studies have looked at glutamate levels in postmortem brain tissue. One found no differences whereas the other found specific reductions in the hippocampus and prefrontal cortex in patients with schizophrenia. The latter study also looked at a neuropeptide co-localized with glutamate N-acetylaspartylglutamate [NAAG]. The NAAG pathway has recently been identified as an important comodulator of glutamate neurotransmission. The reported changes in NAAG and its metabolism in brains of patients with schizophrenia open up a provocative new area to explore possible alterations in glutamate neurotransmission. Postmortem receptor studies have been more promising. In general, these studies have tended to find increased receptor binding in prefrontal regions and reductions in temporal areas. Two reports have found increased kainate binding in the medial frontal cortex; a third found increases in orbitofrontal NMDA receptors. An increase of prefrontal cortical glutamate uptake sites has also been described. A recent molecular study using in situ hybridization and probes for all five NMDA receptor subunits, while not finding an overall increase in receptor mRNA did find a 53 percent increase in the expression of a subunit (NR2D), suggesting a change in the functional properties of prefrontal NMDA receptors. In the temporal lobe, several abnormalities of the glutamate system have been published. Autoradiographic studies have reported that KA receptor binding is reduced, particularly in the hippocampus. Consistent with this finding, reduced expression of mRNA for receptor subunits has been found in temporal lobe areas. Reduced density of temporal lobe AMPA receptors has been seen, but less consistently. In a recent extension of this work, mRNA transcripts for Glu R1 and Glu R2 were assayed; these transcripts code for AMPA receptor subunits. Consistent with receptor studies, reductions were seen in the hippocampus and other temporal lobe areas. Finally, the glutamate reuptake site has been assayed in the temporal lobe as an index of presynaptic glutamate terminal number. Reduced levels of mRNA for the reuptake site suggest a possible reduction in terminal number and thus in axonal projections. Regarding other brain regions, some receptor studies have performed on material from the basal ganglia. Increases in AMPA receptors and reduced NMDA receptors have been reported; some, studies, but not all, have found reduced glutamate uptake sites. Taken together, the postmortem literature is notable for a myriad of findings implicating alterations in glutamatergic neurotransmission. However, given the typical small number of brains studied and large number of variables, replication of specific findings is critical. Some have theorized that there is a loss of glutamatergic neurons in temporal areas, consistent with structural neuroimaging findings of reduced volume. In this schema, increased glutamate receptors in the cortex and putamen are hypothesized to be secondary to reduced glutamatergic inputs or neurotransmission. The increased focus on glutamate in postmortem studies will bring

increasingly sophisticated assessment of this neural system. Serotonin The idea that serotonin may play a role in schizophrenia was first postulated when the hallucinogen lysergic acid diethylamide (LSD) was found to block serotonin receptors. Since then, basic studies have begun to unravel the surprising complexity of this system and have provided new targets for investigation. Studies of schizophrenia have looked at a variety of parameters, including plasma serotonin levels, brain receptor levels, and clinical response to serotonergic drugs. Two findings are particularly promising: first, data from postmortem studies have found changes in frontal cortical receptor number; second, new “atypical” antipsychotic medications that are both serotonergic and dopaminergic antagonists appear to have clinical advantages over pure D 2 antagonists. These developments have increased the focus on serotonin in schizophrenia. Basic Neurobiology Serotonin (5-hydroxytryptamine) is synthesized from tryptophan and is broken down into 5-hydroxyindolic acetic acid (5-HIAA) by monoamine oxidase (MAO). Tryptophan is an essential amino acid; dietary intake of tryptophan can affect CNS synthesis of serotonin. Serotonin synthesis is also modulated by autoreceptors on nerve terminals. Synaptic serotonin is inactivated primarily by reuptake pumps on presynaptic neurons and glia; following uptake, serotonin is repackaged into vesicles or broken down to 5-HIAA. Both serotonin itself and its uptake pumps are found in blood platelets, where they play a role in clotting. In the CNS, serotonin neuronal cell bodies are located in the brainstem in nine separate nuclei. Axons from these cells project through the median forebrain bundle to virtually all regions of the CNS, including the cortex, limbic regions, and the striatum. The effects of serotonin are mediated by an ever-increasing number of receptor subtypes. Currently, seven classes of serotonin receptors have been characterized: serotonin (5-hydroxytryptamine [5-HT])-type 1 (5-HT 1) through 5-HT 7. Ten subtypes have been described in the 5-HT 1 family (5-HT 1a through 5-HT1e), three in the 5-HT 2 family (5-HT 2a through 5-HT2c) and one for 5-HT 3. Most relevant for schizophrenia are the 5-HT 2 and 5-HT 3 subtypes. 5HT 2 receptors are found in the prefrontal cortex, striatum, and nucleus accumbens; 5-HT 3 receptors are found in cortical, limbic, and subcortical areas, such as the amygdala and hippocampus. The serotonin system subserves a bewildering array of physiological and behavioral functions. For example, somatodendritic 5-HT 2 receptors regulate dopaminergic neuronal firing. Striatal nerve terminal serotonin receptors inhibit dopamine release. Behaviorally, serotonin has effects on cardiovascular, respiratory and motor activity, emesis, sexual behavior, aggression, anxiety, mood, and pain. Frontal serotonin, in concert with dopamine, may play an important role in the modulation of attention and arousal. Recently, basic research using aplysia has shown that serotonin plays a critical role in synaptic mechanisms associated with learning and memory; it may also have important neurotrophic effects during development and in the adult organism. Serotonin in Schizophrenia The earliest studies to examine serotonin in schizophrenia looked at peripheral measures, such as serotonin concentrations in plasma and uptake in platelets. These studies found increased concentrations in plasma and, less consistently, reduced uptake in platelets. Studies of CSF metabolites have been mixed and suffer from the same methodological confounds described for dopamine. More direct measures of CNS neurotransmission include postmortem assays of serotonin activity, including concentrations in brain tissue; receptor-binding density; reuptake site binding; and levels of mRNA for receptor subtypes, reuptake sites, and synthetic enzymes for serotonin itself. Although there have been multiple reports of abnormal serotonin levels in a variety of neural structures, only two findings have been replicated: increased levels in the putamen and increased levels in the globus pallidus. One difficulty with this approach is that measurement of neurotransmitters and their metabolites is notoriously unreliable because of their instability in postmortem tissue. In comparison, receptors, reuptake sites, and the mRNA for receptors, reuptake sites, and synthetic enzymes are more stable. Of studies looking at these parameters, the 5-HT 2 subclass has received the most attention. Following an initial report of a reduction in prefrontal cortex in the density of this receptor, two other research groups replicated this finding although a third did not. Whereas this abnormality may be intrinsic to schizophrenia, it is also possible that reduced 5-HT 2 receptor density is a consequence of therapy with antipsychotic drugs. The density of reuptake sites for serotonin also appear to be reduced in schizophrenia, particularly in frontal and anterior cingulate cortices. Studies looking at the mechanism of action of atypical antipsychotic drugs, such as clozapine, have fueled much of the recent interest in serotonin's role in schizophrenia. Clozapine has a variety of therapeutic properties different from the dopamine receptor antagonists. These could be due to clozapine's ability to block 5-HT 2a, 5-HT2c, 5-HT3, 5-HT6, or 5-HT 7 receptors, or to increased serotonin release in the prefrontal cortex. When one compares serotonin-dopamine antagonists, which share some of clozapine's properties, such as the reduced liability to produce parkinsonian symptoms, two impressive similarities are their 5-HT 2-binding affinity and the ratio of 5-HT 2 to D2 binding. This suggests that serotonergic antagonist properties may account for the improved adverse effects profile and perhaps also the enhanced therapeutic efficacy often attributed to the serotonin dopamine antagonists. In summary, both postmortem studies and drug trials using 5-HT 2–D2 antagonists suggest that serotonin may play an important role in schizophrenia. Data implicating frontal and anterior cingulate cortices are particularly striking. It is unclear, however, whether alterations in serotonin neurotransmission are primary or secondary and how they may relate to the other neurobiological processes described. Some preliminary investigations suggest that maternal exposure to toxins can produce long-term changes in serotonin neurotransmission. This raises the possibility that neurodevelopmental insults could alter serotonin neurotransmission in adults. Researchers interested in the mechanisms of amphetamine-induced behavioral sensitization have also begun to suspect that serotonin may play a significant role. If sensitization were to be involved in schizophrenia, as has been suggested, serotonin could be a factor. Although research in serotonin has typically taken a backseat to research on dopamine, its relevance for schizophrenia continues to increase as more is revealed about its many neurobiological properties. Other Neurotransmitters A wide variety of additional neurochemical systems have been studied in schizophrenia, several of which are noteworthy because of potentially interesting findings or because of how extensively they have been studied. These include GABA, norepinephrine, neurotensin, and cholecystokinin. As with other neurotransmitters, studies of these systems have typically looked at transmitter and metabolite levels in brain, CSF, or plasma, as well as receptor protein and mRNA expression in specific brain regions. GABA Particularly intriguing is research into the role of GABA, which is the major inhibitory neurotransmitter in the brain. Virtually all neurons are inhibited by GABA, and up to 40 percent of neurons use GABA as their major neurotransmitter. Many GABA neurons are local inhibitory interneurons, but GABA neurons in some regions (such as the striatum) are also primary efferent neurons. GABA is synthesized from glutamate via the enzyme glutamic acid decarboxylase (GAD). GABA acts at two receptor subtypes, GABA A and GABAB, the former being the more important in the CNS. A variety of drugs act at GABA receptors, including alcohol, benzodiazepines, and barbiturates. Findings implicating GABA in schizophrenia include reduced number of GABAergic cortical interneurons, increased GABA A receptor density in the prefrontal cortex, and reduced GABA uptake sites in the hippocampus. All three findings are consistent with reduced GABA cell number or GABA neurotransmission. Studies of mRNA have found reduction in prefrontal GAD mRNA but not in prefrontal GABA A receptor mRNA. The former is consistent with reduced GABA neuronal activity; the latter is not. This preliminary effort suggests that GABA cell number or activity is reduced in schizophrenia. As with other postmortem findings, however, further replication is necessary before they can be accepted with confidence. Norepinephrine Norepinephrine, another monoamine neurotransmitter, has been intensively studied in schizophrenia, although interest has waned recently. Similar to dopamine and serotonin, norepinphrine neurons are located in the brainstem in a group of nuclei (including the locus ceruleus) that project to a variety of cortical and subcortical regions. Norepinephrine acts at two receptor families, adrenergic and b-adrenergic receptors; at least seven a and three b subtypes have been cloned. Both receptor families exert their effects via changes in G-protein–mediated second messenger systems, including cAMP and phosphoinositol. Two neuropeptide transmitters, galanin and neuropeptide Y, are colocalized in noradrenergic neurons. Norepinephrine and its co-transmitters are involved in a number of physiological and behavioral processes including the sleep-wake cycle, arousal, stress, and memory. Both basic and clinical studies support a role for this system in psychiatric disorders such as anorexia nervosa, bulimia nervosa, anxiety disorders, post-traumatic stress disorder, depressive disorders, substance dependence, and substance withdrawal. Many of the behavioral states mediated by the noradrenergic system are markedly altered in schizophrenia, suggesting a role here as well. However, more direct evidence is lacking and any changes in noradrenergic function in schizophrenia may be secondary to the agitation that frequently accompanies psychosis. Initial studies of norepinephrine examined concentrations in plasma, CSF, and brain tissue. Both plasma and CSF concentrations of norepinephrine and its metabolite appear to be increased in patients with schizophrenia, although this has not been a consistent finding. Concentrations are reduced with treatment with antipsychotic agents and are correlated with clinical improvement. Recently, increased plasma concentrations have been associated with deficit symptoms whereas reduced plasma levels have been associated with depressive symptoms. These two findings seem contradictory and cast doubt on the usefulness of this approach. Furthermore, conclusions from such studies are limited by the same methodological pitfalls described above for other neurotransmitters, including the confounds of treatment with antipsychotic agents and the meaning of peripheral measures. Studies of brain norephinephrine and its receptors have been mixed, with some finding elevations and others finding no changes. The clinical effects of adrenergic agents have generally not been impressive. At least one report found that the presynaptic a2-adrenergic receptor agonist clonidine (Catapres) reduces psychotic symptoms, presumably by reducing norepinephrine release. On the other hand, several other

studies did not find this effect, and at least one group has reported therapeutic effects for an a 2-adrenergic receptor antagonist, idazoxane. Finally, a number of genetic association studies have looked at the incidence of polymorphisms for genes related to norepinephrine neurotransmission, including dopamine beta hydroxylase and the norepinephrine transporter. Although relatively common polymorphisms have been reported for both, no association with schizophrenia has been reported. Neuropeptides Two other interesting candidate molecules that have been studied in schizophrenia are the neuropeptides cholecystokinin and neurotensin. Both are found in a number of brain regions implicated in schizophrenia, such as the substantia nigra, nucleus accumbens, hippocampus, and various cortical regions. Both are colocalized with dopamine, GABA, glutamate, and other neurotransmitters. Several studies have reported changes in the levels of the peptides themselves, mRNA, or receptors. For example, the following findings have had some degree of replication: reduced temporal lobe cholecystokinin peptide concentrations, reduced cholecystokinin receptor density in both temporal and frontal regions, and reduced cholecystokinin mRNA in the temporal lobe. In general, further replication is required. Drug trials with the cholecystokinin agonist ceruletide have been mixed. Several open trials were promising, but double-blind trials were not. Unfortunately, it is not certain that ceruletide crosses the blood-brain barrier. Neurotensin's appeal is due in part to its endogenous antipsychotic-like properties. Not only is it colocalized in dopaminergic neurons, but infusions of neurotensin into the nucleus accumbens block the excitatory effects of stimulants and reduce behavioral activation. Neurotensin levels in the nucleus accumbens are markedly increased by treatment with antipsychotic medication. CSF studies have shown reduced neurotensin concentrations and correlations between reduced concentrations and increased psychopathology in drug-free patients with schizophrenia. However, postmortem studies have not shown differences between patients and controls in concentrations of the peptide itself. Such studies are confounded by the pronounced effects of antipsychotic drugs on central nervous system (CNS) neurotensin. One recent report found a 40 percent reduction of neurotensin receptors in the entorhinal cortex in patients with schizophrenia. Further replication and exclusion of effects of treatment with antipsychotic agents will clarify the significance of this finding.

NEURAL CIRCUITS The variety of structural, functional, and neurochemical abnormalities described implicate disordered information processing in several interconnected neural pathways in patients with schizophrenia. A description of the anatomical components of these pathways and their possible function will provide a basis for integrating the many abnormalities noted in schizophrenia ( Figs. 12.4-5).

FIGURE 12.4-5 A, Neural networks implicated in the neurobiology of schizophrenia. Cortico-striatal-thalamic pathway. Prefrontal glutamatergic projections synapse on GABAergic striatal neurons that express either D 1 or D2 receptors. The independent D 1 and D2 pathways are referred to as the direct and indirect pathways respectively. They have separate efferent pathways projecting to either the globus pallidus, pars externa = E, or pars interna = I. Both pathways ultimately project back to the anterior thalamus. B, Ascending dopamine projection pathways modulate circuits in A. Dopamine neurons (DA) from the substantia nigra tend to project mainly to the striatum, while the adjacent ventral tegmental area DA neurons projects primarily to the prefrontal cortex, ventral striatum, and limbic regions. C, Limbic projections to circuits from A and B. The hippocampal formation and amygdala project to the prefrontal cortex and ventral striatum. They receive glutamatergic cortical input and dopamine projections from the VTA. (Drawn by Kyle Christensen.)

As cortical abnormalities have played a dominant role in theories of schizophrenia, understanding the functional connectivity of these areas is important. One of the most intensively studied pathways is the cortico-striato-thalamic loop. The prefrontal cortex, the most highly and recently evolved part of the primate brain, sends a massive glutamatergic projection to subcortical regions, most notably the striatum (putamen and caudate in humans). The striatum in turn sends GABAergic projections through a number of downstream basal ganglia nuclei that ultimately feed into the anterior thalamus. Completing the loop, the anterior thalamus sends a massive glutamatergic projection back to the prefrontal cortex. Several salient features are noteworthy. First, this loop appears to consist of at least five separate but parallel channels processing different types of information (such as cognitive, emotional, and motoric information). Second, output from the striatum is split into two opposing, counterbalancing pathways. The so-called direct and indirect loops are modulated by D 1 and D2 receptors, respectively. Their coordinated output modulates information returned to the cortex via the anterior thalamus. Third, within the striatum itself, the ventral portion (commonly referred to as the nucleus accumbens) receives predominantly limbic inputs, while dorsal regions receive inputs more relevant for motor function. This functional segregation is maintained in downstream projection regions. A second important system that modulates activity of the cortico-striato-thalamic pathway is the dopamine system. Dopamine neurons in the substantia nigra and ventral tegmental area project to the striatum, nucleus accumbens, and prefrontal cortex. Dopamine modulates cortical output to the striatum via input to glutamatergic pyramidal neurons. In the striatum, dopamine axons synapse on the primary output neurons, the medium-sized, spiny, GABAergic neurons. Coordinated cortical and subcortical dopamine neurotransmission may be important for normal information processing through this loop. Furthermore, dysfunction in one area may produce changes in another. For example, lesions of the prefrontal cortex can induce alterations in subcortical dopamine neurotransmission. A third neural system interacting with the first two is the limbic system. This complex system involves hippocampus, amygdala, thalamus, hypothalamus, and cingulate gyrus, among others. This immense circuit, subserving functions related to memory and emotional experience, among many others, has direct projections to both prefrontal cortex and ventral striatum. The prefrontal cortex has reciprocal projections back to the mesial temporal lobe and hippocampus. The hippocampus, amygdala, and cingulate have important projections to the ventral (or limbic) aspect of the striatum. This area, in turn, projects to the thalamus via the ventral aspect of the globus pallidus, the pars interna. In this way, three major brain regions—the cortex, limbic system, and basal ganglia—communicate and interact. Information-processing abnormalities in one area, such as in the hippocampus, would have significant downstream effects on other regions, such as prefrontal cortex and striatum. Structural and functional measures have implicated some abnormality in all three components of these interacting systems. It is uncertain which are primary and which are secondary. It seems very possible that different types of lesions could alter the function of individual components, which could then produce secondary downstream changes in connected circuits.

NEUROBIOLOGICAL MODELS The essential neurobiological features of schizophrenia may place some constraints on plausible pathophysiological processes. First, there is a major genetic contribution. Many genes are likely to be involved and these may function in part by increasing vulnerability to the deleterious effects of environmental factors. Several environmental factors have been hypothesized to increase the risk of schizophrenia, perhaps by producing subtle brain damage. Structural abnormalities have played an important role in placing theoretical constraints on mechanisms. Since they are present from early in the illness and do not appear to progress, they may predate the onset of illness. Neuropathological data and studies of obstetric and perinatal complications support the idea that an early lesion may account for structural changes. The apparent lack of gliosis in postmortem studies is particularly critical and implicates in utero factors. Structural and functional neuroimaging, as well as neuropsychological data and animal studies present converging evidence for the importance of frontal and temporal regions. Finally, altered dopamine and glutamate neurotransmission are likely to play a part in the expression of psychotic symptoms. The neurodevelopmental model can account for many of these findings. In short, some process (genetic or environmental) produces damage to selected brain areas

early in life. Temporal lobe regions such as the hippocampus may be particularly vulnerable. Secondary functional abnormalities develop later. As the prefrontal cortex matures in late adolescence, the behavioral and cognitive sequelae of subtle structural deficits become manifest. One result is hypofrontality and cognitive impairment. Alterations in limbic and prefrontal function then produce downstream, secondary alterations in subcortical dopamine, glutamate, and other neurotransmitter systems. Dopamine dysfunction, in particular, may lead to positive psychotic symptoms. The feasibility of this model has received substantial validation from animal studies showing the delayed behavioral and neurobiological effects of minor damage to the hippocampus in neonatal rats. Observations that children at risk for schizophrenia have a number of subtle neuropsychiatric abnormalities, such as deficits in attention, motor control, and social interactions, also support the neurodevelopmental model. Although the neurodevelopmental hypothesis has been an important organizing heuristic since the mid-1980s several critical issues remain unresolved. First, it remains unclear when structural abnormalities actually develop. Finding such abnormalities in young children who go on to develop schizophrenia would offer strong support for this hypothesis. Alternatively, if these abnormalities develop later in life (e.g., in mid-adolescence), other mechanisms would be implicated. For example, it is unclear whether dendritic “pruning” or an apoptotic mechanism could account for volumetric reductions in areas such as the hippocampus. Observations of reduced neuronal size suggest that factors regulating this parameter could play a role. Second, despite the myriad of findings, the lack of any consistently replicable neurodevelopmental lesion in postmortem studies continues to leave the issue in doubt. It is entirely possible that no single lesion exists. Third, the issue of heterogeneity remains unresolved. Although patients with schizophrenia have structural and functional alterations as a group as compared to controls, it remains unclear whether these are necessary features of the illness. Certainly many patients are in the normal range in some or many of these measures. The same is true for most neurodevelopmental parameters. Many patients have completely normal or even above-average function in childhood and adolescence. Most patients with schizophrenia have no known history of pregnancy, obstetric, or neonatal insults. Is it possible that different patients have abnormalities restricted to differing prefrontal, temporal, or subcortical areas? Such primary lesions could induce secondary dysfunction in connected regions. Fourth, the delayed onset of psychosis presents some problems for the neurodevelopmental model. Although onset is typically in the early 20s, some patients do not develop symptoms until the fourth or even fifth decade of life. It seems most likely that such cases involve mechanisms other than or in addition to neurodevelopmental processes. Several alternative models have been put forward to deal with some of these problems. For example, structural abnormalities could develop in adolescence, very early in the illness. It is unclear what could account for this, but candidate mechanisms might include reduction in neuronal size or excessive dendritic pruning. Neurotransmitter abnormalities, such as in the dopamine and glutamate systems, may follow. Another possibility is that some cases of schizophrenia are due to increased stress associated with entry into adulthood. This could trigger dopamine abnormalities in genetically vulnerable individuals. Structural abnormalities, in these cases, could be nonspecific vulnerability factors or could be secondary to psychosis itself. A third possibility is that schizophrenia is a heterogeneous illness with several dimensions, none of which is necessary or sufficient. Different domains could involve neurodevelopmental cortical dysfunction, dopamine and glutamate function, cortical regulation of dopamine, and interdependent functioning of a myriad of heteromodal cortical neural networks. In this model, a complex web of genetic and environmental factors could impact on these many neural networks. One approach toward settling this issue is to examine neurobiological traits associated with schizophrenia. Such traits may be closer to the underlying physiological deficits induced by genes associated with the illness. As such, these traits may have a simpler genetic architecture, making it easier to detect their genes in linkage studies. A number of potential phenotypes have been identified that are clearly familial and thus may have a significant genetic basis. These include impaired sensory gating, eye-tracking dysfunction, perceptual aberrations, schizotypal symptoms, attentional impairment, deficit symptoms, structural brain abnormalities, and cognitive deficits. The feasibility of this approach has been validated by a recent report of linkage using a measure of impaired sensory gating. Suppression of the auditory p50 wave in a sensory gating paradigm has been linked to 15q13–14. This is very close to the a7 nicotinic cholinergic receptor, previously implicated in impaired p50 suppression. Several other preliminary reports have used eye tracking and positive psychotic symptoms. The use of such intermediate phenotypes may also reveal genes that are more important to functional outcome. Unfortunately, the heritability and genetic architecture of most intermediate phenotypes are uncertain, despite a wealth of data showing that many such traits are familial. Studies to assess these parameters and attempt linkage will require phenotyping large numbers of patients. The underlying neurobiology of schizophrenia remains a mystery. Genetically, the disorder is complex, confounding efforts to locate causative genes. Similarly, the effects of environment are subtle, with no clear major factor emerging. Pregnancy, labor, and delivery complications may play a limited role. Increasingly sophisticated techniques, guided by greater understanding of basic neurobiology, are being used to uncover alterations in a number of brain parameters. Neurobiological abnormalities include reduced volume of several brain structures, sulcal widening, and increased ventricular size. Cortical abnormalities, particularly in the prefrontal and temporal cortices, have also been implicated by cognitive testing and functional neuroimaging. Postmortem studies have failed to find a major lesion or gliosis that could account for structural abnormalities. They have, however, detected a variety of subtle cytoarchitectural changes, perhaps caused by abnormal neurodevelopment. Several neurotransmitters, including dopamine, glutamate, and serotonin, have been implicated. The putative structural, functional, and neurochemical abnormalities can be understood in the context of the neural systems they comprise. These include cortical-striatal-thalamic loops, ascending dopamine projection pathways, and the limbic system. Interconnections between these systems make it difficult to determine which lesions are primary and which are secondary. The neurodevelopmental model has been a critical organizing heuristic that synthesizes these seemingly disparate observations. This theory suggests that nonspecific lesions in early life, perhaps in utero, produce subtle behavioral anifestations in childhood. The onset of psychosis is delayed until brain maturation reaches later stages in late adolescence. Many questions remain unanswered, however, leaving some aspects of this theory in doubt. Combining techniques such as neuroimaging with molecular genetics provide fertile areas for future research to separate the strands that make up the tangled web of schizophrenia.

SUGGESTED CROSS-REFERENCES Section 1.2 reviews functional neuroanatomy in greater detail. Section 1.3, Section 1.4, and Section 1.5 contain additional information on dopamine, glutamate, and other neurotransmitters. Section 1.18 describes the basic principles of genetic linkage analysis and Section 1.15 and Section 1.16 provide a more thorough discussion of the principles of neuroimaging. SECTION REFERENCES Akbarian S, Bunney WE, Potkin S, Wigal SB, Hagman JO, Sandman CA, Jones EG: Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbance of cortical development. Arch Gen Psychiatry 50:169, 1993. *Bachus SE, Kleinman JE: The neuropathology of schizophrenia. J Clin Psychiatry 57:72, 1996. Benes FM, Sorensen I, Vincent SL, Bird ED, Sathi M: Increased density of glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain. Cereb Cortex 2:503, 1992. Bertolino A, Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CT, Frank JA, Tedeschi G, Weinberger DR: A regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 153:1554, 1996. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D: Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 94:2569, 1997. Buka SL, Tsuang MT, Lipsitt LP: Pregnancy/delivery complications and psychiatric diagnosis. A prospective study. Arch Gen Psychiatry 50:151, 1993. Carlsson A, Lindquist M: Effect of chlorpromazine and haloperidol on formation of 3-methoxytyramine and norepinephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 20:140, 1963. *Casey BJ: Brain development: Maturization in brain activation. Am J Psychiatry 156:505, 1999. *Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481, 1976. Crow TJ: Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 137:383, 1980. *Davis KL, Kahn RS, Ko G, Davidson M: Dopamine in schizophrenia: A review and reconceptualization. Am J Psychiatry 148:1474, 1991. Degreef G, Ashtari M, Bogerts B, Bilder RM, Jody DN, Alvir JM, Lieberman J: Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Arch Gen Psychiatry 49:531, 1992. Done DJ, Johnstone EC, Frith CD, Golding J, Shepherd PM, Crow TJ: Complications of pregnancy and delivery in relation to psychosis in adult life: Data from the British perinatal mortality survey

sample. Br J Med 302:1576, 1991. Egan MF, Chrapusta S, Karoum F, Lipska BK, Wyatt R: Effects of chronic neuroleptic treatment on dopamine release: Insights from studies using 3-methoxytryamine. J Neural Transm 103:777, 1996. Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordstrom AL, Hall H, Sedvall G: D

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dopamine receptors in neuroleptic-naive schizophrenic patients. Arch Gen Psychiatry 47:213, 1990.

Fish B, Marcus J, Hans SL, Auerbach JG, Perdue: Infants at risk for schizophrenia: Sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study. Arch Gen Psychiatry 49:221, 1992. Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W: Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 94:587, 1997. Goldberg TE, Gold JM: Neurocognitive functioning in patients with schizophrenia: An overview. In Psychopharmacology, The Fourth General of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. Gottesman II, Shields J: A polygenic theory of schizophrenia. Proc Natl Acad Sci USA 58:199, 205, 1967. Harrison PJ: On the neuropathology of schizophrenia and its dementia: Neurodevelopmental, neurodegenerative, or both? Neurodegeneration 4:1, 1995. Hyde TM, Casanova MF, Kleinman JE, Weinberger DR: Neuroanatomical and neurochemical pathology in schizophrenia. In American Psychiatric Press Review of Psychiatry, vol 10, A Tasman, SM Goldfinger, CA Kaufmann, editors. American Psychiatric Association Press, Washington, DC, 1991. Ingvar DH, Franzen G: Distribution of cerebral activity in chronic schizophrenia. Lancet 2:1484, 1974. Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301, 1991. Kane J, Honigfeld G, Singer J, Meltzer HY: Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789, 1988. Krimer LS, Herman MM, Saunders RC, Boyd JC, Hyde TM, Carter JM, Kleinman JE, Weinberger DR: A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia. Cereb Cortex 7:732, 1997. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB: Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93:9235, 1996. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS: Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry 160:179, 1992. Lipska BK, Weinberger DR: Genetic variation in vulnerability to the behavioral effects of neonatal hippocampal damage in rats. Proc Natl Acad Sci U S A

1292:8906, 1995.

*McGuffin P, Owen MJ, Farmer AE: Genetic basis of schizophrenia. Lancet 346:678, 1995. McNeil TF: Obstetric factors and perinatal injuries. In Handbook of Schizophrenia, vol 13, Nosology, Epidemiology and Genetics, MT Tsuang, JC Simpson, editors. Elsevier Science, New York, 1988. Mednick SA, Machon RA, Huttunen MO, Bonett D: Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 45:189, 1988. Meltzer HY, Matsubara S, Lee JC: Classification of typical and atypical antipsychotic drugs on the basis of dopamine D 1, D2 and serotonin 2 pK i values. J Pharmacol Exper Therap 251:238, 1989. Ohuoh DC, Hyde TM, Kleinman JE: The role of serotonin in schizophrenia: An overview of the nomenclature, distribution, and alterations of serotonin receptors in the central nervous system. Psychopharmacology 112(Suppl):S5, 1993. Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M: Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: A pilot study of the dorsal prefrontal cortex by in vivo phosphorous 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 48:563, 1991. Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter VK, Kasch L, Nestadt G, Antonarakis S, Housman D, Kazazian HH, Meyers D: Sequential strategy to identify a susceptible gene for schizophrenia: Report of potential linkage on chromosome 22q12-q13.1: Part 2. Am J Med Genet 54:36, 1994. Reveley AM, Reveley MA, Clifford CA, Murray RM: Cerebral ventricular size in twins discordant for schizophrenia. Lancet 2:540, 1982. Schultz W, Dayan P, Montague PR: A neural substrate of prediction and reward. Science 275:1593, 1997. Seeman P, Lee T, Chau-Wong M, Wong K: Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717, 1976. *Selemon LD, Goldman-Rakic PS: The reduced neuropil hypothesis: A circuit based model of schizophrenia. Biol Psychiatry 45:17, 1999. Selemon LD, Rajkowska G, Goldman-Rakic PS: Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52:805, 1995. Shelton RC, Weinberger DR: X-ray computerized tomography studies in schizophrenia: A review and synthesis. In Handbook of Schizophrenia vol 1, The Neurology of Schizophrenia, HA Nasrallah, DR Weinberger, editors. Elsevier, Amsterdam, 1986. Straub RE, McLean CJ, O'Neill FA, Burke J, Murphy B, Duke F, Shinkwin R, Webb BT, Zhang J, Walsh D, Kendler KS: A potential vulnerability locus for schizophrenia on chromosome 6p24-22: Evidence for genetic heterogeneity. Nature Genet 11:287, 1995. Suddath R, Christison GW, Torrey EF, Casanova MF, Weinberger DR: Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 322:7879, 1990. Torrey EF, Miller J, Rawlings R, Yolken RH: Seasonality of births in schizophrenia and bipolar disorder: A review of the literature. Schizophr Res 28(1):1, 1997. van Kammen DP, Kelley M: Dopamine and norepinephrine activity in schizophrenia: An integrative perspective. Schizophr Res 4:173, 1991. *Weinberger DR: Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660, 1987. *Weinberger DR, Berman KF: Prefrontal function in schizophrenia: Confounds and controversies. Philos Trans R Soc Lond B Biol Sci 351:1495, 1996. Wyatt RJ: Neuroleptics and the natural course of schizophrenia. Schizophr Bull 17:235, 1991.

Textbook of Psychiatry

12.5 SCHIZOPHRENIA: GENETICS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.5 SCHIZOPHRENIA: GENETICS KENNETH S. KENDLER, M.D. Is Schizophrenia Familial? Familial Aggregation: Genetic Versus Environmental Factors Psychiatric Disorders Transmitted within Families Most Likely Mechanisms of Kinds of Genetic Transmission Mechanisms Current Status and Future Prospects for Identifying Specific Genes that Predispose to Schizophrenia Future Directions Suggested Cross-References

The goal of this section is to provide an overview of the current state of knowledge of the genetics of schizophrenia. The following key questions are relevant. Is schizophrenia a familial disorder? To what extent is any familial aggregation of schizophrenia the result of genetic versus environmental factors? What kinds of psychiatric disorders are transmitted within families? The author believes that genetic factors play an important role in the familial transmission of schizophrenia, thus the following additional questions are pertinent: What are the most likely kinds of genetic transmission mechanisms? and What is the current status of and future prospects for identifying the chromosomal location of specific genes that predispose to schizophrenia?

IS SCHIZOPHRENIA FAMILIAL? The most basic question in the genetics of schizophrenia is whether the disorder aggregates (or runs) in families. Technically, familial aggregation means that a close relative of an individual with a disorder is at increased risk for that disorder compared to a matched individual chosen at random from the general population. This chapter reviews family studies of schizophrenia examining primarily first-degree relatives (parents, full siblings, and offspring) because little systematic information on more distant relationships has been gathered in recent years. In a 1967 review paper Edith Zerbin-Rüdin listed 17 major family studies of schizophrenia involving first-degree relatives. By 1980 at least 9 other major studies had been reported. All these studies consistently showed a substantially greater risk for schizophrenia in the close relatives of persons with schizophrenia than would be expected in the general population. However, nearly all these studies suffered from three methodological limitations. First, because no control groups were used, the rates of schizophrenia in the general population required for comparison had to be derived from the literature. Second, diagnoses were made nonblind, with the research team always knowing that the individual being evaluated was a relative of a schizophrenic individual. Third, neither structured personal interviews nor operationalized diagnostic criteria were used. In fact in many of the early studies it is unclear how many individuals were personally examined and how many were evaluated from indirect information such as reports of relatives or doctors, or from hospital notes. In the early 1980s several research groups questioned the validity of earlier family studies of schizophrenia. These researchers suggested that the evidence for the familial aggregation of schizophrenia may result from consistent biases in the previous studies. In addition, they were concerned that the diagnostic approach to schizophrenia in these earlier studies might have been overly broad. They argued that the familial aggregation of schizophrenia might be weak or absent when narrowly diagnosed. Since 1980, 11 major family studies of schizophrenia have been reported that used blind diagnoses, control groups, personal interviews, and operationalized diagnostic criteria. These studies permit a more rigorous evaluation than has hitherto been possible of the degree to which schizophrenia aggregates in families. The key results from these studies are summarized in Table 12.5-1, which contains the diagnostic criteria used in the study, the nature of the control proband group, and the p value (i.e., the probability of observing such a difference in the rates of schizophrenia in the two groups by chance, if the true rates were identical). The term proband refers to the individual through whom the family was identified for study. A typical family study of schizophrenia would then begin with two types of probands: those with schizophrenia and a matched group of control probands. Relatives of these probands would then be systematically assessed. Table 1 also presents the lifetimes at risk in the assessed relatives of schizophrenia and control probands, and the morbid risk for schizophrenia in the two groups. Lifetimes at risk is the sum for all assessed relatives of the proportion of their lifetime risk for schizophrenia they have completed thus far. Morbid risk (MR) is a statistic commonly used in genetics and equals the total proportion of individuals who would be expected to be affected with a disorder in a given population if all members of that population have completed their age at risk. Finally, the table includes the correlation of liability. If schizophrenia is caused by several genetic and environmental factors that act approximately additively in influencing an individual's liability or predisposition to schizophrenia, then this figure represents the degree of correlation between first-degree relatives in overall risk of the disease. This is a very useful figure because it combines into a single, easily understood statistic the risk figures for schizophrenia in relatives of schizophrenic and control probands. The higher the correlation of liability, the stronger is the degree of familial aggregation of schizophrenia.

Table 12.5-1 Summary Results of Major Recent Family Studies of Schizophrenia That Included a Normal Control Group, Personal Interviews With Relatives, and Blind Diagnosis of Relatives*

Before turning to the major results summarized in this table, two preliminary comments are in order. First, the sample of relatives studied varies very widely in the different investigations. For example, the lifetimes at risk in relatives of schizophrenic patients range over tenfold, from over 700 to 54. On average, the larger studies will provide more stable statistical estimates for the true risk of schizophrenia in relatives of schizophrenia and control probands. Second, various diagnostic criteria were utilized in the different studies. However, eight studies used criteria from either the third edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-III), Research Diagnostic Criteria (RDC) (for chronic schizophrenia), or revised third edition of DSM (DSM-III-R) criteria, all of which require at least 6 months of illness, usually with functional impairment, in addition to specified psychotic symptoms. Third, while nine of the studies examined all available first-degree relatives (parents, full-siblings, and offspring), two studies examined only offspring. There are five major conclusions that can be drawn from the large body of work summarized in the table. First, the risk for schizophrenia in relatives of schizophrenic probands varies widely across studies, from a low of 1.4 percent to a high of 16.2 percent. Much of this fluctuation may probably be attributable to differences in diagnostic criteria or statistical fluctuations in small samples (the lowest risk is found in the smallest study). However, it remains possible that there are true population differences in the risk for schizophrenia in relatives of schizophrenic probands. Second, the risk for schizophrenia in the relatives of nonpsychiatric control probands is relatively similar across studies, ranging—with the exception of the study of

Parnas et al—from only 0.2 to 1.1 percent, corresponding closely to the range of risks for schizophrenia found in general population studies. Third, in every study the risk for schizophrenia was higher in the relatives of schizophrenic probands than in relatives of control probands. Across these studies the risk of schizophrenia was, on average, 11 times greater in relatives of schizophrenic probands than in relatives of matched control probands. Fourth, in all but one study, the difference in risk for schizophrenia in the relatives of schizophrenic and control probands was quite unlikely to be attributable to chance ( p-value < 0.05). In a number of studies, the p-values were very low (less than 0.001), indicating that such differences in risk would be extremely unlikely to occur by chance. Finally, although there was some variation, the correlation in liability for all studies fell in the range from +0.23 to +0.53, with a weighted mean across the 11 studies of +0.35. Most of the largest studies that used relatively narrow diagnostic criteria for schizophrenia obtained correlations of liability in the narrow range of +0.32 to +0.41 because the highest and lowest correlations in the table come from the smallest and next to smallest studies, respectively. These results suggest that most of these studies can be seen as replications of one another because they provide similar results on the observed degree of familial aggregation of schizophrenia. The correlation of liability between first-degree relatives in the range of +0.30 to +0.40 indicates a relatively strong degree of familial aggregation. In conclusion, the questions raised in the early 1980s about the degree of familial aggregation of schizophrenia can now be addressed satisfactorily. The results of a large number of recent, carefully performed family studies support the conclusions of earlier and less methodologically rigorous investigations in finding that schizophrenia strongly aggregates in families. The familial aggregation of schizophrenia appears to be quite substantial when it is defined using modern, relatively narrow diagnostic criteria such as those found in DSM-III-R and DSM-IV. On average, the risk for schizophrenia in the relatives of controls is between 0.5 and 1.0 percent, compared to between 3 and 7 percent in relatives of schizophrenic probands in most studies. The best estimate of the correlation in liability to schizophrenia in first-degree relatives is probably between +0.3 and +0.4.

FAMILIAL AGGREGATION: GENETIC VERSUS ENVIRONMENTAL FACTORS Twin Studies Resemblance among relatives can be ascribed to shared environment (nurture) or shared genes (nature). A major goal in psychiatric genetics is to determine the degree to which familial aggregation for a disorder like schizophrenia results from environmental versus genetic mechanisms. Although sophisticated analyses of family data can begin to make this discrimination, nearly all that is known about this problem in schizophrenia comes from twin and adoption studies. Twin studies are based on the assumption that monozygotic (MZ) and dizygotic (DZ) twins share a common environment to approximately the same degree. However, MZ twins are genetically identical, whereas DZ twins (like full siblings) have on average only half of their genes in common. Although the validity of the second assumption is beyond question, the first (equal environment) assumption has been a focus of considerable controversy. Several studies have shown that measures of the social environment (for example, common friends, attitudes of parents and teachers) are more highly correlated among young MZ twins than among young same-sex DZ twins. These results at first appear to suggest that the equal environment assumption is false. However, there is another possible interpretation. Similarity in environment might make MZ twins more similar, but it is also plausible that by behaving alike, MZ twins seek out or create more similar environments for themselves. These two alternative hypotheses have been empirically evaluated in a number of studies, nearly all of which suggest that the environmental similarity of MZ twins is the result and not the cause of their behavioral similarity. Current evidence from an increasingly wide range of studies supports the general validity of the equal environment assumption of twin studies. Results are available from 13 major twin studies of schizophrenia ( Table 12.5-2). None of these, however, meets all the methodological criteria outlined above for family studies and the additional criterion that zygosity assignment be made blind with respect to psychiatric diagnosis. Some studies come closer to this model than others. For example, a variety of different clinicians made diagnoses from blind case abstracts in the original report from the Maudsley twin series of Irving Gottesman and James Shields. These case records have more recently been examined using modern operationalized criteria with similar overall results. In the study by Kenneth Kendler and Dennis Robinette from the National Academy of Sciences-National Research Council (NAS-NRC) Registry, psychiatric diagnoses were collected from a wide variety of clinical settings in which clinicians could not possibly have been aware of any research hypotheses. Furthermore, it could be shown that zygosity assignment was not biased with respect to psychiatric diagnosis. The new Norwegian and Finnish studies used the high-quality twin and psychiatric registries in Norway and Finland and thus should be representative of all treated cases of illness. Whereas the Norwegian study was based on personal psychiatric assessments and performed with structured instruments and DSM-III-R operationalized criteria, the Finnish study used previously recorded hospital and disability diagnoses. The sample size of the Finnish study was relatively large (253 pairs) while the Norwegian sample was much more modest in size (52 pairs). Unfortunately, both studies relied on self-report zygosity measures and the interviews and diagnoses in the Norwegian study were performed nonblind.

Table 12.5-2 Concordance With Respect to Probands and the Heritability of Liability to Schizophrenia in the Major Twin Studies Reported to Date

All these studies agree that proband-wise concordance for schizophrenia (the risk for schizophrenia in the cotwins of a schizophrenic proband twin) is much higher in MZ than in DZ twins, but the absolute rates of concordance vary widely. Two factors are probably responsible for most of this variation. First, some studies defined schizophrenia more broadly than others. Second, some studies obtained most of their proband twins from chronically hospitalized populations; others used population-based registries where milder cases would commonly occur. Twin studies have often but not always found a positive relationship between concordance and severity of illness. Heritability of Liability The diagnostic approach to schizophrenia and the method of ascertaining probands should equally affect concordance rates in MZ and DZ twins. Therefore, a better method of comparing results across studies would be a summary statistic based on concordance in both MZ and DZ twins. One of the best of these is the heritability of liability as calculated from the correlations in liability in MZ and DZ twins. This statistic ranges from 0.0 if genetic factors play no role in susceptibility to a disorder to a maximum of 1.0 if genes entirely determine disease risk. Because this statistic is based on the polygenic multifactorial threshold model, which may or may not be appropriate for schizophrenia, these results should be regarded as only one plausible way of approximating reality. Nonetheless, the major twin studies of schizophrenia agree in estimating the heritability of liability of schizophrenia at between 0.6 and 0.9 ( Table 12.5-2). These results suggest that genetic factors play a major role in the familial transmission of schizophrenia. Genetic theory predicts that if all the familial aggregation of schizophrenia were due to genetic factors, then the heritability of liability should be approximately double the correlation in liability found in first-degree relatives (because, on average, first-degree relatives have half of their genes in common). Comparing the results of Table 12.5-1 and Table 12.5-2 indicates that, at least as a rough approximation, this hypothesis is supported. The range of the heritability of liability to schizophrenia calculated from twin studies is approximately twice the range of the correlation in liability to schizophrenia found in first-degree relatives in most family studies. Nongenetic Familial Transmission Twin studies also provide two powerful tests for the role of nongenetic familial transmission in the liability to schizophrenia. First, one can ask whether the correlation in liability in DZ twins is more than half that which would be predicted in MZ twins if only additive genetic factors were operating. A review of all major twin studies to date suggests that nongenetic factors may play at most a modest role in the transmission of schizophrenia. Second, the risk for schizophrenia in DZ co-twins can be compared with that in siblings of schizophrenic probands. Although having the same degree of genetic relationship to the affected proband, DZ co-twins certainly share more of the familial environment that do ordinary siblings. Several twin studies have suggested that a difference in risk does exist between these two groups. However, such a difference has not been consistently found across all studies and was not found in the recent Norwegian

small-sample twin family study of schizophrenia. Adoption Studies Adoption studies can clarify the role of genetic and environmental factors in the transmission of schizophrenia by studying two kinds of rare but informative relationships: (1) individuals who are genetically related but do not share familial-environmental factors, and (2) individuals who share familial-environmental factors but are not genetically related. Table 12.5-3 summarizes, in the order discussed, the major adoption studies of schizophrenia, reporting raw data and statistical tests. Our summary here will be organized by the kind of adoption design utilized.

Table 12.5-3 Summary Results of Major Adoption Studies of Schizophrenia*

Affected Biological Parent Design Three studies have compared the adopted-away offspring of schizophrenic parents with the adopted-away offspring of matched controls. In the first of these, Leonard Heston found a significant excess of schizophrenia in adopted-away offspring of schizophrenic versus control mothers. The second such study was performed in Denmark under the direction of David Rosenthal and found similar results, which, however, fell short of statistical significance, particularly when only parents with a consensus diagnosis of schizophrenia or schizophrenia spectrum were included. This study has been the subject of a blind reanalysis using DSM-III criteria, which, when including only biological parents with a consensus diagnosis of schizophrenia from the original investigators, found a significant excess of schizophrenia spectrum in adopted-away offspring of schizophrenic versus control parents. The third and by far the largest such study is still under way in Finland under the direction of Pekka Tienari. Preliminary results indicate a highly statistically significant excess of schizophrenia and schizophrenia spectrum disorders in the adopted-away offspring of schizophrenic mothers compared to the adopted-away offspring of matched control mothers. Affected Adoptee Design Another major adoption strategy used for studying schizophrenia begins with ill adoptees rather than with ill parents. The full implementation of this design permits two separate experiments: (1) a test for the etiological role of shared environmental factors by comparing the nonbiological adoptive relatives of the schizophrenic with the control adoptees and (2) a test for the etiological role of genetic factors by comparing the biological relatives of the schizophrenic with control adoptees who were raised in households away from their ill relatives. This strategy has been used by Seymour Kety and colleagues in a series of adoption studies carried out in Denmark. The first sample, called the Copenhagen sample, began with 34 adoptees located in Copenhagen who received a consensus diagnosis of chronic, borderline, or acute schizophrenia. These adoptees and their matched controls had been separated from their biological parents at an early age and raised by individuals with whom they had no biological relationship. The first report on this series was based on hospital abstracts of all relatives located by the population and psychiatric registries available in Denmark. Schizophrenia and related disorders were significantly concentrated only in the biological relatives of the schizophrenic adoptees. The next phase of this project involved personal interviews of all available and cooperative relatives. After these interviews had been dictated into English and blinded, a diagnostic review also indicated a substantial concentration of schizophrenia spectrum disorders only in the biological relatives of the schizophrenic adoptees. A second sample beginning with 41 schizophrenia spectrum adoptees from outside of Copenhagen (termed the Provincial sample) has also been collected. On the basis of personal interviews with biological and adoptive relatives, the results basically replicated the parallel findings from the Copenhagen sample. Schizophrenia and the spectrum disorders were significantly more common in the biological relatives of schizophrenic versus control probands, while these disorders were equally uncommon in the two groups of adoptive relatives. In an independent review of the interviews from both the Copenhagen and the Provincial samples, using DSM-III criteria, Kendler and Gruenberg replicated and extended all the major earlier findings of Kety and his coworkers. Vertical Cultural Transmission Because studies of twins contain no parent-offspring pairs, they are not helpful in clarifying whether parents influence their children's risk for schizophrenia in ways that are other than genetic. However, several adoption strategies have been used to clarify the role of parent-offspring environmental transmission (termed vertical cultural transmission) in schizophrenia. First, if offspring of schizophrenic persons in part “learn” schizophrenia from their parents, then decreasing the amount of contact between schizophrenic parents and their children should decrease their risk for illness; however, two studies have produced results inconsistent with this hypothesis. Jerry Higgins and coworkers compared the adopted-away offspring of schizophrenic parents with the naturally reared offspring of schizophrenics. Although the sample size was small (23 offspring in each group), follow-up personal interviews indicated a nonsignificant excess of schizophrenia in the adopted-away offspring compared to those children reared by a schizophrenic parent. In a variation of a full adoption study, a similar design was utilized in Israel to compare 25 offspring of schizophrenic parents reared in a kibbutz (where children are raised together in children's houses, yet have considerable contact with their parents) with 25 offspring of schizophrenic parents raised in conventional nuclear-family settings elsewhere in Israel. A follow-up interview in adulthood with these offspring revealed that the risk for DSM-III schizophrenia was actually higher (nonsignificantly) in the kibbutz-reared offspring (13 percent) than in the town-reared offspring (8.7 percent). When the schizophrenia spectrum disorders were included this difference was even greater (26.1 percent versus 13.0 percent) although still short of statistical significance. Both these results are inconsistent with the vertical cultural transmission hypothesis. A second way to address the vertical cultural transmission hypothesis is to look at the risk for schizophrenia in the adopted-away offspring of normal individuals reared by schizophrenic parents. Although limited by a small sample size and a small number of parents with typical schizophrenia, Paul Wender and coworkers found no evidence for increased rates of illness in such adoptees. Third, vertical cultural transmission of schizophrenia would predict that among adopted individuals who become schizophrenic, schizophrenia should be overrepresented in their adoptive parents, who would culturally “transmit” schizophrenia. In Kety's Copenhagen and Provincial samples, no excess cases of schizophrenia or related spectrum conditions were seen in the adoptive parents of the schizophrenic adoptees. In separate samples Wender et al twice studied psychopathology in the adoptive parents of schizophrenic adoptees. The first of these studies found evidence for an excess of severe psychopathology in the adoptive parents of schizophrenics. In the second study, which the authors believed was better controlled, no such increase was found. Fourth, since step-siblings of schizophrenics would be exposed to the same schizophrenogenic rearing environment as the schizophrenic person but would lack the biological relationship to the parents, vertical cultural transmission would also predict an excess of schizophrenia in the step-siblings of schizophrenic persons. Two studies have been unable to find an excess risk for schizophrenia in relatively small samples of step-siblings of schizophrenic probands. In summary, twin and adoption studies provide strong and consistent evidence that genetic factors play a major role in the familial aggregation of schizophrenia. Evidence for a role for nongenetic familial factors is less clear; some studies suggest that they may contribute modestly to the familial aggregation of schizophrenia, but the majority of studies find no evidence for significant nongenetic familial factors for schizophrenia.

PSYCHIATRIC DISORDERS TRANSMITTED WITHIN FAMILIES The first systematic family study of schizophrenia, performed by Ernst Rüdin in Emil Kraepelin's newly established Psychiatric Institute in Munich in 1916, found that siblings of schizophrenic patients had increased rates not only of schizophrenia but also of other potentially related psychotic disorders as well. Since that time, a major focus of family, twin, and adoption studies of schizophrenia has been to clarify the nature of the psychiatric syndromes that occur in excess frequency in relatives of schizophrenic patients. This effort has been greatly aided by the emergence of operationalized diagnostic criteria in psychiatry, which permit more precise and reliable diagnoses. Hypotheses On the level of psychopathological syndromes, four heuristic hypotheses can be articulated about the nature of the liability to schizophrenia that is

transmitted in families: (1) a general (nonspecific) liability to all psychiatric illnesses; (2) a liability to poor psychosocial functioning, oddness, and suspiciousness (schizophrenialike personality disorders); (3) a liability to many forms of psychosis; and (4) a specific liability to typical schizophrenia. These hypotheses are useful because each generates a different prediction about the kinds of psychiatric disorders that should be seen in excess in families of schizophrenic persons. Nonspecific Liability for All Psychiatric Disorders The first hypothesis predicts that the risk for all major forms of psychiatric illness should be increased in relatives of schizophrenic persons. The hypothesis would be consistent with the unitary hypothesis of mental disorders, which postulates that all psychiatric illness is on a single continuum with schizophrenia at the most deviant end. This hypothesis can be best evaluated in modern family studies and in reanalyses of major adoption studies that have used similar diagnostic criteria and normal control groups. In the modern family studies that have examined this question, there is nearly uniform agreement that the rates of anxiety disorders and substance dependence disorders are not increased in relatives of schizophrenic versus matched control probands. The question of the familial relationship between schizophrenia and affective illness is more controversial. The majority of family and adoption studies that have examined this issue report similar rates for unipolar and bipolar illness in relatives of schizophrenic and control probands. However, at least three recent studies have found a significantly greater risk for unipolar illness in the relatives of schizophrenic probands. The reason for these discrepant findings remain a subject of debate. Schizophrenia-Like Personality Disorders Both Kraepelin and Eugen Bleuler, the two chief architects of our concept of schizophrenia noted that some close relatives of patients with schizophrenia, although never psychotic, had odd or eccentric personalities that were clinically reminiscent of schizophrenia. Since that time, similar observations have been made by a number of clinicians and researchers. The first and probably the most influential rigorous study of what may be termed these schizophrenia-related personality disorders was made by Kety and colleagues in the Danish Adoption Studies referred to previously. Based on a blind diagnostic review with their own diagnostic criteria, Kety and colleagues found a statistically significant excess rate of borderline and uncertain schizophrenia in the biological relatives of schizophrenic versus control adoptees. More recent applications of operationalized criteria have replicated and extended these earlier findings in support of the second hypothesis. Since 1983 11 family studies have examined the risk for schizophrenia spectrum, defined as schizotypal or paranoid personality disorder using DSM-III or DSM-III-R criteria, in relatives of schizophrenic and matched normal control probands ( Table 12.5-4). These studies included two reanalyses of different Danish Adoption samples, a Finnish adoption sample, four family studies conducted in the United States, and one family study each conducted in Greece, Ireland, and Germany. The absolute rates of schizotypal and paranoid personality disorder in relatives of both schizophrenic and control probands differ widely across studies. This might be expected because of the quite different approaches used to assess these personality disorder syndromes. However, every study found that schizotypal or paranoid personality was more common in relatives of schizophrenic versus control probands and this difference was statistically significant in 9 of the 11 studies. In aggregate, these results provide strong support for the second hypothesis articulated—that the familial liability to schizophrenia is in part reflected by a set of personality traits related to social isolation, oddness, and suspiciousness.

Table 12.5-4 Summary Results of Major Family and Adoption Studies Using Personal Interviews to Examine Risk for DSM-III and DSM-III-R Schizotypal or Paranoid Personality Disorder in First-Degree Relatives of Schizophrenic and Normal Control Probands

General Liability to Psychosis or Specific Liability to Typical Schizophrenia Recent family and adoption studies of schizophrenia have also provided us with substantial data in favor of the third hypothesis presented—that what is transmitted in families of individuals with schizophrenia is a liability to many forms of psychosis. In most but not all the studies that have examined this question, the risk for nonschizophrenic psychotic disorders (e.g., schizophreniform disorder, schizoaffective disorder, delusional disorder, and psychotic disorder not otherwise specified) is increased in relatives of schizophrenic probands compared to the risk seen in relatives of controls. Furthermore, although examined in fewer studies, the risk for schizophrenia appears to be usually increased in the relatives of probands with nonschizophrenic psychotic disorders. Another specific test of the third hypothesis is to examine the frequency of psychotic affective illness in relatives of schizophrenic patients. In large-scale family studies in Iowa and in Ireland, the author and colleagues found that while relatives of patients with schizophrenia were not at increased risk for affective illness, if affectively ill, they were more than twice as likely to become psychotic as affectively ill relatives of controls. Furthermore, compared to controls, in both studies the relatives of probands with psychotic affective illness were at increased risk for schizophrenia. Results to date provide strong evidence against the validity of the first and fourth hypotheses. The familial predisposition to schizophrenia is neither completely nonspecific nor highly specific. Results are available to strongly support the second hypothesis and also to provide some evidence in favor of the third hypothesis. Current evidence suggests that the familial liability to schizophrenia increases not only the risk for schizophrenia as it is narrowly defined but also for schizotypal and paranoid personality disorder and probably several nonschizophrenic psychotic illnesses. These findings provide an increasingly complex but informative picture of the nature of the transmitted liability to schizophrenia.

MOST LIKELY MECHANISMS OF KINDS OF GENETIC TRANSMISSION MECHANISMS The conclusion that genes account for a substantial proportion of the risk for schizophrenia and related psychiatric disorders naturally leads to a desire to understand the mechanisms that underlie such genetic transmission. Is the risk for schizophrenia the result of many genes of small individual effect or can a single gene, acting alone, transmit a major risk of developing schizophrenia? For many years, genetic epidemiological studies have been carried out with the goal of answering these questions. Unfortunately, for reasons we will discuss fourth most of these questions have not yet been definitively answered. The major genetic-epidemiological approach to this question prior to the advent of linkage studies was statistical modeling either of risk figures for the various classes of relatives of schizophrenia or of the observed pattern of schizophrenia within systematically collected samples of nuclear families or extended pedigrees. This latter technique is called complex segregation analysis. In contrast to linkage analysis, complex segregation analysis examines phenotypes only, and not genetic marker information. Both these strategies compare the observed patterns of co-occurrence of schizophrenia among family members of close versus more distant genetic relatives with the degree of sharing expected under alternative genetic models. Studies of the patterns of risk for schizophrenia in major classes of relatives (e.g., monozygotic and dizygotic co-twins, parents, siblings, offspring, nieces/nephews) have usually concluded that the familial transmission of schizophrenia cannot be explained solely by a single major locus (SML). In particular, the concordance rate in monozygotic twins (~50 percent) is too high, relative to the risk in siblings and dizygotic twins (5–10 percent). Such a pattern is more consistent with multiple interacting (or epistatic) loci. With regard to complex segregation analysis, the results to date have been frustratingly inconclusive; however, they have been more frequently inconsistent than consistent with an SML etiology for schizophrenia. Given the genetic complexity of schizophrenia, it is likely that even the most mathematically sophisticated methods of complex segregation analyses are analytic tools too blunt to provide definitive answers.

CURRENT STATUS AND FUTURE PROSPECTS FOR IDENTIFYING SPECIFIC GENES THAT PREDISPOSE TO SCHIZOPHRENIA Two fundamentally distinct strategies have been employed in attempts to find specific genes that confer susceptibility to schizophrenia: tests of linkage and association. What follows is a review of the current progress using both these methods. Linkage Studies of Schizophrenia Linkage has proven to be an immensely powerful method for simple or Mendelian disorders in which a small number of families can usually unambiguously produce strong evidence for linkage to a small chromosomal region. As discussed later, despite much effort such a result has not emerged for schizophrenia. Why? As outlined in Table 12.5-5, schizophrenia differs from Mendelian disorders in at least five critical ways, all of which make successful linkage studies much more difficult.

Table 12.5-5 Characteristics of Classical Mendelian Disorders Versus Schizophrenia

First, most Mendelian disorders are fully penetrant. That is, if you inherit a “disease gene” and live through the period of risk, you will nearly always suffer from the disorder. As outlined above, the pattern of illness in families—in which first-degree relatives of schizophrenic probands have a risk of schizophrenia of ~5 to 8 percent—and the concordance rate in monozygotic twins (40 to 55%) are inconsistent with the action of a highly penetrant SML. Unlike in Alzheimer's disease when a well-recognized series of pedigrees exist in which the disorder segregates as a Mendelian dominant, no one has ascertained pedigrees in which schizophrenia is transmitted as a classical Mendelian disorder. Finally, the offspring of unaffected MZ cotwins have an elevated risk of illness, suggesting that cases of schizophrenia cannot be simply divided into “genetic” and “sporadic” forms. These results all suggest that, in aggregate, genes that exist for schizophrenia have reduced penetrance. That is, it is possible to carry a susceptibility gene or genes for schizophrenia and not manifest the illness. Second, for most Mendelian conditions, in all individuals who manifest typical symptoms of the disease, the symptoms are caused by the disease gene. This is not true for schizophrenia as schizophrenia-like symptoms can be produced by drugs of abuse and more rarely by metabolic or neurological conditions; these are called phenocopies. Third, in nearly all Mendelian disorders, disease development is independent of the environment. This is not the case in schizophrenia, however, when several environmental risk factors, including season of birth, obstetric complications, and intrauterine influenza infections have been shown to increase the risk of illness. Fourth, in most Mendelian disorders there is an obvious discontinuity between affected and unaffected individuals. Diagnostic boundaries are less clearly delineated for psychiatric illness and are the subject of continued debate in linkage studies. The correct phenotypic boundaries for schizophrenia to use in linkage and association studies are not known. Fifth, the disease genes that cause Mendelian disorders are sufficiently rare that for all practical purposes the same disease locus will be responsible for all the cases of illness in a pedigree. Schizophrenia is much more common and it is plausible, although unproven, that two or more loci contribute to disease susceptibility in many high-density families. Across families the situation with Mendelian disorders is variable. In most disorders (e.g., Huntington's disease, cystic fibrosis) mutations at a single locus are responsible for all known cases of illness. However, for some Mendelian syndromes (e.g., limb-girdle muscular dystrophy and retinitis pigmentosa) a number of distinct loci, usually on different chromosomes, have been found in different families. Given that schizophrenia is not a disease but a broad behavioral syndrome, and given the great complexity of the human brain, it is plausible that mutations in many different genes might result in the condition we call schizophrenia. The tight 1:1 relationship that exists between disease gene and phenotype that is characteristic of Mendelian genetic disorders does not apply to schizophrenia. Locus heterogeneity both within and between families is likely to further complicate this picture. These problems all mean that the signal:noise ratio for linkage studies will be much lower for schizophrenia. As is true in any experimental design, the lower the signal:noise ratio the larger the sample size required to detect an effect reliably. This principle is particularly applicable to linkage studies of complex diseases like schizophrenia. As has been demonstrated by a range of formal power analyses, much larger sample sizes are likely be required to detect linkage reliably for schizophrenia than were needed for the genetically simple Mendelian disorders. Developments and Early Results The field of linkage studies of schizophrenia is in flux and changing rapidly. Certainly the most important development in the last several years has been the emergence of a small handful of replicated findings. Given the vast number of statistical tests that are now performed in most linkage studies (many markers, several diagnostic models, several genetic models, often several different linkage programs), the true error rate emerging from any individual study is nearly impossible to quantify with precision. It remains a major concern that results of quite high apparent statistical significance could occur by chance alone because so many individual tests are performed. Thus, replication is critical. However, there remain many justifications for nonreplication, including genetic variation between populations and differences in sample size, composition, and diagnostic approach. Given the evidence of replication across several groups for regions on 22q, 6p, and 8p, many would argue that it is increasingly unlikely that all these regions represent false positives. It is difficult to conceive of some inbuilt bias that would produce spuriously positive results across multiple groups in the same chromosomal region. A further important development in the field has been the recent emergence of results from total genome scans for other complex disorders including juvenile-onset diabetes mellitus, multiple sclerosis, and asthma. These studies may hold important lessons for our struggles with schizophrenia. For juvenile-onset diabetes and multiple sclerosis, a “major” gene appears to exist in the HLA region that has been detected in nearly all studies. However, in other regions, nonreplication across groups is as frequent as replication and this is the pattern seen in initial studies of asthma. A recent study of asthma performed a genome scan in sibling pairs from three different U.S. ethnic groups; almost no replication for putative regions of linkage was seen across these three samples. These results suggest that the difficulties in detecting replicable linkages for schizophrenia may not be unique to the psychiatric disorders, but rather may reflect a general pattern of problems associated with linkage studies of complex disorders. When the simple and powerful one-to-one relationship between gene and phenotype that is seen in Mendelian disorders breaks down, linkage studies change from being relatively straightforward although arduous tasks to uncertain and murky endeavors. Detecting genes of modest-effect size for complex moderately heritable diseases is likely be a difficult and sometimes frustrating task. The first linkage study of schizophrenia was reported by Constantinidis in 1958. This study of 36 pairs of siblings was unusual in that in addition to blood groups, it used as “markers” a wide array of phenotypic traits such as hair color, handedness, and hair whorl. Seven further linkage studies of schizophrenia published between 1973 and 1987 examined, in relatively small samples of sib pairs or pedigrees, single markers (dopamine-b-hydroxylase, Gc, and albinism), HLA or a limited range of traditional polymorphisms (e.g., blood groups, proteins, and red cell enzymes). Although prior evidence for linkage in schizophrenia had been reported (e.g., Turner reported a logarithm of the odds [LOD] score for HLA and “schizotaxia” of 2.57,

which could not be replicated by subsequent investigators), the first widely noted positive evidence for linkage in schizophrenia and the first study to use DNA polymorphisms was reported by Sherrington et al in 1988. Following up on the report of an association of schizophrenia with a partial trisomy of chromosome 5q, these researchers examined the proximal portion of the trisomy, including the 5q11.2 breakpoint, with 2 RFLP polymorphisms in seven British and Icelandic families. The strong evidence they reported for linkage in this region (5q11-13) (LOD scores maximizing over 6 with a broad phenotypic definition), could not, however, be replicated by many other groups nor by the original investigators themselves. Current State of the Field Space limitations preclude an exhaustive review of linkage studies of schizophrenia here. Instead selective current developments are reviewed. Several complete or nearly complete genome scans for schizophrenia (in which markers are placed at 10- to 20-cM intervals over the entire human genome) have now been completed or published on relatively small high-density family sets. None of these scans have revealed evidence for a large single major locus for schizophrenia. Consistent with the evidence just reviewed, these results suggest that the existence of a single susceptibility locus that accounts for a large majority of the genetic variance for schizophrenia is unlikely. Within the last 3 years we have seen the first tentative evidence for replicated linkages for schizophrenia susceptibility loci. To date, three regions appear most promising: 22q12-13, 6p24-22, and 8p22-21. It should be noted, however, that the interpretation of these results is quite controversial, particularly as the definition of replication for linkage to a complex trait remains uncertain. 22q12-13.1 In 1994 Ann Pulver and colleagues reported that, in a preliminary genome scan of 240 randomly distributed markers in 39 multiplex schizophrenia families ascertained through the Maryland Epidemiology Sample, the strongest evidence for linkage was found for three markers spanning ~23 cM in the 22q13.1 region: D22S268, IL2RB, and D22S307. The maximum homogeneity LOD score (which assumes that all families were segregating a susceptibility gene for schizophrenia in this region) using their initial genetic model was modest: 1.54 for IL2RB. By altering their genetic model across a range of parameters, they were able to maximize the LOD score, again at IL2RB at 2.82. No evidence for linkage heterogeneity was found. Pulver organized an attempted replication study of this finding with three other research groups from Virginia, the United Kingdom, and France that examined these three markers on 22q in a total of 217 multiplex schizophrenia pedigrees. Overall, the evidence for linkage was not confirmed by the new samples, although some subsequent analyses by the Virginia group produced weakly positive findings. Quickly following these reports, a number of attempted replications by other individual groups were published. Two of these reports were positive, including a maximum LOD of 2.09 in nine Mormon pedigrees to marker D22S276 (~4 cM telomeric of IL2RB) and a maximum LOD of 1.51 at marker D22S278 (~7 cM centromeric of IL2RB) in 23 high-density British and Welsh pedigrees. Three other reports were largely negative: in 23 British and Icelandic pedigrees, 105 multiplex American families, and 30 German and Israeli families. In addition, Pulver and her colleagues followed up with a report when their family number had increased to 57. They found the 22q region remained most significant in their genome scan, although their most positive marker shifted from IL2RB to D22S278. These reports were followed by a large collaborative data-pooling effort led by Michael Gill. Eleven groups contributed with the typing of a single marker, D22S278, which they analyzed by the sib-pair method. Using all available data (620 sib pairs), the excess sharing of alleles in affected sib pairs was modest, but significantly deviated from chance expectation (p = 0.006). If they used only the sib pairs where both parents were also typed (296 pairs), the evidence in favor of linkage was somewhat stronger (p = 0.001). Although 25 percent of random siblings would be expected to share both alleles at a locus identical by descent, the investigators found that 31 to 32 percent of the sib pairs concordant for schizophrenia shared their alleles at the D22S278 marker. The authors calculated that if this locus truly impacts on the liability to schizophrenia, it is likely of rather small effect, being responsible for ~2 percent of the variance in liability. Another line of research has impacted on the interest in this region on 22q. Microdeletions in this region are responsible for a range of congenital malformation syndromes, including DiGeorge syndrome and velo-cardio-facial syndrome (VCFS). Individuals with VCFS demonstrate excess rates of psychopathology, although some debate remains as to whether these syndromes more closely resemble schizophrenia or bipolar illness. M. Karayiorgou et al found that 2 of 100 schizophrenic patients had microdeletions in this region, a finding that is in excess of the estimated general population frequency of such deletions of 1 of 4000. 6p24-22 The first evidence for linkage for schizophrenia to the 6p region came from the early phases of a genome scan in the 265 small to medium-sized families constituting the Irish Study of High-Density Schizophrenia Families. In the initial publication of this finding in 1995, 16 markers were examined over a 38-cM interval. When a narrow diagnostic model was used, the evidence for linkage was modest (max LOD = 1.18), but increased substantially as the diagnostic definition broadened to include other disorders within the schizophrenia spectrum (max LOD = 3.51 at D6S296). Evidence for linkage fell when the definition was broadened further to include nonspectrum disorders such as anxiety conditions and alcoholism. Using multipoint linkage analysis and a larger number of markers, the relationship between diagnostic breadth and evidence for linkage in this sample is illustrated in Figure 12.5-1.

FIGURE 12.5-1 Linkage with homogeneity. LOD scores were obtained from computer analysis of 25 simulated nuclear families (described in the text) in which a disease gene is located at the 0.0 centimorgan map position in all families (genetic homogeneity) and flanked on both sides by genetic marker loci located about 5 centimorgans on either side. Support for four alternative tests of linkage are shown. The hypotheses differ in the hypothesized proportion of families in the collection of families that might contain a major gene conferring susceptibility to schizophrenia. Those hypotheses of linkage with varying levels of genetic heterogeneity are contrasted with the null hypothesis that none of the families contains such a gene (proportion linked = 0.0). When all families are actually linked to the candidate region, as in this example, all four hypotheses show strong support for linkage. However, because LOD scores are based on a log 10 scale, the LOD score of 12.0 in support of the true hypothesis (proportion linked = 1.00) provides over one million times (10 6) greater odds of linkage than the hypothesis that receives the lowest support (proportion linked = 0.25), which has an LOD score of 6.0.

Strong evidence for linkage heterogeneity was found—perhaps because of the large sample size. Using several methods, the proportion of families carrying a pathogenic mutation at this putative vulnerability locus was estimated at 15 to 30 percent. Eleven other published reports on this region have appeared from individual groups. Seven of these studies provide additional evidence of variable strength for a susceptibility locus for schizophrenia in this region; four do not. Briefly, the positive results include: (1) in 43 German and Israeli pedigrees, a maximum LOD of 2.2 near marker D6S274 (~15 cM centromeric of D6S296); (2) in a collaborative sample of 5 large pedigrees and 65 multiplex families, a nonparametric p value for linkage of 0.005 at marker D6S274; (3) in 57 pedigrees from Maryland, a maximum LOD of 1.17 at D6S296 and a sib-pair analysis at the same marker at p = 0.004; (4) in 10 German families, modest evidence for linkage (max LODs ranging from 1.41 to 2.08 over a large interval from markers D6S274 to D6S459), which increased substantially when eye-tracking dysfunction was examined (max LOD of 3.51 at D6S271—over 30 cM centromeric to D6S296); (5) an LOD of 2.49 in one mixed French-Canadian family containing cases of both schizophrenia and mood disorder; (6) initially negative results using 5 markers in 19 Southern African Bantu-speaking families which produced mildly positive findings on reanalysis with other statistical methods; and (7) strong evidence for linkage to a quantitative trait reflecting positive symptoms of schizophrenia in 10 moderately large Canadian families of Celtic origin. The negative results include an examination of 4 markers in the region in 45 pedigrees from the United States and Australia, 2 markers in 23 British and Icelandic pedigrees, 17 markers in 211 U.S. families, and 9 markers in 86 Welsh and English families. In 1996, results of a 14-group collaborative effort on linkage in the 6p region were published. Most of the groups that had previously reported their findings individually

participated in this collaborative effort. Typing 5 markers on 6p on over 400 new families (excluding the Irish sample in which the linkage was first found) and using a narrow diagnostic definition of schizophrenia, a maximum LOD score of 2.19 (which equals a p value of ~0.001) was found. It is noteworthy that these modest results for linkage, which were interpreted as suggestive but not definitive, were relatively widely dispersed amongst the groups. For one particular model, for example, modestly positive results (LOD >0.3) were seen in the 6p region by 9 of the 13 new samples examined. 8p22-21 Pulver et al were also the first to report evidence for linkage of schizophrenia to the 8p region. In the 57 high-density schizophrenia families that she and her colleagues ascertained in Maryland, 18 markers were typed over an 81 cM region. Using a relatively narrow definition of schizophrenia, they found evidence for linkage over a ~15 cM interval from markers D8S258 to D8S136. The maximum LOD score was 2.35 at D8S136. Using an analysis based on affected sib-pairs, maximum evidence for linkage (at p = 0.00004) was found at D8S258. Three other reports from individual groups have examined linkage for schizophrenia in this genomic region. A genome scan of five large Icelandic pedigrees found modest evidence for linkage ( p = 0.04) at marker D8S298 (which maps between D8S258 to D8S136). In 25 Welsh and English families, however, examining 4 markers in this region Kunugi et al could find no substantial evidence for linkage. By contrast, results from the Irish Study of High-Density Schizophrenia Families were quite positive. Examining 15 markers in this region in 265 multiplex families, the strongest evidence for linkage was found for marker D8S1715 (which maps 1-2 cM telomeric of D8S258—maximum LOD = 2.52). Multipoint analysis—which produced the strongest evidence for linkage using a broad definition of the schizophrenia spectrum—demonstrated a 10cM region with LOD scores above 1.90, from markers D8S1715 to D8S1739 (which is ~4 cM centromeric of D8S136). Again, given such a large number of families, strong evidence was found for linkage heterogeneity, with results suggesting that a susceptibility locus in this region was present in only around 10 to 25 percent of families. The fourteen-group collaborative effort also examined 5 markers in the 8p22-21 region. The maximum LOD score obtained (excluding the families of Pulver et al in which the initial linkage was first found) was 2.22 ( p = 0.001), which again is suggestive but not definitive. Of the 13 groups that reported new results from this region, positive evidence for linkage (defined as a maximum LOD >0.30) was found in 10. 22q, 6p, and 8p Table 12.5-6 summarizes the current status of linkage findings for these three regions. Results in each of these areas share three features: (1) they have been replicated in at least two other samples in addition to the one in which they were first reported, (2) they have not been replicated in all studies, and (3) a collaborative effort has pooled results across many groups and produced suggestive results.

Table 12.5-6 Current* Potentially Replicated Linkages in Schizophrenia

Other Linkage Regions of Interest: Dopamine Receptors, X Chromosome, and 5q22-31 Many other linkage reports for schizophrenia have been published since 1990. The largest single collection of such reports has examined the five types of dopamine receptors (D 1 through D5), with at least ten reports examining the 11q22-23 region containing the D 2 receptor, five reports each examining the 3q13.3 region containing the D 3 receptor and the 11p15 region containing the D 4 receptor, and at least two reports examining the 5q35.1 region containing the D 1 receptor, the 4p16 region containing the D 5 receptor, and the 5p15.3 region containing the dopamine transporter gene. These studies have been consistently negative. Genetic variation in or around the genes coding for the dopamine receptors and transporter do not appear to play a major role in the etiology of schizophrenia. Other negative linkage reports include the GABA A receptor subunit genes; the glutamate GluR5, GluR6, and NMDAR1 subunit genes; and the 5-HT 2 receptor. Based in part on the observation of an excess of same-sex affected sibling pairs, particularly in families where the illness appears to be paternally transmitted, several investigations have been conducted for linkage of schizophrenia to markers in the pseudo-autosomal region—with mixed results. Finally, linkage in the 5q21-31 region was recently independently found by two groups. In the genome scan of the Irish study, marker D5S818 in 5q22 produced the second best of the first 223 markers tested. Thirteen additional markers were typed over ~45 cM. The largest two-point LOD score found was with marker D5S393 (LOD = 3.04) and assumed a narrow phenotypic definition (schizophrenia plus poor-outcome schizoaffective disorder.) Multipoint analysis produced substantial evidence for linkage (LOD > 2) over ~20 cM, from markers D5S818 to IL-9, with the peak at D5S804 (LOD = 3.35). Evidence for heterogeneity was found, with estimates that between 10 to 25 percent of the families were segregating a mutation at this locus. At the same time, Schwab and colleagues in Germany, in a study on 44 nuclear families found a maximum multipoint LOD score calculated from affected sibling pairs of 1.8 around marker D5S399, which is only ~3 cM distal to IL-9. Association Studies of Schizophrenia Association studies examine whether individuals affected by a disease more frequently have a particular allele at some “candidate” genetic locus than individuals not affected by the disease. This association can occur for two reasons. Either the allele being studied directly influences risk for the disorder or, more commonly, the allele is in linkage disequilibrium (LD) with the disease-predisposing mutation. In addition, association can occur for spurious reasons unrelated to disease etiology, such as population stratification. While linkage—the co-segregation of a marker and a disease—is a family-based phenomenon, linkage disequilibrium is a population phenomenon and relies on the specific population history of the marker and disease mutation. It will be seen when a marker is close enough to the disease gene so that the original association created when either the disease or marker gene mutated or entered into a population through a population bottle-neck has not had time to be broken apart by genetic recombination. Association studies have two important advantages when compared to linkage studies. First, association studies can study individual patients. Second, under many circumstances, association studies are considerably more powerful than linkage studies at detecting genes of modest effect. However, association studies have two disadvantages. First, they “scan” much smaller regions of the genome that do linkage studies. The practical effect of this is that association studies must be used for candidates genes only. Currently a genome scan using the association method is not technically feasible. Also, obtaining proper controls for association studies can be difficult and if done improperly can lead to false-positives results. Recently, a new approach to association studies has been adopted that solves this problem. By studying individual patients and their parents, researchers can use as a “control group” the parental genes that did not get transmitted to the patient. Certainly the longest history of LD studies in schizophrenia have involved the HLA region on chromosome 6p. The earlier literature suggested the possibility of replicated positive associations with HLA A9 and B5 and negative associations with BW35. Furthermore, the positive association with the A9 allele was particularly noted in cases of paranoid schizophrenia. More recent reports using molecular genetic genotyping methods have focused on possible associations of schizophrenia with DQB1 and DRB1 HLA loci. As polymorphic markers became available near or within neurotransmitter receptors, many reports have examined the association between schizophrenia and serotonin and especially dopamine receptors. Sometimes these studies employed polymorphisms within the gene, such as the Ser 311/Cys311 structural polymorphism within the D2 receptor gene, a glycine-to-serine missense polymorphism at position 9 in the N-terminal extracellular domain of the D3 receptor and the 48 base-pair sequence repeat in the D4 receptor. Few replicated findings have emerged to date; however, there is a suggestion in some but not all studies of excess homozygosity at the D3 receptor gene in patients with schizophrenia. A European multicenter collaborative group recently reported evidence for a modest association (OR ~ 1.2) between schizophrenia and the T102C polymorphism in the serotonin type 2a receptor. Whereas association studies remain of major interest in studies attempting to clarify the nature of the genetic liability to schizophrenia, it is probably fair to conclude that a powerful, widely replicated finding has yet to emerge with this technique. Anticipation and Expanded Trinucleotide Repeats In the last decade a new mutational class of expandable trinucleotide repeat (TNR) sequences have been shown to be etiologic in a number of human genetic disorders, including several—such as fragile X and Huntington's disease—which are predominantly

neuropsychiatric in their manifestations. A feature of these disorders is anticipation—that the age at onset of the illness decreases and its severity increases across generations. In most of these disorders, anticipation has been clearly related to expansions of the TNR. Anticipation in neuropsychiatric disorders has been observed and commented upon since the early 1800s, when it formed one of the foundations of the degeneration theory of psychiatric illness popular in nineteenth-century France. However, Mott, a student of Pearson, dismissed anticipation as a methodologic artifact early in this century. Motivated by the possibility that schizophrenia might result from TNR expansions, a number of recent studies have examined whether the age at onset of schizophrenia demonstrates anticipation—that is, decreases across generations. Most studies that have examined this question have found evidence in support of anticipation; the interpretation of these results has been more difficult. A number of potential artifacts could explain earlier ages at onset in children than in their parents, aunts, or uncles; several of these artifacts are very difficult to control for. While opinions differ in this field, there is still cause for skepticism on whether “true” anticipation has been conclusively demonstrated for schizophrenia. This is perhaps an increasingly moot point as investigators are now trying to directly detect expanded TNR in patients with schizophrenia. A number of studies have attempted to directly assess expanded repeats using Repeat Expansion Detection (RED). Several groups have produced evidence for expanded CAG/CTG repeats using the RED method in schizophrenic versus control subjects. However, the significance of these findings remains uncertain, for at least two reasons. First, no correlation was observed in one of the best studied samples between the presence of expanded repeats and either clinical features of illness or age at onset. Second, the RED technique itself is entirely nonspecific and the significance of the detection of repeat expansions, which may occur anywhere in the entire human genome, remains unclear.

FUTURE DIRECTIONS The evidence is strong that schizophrenia is a familial disorder and that the familial aggregation of schizophrenia is due largely, although probably not entirely, to genetic factors. Whatever the familial predisposition that operates for schizophrenia, it not only “codes” for the classic, psychotic disorder but also increases liability to “schizophrenia-like” personality disorders and probably for some other nonschizophrenic nonaffective psychoses. Two decades of research using statistical methods have failed to clearly delineate the mode of transmission of schizophrenia, a result that is understandable given its complexity. Advances in molecular biology have opened up realistic opportunities to localize on the human genome the specific genes that influence the liability to schizophrenia. Association studies have yet to provide convincing evidence for the role of a range of candidate genes in the etiology of schizophrenia. Genome scan strategies have, however, provided at least three regions, on chromosomes 6, 8, and 22 where at least three groups have found evidence for linkage. Although false-positive findings cannot be ruled out, it is likely that one or more of these regions do contain one or more susceptibility genes for schizophrenia. The hope is that more comprehensive mapping studies, coupled with advances in sequencing and positional cloning technology, will in the next few years produce the identification of one or more specific gene defects that predispose to the development of schizophrenia. Whereas gene identification will itself represent a major advance, it will also represent the beginning of several new lines of research including (1) rational drug design based on knowledge of basic pathophysiology, (2) characterization of genotype-phenotype relationships based on knowledge of specific pathogenic mutations, (3) identification of environmental risk factors that interact with specific genes, and (4) realistic prevention research based on our ability to identify high-risk individuals.

SUGGESTED CROSS-REFERENCES Population genetics in psychiatry is discussed in Section 1.17, and genetic linkage analysis of the psychiatric disorder is discussed in Section 1.18. SECTION REFERENCES Brzustowicz LM, Honer WG, Chow EWC, Hogan J, Hodgkinson K, Bassett AS: Use of a quantitative trait to map a locus associated with severity of positive symptoms in familial schizophrenia to chromosome 6p. Am J Hum Genet 61:1388, 1997. Cannon TD, Kaprio J, Lonnqvist J, Huttunen M, Koskenvuo M: Genetic epidemiology of schizophrenia in a Finnish twin cohort: A population-based modeling study. Arch Gen Psychiatry 55:67, 1998. Chen WJ, Faraone SV, Tsuang MT: Linkage studies of schizophrenia: A simulation study of statistical power. Genet Epidemiol 9:123, 1992. Cloninger CR: Turning point in the design of linkage studies of schizophrenia. Am J Med Genet 54:83, 1994. Coon H, Jensen S, Holik J, Hoff M, Myles-Worsley M, Reimherr F, Wender P, Waldo M, Freedman R, Leppert M, Byerly W: Genomic scan for genes predisposing to schizophrenia. Am J Med Genet 54:59, 1994. *Gottesman II: Schizophrenia Genesis: The Origins of Madness. WH Freeman, New York, 1991. Kendler KS, Diehl SR: The genetics of schizophrenia: A current, genetic-epidemiologic perspective. Schizophr Bull 19:261, 1993. Kendler KS, Gruenberg AM, Kinney DK: Independent diagnoses of adoptees and relatives as defined by DSM-III in the Provincial and National samples of the Danish Adoption Study of Schizophrenia. Arch Gen Psychiatry 51:456, 1994. *Kendler KS, McGuire M, Gruenberg AM, O'Hare A, Spellman M, Walsh D: The Roscommon Family Study: I. Methods, diagnosis of probands and risk of schizophrenia in relatives. Arch Gen Psychiatry 50:527, 1993. Kendler KS, O'Neill FA, Burke J, Murphy B, Duke F, Straub RE, Shinkwin R, NiNuallain M, MacLean CJ, Walsh D: Irish study of high-density schizophrenia families: Field methods and power to detect linkage. Am J Med Genet 67:179, 1996. *Kety SS, Wender P, Jacobsen B, Ingraham LJ, Jansson L, Faber B, Kinney DK: Mental illness in the biological and adoptive relatives of schizophrenic adoptees: Replication of the Copenhagen study in the rest of Denmark. Arch Gen Psychiatry 51:442, 1994. Kidd KK: Associations of disease with genetic markers: Dejà vu all over again. Am J Med Genet 48:71, 1993. Maier W, Lichtermann D, Minges J, Hallmayer J, Heun R, Benkert O, Levinson DF: Continuity and discontinuity of affective disorders and schizophrenia: Results of a controlled family study. Arch Gen Psychiatry 50:871, 1993. Maziade M, Bissonnette L, Rouillard E, Martinez M, Turgeon M, Charron L, Pouliot V, Boutin P, Cliche D, Dion C, Fournier JP, Garneau Y, Lavallee JC, Montgrain N, Nicole L, Pirés A, Ponton AM, Potvin A, Wallot H, Roy M-A, le Groupe IREP, Mérette C: 6p24-22 region and major psychoses in the Eastern Quebec population. Neuropsychiatr Genet 74:311, 1997. McGuffin P, Sargeant M, Hetti G, Tidmarsh S, Whatley S, Marchbanks RM: Exclusion of a schizophrenia susceptibility gene from the chromosome 5q11-q13 region: New data and a reanalysis of previous reports. Am J Hum Genet 47:524, 1990. McInnis MG: Anticipation: An old idea in new genes. Am J Hum Genet 59:973, 1996. Onstad S, Skre I, Torgersen S, Kringlen E: Twin concordance for DSM-III-R schizophrenia. Acta Psychiatr Scand 83:395, 1991. Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter VK, Kasch L, Nestadt G, Antonarakis S, Housman D, Kazazian HH, Meyers D, Ott J, Lamacz M, Liang K-Y, Hanfelt J, Ullrich G, DeMarchi N, Ramu E, McHugh PR, Adler L, Thomas M, Carpenter WT, Manschreck T, Gordon CT, Babb R, Puck J, Childs B: Sequential strategy to identify a susceptibility gene for schizophrenia: Report of potential linkage on chromosome 22q12-q13.1: Part 1. Am J Med Genet 54:36, 1994. Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt P, Blouin J-L, Kimberland M, Babb R, Vourlis S, Chen H, Lalioti M, Morris MA, Karayiorgou M, Ott J, Meyers D, Antonarakis SE, Housman D, Kazazian HH: Schizophrenia: A genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. Am J Med Genet 60:252, 1995. Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 273:1516, 1996. Schizophrenia Collaborative Linkage Group (Chromosome 22): A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12. Am J Med Genet 67:40, 1996.

*Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8: Additional support for schizophrenia linkage on chromosomes 6 and 8: A multicenter study. Am J Med Genet 67:580, 1996. Schwab SG, Eckstein GN, Hallmayer J, Lerer B, Albus M, Borrmann M, Lichtermann D, Ertl MA, Maier W, Wildenauer DB: Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis. Molec Psychiatr 2:156, 1997. Sherrington R, Brynjolfsson B, Petursson H, Potter M, Dudleston K, Barraclough B, Wasmuth J, Dobbs M, Gurling H: Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 336:164, 1988. Straub RE, MacLean CJ, O'Neill FA, Burke J, Murphy B, Duke F, Shinkwin R, Webb BT, Zhang J, Walsh D, Kendler KS: A potential vulnerability locus for schizophrenia on chromosome 6p24-22: Evidence for genetic heterogeneity. Nature Genet 11:287, 1995. *Straub RE, MacLean CJ, O'Neill FA, Walsh D, Kendler KS: Support for a possible schizophrenia vulnerability locus in region 5q22-31 in Irish families. Mol Psychiatr 2:148, 1997. Turecki G, Rouleau GA, Joober R, Mari J, Morgan K: Schizophrenia and chromosome 6p. Am J Med Genet (Neuropsychiatr Genet) 74:195, 1997. Zerbin-Rüdin E: Endogene Psychosen. In Humangenetik: ein kurzes Handbuch in fünf Bäde, vol 2, PE Becker, editor. Thieme, Stuttgart, 1967, p 446.

Textbook of Psychiatry

12.6 SCHIZOPHRENIA: PSYCHODYNAMIC TO NEURODYNAMIC THEORIES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.6 SCHIZOPHRENIA: PSYCHODYNAMIC TO NEURODYNAMIC THEORIES THOMAS H. MCGLASHAN, M.D., AND RALPH E. HOFFMAN, M.D. Theory Classical Psychoanalytic Models Interpersonal Models Object-Relations Models Critique of Psychoanalytic Theories Family Dynamics and Transaction Models Stress-Diathesis Models Neuronal Network Model Implications for Treatment Biopsychosocial Model Suggested Cross-References

Schizophrenia is unarguably one of the most devastating of the mental illnesses. It often strikes early in life, and onset can signal the presence of an irreversible vulnerability toward psychosis that creates a lifetime of anguish and burden for patients and their loved ones. Equally devastating is the profound alienation that accompanies the disorder's emergence because the symptoms can be strange, unreal, and frequently impossible to connect with empathically. The derailment from normality is profound; in no other disorder is there the sense that one is literally losing his or her mind. Yet it is hard not to conclude that such a travesty is transpiring when one's thoughts become another's voice, one's will becomes enslaved by outside forces, one's capacity to focus and think straight shatters like broken glass, one's wellspring of initiative dries up, and one's apprehension of this tragic change becomes submerged beneath waves of denial, passivity, and nonreactive apathy. Because schizophrenia is disabling and strange, the disorder has had many explanations and has been the object of more attempts to render it meaningful than any other mental illness. Prior to Galileo, most of these explanations were found in religious texts. From Galileo to Emil Kraepelin, the explanations were found in medical texts alongside neurological disorders and idiocy. Inspired by psychoanalytic thinking, by the early twentieth century the nature and cause of schizophrenia was explained as functional. No longer supernatural or organic in etiology, schizophrenia became a clash of ideas, of wishes, of learned habits (i.e., psychological in its genesis and manifestations). From this milieu came the various psychodynamic theories of schizophrenia. By the late twentieth century, the organic substructures underlying psychological processes received greater attention, leading to models focusing at the mind-body interface, here labeled the neurodynamic theories of schizophrenia. Neurodynamic theories assert that in addition to psychodynamics, one must look at the neurobiological structures that generate psychology to comprehend symptom formation in schizophrenia more fully. To use the computer metaphor, symptoms arise in schizophrenia because of shifts or defects in the hardware of mentation as well as from conflicts and warps in the software of psychology. This hardware consists of biologically programed neuronal networks in dynamic communication via chemical and electrical connections, hence the term neurodynamic. While purely psychological theories have advanced our understanding of schizophrenia to some degree, this body of thought has not progressed much in the past 30 years. Modern thinking about the psychodynamic contributions to psychopathology has increasingly recognized the central influence of nature as well as experience. The authors feel that schizophrenia, more than any other psychiatric disorder, challenges the boundaries of what is meant by psychodynamic and argue that a broad definition that includes both organic and psychological contributions to mental phenomena is most valid, certainly for schizophrenia and possibly for many other mental disorders as well. Historically, the 1911 publication of Sigmund Freud's case of Daniel Paul Schreber probably marks the formal beginning of the systematic psychodynamic theories of schizophrenia. For the next 50 years, virtually all thinking in this realm was connected with the various psychanalytic schools, here labeled the classical, interpersonal, and developmental. The next major body of theory emerged from psychoanalytic theories around the middle of the century as family transaction models. Shortly thereafter, following the biological revolution in psychiatry and genetic studies of schizophrenia, the neurodynamic theories emerged, introduced by the stress-diathesis, or vulnerability-stress, hypothesis. Finally, the advent of artificial intelligence and computer simulations of brain functioning gave rise to the most recent parallel distributed processing model of schizophrenic symptom formation.

THEORY A rigorous and operationally oriented definition of theory envisions it as a set of assumptions and definitions that can generate testable and refutable hypotheses or predictions about a phenomenon. This form of theory constitutes the backbone of modern scientific empiricism. It is not, however, the form of theory that characterized the psychodynamic theories of schizophrenia. The latter are, according to Joseph Lichtenberg, an aesthetically oriented set of assertions explaining something in a manner that is “balanced, logical, and comprehensive while at the same time parsimonious in its assumptions.” Few, if any, of the psychodynamic theories considered here could be operationalized and tested. They are too abstract or based on data collected empathically rather than objectively. None of them can be validated on the basis of empirical data per se. While these theories in general must conform to rules of evidence, their veracity derives from their capacity to help one understand schizophrenia. These theories are compelling in proportion to the degree to which they generate meanings about schizophrenia that make communicable sense and that are useful in one's empathic encounters with afflicted patients. The validity here is face validity and stems from a theory's vividness, connectedness, and depth as well as its parsimonious integration of complexity. Such theory is also useful in alerting doctor and patient as listeners and hunters for what is missing from the latter's experience. Psychodynamic theory is not, however, useful in posing a series of testable hypotheses that can build a path of knowledge toward a specific causality of schizophrenia. The psychodynamic theories reviewed here ultimately failed at this task and have receded in importance as a result. They remain an important contribution to the total picture of the patient, however, insofar as they provide us with usefully parsimonious metalevel descriptions of both normal and schizophrenic mental phenomena and mechanisms.

CLASSICAL PSYCHOANALYTIC MODELS Sigmund Freud The classical psychoanalytic model postulates that manifest psychopathology is generated by active and sustained psychological conflict between drive-created wishful impulses and antithetical wishes, reality, or conscience. This conflict generates defenses against the wishful impulse, and these defenses can often be seen in the form of symptoms. Any or all of this drama may be carried on outside of awareness (i.e., unconsciously). This model finds its most complete elaboration in the structural theory, which postulates the existence of three functional entities in the mind. The id is the wellspring of peremptory sexual and aggressive drives and wishes. It is largely unconscious and primitive in structure. The superego, or conscience and ego ideal, is the repository of rules and values learned (internalized) from parents and society during development. It is also largely unconscious but makes its presence known through the affects of guilt and shame. The ego is a group of psychological functions that mediate adaptation between the person and the environment (e.g., reality testing) and among conflicting psychological forces within the person (e.g., repression of forbidden impulses). The ego is complex and develops slowly over the course of life. Many of its functions (e.g., defense) are activated by anxiety, the danger signal generated by conflict among psychological forces or with reality. Ego functions, too, operate mostly out of awareness. Freud postulated that these structures develop during infancy and childhood and are in place by the end of the oedipal period (ages 3 to 5 years). The person at this point has a stable, integrated ego, seen as a sense of self that is enduring and cohesive. Conflict within and among these structures produces the symptomatic and character neuroses. Freud regarded schizophrenia as deriving from psychological development arrested prior to the oedipal stage, prior to development of an integrated ego. According to Freud, this arrest severely compromised the schizophrenic patient's capacity to relate and rendered psychoanalytic treatment problematic, if not impossible. Although he had virtually no clinical experience with schizophrenic patients, Freud was the first analyst to elaborate a systematic psychodynamic model for this

syndrome. He formulated two models—one emphasizing conflict and defense and the other emphasizing deficiency—as the cause of schizophrenic symptoms. The conflict-defense model basically explains schizophrenic symptoms by use of the structural model. In this model schizophrenia, like all psychopathology, is the result of conflict and defense. The difference between schizophrenia and the neuroses is purely quantitative, not qualitative. Schizophrenic conflict is more intense and requires frequent use of primitive (i.e., developmentally early) defenses such as denial and projection, which frequently involve a break with reality. The ego functioning of the schizophrenic patient regresses to developmentally earlier stages or levels of organization, the exact level being determined (or fixated) by one or more past psychological traumas. The difference between schizophrenia and neurosis lies in the depth of regression and the point of fixation, which Freud placed in the preoedipal phase of development. Freud used a deficiency (or deficit) model to explain schizophrenic symptom formation in the case of Schreber. Freud worked from Schreber's published autobiographical account of his paranoid psychosis. Clinically, Schreber's illness began with hypochondriacal preoccupations. These were followed by an apocalyptic panic leading to catatonia, personality change, and symptoms of psychosis, particularly, grandiose and paranoid delusions. Freud, who was elaborating his libido theory at the time, explained Schreber's psychosis as follows. Conflict initiates the sequence, as it does in all psychopathology. In schizophrenia, however, another process supersedes defense. This process is described as the patient's withdrawal of libidinal or energic investments (cathexes) from the real outside world, especially people (objects, in psychoanalytic parlance). There is a concomitant withdrawal of libidinal investments from the inner, fantasied, mental representations or images of this world and these people. In the developing schizophrenic process, the withdrawn libidinal energy increasingly becomes invested in the patient's self-image, seen clinically as self-aggrandizement or megalomania, or invested in the patient's body image, seen clinically as hypochondriasis. In neurosis, a similar process of withdrawal from real, external relations occurs in response to conflict, but here, the withdrawn libido remains invested in the fantasied objects. This withdrawal reaches a state so profound as to constitute a break with external reality and relationships and with internal object representations and relationships in fantasy. At this stage, one can see the apocalyptic panic clinically. It represents a projection outward of this internal catastrophe or collapse of psychological investments. This collapse and profound withdrawal constitutes the deficit of schizophrenia. It renders the patient incapable of relationships, including transference, and thus precludes treatment by psychoanalysis. Following this catastrophe, the patient tries to recover and reinvest libido. Since there has been a break with reality, however, these efforts produce the well-known symptoms of schizophrenia, especially hallucinations, delusions, and disordered thinking. The patient has reinvested interest and attention but in objects that are not part of the real world. In Freud's defense theory, the sequence of conflict, anxiety, and defense is regarded as sufficient to account for schizophrenic psychopathology. In the deficit theory, conflict and anxiety initiate pathogenesis but trigger a withdrawal process that is qualitatively different from defense. Freud never resolved the difference between his two theories. He seemed to say that schizophrenic people are very much like normal and neurotic people in some ways but profoundly different in others. His two theories formed the nidus for much subsequent controversy. Freud's other theoretical contributions to schizophrenia concern the psychodynamics of delusion formation. Early in his career, he postulated the mechanism of projection, whereby the subject's wish is disavowed and projected onto (or attributed to) another person (the object). Later he suggested that delusions of persecution arise from latent homosexual impulses that undergo reversal and projection. Thus, the situation “I (a man) love him (a man)” is reversed to “I do not love him; I hate him” and projected into “He hates (and persecutes) me.” Later in his career, Freud maintained that the hostility inherent in any form of intense ambivalence toward an object could be projected into feelings of being persecuted by that object. Paul Federn If Freud was the first major psychodynamic theoretician of schizophrenia, Paul Federn was the first major psychodynamic clinician of schizophrenia. A contemporary of Freud's, he disagreed with his Viennese colleague's pessimism about the schizophrenic patient's capacity to develop transference and to be treated by psychoanalytically informed therapy. He treated many schizophrenic patients and developed techniques that were half a century ahead of his time. Federn greatly expanded the notion of ego set down by Freud in the structural theory. He was perhaps the first psychoanalytic theoretician to introduce the notion of self. To him, the ego was not just a collection of psychological functions. It also had its own existential being or ego feeling. The various ego functions aggregate into a sum or self that has a feeling of permanence and continuity vis-a-vis time, space, and causality. This is ego feeling, the totality of feeling an individual has of his or her own living being. Ego feeling as subject is “I.” Ego feeling as object is “self.” Federn also elaborated the concept of ego boundary originally introduced by Viktor Tausk. To Federn, each person possessed an inner and an outer ego boundary. The outer boundary consists of the ego versus the external world; it divides and distinguishes mental phenomena from real phenomena. The inner boundary consists of the repression barrier or the line between conscious and unconscious experience. According to his scheme, which utilized Freud's libido theory, schizophrenia is a disease of the ego. The psychopathological process involves a loss of investments in ego boundaries. Attenuation at the inner boundary means derepression or a reemergence of developmentally earlier (archaic) ego states. Attenuation at the outer boundary means a loss of the distinction between mental and real, seen in the typical schizophrenic symptoms. Mature and archaic ego states, however, can coexist, thus making it possible for the patient to adjust to the real world while still symptomatic and to engage in psychodynamically oriented therapeutic discourse despite illness. Federn's basically descriptive model follows the theme of defect. Nevertheless, his concepts prefigure the later distinction between psychotic and nonpsychotic aspects of the patient's personality. For him, the schizophrenic process is never total. Furthermore, by highlighting the self phenomenology in the ego of Freud's structural model, Federn anticipated the development of self psychology. Heinz Hartmann Working within Freud's classical structural theory, Heinz Hartmann was impressed with the ego's complexity and versatility, its strength in opposition to the drives, and its primary aim of serving reality adaptation and survival. Defenses such as intellectualization and sublimation, could also be coping devices. He regarded humans as biological organisms phylogenetically equipped at birth for adaptation to an average expectable environment. This includes primary ego functions like perception, memory, and motility, which are not derived from conflict. Also, ego functions developing later out of conflicts can become autonomous of id and superego or free of conflict to function independently and to serve adaptation. Such functions include language, intellect, thinking, will, judgment, attention, affectivity, reality testing, intention, and object relations in addition to the defenses and primary functions already mentioned. The existence of psychopathology indicates that these ego functions can become reinstinctualized or involved in conflict situations. The ego, according to Hartmann, also possesses a synthetic function, its aim being to promote homeostasis, or a harmonious equilibrium between the drives of sex and aggression, among the intrapsychic tripartite systems of id, ego, and superego, and between the individual and his or her environment. This supraordinate integrative function carries echoes of Federn's ego feeling. Hartmann, however, regarded the self as an idea (representation) rather than an entity or functioning mental system. Compared with his extensive contributions to general psychodynamic theory, Hartmann's specific postulates regarding schizophrenia are abbreviated, perhaps because such patients did not constitute a large part of his practice. His theory was a mixture of defense and defect. Like Freud, Hartmann felt that schizophrenic symptoms can result from conflicts secondary to intolerable realities or amplified drive pressures. In addition, he postulated an inborn primary defect in the ego of the preschizophrenic patient that renders the ego incapable of neutralizing certain drive pressures, especially aggression. Aggression generated later in life by conflict or narcissistic injury floods this ego (especially its synthetic functioning) and draws it easily into conflict. The ensuing regression is substantial and mobilizes primitive defenses such as denial and projection, which are viewed as the symptoms of schizophrenia. Not all ego functions regress to the same extent, however, thus accounting for the heterogeneity of the clinical picture. Hartmann's theory added the importance of aggression to the pathogenesis of schizophrenia. It also placed the source of the syndrome in the preschizophrenic patient's constitution, thus marking such people as qualitatively different from those who later develop normally or neurotically. Finally, Hartmann conceptualized the ego as multidimensional. Schizophrenia affects ego functioning selectively and can therefore be graded in severity. In Hartmann's scheme, it is possible to have greater or lesser degrees of schizophrenia. Overall, he emphasized the biological underpinnings of many psychological functions and thus presaged later neurodynamic theories of schizophrenia.

INTERPERSONAL MODELS Harry Stack Sullivan While psychodynamic in structure, the interpersonal model of Harry Stack Sullivan, differs fundamentally from psychoanalytic drive theory in content. Drive theory works from the perspective of the person as an individual encountering and shaping the world according to inner arising drives and satisfactions.

Interpersonal theory elaborates the perspective of the individual as a social creature who, from the very beginning, is object related and relationship seeking. Sullivan's model still postulates motivational drives and needs—namely, the need for satisfaction, (mostly biological, in the form of hunger and lust), and the need for security, (mostly psychosocial, in the form of power). All of these needs require interaction with at least one other human being and serve to mediate the interpersonal exchange. The developmental aspect of Sullivan's theory regards the human infant as being without a psychology separate from the initial mother-infant dyad. Psychological awareness consists of successive discoveries of one's self in relationship with significant others (objects). The first self consists of a we, not an I. Development proceeds according to an increasingly complex hierarchy of needs, all interactional. These are the needs for maternal contact in infancy, parental mirroring in childhood, peer play in latency, chum closeness in early adolescence, and sexual intimacy in late adolescence and beyond. Anxiety, the affect driving psychopathology, was viewed by Sullivan as external to the infant but imparted to the latter by an anxious parent, usually mother. Anxiety in the interpersonal situation develops three self-states: a good me (low anxiety), a bad me (high anxiety), and a not me (intolerable anxiety). Not-me anxiety is extreme awe, dread, loathing, or panic—so dysphoric as to be experienced rarely, as in nightmares or during severe schizophrenic end-of-the-world panic experiences. Anxiety leads to the organization of defensive structures, which Sullivan described as self-dynamism or self systems. These function to maximize satisfactions and to maintain security or to minimize anxiety through the use of “security operations” such as selective inattention (dissociation), sublimation, or projection. The self system, in content, is what one takes oneself to be. This is largely secondary to what others take one to be (i.e., it consists mostly of reflected appraisals). The self system security operations establish and protect this content of the self system. In the face of anxiety, this leads to the creation of fantasied defensive self-other constellations such as the self as helpless but deserving and the other as magical and merciful, the self as victimized and hurt and the other as powerful and persecutory, and the self as special and the other as idealizing. Such illusory configurations become superimposed upon and distort a person's here-and-now relationships, a process akin to transference, which Sullivan labeled parataxic distortion. Sullivan's psychodynamic theory of schizophrenia was informed by extensive clinical experience with acutely and subacutely affected inpatients. These disorders he regarded in the Meyerian tradition as purely functional reactions to encounters between the person and the environment. Central to the psychopathological process is a disturbance in the capacity to relate to others that is not biological in origin but reflects the history of the patient's interactions with significant others, especially with the mother in the formative years. The syndrome itself represents a massive dissociation caused by intense anxiety generated by low self-esteem during interpersonal experience. Sullivan acknowledged the probable existence of hereditary or organic determinants in some disorders, such as chronic process schizophrenia. He did not, however, consider them to be schizophrenia per se, or at least the subtype of schizophrenia to which he felt his theory applied. The pathogenesis of schizophrenia, according to Sullivan's etiological scheme, begins with a mother who is more anxious than normal and who imparts this tension to her child as excessive not-me experiences. The child's self system, developing around the time of speech acquisition, overcompensates with excessive dissociation and warps its own further development. The adolescent surge of new sexual needs (lust dynamism) assaults this compromised self system. The defensive wall of selective inattention fractures; not-me disorganizing anxiety returns, and panic ensures. This state of terror is characterized not only by the uncanny eruption into awareness of developmentally primitive states of mind, but also by collapse of the integrated self systems into what Sullivan described as “an exceedingly unpleasant form of nothingness.” The afflicted person's primary urgencies at this point are to avoid the not-me menace and to reorganize the self to reestablish meaning and become human again. This reorganization, known as schizophrenia, is effected at the price of reality testing. According to Sullivan, schizophrenia is more than a disorder. It is also an adaptive strategy for avoiding fragmentation and chaos (panic and terror) and for reconstructing a self with human identity, meaning, and purpose, no matter how fantastic that defensive self-other constellation may be. It is better, for example, to be the helpless victim of tyrannical persecutors than to be nothing at all. One must have character, even if it manifests as caricature. With schizophrenia, the needs for satisfaction and reality are secondary to the needs for security and self meaning. The descriptive aspects of Sullivan's theory highlight the self, both as a content (idea) and as a functional system. Though Federn may have been the first to describe the self as part of a psychodynamic system (as ego feeling), Sullivan was the first to postulate its functional centrality to human psychology. To him, creating and maintaining the integrity and functional alacrity of a self are primary motivating forces of human beings. With schizophrenia, in fact, the drive for meaning exerts hegemony over all other needs. Sullivan viewed schizophrenia as the result of cumulative experiential traumas during development. His own bias was to regard the preschizophrenic infant as a tabula rasa on which mother's anxieties became etched. The source of pathogenic anxiety is clearly external to the infant, and schizophrenia is seen as an adaptive attempt to cope with that dysphoric milieu.

OBJECT-RELATIONS MODELS The British object-relations school operated independently of Sullivan but pursued many of the same ideas, regarding humans as inherently social or object related. Their major spokespersons are Melanie Klein and W. R. D. Fairbairn. Latter-day American theorists contributing to a psychodynamic understanding drew heavily on theories of human development. Their major proponents are Margaret Mahler and Ping-Nie Pao. Melanie Klein For Klein, psychodynamic conflict involved love versus hate in relationships (rather than the tension between wish and reality of classical psychoanalysis). She emphasized the importance of fantasy, both conscious and unconscious, in determining behavior. Such fantasy usually takes the form of a drama involving the self relating with another, constellations that have come to be labeled internal object relationships. She added two coping or defense mechanisms to the ego's repertoire: splitting and projective identification. During infancy, these mechanisms promote development and adaptation; during adulthood, they signal trouble. Klein related psychopathology to an overabundance of aggression and hate in relationships. Envy (mostly innate) is especially pathogenic, because it is directed at good objects and their capacity to give, thus destroying hope by devaluing healthy relationships. Klein conceived of human development as a hierarchy of relational patterns (i.e., positions rather than phases). Two positions, both within the first year of life, are central to normal development—or to later psychopathology: the paranoid position, wherein aggressive, dysphoric interpersonal experiences are split off and projected onto significant others who are then regarded anxiously as persecutory and the depressive position, the infant's guilty recognition of personal responsibility for being the aggressive persecutor at times. While the accuracy of this scheme may be questionable vis-a-vis contemporary infant observation, it is compelling in its description of two mental constellations frequently encountered in patients with severe psychopathology. Klein's theory of schizophrenia closely followed her developmental scheme. She regarded the potential schizophrenic patient as endowed with strong sadistic and envious impulses that rendered the infant prone to intense paranoid anxieties and, therefore, to the overuse of withdrawal, splitting, and projective identification. Such infants never negotiate the depressed position and remain fixated at the paranoid position, to which they regress in the face of later stress after further development through adolescence. W.R.D. Fairbairn To Fairbairn, the primary aim of human behavior was contact with another, even if it was unpleasant. He viewed psychopathology entirely from a developmental perspective as the product of failure to establish good object relationships in infancy. Maternal absence or withdrawal during the paranoid-schizoid position leads infants to regard their love as noxious or bad. The resultant schizoid conflict—to love or not to love—sets off a withdrawal from relatedness in reality with compensatory investments in defensive internal object relations. These, like Sullivan's fantasied self-other constellations, provide a sense of security and continuity that is missing in real relationships, especially the earliest ones with parents. Fairbairn conceived of schizophrenia on a continuum with schizoid psychopathology, the difference being one of degree. The schizophrenic patient withdraws loving investments to such an extent that emotional contact with others and with external reality is renounced. Margaret Mahler Mahler clearly related early developmental experiences to later mental function. Her developmental phases of autism, symbiosis, and separation-individuation captured the attention and imagination of many theorists who saw different forms of psychopathology corresponding to different levels in her developmental progression. Schizophrenia, for example, is regarded as corresponding to Mahler's autistic phase of development. It is assumed or postulated that the preschizophrenic infant fails to form an adequate and stable symbiosis with the mothering object, a developmental failure rendering the child's image of mother inconstant. This developmental failure leaves the individual vulnerable to regression when facing the second and final phase of individuation in late adolescence. The regression itself goes back to the preverbal, presymbiotic stage of autism with loss of ego boundaries, merger experiences, and replacement of reality by autistic fantasy. Ping-Nie Pao Pao attempted to synthesize the theoretical threads of many schools and forebearers. Based upon extensive clinical experience, he subtyped schizophrenic patients into those with acute cases, for whom conflict plays a more pivotal role, and those with chronic cases, with higher genetic-biological loading.

Pao, like Freud, was impressed with the catastrophic panic experience that signaled the onset of the schizophrenic process and symptom formation. This process is precipitated by psychodynamic conflicts no different in content from those experienced by all people. In the schizophrenia-vulnerable person, however, these conflicts no longer generate neurotic levels of anxiety but at some point catalyze a crisis known as organismic panic, a term modeled after Mahler's developmental observations of states of extreme infantile distress. This panic brings with it paralysis of the ego's integrative capacity and fragmentation of the sense of continuity of self. The latter process constitutes an unbearable loss of a basic sense of safety, leading the ego to mobilize primitive or regressive defenses to reestablish and protect a sense of self, albeit pathologically. This attempt at adaptation or recovery results in postpanic emergence of a different personality, either pieced together with or distorted by psychotic symptoms. Typical delusions, for example, help to construct a new sense of meaningful self and, though often very unpleasant, are clung to tenaciously because their loss threatens return of disorganization and panic. Pao's etiological-developmental theory attempts to explain the origin of the schizophrenic vulnerability or organismic panic and regression. Like other relationalists, he placed etiology in the experiences of early development. Aberrant constitution and inappropriate mothering combine to generate a series of failed emotional cuings within the dyad, leading to frequent episodes of infantile organismic distress or “pain in being held and pain in being laid down.” Cumulative exposures to such distress bend further development in maladaptive directions, including a tendency toward primitive defensive, impaired capacity for instinctual neutralization; an inability to maintain a sense of reality constancy, heightened aggressive responses to frustration; and heightened wishes for closeness with others, coupled with a dread of self dissolution in symbiosis (the need-fear dilemma originally described by Donald Burnham, Arthur Gladstone, and Robert Gibson). These vulnerabilities lie dormant and do not produce symptoms until the advent of adolescent drive demands and stress.

CRITIQUE OF PSYCHOANALYTIC THEORIES Psychoanalytic theories of schizophrenia have become increasingly criticized in recent years, especially by analysts such as Martin Willick, mainly because the traumatic-developmental perspective on etiology lacks credibility. Virtually all psychoanalytic theorists postulate an experiential disharmony between the mother and her preschizophrenic infant. Whether this derives from genetic or constitutional factors in the infant or from psychological factors in the parent is secondary, as the purported central pathogenic elements are dysphoric experiences that become internalized as aberrant psychological structures. Explicitly or implicitly, the psychogenic models of schizophrenia regard these experiences as sufficient to explain most, if not all, cases of the syndrome. Several considerations cast doubt on this postulate. First, recent findings from infant and childhood development challenge many of the assumptions put forth by psychoanalytic developmentalists. For example, normal development is not like pathological stages projected backward. Infants and children are active, stimulus seeking, and socially oriented from day one. Stages such as the narcissistic, autistic, symbiotic, or schizoid-paranoid are not observed, so it is doubtful that schizophrenia could represent regression to one or more of them. Schizophrenia does represent a regression of mental capacity insofar as mentation becomes less complex, especially during active phases. However, as Willick points out, regressive phenomena can result from a primary disturbance in brain function later in life rather than represent a return to experientially determined earlier fixation. Also, infants and children are far more powerfully and intricately preprogrammed for adaptation and survival than psychoanalytic theorists assumed; almost without exception they saw infants as helpless, utterly dependent, and mindless creatures of infinite malleability. The fact that many infants and children survive despite unusually bleak or traumatic rearing suggests that factors orthogonal to nurture may be operative. Second, clearly some people who develop schizophrenia as adults come from basically healthy families and undergo normal growth and development—a direct challenge to trauma hypotheses of etiology. Furthermore, the reported childhood suffering of schizophrenic patients is often no more severe or profound than that of patients with other forms of mental illness, suggesting the necessary presence of additional, nonexperiential, pathogenic factors. For example, why might similar adverse life circumstances result in anxiety or depression in one person and hallucinations and thought disorder in another? Finally, the psychogenic theories have difficulty explaining why in most cases of schizophrenia some two decades intervene between the purported pathogenic infantile traumatic experiences and the onset of overt symptoms. If the experiences postulated by these theories do indeed occur, one might expect to see symptom formation at the time followed by predictable and nonrepressible (i.e., observable) deformities in subsequent development, at least in some cases. An infantile catastrophe severe enough to produce an illness of the magnitude of schizophrenia is not likely to go unnoticed, yet such catastrophes and their immediate behavioral consequences have not been documented. Generally, psychoanalytic theories of schizophrenia (especially those with a more descriptive perspective) continue to inform and help clinicians understand the patients they encounter. In this context, they are worthy of study. Furthermore, while exploring the past with schizophrenic patients may no longer be expected to yield etiological or historical truth, it does provide meaningful metaphors that can be useful in the empathic dialogue between doctor and patient.

FAMILY DYNAMICS AND TRANSACTION MODELS The family transaction models of schizophrenia represent attempts to understand and explain the syndrome as the transmission of aberrant interactions from the family to the patient. The models are compatible with object-relation-oriented psychoanalytic psychogenic theories in assuming that psychopathology is determined largely by experience and learning within the family during growth and development. The models differ, however, in their respective hypothesis-generating and hypothesis-validating databases. For psychoanalytic theories, the data are the associations of individual patients for family transaction theories, the data are observed interactions in families with one or more schizophrenic members. These models emerged following World War II, when clinical work with the families of schizophrenic patients revealed with increasing frequency that irrationality was not limited to the identified patient. Unusual and unpredictable interactions were observed between dyads within the family or among family members as an entire unit. Motivated by the idea that these interactions might be schizophrenogenic, several clinical investigators began describing these families and their transaction patterns in some detail. Gregory Bateson and Donald Jackson Gregory Bateson and Donald Jackson outlined a form of family interaction that they labeled the double bind. The interaction usually occurs between a parent and the schizophrenic offspring; it consists of the former giving the latter incompatible (if not antithetical) messages (e.g., stiffly avoiding a physical embrace while asking, “Why don't you show me more affection?”). This sets up an inescapable damned-if-you-do-and-damned-if-you-don't situation, or double bind, in which the offspring feels paralyzed. Bateson and Jackson hypothesized that repeated exposure to such a dilemma generates or aggravates the schizophrenic state. Ruth and Theodore Lidz Ruth and Theodore Lidz studied the characteristics of families that had a schizophrenic offspring. They looked for and observed disorders in the relationships among family members, especially the triad of mother, father, and schizophrenic child. They described several irrational patterns, such as marital schism between parents who remain married because of pathological interdependence despite considerable overt conflict; marital skew between parents who hide chronic disagreement behind a facade of harmony; permeable generational boundaries, where one parent requires the schizophrenic child to assume a parental role; eroticized parent-child relatedness, wherein one parent treats the schizophrenic child as a peer or contemporary; and emotional divorce, in which family members fail to acknowledge and confirm one another's psychological integrity. The Lidzs asserted that such rrational family functioning sufficed to account for schizophrenia in certain offspring exposed over their formative years. Lyman Wynne and Margaret Singer Lyman Wynne, Margaret Singer, and colleagues explored communication and cooperation within families with a schizophrenic offspring. From their careful observational work came the concept of communication deviance. This includes parental communications that lack commitment to ideas and percepts; parental communications that are unclear because they are filled with idiosyncratic themes and ideas or have language anomalies, discursive speech, and problems with closure; and parental communications that reflect an inability to establish or maintain a shared focus of attention during transactions with another family member. Among parental communications, they identified two common forms: an amorphous style in which communications are vague, indefinite, and loose and a fragmented style in which communications are easily disrupted, are poorly integrated, and lack closure. They also described familial displays of mutuality, hostility, or both, which serve as facades hiding antithetical themes and conflicts. Unlike most other family transactional theorists, Wynne and Singer were able to operationalize their concepts into reliable measures, thus allowing their hypotheses to be tested more systematically. They found communication deviance to be more specific to families of schizophrenic patients than to families of patients with depression, personality disorders, neuroses, or no pathology. Furthermore, amorphous patterns of communication deviance correlated more frequently with process schizophrenia, and the fragmented patterns with reactive schizophrenia. They also found significant quantitative correlations between the amount of communication deviance in the parents and the severity of psychopathology in their offspring. For example, schizophrenic offspring were in families in which both parents had high levels of communication deviance; normal and neurotic offspring were in families in which both parents had low levels; and borderline offspring were in families in

which one parent's level was high and the other parent's was low. Expressed Emotion More recently, family investigators have described several family factors that interact powerfully with schizophrenia, either to precipitate its emergence or to aggravate its course. One factor, called expressed emotion, consists of critical or emotionally overinvolved attitudes and behaviors displayed by parents toward their ill offspring. Another family transactional factor of interest and current study is negative affective style. It includes four kinds of parental behavior: criticism, guilt induction, intrusiveness, and inadequate support. Schizophrenic patients living with families with high expressed emotion or negative affective style relapse significantly more often than those living in families with low expressed emotion or normal affective style. Critique of Family Transaction School Like the psychoanalytic theories of schizophrenia, the family transaction theories have come under considerable criticism as etiological models. With the exception of communication deviance, few of the family transactions described above are demonstrably specific to schizophrenia. Furthermore, the observed irrational transactions among these families may possibly derive from the necessity of dealing with a child whose deviance is independently determined, thus reversing the hypothesized causal vector. In the absence of hard etiological data, assuming that families transmit and concentrate their irrationalities on a designated family member–victim is a nonproductive assignation of blame that does little to advance understanding but much to undermine working alliances between professionals and afflicted families. Like the psychoanalytic theories of schizophrenia, the family transaction theories remain viable and useful as descriptive constructs. While irrational behaviors in the families of schizophrenic patients may not cause the illness, these behaviors are nevertheless present and real in their evocative effects. As demonstrated by the expressed emotion and affective style studies, the family's emotional milieu can profoundly influence the onset or course of schizophrenia. Family transactional stress may not be causative. However, strong evidence, indicates that it can be powerfully facilitative in both pathological as well as therapeutic directions. As such, the family theories also fit well into the earliest neurodynamic theory of schizophrenia: the vulnerability-stress, or stress-diathesis, hypothesis.

STRESS-DIATHESIS MODELS Antecedents The first neurodynamic model, the stress-diathesis hypothesis, views schizophrenia dynamically as a product of interacting forces, some genetic or biological and some psychological, some innate or constitutional and some learned through experience. Unlike the purely psychodynamic theories, nature is more important, as suggested by genetic studies and the efficacy of biological treatments. Both nature and experience, however, are considered necessary to describe and understand schizophrenia. The Finnish adoption study of Pekka Tienari and colleagues illustrates this model. Comparing adopted-away children of schizophrenic mothers (high genetic-risk probands) with adopted-away children of nonschizophrenic mothers (low genetic-risk controls), they found that schizophrenia developed only in probands with genetic vulnerability who were raised in adoptive families in which the emotional environment was demonstrably stressful. None of the high genetic-risk probands raised in less stressful adoptive families developed psychosis. Likewise, none of the low genetic-risk probands raised in unhealthy adoptive families developed psychosis, although many developed other forms of psychopathology. These results strongly suggest that both a stressful rearing environment and an innate vulnerability to schizophrenia are necessary to generate the syndrome. The concept of such an interaction began with Freud. Describing the origin of neurosis in On the History of the Psycho-Analytic Movement, he wrote: Disposition and experience are here linked up in an indissoluble etiological unit. For disposition exaggerates impressions which otherwise have been completely commonplace and have no effect, so that they become traumas giving rise to stimulations and fixations; while experiences awaken factors in the disposition which, without them, might have long remained dormant and perhaps never have developed. Freud could well have been writing about the origins of psychosis. Certainly, subsequent psychoanalytic theorists took this model seriously in explaining schizophrenia, especially those that emphasized deficit. The true conceptual fathers of today's stress-diathesis model of schizophrenia, however, are Sandor Rado and Paul Meehl. Rado hypothesized that schizophrenia begins with an inherited disposition, or genotype. Interaction of this genotype with the environment produces the schizophrenia phenotype, a personality type or trait called the schizotype. Central to this trait is an inherent incapacity to experience pleasure. “In the schizotype the machinery of psychodynamic integration is strikingly inadequate, because one of its essential components, the organizing action of pleasure—its motivational strength—is innately defective.” This defect impairs the development of initiative and leads to schizo-adaptations such as compensatory overdependence on others (especially parents) and the elaboration of intricate cognitive processes devoid of affect. Anhedonia results in weak emotional bonds and leads to attenuated relationships. A well-compensated schizotypical person retains a stable schizoid personality. One of poorly compensated schizotype develops exaggerated, bizarre behaviors. Schizophrenia proper represents a decompensated schizotype with adaptive incompetence. The nature and severity of the schizo-adaptation depends on genotypic loading and the degree of familial and environmental stress. To Meehl, the inherited schizophrenic phenotype (which he labeled schizotaxia) consists of a defect in neural integration. This defect plus social learning (environment) leads to an abnormally organized personality (the schizotype) characterized by cognitive slippage (thought disorder), anhedonia, ambivalence, and aversion to human relationships. Further progression from schizotypy to schizophrenia is a function of the nature and severity of environmental stress versus the availability of help and support. Model This hypothetically pathogenic interaction between nature and experience came to be known as the stress-diathesis model. As currently conceived, this model accepts that the relative roles of nature and nurture in the etiology of schizophrenia will remain obscure until there are markers for genetic predisposition or constitutional vulnerability. It shifts emphasis from the etiological role of psychodynamic factors to their role in facilitating and preventing the expression of the disease process. Vulnerability to schizophrenia is seen as an enduring proclivity toward developing clinical symptoms. It is a stable trait independent of nonenduring psychopathological states, meaning that it is present premorbidly, at onset, during symptomatic efflorescence, and during remission. This trait should not, however, be regarded as developmentally static or fixed. Rather, vulnerability may be shaped epigenetically at each developmental phase. Aspects of vulnerability are undoubtedly genetic. Some may be acquired biologically throughout intrauterine, birth, and postnatal complications. Season of birth may also contribute, for reasons yet to be ascertained. The evidence for psychosocially acquired vulnerability is meager at present, but this hypothesis cannot be ruled out. The stress side of this model postulates that a variety of stressors (i.e. internal or external events requiring adaptation) can convert vulnerability into symptoms. Therefore, coping strengths or supports that diminish stress should minimize or prevent clinical expression of vulnerability. Following the model, the vicissitudes of schizophrenia are determined by the nature of vulnerability and stress and by the individual's strengths and environmental supports. Interaction of sufficient stress with sufficient vulnerability can lead to transient, intermediate (prodromal) states of dysfunction that amplify existing cognitive, affective-autonomic, and social-coping deficits. This compromised mental state, in turn, interacts negatively with stressors and magnifies their effect in a downward spiraling deterioration that culminates in a full-blown clinical syndrome. Vulnerabilities to Schizophrenia Finding, mapping, and integrating these vulnerabilities have become a central effort in current schizophrenia research. Virtually all of this investigation has focused on demonstrable phenotypic manifestations of hypothetical genotypic vulnerabilities in children and adolescents at risk for schizophrenia. The list of these vulnerabilities is extensive and grows each year. First are deficits in processing complex information, in maintaining a steady focus of attention, in distinguishing between relevant and irrelevant stimuli, and in forming consistent abstractions. Second are dysfunctions in psychophysiology, suggesting deficits in sensory inhibition and poor control over autonomic responsibility, especially to aversive stimuli. Third are impairments in social competence, such as processing interpersonal stimuli, eye contact, assertiveness, or conversational capacity. These deficits probably reflect both a core disturbance of schizophrenia (vulnerability) and the social outcomes of severe psychopathology. In the past, the source of these difficulties was often attributed to such external elements as neuroleptic drugs or institutions, a perspective that unduly diverted attention from their primacy in the disorder. Fourth are general coping deficits such as overevaluating threat, underestimating internal resources, and extensive use of denial. Phenotypic manifestations of vulnerability may not be observable premorbidly, especially if the genotypic vulnerability has variable onset of expression. Huntington's disease, for example, is an adult-onset neurological deterioration leading to psychosis and dementia; in a similar fashion, many cases of schizophrenia could result from a genotype whose phenotypic expression is not triggered until late adolescence or early adulthood. This phenotype may be a deficit in the neurophysiological

maturation of self systems during adolescence or a still later-onset neural deterioration or inhibition of these same systems in adulthood. Early-onset genotypes may help to account for patients with easily identifiable phenotypic deviations that begin in childhood as schizotypal aberrations and progress to chronic process schizophrenia later on. Later-onset genotypes may help explain the sudden occurrence of schizophrenia later in life in persons with normal growth and development and healthy premorbid personalities. Stressors Systematic studies of the stresses that affect the course of schizophrenia, aside from the family environment, have focused on social class and culture, social networks and life events. Socioeconomic and cultural factors have a long history of empirical association with schizophrenia. One of the most replicated findings in the schizophrenia literature is the clustering of schizophrenic patients in the lowest social classes, especially in urban communities. Few now hold that a poor socioeconomic environment causes schizophrenia, but few doubt that it has a major impact on its course. Poverty, ignorance, unemployment, social isolation, poor nutrition, and marginal health care are powerful chronic stressors that lead to frequent breakdown in vulnerable persons. Schizophrenia and social network are highly interactive, cross-sectionally and longitudinally. Schizophrenic patients usually have social networks that are smaller, less interconnected, simpler, more dependent, casual, nonintimate, and peopled with family as opposed to peers. The interplay between schizophrenia and social networks appears to be circular rather than linear. Initially, the major vector is schizophrenia on social network. Following the appearance of clinical symptoms, however, social network is likely to exert a powerful influence on the subsequent vicissitudes of schizophrenia. Stressful life events have demonstrated association with schizophrenia, but it may not always be necessary or direct. Questions often arise concerning whether stress has different effects on disease onset and recurrence and whether a stressful event precedes illness or represents a product of symptom exacerbation. Convention dichotomizes stressful events into those that are ambient, nonindependent, or chronic and those that are independent or acute. The former are stresses associated with everyday living, such as family, work, poverty, physical disability, and mental deficit; the latter are stresses associated with largely external or unusual changes, such as loss, death, acute illness, and moves, especially if these changes are unanticipated, undesired, and uncontrolled. Research suggests a high frequency of such events shortly before schizophrenia onset or symptom exacerbation. Furthermore, there appears to be an important interaction between maintenance antipsychotic medication and life-event stress. Patients in the community without medication are vulnerable to both acute and chronic stress. Patients taking medication, however, appear to be protected against either type of stress but are likely to suffer relapse if both types occur concurrently.

NEURONAL NETWORK MODEL The latest neurodynamic model of schizophrenia hypothesizes with greater specificity the neuroanatomic nature of the vulnerability to schizophrenia and its biophysical contribution to symptom formation. It is build upon postulates that most human mentation arises from neuronal networks organized in parallel distributed processing systems. Furthermore, these systems can, under certain physiological conditions, generate thoughts or feelings in ways orthogonal to the normal processes by which psychology is generated. This pathological development, called “memory parasitism,” can produce mentations that are literally products of aberrant connectedness among the neurons of the brain and are experienced and interpreted psychodynamically as unintended and alien by the bearer of the brain. The physical conditions conducive to such developments are unknown but hypothesized to involve a loss of parallel distributed processing neural circuit density from perinatal insults or from a genetically or developmentally programed excessive pruning of connections between cortical nerve cells. Parallel Distributed Processing Model Mental events are basically neuronally constructed representations of experience as memory. Memories in general are accessible to consciousness in a manner that is content addressable, i.e., the brain can use part of a memory to access the memory in its entirety. Artificial intelligence researchers such as Donald Hebb, Warren McCulloch, Walter Pitts, John Hopfield, and James McClelland and David Rumelhart have discovered that certain types of computer-assisted computations retrieve content-addressable information in a fashion that partially simulates nature. These systems are composed of large numbers of very simple computing units, generally referred to as “neurons,” which are densely interconnected via synapses. There is no single command unit; the effectiveness of the network as a whole reflects the cooperative interactions of its parts. Each neuron simultaneously receives information from a large number of other neurons and computes its response to these inputs in parallel with the computations of the other neurons of the system. No one-to-one correspondence exists between a memory and activation of a particular neuron. Instead, a memory corresponds to a pattern of activation involving many neurons of the network; memories are created by modifying functional connections among arrays of neurons. Networks that store and retrieve information on the basis of distributed patterns of activation are referred to as parallel distributed processing systems. An increasing body of neurobiological research suggests that the functional architecture of the mammalian cerebral cortex can be broken down into a number of linked parallel distributed processing-type neuronal assemblies. Of special interest is the long-term memory system, which probably involves the brain's hippocampal and cortical areas. The hippocampus is active during a critical “gestational” period (ranging from minutes to hours), during which input information is distributed to interconnected circuits linking frontal, parietal, and sensory-association cortical areas. If hippocampal functioning is temporarily impaired, memories due to be distributed will be permanently lost. However, once information is functionally linked within the cortex, its retrieval seems not to require an intact functioning hippocampus. Activating a posterior sensory area via an image representation or a frontal area via an abstract concept such as a goal or generalization can immediately “seed” widely distributed cortical circuits to yield complex memories. Parallel distributed processing systems with content-addressable mnemonic representations probably constitute the nemodynamic underpinning that is normal mental activity and psychology. The psychoanalytic method of free association, for example, relies on the content addressability of mental representations. Freud first observed that human mentation follows patterns that are seldom logical or governed by the rational rules of secondary process. More often than not, mental representations are connected by condensations, displacements, and symbolizations of mnemic content, whether that content is concrete imagery, stories, or abstract theories. These are the primary processes of mentation postulated by Freud to underlie the formation of dreams and neurotic-level symptoms. Content addressability is a new term for an old psychoanalytic postulate that every mental event (thinking, feeling, acting) is overdetermined and can be attained via multiple pathways. This is Robert Waelder's principle of multiple function, wherein a vast array of related factors (e.g., id, ego, superego) must be considered in understanding any behavior. The functional dynamics of parallel distributed processing systems also suggest that an enormous amount of neuronal activity accompanies any single mental event or idea, thus accounting for the dynamic unconscious of psychoanalysis. Attractor Dynamics in Parallel Distributed Processing Systems Most psychiatric syndromes include some form of repetitively reproduced mental content ranging from obsessional thoughts to the idea fixe of psychotic delusions. Such repetitive memories can be produced in simulated parallel distributed processing systems on the basis of “attractor dynamics.” As noted by Hopfield, these systems tend to be attracted to particular activation patterns, which are low-energy states of the system. Energy here is defined on the basis of a branch of physics known as statistical mechanics. Statistical energy corresponds to the degree of disorder in the system. Neurons that interact freely in a parallel distributed processing network will tend to be attracted to activation patterns that minimize its statistical energy. These patterns correspond to the memories of the system, which tend to be reproduced because of these energy minima. Particularly strong memories correspond to very deep energy minima that tend to pull new information to the existing activation pattern to the exclusion of other activation patterns. That is, a memory with a particular deep-energy minimum strives relentlessly to express itself. It is called “parasitic” because it coerces a wide range of input information into a single memory-activation pattern. One of the authors (R. H.) demonstrated that computer-simulated parallel distributed processing models can provide an account of how such pathological memories are induced. Under varying circumstances described below, a memory can be created that does not reflect any specific prior experience. These spurious memories are not linked to naturally occurring and stored input-activation patterns, but are created de novo by the brain itself and can be triggered by the most irrelevant internal or external cures. These memories link or condense quite disparate contents and may appear at times to be the products of primary process. However, they cannot be grasped by the empathic primary processes of others, i.e., they remain strange and beyond understanding in Karl Jasper's sense of being self-evident or common to human experience. These memories tie together representations or fragments of representations that are ordinarily not linked even by the weakest and most remote primary process pathways, hence the term “loose association.” In a sense, they are violations of content addressability, in which associations are no longer free but are constrained by disturbed attractor dynamics. Parasitic memories are the product of biophysical energic processes, not primary and secondary psychological processes. At the same time they arise in the midst of other neural networks that are not compromised and that generate normal and abnormal psychology in the usual way (i.e., by primary and secondary processes). As such, persons experiencing parasitic memories may feel as if parts of their brain or mind are functioning out of their control. They may experience these unintended mental events as if someone else were putting thoughts into their minds. Such post hoc reasoning that an outside force is inserting thoughts into one's mind may reflect the difficult task of describing and making sense of the experience of one's mind being repeatedly “captured” by a perseverative attractor seemingly acting according to its own will. In this fashion “parasitic” memories in a parallel distributed processing system can account for many of the seemingly bizarre symptoms of schizophrenia. Pathophysiology of Memory How might such memories come about? In computer-based parallel distributed processing systems, parasitic memories are known to

derive from two different types of “pathology.” First, parasitic memories can be produced when the system attempts to store too many memories for its capacity. Second, parasitic memories can be produced when an insufficient number of synaptic connections link the neurons of the system. It is further hypothesized that these two types of pathology are “located” in the system of long-term memory storage and recall involving the hippocampus and diffuse cortical circuits of the brain. There is considerable recent interest in pathology involving the hippocampus in schizophrenia. Neuroradiological and postmortem studies have suggested reduced hippocampal volume and disarray of its pyramidal cells in some schizophrenic patients. Reductions in pyramidal cell number, functional efficiency, or information transfer capacity—perhaps occurring secondary to prenatal complications such as viral infection—could downsize memory storage capability in the hippocampus, thereby rendering it vulnerable, as a parallel distributed processing system, to the induction of memory parasitism. A second form of schizophrenia may reflect abnormalities in postnatal brain development. Considerable evidence in humans and other primates now indicates that following birth, an overabundance of corticocortical connections exists; these connections are then selectively pruned and shaped during later developmental periods. In humans pruning of cortical synapses seems to extend well into adolescence for connections involving frontal areas. Moreover, the continued elaboration and pruning away of cortical synapses probably continues, albeit at a much reduced rate, throughout adulthood. These developmental studies, when considered in light of parallel distributed processing simulations, suggest a second mechanism leading to parasitic or spurious memories—reductions in corticocortical connections which are a part of these developmental processes. As suggested by Erwin Feinberg, if excessive developmentally induced pruning of these connections leads to a form of schizophrenia, a ready explanation for this age of onset and involvement in frontal areas is provided; synapse pruning is most prolonged in frontal areas, and the end of adolescence is when the effects of this pruning process would first be fully felt. An example of a specific model of psychotic symptomatology that is empirically testable has been described by Hoffman and colleagues. A neural network was created to simulate certain aspects of speech perception. Pruning connections between the working memory component of the network caused perceptions to emerge spontaneously. This observation thus provides a model for hallucinated speech (“voices”). The model also permitted simulation of the hypodopaminergic state, and this neuromodulatory state tended to eliminate voices. The testability of the model derived from the fact that hallucinogenic networks also demonstrated subtle but definite speech perception impairments. Empirical study with actual schizophrenic patients demonstrated these speech perception impairments, which were not detected in schizophrenic patients who did not hallucinate. These simulations suggest that hallucinated voices correspond to parasitic memories that usurp working memory circuits of speech perception. Implications The parallel distributed processing paradigm is neurodynamic because it postulates the creation of symptoms, at least in part, on the basis of defects in the hardware of the brain. Purely psychodynamic paradigms account for pathology solely as a reflection of aberrant “software” or conflicting functional programs in the mind. The parallel distributing processing model regards psychodynamics as necessary but often not sufficient to explain most schizophrenic symptoms. It is a model at the mind-body interface and views psychotic psychopathology as the product of a complex interaction of skewed mentation arising organically with normal or abnormal psychology arising psychodynamically. The model remains speculative but offers an advantage of being falsifiable. Many of the functional and neuroanatomic predictions of this model may be subject to hypothesis testing and validation, thus bringing theorizing about schizophrenia closer to the realm of scientific empiricism. In terms of sheer volume, the bulk of psychodynamic theories belong to psychoanalysis. In terms of content, the major issues have not changed much since Freud posited two theories—the structural-conflict theory and the withdrawal-deficit theory. By never integrating these two, Freud seemed to be saying that schizophrenia may be both, in part explained by intrapsychic conflict and in part by something else. Psychodynamic theories became more elaborate over the ensuing years, yet one can still follow the thematic threads of Freud's original part-explanations. Conflict theory has seen a line of development polarized toward object relations, experiential learning within the family, stressors that interact with vulnerability, and the psychological sequelae of organically disturbed neural circuitry. Deficit theory has seen a line of development polarized toward individual drives, complex constitutional inborn factors, the physical vulnerabilities of the stress-diathesis model, and the hard-wiring defects of parallel distributed processing neural networks. Today, these threads are each regarded as valid facets of the overall phenomenon. Both are necessary for a comprehensible and potentially workable theory of schizophrenia. While none of these psychodynamic models of schizophrenia has solved the mystery of its etiology, each system has offered cogent hypotheses or educated guesses. The neurodynamic models see nature as primary or at least as initiating a process of negative interaction with environmental experience, which becomes pathogenic sooner or later in life, depending on the onset trigger of the genotype. The family transactional model, at least as originally conceived, sees nature or experience as primary and, frequently, as sufficient for generating schizophrenia. Psychoanalytic models have posited one or the other or both. Since Sullivan and Mahler, however, the emphasis has shifted more uniformly toward the etiological primacy of traumatic nurturing experiences during early development, a shift that has come under increasing criticism as outlined. Overall, the impressive evidence for the existence of genetic and constitutional factors in schizophrenia has raised questions about the etiological hegemony of experience and learning in early development. Hypothetically, some (if not many) cases of schizophrenia may possibly arise from an adolescent-onset neurological dysfunction or deterioration in people who are, up to that point, developmentally normal. Such a process, along the model of overpruned parallel distributed processing neural networks, selectively inhibits or destroys later developmental levels of personality, especially those neuronal networks involved with structures, functions, and representations of the self. In response, the individual falls back on more primitively organized levels of personality and development. Such regression is compensatory and adaptive rather than primary and motivated. It does not occur because of developmental fixation but because simpler developmental levels and patterns may be the only ones left.

IMPLICATIONS FOR TREATMENT Psychodynamic theories of schizophrenia carry with them distinct implications for treatment. Early proponents of the psychoanalytic conflict model advocated the classical techniques of clarification, confrontation, and interpretation. Early proponents of the psychoanalytic deficit model introduced additional strategies. Federn, for example, felt that the usual psychoanalytic techniques aimed at depression, whereas with schizophrenia, the goal was to foster rerepression. As such, he encouraged positive transference, avoided negative transference, protected patients from undue anxiety and insomnia, taught them to improve their capacities for attention and thinking, exhorted them to give up unrealistic life goals, provided support beyond analytic hours in the form of a skilled nurse-assistant available to the patients at home, and offered consultation to the patient's family (recognizing the importance of the home environment to outcome). Proponents of the family transactional theories uniformly advocate family therapy in some form. Those that view the family milieu as causing schizophrenia usually regard the entire family as the patients or as the problem and focus interventions accordingly. Those that regard the family as facilitative rather than etiological emphasize the positive and negative effects that domestic tensions can have on the course of the identified patient. Technical strategies in the first instance are more interpretive. In the second instance, they are more psychoeducational. Proponents of the stress-diathesis and parallel distributed processing models advocate any intervention that enhances strength and support and minimizes stress and vulnerability. This includes psychobiological as well as psychodynamic treatments. The neurodynamic models are the only ones that formally (i.e., theoretically) incorporate biology and endorse it therapeutically. They also define psychodynamic treatment more liberally. Any and all forms of psychosocial intervention, from individual psychotherapy to social skills training, are potentially useful, depending on the modality's track record of efficacy with the specific clinical situation or condition. Conflict psychodynamic models, in keeping with their bias toward object relations and development in the family, emphasize the therapeutic centrality of the doctor-patient relationship. This relationship is facilitating, parental, soothing, mirroring, and protective, and the patient grows by internalizing the interactions that transpire within the dyad. The patient's actual interpersonal experience of the therapist is crucial: the therapist's reality and benignity serve as reality tests for the patient's transferentially distorted images. Deficit psychodynamic models, in keeping with their bias toward the patient as an individual with phenotypic abnormalities, emphasize the therapeutic centrality of cognitive perspective and control. The goal of treatment is to enhance the power of the ego by expanding its knowledge and control over the inner drives and psychopathological idiosyncracies. Enlightenment replaces unconscious defense with conscious choice. Therapy from this perspective focuses primarily upon developing the patient's cognitive systems through psychoeducation, training, and rehabilitation. The patient comes to realize that something is wrong, what that something is, and how it can be dealt with.

The conflict psychodynamicists once eschewed deficit theories as therapeutically nihilistic, insisting that there was no way to make up for a biological defect by psychological means. Such an assertion may be literally correct but operationally erroneous. For example, psychological manipulation cannot make paraplegics walk under their own power, but it can train them in prosthetic ambulation, and it can enhance their adaptation and quality of life. Whatever the origin of schizophrenia, its successful psychological treatment involves both the resolution of intrapsychic conflict through insight and the acquisition of psychic structure through affective relationships. If the core of schizophrenia is psychological, then treatment addresses the sick self; if the core is defect, then treatment addresses the healthy self. In the former, it minimizes weakness; in the latter, it maximizes strength. In most cases, it does both.

BIOPSYCHOSOCIAL MODEL One body of theory encompasses all of the foregoing twentieth-century trends—the biopsychosocial medical model of George Engel. According to this model, each individual patient consists of and participates in multiple systems that are related but also distinct from each other. Common systems are subatomic particles, atoms, molecules, organelles, cells, tissues, organs, organ systems, central nervous system, individual, dyad, family, community, culture and subculture, society and nation, and biosphere. In understanding health and disease, all systems are relevant. Each system of this model has a functional structure, one of its purposes being the reduction of complexity and randomness to protect that system's integrity. The functional structure of the psychological systems in this model consists of meanings that serve to order experience through understanding and explanation. Psychodynamic approaches to treatment should not ignore biology because the latter exists outside the realm of empathy and meaning. Biological approaches to treatment should not justify psychological retreat from patients because conflict cannot be teased apart by electrophoresis. Finally, treatment advocates of both approaches should be aware of patients' social, cultural, and political need for a place of dignity and safety within society. That is, patients also require adequate attention at the social level of the biopsychosocial system. Schizophrenia presents most dramatically at the psychological level as a loss or distortion of the self as a meaningful entity. Despite this, schizophrenia is not entirely or even essentially psychological in its nature. Accordingly, proper medical attention to this disorder should be aimed at any and all relevant systems in the biopsychosocial hierarchy. Whatever schizophrenia may be, it is profoundly disabling and usually chronic. Anything therapeutic that works with sufficient safety is relevant, whether it is biological, psychological, or sociological.

SUGGESTED CROSS-REFERENCES The relevance of brain structure and function in schizophrenia is discussed in Section 12.3; neurobiology is discussed in Section 12.4; and genetics in schizophrenia is discussed in Section 12.5. Somatic treatment is discussed in Section 12.8, psychosocial treatment in Section 12.9, and individual psychotherapy in Section 12.10. Theories of personality and psychopathology are discussed in Chapter 6. Schizophrenia in childhood is discussed in Chapter 38, and schizophrenia in late life is discussed in Section 51.3f. SECTION REFERENCES Burnham DL, Gladstone AI, Gibson RW: Schizophrenia and the Need-Fear Dilemma. International Universities Press, New York, 1969. Cohen JD, Servan-Schreiber D: Context, cortex and dopamine: A connectionist approach to behavior and biology in schizophrenia. Psychol Rev 99:45, 1992. Engel GA: The need for a new medical model: A challenge for biomedicine. Science 196:129, 1977. Federn P: Ego Psychology and the Psychoses. Basic Books, New York, 1952. Feinberg I: Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 4:319, 1982. Freud S: The interpretation of dreams. In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 5. Hogarth Press, London, 1953. Freud S: On the history of the psycho-analytic movement. In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 14. Hogarth Press, London, 1957. *Freud S: Psychoanalytic notes on an autobiographical account of a case of paranoid (dementia paranoides). In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 12. Hogarth Press, London, 1958. Friston KJ: Theoretical neurobiology and schizophrenia. Br Med Bull 52:644, 1996. Greenberg JR, Mitchell SA: Object Relations in Psychoanalytic Theory. Harvard University Press, Cambridge, MA 1983. Hebb DO: The Organization of Behavior. New York, Wiley, 1949. *Hinshelwood RD: The difficult patient. Br J Psychiatry 174:187, 1999. Hoffman RE: Computer simulations of neural information processing and the schizophrenia/mania dichotomy. Arch Gen Psychiatry 44:178, 1987. Hoffman RE: The mechanism of positive symptoms in schizophrenia. Behav Brain Sci 14:33, 1991. Hoffman RE, Dobscha SB: Cortical pruning and the development of schizophrenia: A computer model. Schizophr Bull 15:477, 1989. Hoffman RE, McGlashan TH: Alterations of speech, thought, perception, and self-experience. In Psychiatry, vol 1, A Tasman, J Kay, JA Lieberman, editors. Saunders, Philadelphia, 1997. Hoffman RE, McGlashan TH: Corticocortical connectivity, autonomous networks and schizophrenia. Schizophr Bull 20:257, 1994. *Hoffman RE, McGlashan TH: Parallel distributed processing and the emergence of schizophrenic symptoms. Schizophr Bull 19:119, 1993. Hoffman RE, McGlashan TH: Reduced corticocortical connectivity can induce speech perception pathology and hallucinated “voices.” Schizophr Res 30:137, 1998. Hoffman RE, McGlashan TH. Synaptic elimination, neurodevelopment, and the mechanism of hallucinated “voices” in schizophrenia. Am J Psychiatry 154:1683, 1997. Hoffman RE, Rapaport J, Rezuan A, McGlashan TH, Harcherik D, Servan-Schreiber D: The neural network simulation of hallucinated “voices” and associated speech perception impairment in schizophrenia patients. J Cogn Neurosci 7:479, 1995. Hopfield JJ: Neural networks and physical systems with emergent collective computational abilities. Proc Natl Acad Sci USA 79:2554, 1982. Jaspers K: General Psychopathology. Grune & Stratton, New York, 1959. Lichtenberg JD: Pao's theory: Origins and future directions. In Towards a Comprehensive Model for Schizophrenic Disorders, DB Feinsilver, editor. Analytic Press, Hillsdale, NJ, 1986. Lidz T: Schizophrenia and the Family. International Universities Press, New York, 1965. McCulloch WS, Pitts W: A logical calculus of the ideas imminent in nervous activity. Bull Math Biophys

5:115, 1943.

McGlashan TH: Early detection and intervention of schizophrenia: Rationale and research. Br J Psychiatry 172:3, 1998. McGlashan TH: The profiles of clinical deterioration in schizophrenia. J Psychiatr Res 32:133, 1998. McGlashan TH: Psychosocial treatments of schizophrenia: The potential of relationships. In Schizophrenia: From Mind to Molecule, N C Andreasen, editor. American Psychiatric Press, Washington, DC, 1994, p 189. McGlashan TH, Fenton WS: Subtype progression and pathophysiologic deterioration in the course of early manifest schizophrenia. Schizophr Bull 19:71, 1993.

*Meehl PE: Toward an integrated theory of schizotaxia, schizotypy, and schizophrenia. J Pers Disord 4:1, 1990. Mesulam MM: Large-scale neurocognitive networks and distributed processing for attention, language and memory. Ann Neurol 28:567, 1990. Pao P-N: Schizophrenic Disorders. International Universities Press, New York, 1979. Rado S: Psychoanalysis of Behavior. Grune & Stratton, New York, 1956. Rumelhart DE, McClelland JL: Parallel Distributed Processing: Explorations in the Microstructure of Cognition, vol 1. MIT Press, Cambridge, MA, 1986. Segal H: Introduction to the Work of Melanie Klein. Basic Books, New York, 1973. *Spring B, Zubin J: Vulnerability to schizophrenic episodes and their prevention in adults. In Primary Prevention in Psychopathology: The Issues, vol 1, GW Albee, JM Joffee, editors. University Press of New England, Hanover, NH, 1977. Stern D: The Interpersonal World of the Infant. Basic Books, New York, 1985. Sullivan HS: Clinical Studies in Psychiatry. Norton, New York, 1956. Tienari P, Sorry A, Lahti I, Narala M, Wahlberg K-E, Ronkko T, Pohjola J, Moring J: The Finnish adoptive family study of schizophrenia. Yale J Biol Med Waelder R: The principle of multiple function. Psychoanal Q 5:45, 1936. *Willick MS. Psychoanalytic concepts of the etiology of severe mental illness. J Am Psychoanal Assoc 38:1049, 1990. Wynne LC, Singer M: Thought disorder and family relations of schizophrenics: II. Classification of forms of thinking. Arch Gen Psychiatry 9:199, 1963.

Textbook of Psychiatry

58:227, 1985.

12.7 SCHIZOPHRENIA: CLINICAL FEATURES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.7 SCHIZOPHRENIA: CLINICAL FEATURES ROBERT CANCRO, M.D., MED.D.SC., AND HEINZ E. LEHMANN, M.D. History Comparative Nosology Diagnosis Subtypes Other Types and Related Syndromes Other Diagnostic Criteria Signs and Symptoms Differential Diagnosis Psychological Tests Course and Prognosis Prognosis Future Directions Suggested Cross-References

The major public health problem faced by psychiatry is the group of disorders that constitutes the diagnostic category of schizophrenia. These disorders affect approximately 1 percent of the population and most commonly have their onset in early adult life. More importantly, they usually leave the patient with varying degrees of cognitive, affective, and psychosocial impairment. This combination of impairments prevents most patients from achieving their full potential. In all known societies, adulthood is defined in terms of work and procreation. Individuals diagnosed with schizophrenia are frequently unable to perform the complex work tasks seen in the industrialized nations. The more severely impaired are not even able to perform the simpler work tasks associated with developing nations. Interpersonal relationships are frequently impaired enough to prevent courtship and subsequent marriage and procreation. The result is that people with these disorders are denied the social and personal benefits of adulthood to a considerable degree. No objective criteria exist for the diagnosis of schizophrenia. No characteristic morphological changes in the brains of patients with schizophrenia have been demonstrated; no specific laboratory findings signal its presence; no consistent premorbid history, course, or outcome can be ascertained; and no single cause is known. However, a group of symptoms and signs are basic to and characteristic of schizophrenia; certain drugs, many with a common neurophysiological property, can often eliminate those symptoms almost selectively, and there is enough consensus about its diagnosis, treatment, and prognosis among experienced clinicians to warrant the acceptance of the concept of schizophrenia as a syndrome.

HISTORY Emil Kraepelin Emil Kraepelin (Fig. 12.7-1) translated Benedict A. Morel's demence precoce to dementia precox, a term that emphasized the distinct cognitive process (dementia) and early onset (precox) of the disorder. Patients with dementia precox were described as having a long-term deteriorating course and the common clinical symptoms of hallucinations and delusions. Kraepelin distinguished these patients from those classified as having manic-bipolar psychosis who underwent distinct episodes of illness alternating with periods of normal functioning. The major symptoms of patients with paranoia were persistent persecutory delusions, and these patients were described as lacking the deteriorating course of dementia precox and the intermittent symptoms of manic-depressive psychosis. Although Kraepelin had acknowledged that about 4 percent of his patients recovered completely and 13 percent had significant remissions, later researchers sometimes mistakenly stated that he had considered dementia precox to have an inevitable deteriorating course.

FIGURE 12.7-1 Emil Kraepelin, 1856–1926. (Courtesy of National Library of Medicine, Bethesda, MD.)

Eugen Bleuler Eugen Bleuler (Fig. 12.7-2) coined the term schizophrenia, which replaced dementia precox in the literature. He chose the term to express the presence of schisms between thought, emotion, and behavior in patients with the disorder. Bleuler stressed that, unlike Kraepelin's concept of dementia precox, schizophrenia need not have a deteriorating course. Before the publication of the third edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-III), the incidence of schizophrenia increased in the United States (where psychiatrists followed Bleuler's principles) to perhaps as much as twice the incidence in Europe (where psychiatrists followed Kraepelin's principles). After publication of DSM-III, the diagnosis of schizophrenia in the United States moved toward Kraepelin's concept. Bleuler's term schizophrenia, however, has become the internationally accepted label for the disorder. This term is often misconstrued, especially by laypeople, to mean split personality. Split personality, now called dissociative identity disorder, is categorized in the fourth edition of DSM (DSM-IV) as a dissociative disorder and differs completely from schizophrenia.

FIGURE 12.7-2 Eugen Bleuler, 1857–1939. (Courtesy of National Library of Medicine, Bethesda, MD.)

The Four As Bleuler identified specific fundamental (or primary) symptoms of schizophrenia to develop his theory about the internal mental schisms of patients. These symptoms included associational disturbances (especially looseness), affective disturbances, autism, and ambivalence, summarized as the four As: associations, affect, autism and ambivalence. Bleuler also identified accessory (secondary) symptoms, which included those Kraepelin saw as major indicators of

dementia precox: hallucinations and delusions. Manfred Bleuler Manfred Bleuler, Eugene Bleuler's son, stressed the essential psychotic nature of the schizophrenic disorders. He recognized that patients might not be psychotic at any given moment but considered that the diagnosis of schizophrenia should only be made when psychosis had been present at some time in the history of the illness. He stated that patients whose primary characteristics were impaired memory or intellectual function were not schizophrenic. Schizophrenia in his conceptualization tended to be chronic and did not show a tendency toward rapid recovery. He felt that a major element of the illness was the coexistence of both psychotic and normal mental processes in the same person at the same time. He emphasized that the mechanisms he described in patients with schizophrenia could be found to some degree in normal people as well. In his conceptualization what was specific for the schizophrenic disorders was the patient's inability to distinguish between the inner and outer realities, as if an individual could not distinguish between dreams and waking experiences. This inability allowed the simultaneous presence of incompatible components to coexist within the patient's personality and consciousness. Bleuler's conceptualization of etiology was that the genetic component was not necessarily pathological but that the particular constellation of genes in these individuals left them more vulnerable to stress. Adolph Meyer Adolph Meyer emphasized the reactive nature of the schizophrenic disorders. He felt that the illness involved a biological predisposition of the individual and environmental stresses that interacted with it to produce the illness. In this Meyerian vision, neither the stress nor the diathesis alone sufficed to produce illness; vulnerable individuals had to face an adequate and appropriate stress at the right developmental phase of their life. Emphasizing the fortuitous element of life events in the etiopathogeneses of these illnesses led to a more optimistic view of the disorders and raised the possibility that eliminating certain stresses at certain developmental phases could markedly reduce the frequency of the illness. The reaction-pattern approach was carried to an extreme by some workers who believed that enough stress could produce a schizophrenic disorder in anyone. These workers unfortunately failed to recognize the importance placed by Meyer on the preexisting diathesis. Other Theorists Harry Stack Sullivan, Ernst Kretschmer, Gabriel Langfeldt, Kurt Schneider, and Karl Jaspers added much to the understanding of schizophrenia. Sullivan, who founded the interpersonal psychoanalytic school, emphasized social isolation as a cause and a symptom of schizophrenia. Kretschmer compiled data to support the idea that schizophrenia occurred more often among people with asthenic, athletic, or dysplastic body types rather than among people with pyknic body types; the latter, he thought, were more likely to incur bipolar disorders. These observations may seem strange, but they are not inconsistent with a superficial impression of body types in many homeless persons. Langfeldt classified patients with major psychotic symptoms into two groups, those with true schizophrenia and those with schizophrenic-like psychosis. In his description of true schizophrenia, Langfeldt stressed several factors: insidious onset, feelings of derealization and depersonalization, autism, and emotional blunting. Researchers after Langfeldt gave true schizophrenia other names: nuclear schizophrenia, process schizophrenia, and nonremitting schizophrenia. Schneider described a number of first-rank symptoms of schizophrenia. They are not identical to Eugene Bleuler's fundamental signs nor do they mean the same thing. The Schneider first-rank symptoms of schizophrenia are not pathognomonic for the disease but are of great pragmatic value in making a diagnosis. When a number of those symptoms are present in a patient in whom other pathology—of toxic or organic origin—can be excluded, then a diagnosis of schizophrenia is indicated. Schneider's first-rank symptoms include hearing one's own thoughts spoken aloud, auditory hallucinations that comment on the patient's behavior, somatic hallucinations, the experience of having one's thoughts controlled, spreading one's thoughts to others, delusions, and the experience of having one's actions controlled or influenced from the outside. Jaspers, a psychiatrist and philosopher, played a major role in developing existential psychoanalysis. In his view, psychopathology had no fixed concepts or basic principles. Thus his theories of schizophrenia were free of traditional concepts like subject and object, cause and effect, and reality and fantasy, and his philosophic attitude led to an interest in the content of psychiatric patients' delusions. The emphasis on attempting to understand the phenomenology of the schizophrenic experience can be traced to Jaspers.

COMPARATIVE NOSOLOGY DSM DSM-III and the revised third edition of DSM (DSM-III-R) were major efforts to increase reliability over the earlier versions. It was recognized that independent validation was not yet attainable and therefore the goal of reliability was seen to be of great importance. That emphasis was also reflected in the development of DSM-IV. DSM-IV requires the presence of at least two characteristic symptoms for a significant portion of time during a 1-month period (or less if the patient responded successfully to treatment). The list of characteristic symptoms includes delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms (e.g., anhedonia, mutism). One symptom suffices for a diagnosis if that one symptom consists of bizarre delusions, hallucinations of a voice sustaining a running commentary on the person's behavior or thoughts, or hallucinations of two or more voices conversing with each other. DSM-IV requires social and occupational deterioration. There must be a diminution in functional level in both social and occupational activities following the onset of illness. These functional disturbances must last for at least 6 months. That 6-month period may include the 1 month of symptoms necessary to fulfill the requirement of characteristic symptoms plus prodromal or residual symptoms or both. Finally, DSM-IV requires diagnostic exclusion of mood disorders with psychotic features and schizoaffective disorder. The disorder may not be a consequence of substance abuse or a general medical disorder. ICD The definition of schizophrenia in the tenth revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) parallels that in DSM-IV. The schizophrenic disorders are characterized in general by fundamental and characteristic distortions of thinking and perception, and affects that are inappropriate or blunted. Clear consciousness and intellectual capacity are usually maintained, although certain cognitive deficits may evolve in the course of time. The most important psychopathological phenomena include thought echo; thought insertion or withdrawal; thought broadcasting; delusional perception and delusions of control; influence or passivity; hallucinatory voices commenting on or discussing the patient in the third person; thought disorders and negative symptoms. The course of schizophrenic disorders can be either continuous or episodic with progressive or stable deficits, or there can be one or more episodes with complete or incomplete remission. The diagnosis of schizophrenia should not be made in the presence of extensive depressive or manic symptoms unless it is clear that schizophrenic symptoms antedate the affective disturbance. Nor should schizophrenia be diagnosed in the presence of overt brain disease or during states of drug intoxication or withdrawal.

DIAGNOSIS The DSM-IV diagnostic criteria include course specifiers that offer clinicians several options and describe actual clinical situations ( Table 12.7-1). The presence of hallucinations or delusions is not necessary for the diagnosis of schizophrenia; a patient's disorder is diagnosed as schizophrenia when the patient exhibits two of the symptoms listed as symptoms 3 through 5 in criterion A. Criterion B requires that impaired functioning, although not deteriorations, be present during the active phase of the illness. DSM-IV stipulates that symptoms must persist for at least 6 months and that a diagnosis of schizoaffective disorder or mood disorder must be absent. ICD-10 lists certain symptoms as the general criteria for all forms of schizophrenia with the exception of simple schizophrenia. At least one of the following must be present: (1) thought echo, thought insertion or withdrawal, or thought broadcasting; or (2) delusions of control, influence or passivity, clearly referred to body or limb movements or specific thoughts, actions or sensations, delusional perception; (3) hallucinatory voices giving a running commentary on the patient's behavior or discussing the patient between themselves, or other types of hallucinatory voices coming from some part of the body; and (4) persistent delusions of other kinds that are culturally inappropriate and completely impossible, (e.g., being able to control the weather or being in communication with aliens from another world).

Table 12.7-1 DSM-IV Diagnostic Criteria for Schizophrenia

The diagnosis can also be made if at least two of the following are present: (1) persistent hallucinations in any modality, when occurring every day for at least one month, when accompanied by delusions (which may be fleeting or half-formed) without clear affective content, or when accompanied by persistent overvalued ideas; (2) neologisms, breaks or interpolations in the train of thought resulting in incoherence or irrelevant speech; (3) catatonic behavior, such as excitement, posturing or waxy flexibility, negativism, mutism and stupor; and (4) negative symptoms, such as marked apathy, paucity of speech, and blunting and incongruity of emotional responses (it must be clear that these are not due to depression or to antipsychotic medication). The ICD-10 criteria, used throughout the world, are listed in Table 12.7-2.

Table 12.7-2 ICD-10 Diagnostic Criteria for Schizophrenia

Key Symptoms The presence of some key symptoms for schizophrenia (e.g., blunting of emotional response or a strikingly inappropriate emotional response) weighs heavily in favor of a diagnosis of schizophrenia. But what is emotional blunting, and what is an inappropriate emotional reaction? For example, is the embarrassed adolescent's sheepish or defying smile an inappropriate emotional reaction? Considerable clinical experience is required to be certain about the presence of such symptoms. Loosening of Associations The loosening of associations—the specific thought disorder of the schizophrenic—is perhaps one of the most valuable diagnostic criteria, but a good knowledge of psychopathology is required to be sure of its presence and to avoid confusing it with other forms of disturbed thinking, such as manic flight of ideas, disintegration of thought processes due to clouding of consciousness, and impaired reasoning due to fatigue or distraction. It is not sufficient to ask a patient the meaning of a proverb and then, on the basis of one's personal impression, declare that the patient has a pronounced schizophrenic thinking disturbance. It is sometimes impossible to distinguish, on the basis of a proverb test, between the disordered thinking of a schizophrenic and a manic patient, except for the greater verbosity of the manic. Bizarre Behavior The patient's behavior may furnish significant clues for the diagnosis of schizophrenia. Bizarre postures and grimacing are certainly characteristic of schizophrenic conditions, but identifying a bizarre posture is not always easy. Religious rituals and special positions for meditation or dancing with which the observer is not familiar may be called bizarre. But in a recent case of a withdrawn, suicidal young girl, a possible diagnosis of depression was ruled out in favor of schizophrenia when the girl began eating raw chicken, pouring hot tea over herself, and openly trying to get into bed with her brother-in-law during a weekend home visit. True catalepsy may be almost pathognomonic of schizophrenia, but it is not a common symptom. A stupor strongly suggests catatonic schizophrenia, but hysteria or a depressive stupor must be carefully ruled out in the differential diagnosis. The deterioration of social habits, even involving the smearing of feces, does not suffice for the diagnosis of schizophrenia. Such deterioration can occur in various toxic and organic psychoses, temporarily in hysterical twilight states, and even at the peak of a manic episode in bipolar I disorder. Pronounced social withdrawal also occurs under many conditions, ranging from simple sulking to anxiety and depression ( Fig. 12.7-3). Sustained passivity and lack of spontaneity should suggest the diagnosis of schizophrenia only if organic and depressive conditions can be definitely ruled out.

FIGURE 12.7-3 “Schizophrenic Withdrawal.” (Courtesy of Sid Bernstein, Research Facility, Orangeburg, NY.)

Stereotypes and verbigeration strongly suggest schizophrenia, but they occur almost exclusively in chronic, institutionalized patients and are rarely seen today. Frequent and lengthy staring into a mirror and other odd mannerisms also strongly suggest a diagnosis of schizophrenia.

SUBTYPES

DSM-IV classifies the subtypes of schizophrenia as paranoid, disorganized, catatonic, and undifferentied, and residual, predominantly on the basis of clinical presentation (Table 12.7-3). These subtypes are not closely correlated with different prognoses; for such differentiation, specific predictors of prognosis are best consulted. ICD-10, by contrast, uses nine subtypes: paranoid schizophrenia, hebephrenia, catatonic schizophrenia, undifferentiated schizophrenia, simple schizophrenia, other schizophrenia, residual schizophrenia, post schizophrenic depression and schizophrenia, unspecified, with eight possibilities for classifying the course of the disorder, ranging from continuous to complete remission.

Table 12.7-3 DSM-IV Diagnostic Criteria for Schizophrenia Subtypes

Catatonic Type The catatonic type of schizophrenia is dominated by prominent psychomotor disturbances. In addition to meeting the general criteria for schizophrenia, there must be a period of least 2 weeks of catatonic behavior that can be either stuporous or excited. The behavioral disturbance can also involve posturing, negativism, rigidity, waxy flexibility, or command automatism. Catatonic schizophrenia occurs in two forms: inhibited or stuporous catatonia and excited catatonia. The essential feature of both forms is the marked abnormality of motor behavior. Stuporous Catatonia Patients with stuporous catatonia may be in a state of complete stupor or may show a pronounced decrease in spontaneous movements and activity. They may be mute or nearly so or may show distinct negativism, stereotypes, echopraxia, or automatic obedience. However, even after standing or sitting motionless for long periods of time, they may suddenly and without provocation have a brief outburst of destructive, unprovoked violence. Occasionally, patients with catatonic schizophrenia exhibit catalepsy or waxy flexibility ( Fig. 12.7-4).

FIGURE 12.7-4 Chronic catatonic patient. This patient is immobile, demonstrating waxy flexibility. Her arm is in an uncomfortable position, elevated without support, and her stony facial expression has a Schnauzkrampf, or frozen pout. (Courtesy of Heinz E. Lehmann.)

Patients in a state of complete catatonic stupor usually can be aroused from it dramatically by intravenous injection of a short-acting barbiturate. Within minutes the frozen facial expression changes to one of normal animation. They begin to talk and move about normally and in many instances become relatively lucid for an hour or two. The total inhibition of patients in catatonic stupor may result from excessive cerebral excitatory processes. As in a car engine racing so wildly that one cannot put it in gear, that excess prevents the person from performing and behaving in a normal manner until the excessive cerebral functions have been reduced by a chemical agent that depresses brain metabolism and nervous impulses. But, spectacular as the immediate results seem to be, the technique has no significant therapeutic value. A young, unmarried woman, age 20, was admitted to a psychiatric hospital because she had become violent toward her parents, had been observed gazing into space with a rapt expression, and had been talking to invisible persons. She had been seen to strike odd postures. Her speech had become incoherent. She had been a good student in high school, then went to business school and, a year before admission to the hospital started to work in an office as a stenographer. She had always been shy, and although she was quite attractive, she had not been dating much. Another girl, who worked in the same office, told the patient about boys and petting and began to exert a great deal of influence over her. The second girl would communicate with her from across the room. Even when they went home at night, the patient would get voice messages telling her to do certain things. Then pictures began to appear on the wall, most of them ugly and sneering. Those pictures had names—one was named shyness, another distress, another envy. Her office friend sent her messages to knock on the wall, to hit the pictures. The patient was agitated, noisy, and uncooperative in the hospital for several weeks after she arrived, and required sedation. She was given a course of insulin coma therapy, with no significant or sustained improvement. Later she received several courses of electroconvulsive treatment, which also failed to influence the schizophrenic process to any significant degree. Ten years later, when antipsychotic drugs became available, she received pharmacotherapy. Despite all those therapeutic efforts, her condition throughout her many years of stay in a mental hospital has remained one of chronic catatonic stupor. She is mute and practically devoid of any spontaneity, but she responds to simple requests. She stays in the same position for hours or sits curled-up in a chair. Her facial expression is fixed and stony. Excited Catatonia Patients with excited catatonia are in a state of extreme psychomotor agitation. They talk and shout almost continuously. Their verbal productions are often incoherent, and their behavior seems to be influenced more by inner stimuli than by their environment. Patients in catatonic excitement urgently require physical and medical control, since they are often destructive and violent to others, and their dangerous excitement can cause them to injure themselves or collapse from complete exhaustion.

An unmarried man, aged 27, had been working as a teacher and was admitted to a psychiatric hospital because he had become increasingly agitated and irrational after several nights of wakefulness. He was extremely talkative and ran about aimlessly. His behavior became very strange; for instance, he tried to clean everything in the house, moved his wristwatch up to his shoulder, stripped his clothes off, chewed large wads of paper in the belief that it was good for him, talked about killing himself, and then said that he might already be dead. He heard voices ordering him about incessantly, and he frequently laughed without any apparent cause. After chewing the paper he would spit in it and then drink his saliva. He rolled into odd postures on the bed, with his tongue sticking out. He started to jump and dance when taken to the bathroom by a nursing assistant for a shower and destroyed the bathroom furnishings. His gait was manneristic. His speech was utterly incomprehensible. He refused to take any medication and had to be sedated by parenteral medication. He remained noisy, excited, destructive, and irrational in his behavior for a month; then he improved in response to high dosages of antipsychotic medication and a few electroconvulsive treatments. Three months after admission he was discharged from the hospital, symptom free, with good insight into the nature of his illness. For more than 10 years he has been employed as a teacher. Periodic Catatonia A rare but intriguing form of catatonia, periodic catatonia, was described by R. Gjessing in 1938. According to Gjessing, patients affected with the disorder have periodic recurrences of stuporous or excited catatonic states. Each recurrence of catatonic behavior is associated with an extreme shift in the patient's metabolic nitrogen balance. Most cases of periodic catatonia seen in recent years responded well to antipsychotic medication, and relapses were usually prevented by maintenance medication. Disorganized Type The disorganized (formerly called hebephrenic) subtype is characterized by a marked regression to primitive, disinhibited, and unorganized behavior. Hebephrenic patients are usually active but in an aimless, nonconstructive manner. Their thought disorder is pronounced, and contact with reality is extremely poor. Personal appearance and social behavior are dilapidated, emotional responses are inappropriate, and they often burst out laughing for no apparent reason. Incongruous grinning and grimacing are common in these patients, whose behavior is best described as silly or fatuous ( Fig. 12.7-5).

FIGURE 12.7-5 A 44-year-old chronic schizophrenic woman showing characteristic mannerism and facial grimacing. (Courtesy of New York Academy of Medicine.)

A 15-year-old girl attended a summer camp where she had difficulties in getting along with the other children and developed animosity toward one of the counselors. On her return home, she refused to listen to her parents, and she heard the voice of a man talking to her, although she could not see him. She rapidly began to show bizarre behavior, characterized by grimacing, violent outbursts, and inability to take care of herself. Her school record had always been good, and she was fluent in three languages. Her parents described her as having been a quiet, rather shut-in child, with no abnormal traits in childhood. Family relations were reported as having been satisfactory. When the patient was admitted to a psychiatric hospital, her speech was incoherent. She showed marked disturbances of formal thinking and blocking of thoughts. She was impulsive and seemed to be hallucinating. She stated that she heard voices in her right ear and that a popular singer was running after her with a knife. She also thought that her father was intent on killing her and that she was pregnant because she had hugged one of the residents. Two months of neuroleptic treatment brought no apparent improvement. She was then given a course of intensive electroconvulsive therapy and continuous sleep treatment. Over a period of a year, she received close to 200 electroconvulsive treatments and 50 subcoma insulin treatments, with little improvement. She was then transferred to another mental hospital, where her behavior has remained very disturbed for almost 20 years. She is often incontinent and most of the time neglects her physical appearance. Occasionally she spends hours dressing herself, looking in the mirror, and putting on excessive makeup. At times, she has been discovered eating her feces. Occasionally, she adopts the role of a singer or a dancer. She makes statements like “Will I live forever? Nurse, I didn't throw my love away. It is in my stomach, and it hurts.” In the dining room she attempts to grasp the genitals of male patients. High doses of neuroleptics are continuously required to control her behavior. The ultimate prognosis is very poor. Paranoid Type The paranoid type of schizophrenia is characterized mainly by the presence of delusions of persecution or grandeur. Patients with paranoid schizophrenia are usually older than patients with catatonia or hebephrenia when they break down (i.e., they are usually in their late 20s or their 30s). Patients who have been well up to that age have usually established a place and an identity for themselves in the community. Their ego resources are greater than those of catatonic and hebephrenic patients. Paranoid schizophrenics show less regression of mental faculties, emotional response, and behavior than those with the other subtypes of schizophrenia. Typical patients with paranoid schizophrenia are tense, suspicious, guarded, and reserved. They are often hostile and aggressive. They usually conduct themselves quite well socially, and their intelligence in areas not invaded by delusions may remain high. Paul Murphy, an American chess champion in the first half of the nineteenth century and one of the greatest chess masters in history, developed paranoid schizophrenia in his middle 20s and was hospitalized for years. But even many years after he had become ill, he played an original and masterful game of chess if he could be persuaded to accept the challenge. A woman wrote the letter that is reproduced in part below. Like many patients with schizophrenia, this patient is tortured by the experience of being influenced in her bodily functions through fiendish devices used by her enemies.

Dear Dr. P.T., It is with the nurse's knowledge that I write this letter to you, regretting at the same to trouble you about a maladjustment that need not occur. I am at a loss to understand why those who are responsible are permitted to indulge in this peculiar pastime. Perhaps those with some authority do not desire to check it, but I realize, in any case, that it is rather difficult to do so inasmuch as when one person is checked, she passes the job on to someone else—I refer to this instrument that they use that completely locks up the intestines and prevents them from elimination at all even with a laxative, which is useless to take in such circumstances. It also twists me between my legs occasioning much discomfort, preventing proper rest in bed when my body is so tightened up that it is impossible to relax. I spoke to you several days ago about unexplainable solutions being injected into my body and my rest disturbed continually during the night. You agreed that if any treatments were ordered they should not take place at these hours. I think you said you would find out about any such requirement or order. Well, the hour of interference has changed—interference is the right word to use, because the one whoever is responsible is doing a great deal of harm. I am awakened every morning to the exact minute about 5:30. About 6:00 I drop off again until 7 AM (breakfast not until 8 AM). During this interval some person interferes with both passages of my body, and I find myself going around the rest of the day like a tank—full of burning Salt Water but quite unable to eliminate. At 5:30 I am quite comfortable but if I rose at this time, I suppose something would take place in the washroom—as these things so often do. The bladder is also interfered with, as is indeed every organ in my body with which I have never had any previous trouble. This has taken place nearly every day this week. If they do not get a chance just before I retire, some person in my room, by arrangement I suppose, awaits for me to get out of bed and as soon as I turn my back to them quickly uses this instrument, so as to insure this locked-up condition of the abdominal region. Because of so much interference, it is sometimes necessary for me to encourage the bladder to completely empty by means of the application of heat in the form of towels rung out in hot water and this is only effective in a standing up position—there is obviously some solution injected and as soon as I have withdrawn it in this manner I am very comfortable, but am not allowed to remain that way long. Something has also taken place this week which has been done once before on this ward and once in West House where it was frowned upon after discovery. I have been fixed up—temporarily, I hope, if the above results are going to continue—with two separate outlets for urination, which almost appears to come through two holes in the pelvic bone. All these months, as the previous nurses know, I have had to endure endless damage by interference with the pelvic. Perhaps they have got tired of that at last—and now it has to be something else, and when they get tired of that what next? . . .. There are other means of displacing the intestines, not only by instruments in the hands of other inmates, but by other mechanical tricks probably operated by the same people. Undifferentiated Type Frequently, patients who clearly have schizophrenia do not fit easily into one of the other types. DSM-IV classifies those patients as having undifferentiated type. Residual Type According to DSM-IV, the residual type of schizophrenia is characterized by the presence of continuing evidence of the schizophrenic disturbances in the absence of a complete set of active symptoms or of sufficient symptoms to meet the diagnosis of another type of schizophrenia. Emotional blunting, social withdrawal, eccentric behavior, illogical thinking, and mild loosening of associations commonly appear in the residual type. When delusions or hallucinations occur, they are neither prominent nor accompanied by strong affect.

OTHER TYPES AND RELATED SYNDROMES Simple Deteriorative Disorder Simple deteriorative disorder (simple schizophrenia) is characterized by a gradual, insidious loss of drive, interest, ambition, and initiative ( Table 12.7-4). Hallucinations and delusions are uncommon, and if those symptoms do occur, they do not persist. Patients with simple deteriorative disorder withdraw from contact with other people, tend to stay in their rooms, avoid meeting or eating with other members of the family, stop working, and stop seeing friends. If they are still in school, their marks drop to a low level, even if they were consistently high in the past.

Table 12.7-4 DSM-IV Research Criteria for Simple Deteriorative Disorder (Simple Schizophrenia)

These patients avoid going out into the street during the day but may go for long walks alone at 2:00 or 3:00 AM. They tend to sleep until noon or later, after staying up alone most of the night. During the early stages of the illness they may have many somatic complaints, variously described as fatigue, nervousness, neurosis, psychosomatic disease, and laziness. Patients are often treated for a year or more before the correct diagnosis is made. In many cases patients with simple deteriorative disorder later become homeless. They become increasingly shallow in their emotional responses and are quite content to drift aimlessly through life as long as they are left alone. Although patients appear to be indifferent to their environment, they may react with sudden rage to persistent nagging by family members. The immediate reason for admission of patients with simple schizophrenia to a hospital is often an outburst of violence directed against their mothers or fathers for a trivial reason. An unmarried man, 27 years old, was brought to a mental hospital because he had on several occasions become violent toward his father. For a few weeks he had hallucinations and heard voices. The voices eventually ceased, but he then adopted a strange way of life. He would sit up all night, sleep all day, and become very angry when his father tried to get him out of bed. He did not shave or wash for weeks, smoked continuously, ate very irregularly, and drank enormous quantities of tea. In the hospital he adjusted rapidly to the new environment and was generally cooperative. He showed no marked abnormalities of mental state or behavior, except for his lack of concern about most things. He kept to himself as much as possible and conversed little with patients and staff. His personal hygiene had to be supervised by the nursing staff; otherwise he would quickly become dirty and very untidy. Twenty years after his admission to the hospital, he is described as shiftless, and careless, sullen, and unreasonable. He lies on a couch all day. Antipsychotic drug treatment has failed to alter his mental state or behavior. Although many efforts have been made to get him to accept therapeutic work assignments, he refuses to consider any kind of regular occupation. In the summer he wanders about the hospital grounds or lies under a tree. In the winter he wanders through the tunnels connecting the various hospital buildings and is often seen stretched out for hours under the warm pipes that carry steam through the tunnels. Patients with simple deteriorative disorder may resemble personalities of the schizoid type. The distinguishing feature is the disorder makes its appearance at some time during or after puberty and from then on goes on to definite deterioration; personality deviations usually start earlier and remain the same over the years. To meet the ICD-10 diagnostic criteria for simple schizophrenia, the individual must show over a period of at least 1 year all of the following manifestations: (1) a significant and consistent change in the overall quality of some aspect of personal behavior such as loss of drive and interest; (2) gradual appearance and deepening of negative symptoms such as marked apathy; and (3) a marked decline in social, scholastic, or occupational performance. Postpsychotic Depressive Disorder of Schizophrenia The clinical boundaries of the diagnosis are hard to define operationally. The symptoms of postpsychotic depressive disorder of schizophrenia can closely resemble the symptoms of the residual phase of schizophrenia as well as the side effects of commonly used

antipsychotic medications. Distinguishing the diagnosis from schizoaffective disorder, depressive type, is also difficult. The DSM-IV criteria (see Table 14.6-25) specify that the criteria for a major depressive episode be met and that the symptoms occur only during the residual phase of schizophrenia. The symptoms cannot be substance induced or part of a mood disorder due to a general medical condition. ICD-10 describes a category called postschizophrenic depression. This is a depressive episode that may be prolonged, arising in the aftermath of a schizophrenic illness. The general criteria for schizophrenia must be met, and the depressive symptoms must be sufficiently prolonged or severe to meet the criteria for at least a mild depressive episode. These depressive states are associated with an increased risk of suicide. Early-Onset Schizophrenia Most patients suffering from schizophrenia develop it in late adolescence and early adulthood. A small minority of patients manifest a similar syndrome in childhood. Such children may at first present diagnostic problems, particularly with differentiation from mental retardation and autistic disorder. Recent studies have established that the diagnosis of childhood schizophrenia may be based on the same symptoms used for adult schizophrenia. What characterizes childhood schizophrenia is not the nature but the dramatic intensity of its symptoms. Its onset is usually insidious, its course tends to be chronic, and the prognosis is mostly unfavorable. Briefly, it resembles the typical Kraepelinian case of dementia precox. What gives childhood schizophrenia unique importance for research is the observation that anatomical features of the brain that are often associated with adult-onset schizophrenia (e.g., enlarged ventricles) are also present in this early-onset form of the disease. Neurobiological studies of children with schizophrenia may therefore provide significant clues to the developmental pathogenesis of adult-onset schizophrenia. Late-Onset Schizophrenia Late-onset schizophrenia is usually defined as an illness that is clinically indistinguishable from schizophrenia but has an onset after age 45. Since DSM-IV no longer uses an age cutoff, this distinction may no longer be relevant. This condition tends to appear more frequently in women and also tends to be characterized by a predominance of paranoid symptoms. The prognosis is favorable, and these patients usually do well on antipsychotic medication. Bouffée Délirante (Acute Delusional Psychosis) Since it has been recognized that tardive dyskinesia may develop as a serious complication in a significant minority of patients with schizophrenia on maintenance therapy with antipsychotic drugs, it has become even more important to make a correct initial diagnosis. In French psychiatry the condition known as acute delusional psychosis, or bouffée délirante, is not included in the diagnosis of schizophrenia. Rather, bouffée délirante is considered a disease entity in its own right, a psychiatric disorder that does not require maintenance pharmacotherapy. The following are essential criteria for the diagnosis of bouffée délirante, not all of which need to be present: (1) frequent background of personality disorder; (2) absence of a schizoid premorbid personality; (3) sudden onset; (4) duration of less than 3 months; (5) spontaneous return to premorbid level of adjustment, even without specific antipsychotic treatment; (6) polymorphous symptoms, a disorderly (kaleidoscopic) succession of differing delusional contents; (7) a fascinating intensity of the delusional experience; (8) oscillations between insight and delusion; (9) mood alterations and fluctuations; (10) increase in delusions in sleep-related states; and (11) sudden termination after days or weeks (rarely months). Accordingly, bouffée délirante episodes belong to the schizophrenic spectrum disorders. In American clinical practice those episodes are usually diagnosed as schizophreniform disorder (see Table 13.1-3, schizoaffective disorder (see Table 13.1-1), or brief reactive psychosis (see Table 13.1-4). French psychiatrists report that about 40 percent of patients with the diagnosis bouffée délirante are later reclassified as suffering from schizophrenia. Schizoaffective Disorder Schizoaffective disorder appears to lie conceptually between schizophrenia and the mood disorders. This category is quite ambiguous because it is the middle ground between two almost arbitrary groupings of patients. DSM-IV requires concurrent symptoms that meet the major criteria for schizophrenia and for a major depressive episode or manic episode or mixed episode. There must be a period of illness of at least 2 weeks, with characteristic delusions and hallucinations and the absence of prominent mood symptoms. Patients who carry this label tend to have a better prognosis. Oneiroid In the oneiroid state patients feel and behave as though they were in a dream. ( Oneiros is the Greek word for dream). Patients may be deeply perplexed and not fully oriented in time and place. During the state of clouded consciousness, they may experience feelings of ecstasy and rapidly shifting hallucinated scenes. Illusionary distortions of their perceptional processes (including time perception) and the symptomatic picture may resemble those of a hysterical twilight state. During oneiroid reactions, the observer can most clearly detect the patient's peculiar “double bookkeeping”—patients may be convinced that they are traveling through space on a satellite and at the same time conscientiously follow the regular hospital routine. The patient with oneiroid schizophrenia acknowledges everyday realities but gives priority to contingencies of reality ( Fig. 12.7-6). Oneiroid states are usually limited in duration and occur most frequently in acute schizophrenic episodes.

FIGURE 12.7-6 A 25-year-old schizophrenic man produced this eerie-looking mixture of commercial poster and existential quandary about time. (Courtesy of Heinz E. Lehmann.)

OTHER DIAGNOSTIC CRITERIA A variety of research clinicians, some of whom were mentioned above (e.g., Langfeldt, Schneider, and Jaspers), constructed their own criteria to discriminate for essential features of schizophrenia. However, a number of other diagnostic systems for schizophrenia have been developed ( Table 12.7-5).

Table 12.7-5 Essential Features of Various Diagnostic Criteria for Schizophrenia

SIGNS AND SYMPTOMS General Appearance and Behavior While no specific behaviors or appearances are unique to schizophrenia, experienced clinicians still speak of the precox feeling

(i.e., a failure to emotionally contact with the patient). Schizophrenia patients often give a history of being more sensitive than the average person. This sensitivity involves not only increased responsiveness to sensory stimuli but also increased sensitivity to emotional stimuli and, in particular, critical experiences. Experimental evidence indicates that some individuals who later develop schizophrenia do not screen out stimuli as effectively as normal people, which allows excessive input of stimuli to the nervous system. The failure of selective inhibition can play an important role in symptom production. Patients with chronic schizophrenia tend to show a neglected personal appearance. Their efforts at grooming tend to be minimal. They show poor regard for the social amenities and act as if they are deliberately turning away from society. As a group, schizophrenia patients are characterized by social withdrawal. They may form emotional attachments with other people, but they cannot communicate the quality and strength of those attachments in a manner that is understandable to other people. Unfortunately, this tends to create a lack of empathy or sympathy toward the patient, which further isolates the patient from family and health care providers. A common feature in schizophrenia is the loss of ego boundaries. These patients have difficulty determining where they end and where the outside world begins. This leaves them vulnerable to misinterpretation of external events that can be interpreted as affecting them directly. Many patients show what appears to be an amotivational syndrome. The patient may show a lack of interest in the normal activities of daily living. Nevertheless, a loss of motivation should not be confused with the sudden or gradual intellectual dysfunction that can occur in this disorder. This intellectual dysfunction can lead to failure in school of a young person of good intelligence, which can be misinterpreted as not trying hard enough. This failure may be the earliest diagnostic sign of a developing schizophrenia. Speech Disorders What has been historically referred to as thought disorder is more correctly identified as a speech disorder. It is assumed that the disorders of language reflect an underlying disorder of thinking. A variety of features have been reported by clinicians for the last 100 years as characteristic of this syndrome. These include the loss of the logical relations between antecedent and subsequent associations that is termed loosening of associations. Words can be combined on the basis of sound rather than on meaning called clang association. New words may be generated, which are called neologisms (Fig. 12.7-7). Verbigeration involves the use of words in a stereotypically repetitive fashion. Echolalia involves the repetition of the examiner's words. Thought blocking involves the sudden and inexplicable blocking of thoughts manifested by the patient's inability to speak.

FIGURE 12.7-7 A schizophrenic woman expresses her incoherent thinking combined with neologisms in this drawing. (Courtesy of Heinz E. Lehmann.)

Loosening of associations is based on the late nineteenth-century association theory. According to association theory, language is determined by purpose. This purposefulness is often lost in schizophrenic speech. A sentence completion test illustrates the point. The sentence to be completed was “The man fell on the street . . ..” The patient's response was “because of World War I.” Although the thought of falling might be associated with falling in combat, it was an inappropriate association for the stimulus. It can be helpful to look at disorders of association as disorders of the word and disorders of the sentence. Disorders of the word range from loss of symbolic meaning of the word as in clang associations to inability to maintain the correct semantic context for a word to approximate use of words, to the creation of new words. Disorders of the sentence include associative failures and failures of system placement. Most words have multiple meanings. Even a simple question such as “Where is your husband?” must be answered in terms of the frame of reference. In one context the question might ask for the physical location of the husband, and in another context it might ask for his identification in his graduating class picture. An example of system shifting was reported by Silvano Arieti. Commenting on the Japanese attack on Pearl Harbor, a patient said, “The next time they may attack Diamond Harbor or Emerald Harbor.” The patient had lost the contextual system of Pearl Harbor as a geographical military base and had substituted a contextual system in which pearls are precious stones. Incoherence Language appears to be a means of self-expression in schizophrenia rather than a means of communication. Verbal productions are often empty or obscure. Schizophrenic speech contains more words that do not belong than does normal speech. In speech samples, patients with schizophrenia tend to repeat the same words more frequently than do nonschizophrenic people. When normal individuals are asked to fill in the deleted word in a continuous passage they are more likely to be correct when judging normal speech than when judging schizophrenic speech. The following proclamation was written by a woman with schizophrenia. The repetitive phrases, distorted syntax, and numerous non sequiturs render the text sometimes incoherent. Nevertheless, the paranoid grandiosity, the hostility of the writer, and the content of her delusions are clearly expressed. The French Force orders from now on to the German Force to respect the Queen Sacre in Christianity as well as the Queen in France and in other countries, ill treated and destroyed in all countries since the beginning of this century in Europe and allied countries. The Queens are the copartners in masonry of the order of Grand Masters and by doing so the prosperity and balance of the world have been destroyed, they have been destroyed for homosexuality which is the emblem or grand mastery really instead of being distinguished from the criminals who kill the soul and commit the crime of homosexuality of destroying the emblem of grand mastery. The attack on the Queen Sacre in Masonry comes from an inversion of data in the German spying service in 1903 in the class of sorcerers of this organization, deciding that the Chateau de Chambord en France was going to be the Castle not of the saint to be, but of sorceress and killing in soul that child many times without the effect desired obtained. The following is an example of what may be called concise abstruseness, which sometimes characterizes the communications of patients with schizophrenia and is often used to express undisguished sexual preoccupation. This patient's short apologetic note is to a psychiatrist whom she had bluntly propositioned on frequent occasions. (In this instance she got revenge against him for his rejection by pulling up expensive flowers in his garden.) She had previously inserted a screwdriver into her vagina and later expressed continuing guilt for having done so. The note expresses her sexually laden message briefly and (in her way) to the point. But the letter can be deciphered only with difficulty by the nonschizophrenic person who has not learned to understand the patient's autistic language. Dear doctor, I wasn't thinking too well when I was speaking to you but I do believe you were the postman whom I spent the night with. It is still Dr. David . . . in my heart. Am sick because of the screw driver. Please no hard feelings. Kiss your penis did. I would not harm you . . .. The following brief transcript from a videotaped interview with a young man with schizophrenia illustrates his autistic preoccupation with sex and death; there seems to be some clang association between “feet” and “foetus.” The patient was puzzled that his interviewer had difficulties following him. the fleur de Lys is a castrated ace—you see, the design is the feet—the same as a woman's foetus—now you take five French safes and you put them together between four coffins—that's what it represents Neologisms Occasionally, patients with schizophrenia create a completely new expression, a neologism, when they need to express a concept for which no ordinary

word exists. A woman with schizophrenia who had been hospitalized for several years kept repeating (in an otherwise quite rational conversation) the word “polamolalittersjitterstittersleelitla.” Her psychiatrist asked her to spell it out, and she proceeded to explain the meaning of the various components, which she insisted were to be used as one word. “Polamolalitters” was intended to recall the disease poliomyelitis, because the patient wanted to indicate that she felt she was suffering from a serious disease affecting her nervous system; the component “litters” stood for untidiness or messiness, the way she felt inside; “jitterstitters” reflected her inner nervousness and lack of ease; “leelita” was a reference to the French le lit la (that bed there), meaning that she both depended on and felt handicapped by her illness. That single neologistic production thus enabled the patient to express—in a condensed, autistic manner—information about her preoccupations and apprehensions that otherwise would have taken a whole paragraph to explain in common language. Mutism Functional inhibition of speech and vocalization may last for hours or days, but before the use of modern treatment methods, it often used to last for years in patients with catatonic schizophrenia. Many of these patients tend to be monosyllabic and answer questions as briefly as possible. They attempt to restrict contact with the interviewer as much as possible without being altogether uncooperative. Echolalia Occasionally, patients with schizophrenia exhibit echolalia, repeating in their answers to the interviewer's questions many of the same words the questioner has used. Examiner: How did you sleep last night? Patient: I slept well last night. Examiner: Can you tell me the name of your head nurse?" The name of my head nurse is Miss Brown. Echolalia seems to signal two facts, patients are aware of some shortcomings in their ideation and they are striving to maintain active rapport with the interviewer. They act much like someone learning a new language who answers the teacher's questions with as many of the teacher's words in the strange language as they can possibly manage. Verbigeration This rare symptom is found almost exclusively in chronic and very regressed patients with schizophrenia. It consists of the senseless repetition of the same words or phrases, and it may go on for days (Fig. 12.7-8). Like neologisms and echolalia, verbigeration is a rare symptom today and is almost restricted to long-term institutionalized schizophrenia patients. Many psychiatrists working with schizophrenia patients in the community may never encounter these manifestations of deterioration.

FIGURE 12.7-8 Sample of a chronic schizophrenic's noncommunicative writing. This addressed envelope illustrates manneristic writing, verbigeration, and possibly neologisms. Although the script appears to be exotic, the Arabic numerals and the English street name are recognizable. (Courtesy of Heinz E. Lehmann.)

Stilted Language Some patients with schizophrenia make extraordinary efforts to maintain their social relations, to maintain their relatively stable adjustment. But they may betray their rigidity and artificiality in their interpersonal relations by a peculiarly stilted and grotesquely quaint language. The following excerpt from a letter written by a physician with schizophrenia who was hospitalized for more than 15 years but is now living by himself in an apartment is an example of such stilted language. My dear friend and Professor, A hearty and cheerful. (Please turn the page over) and a magnanimous good morning to you on this first Wednesday of a glorious New Year: And I do hope that our great and our good Lord and our dearly beloved and kind Shepherd, (kindly read page three now). Will be gracious unto both me and thee. I am sure that He be gracious unto both of us; He has some sound common sense. His being, this morning . . . I have not yet heard (Kindly turn over to 4 now) from any one of my own colleagues when I am leaving noble institution of the healing arts; Nor with whom: Nor through which one of the portals. Though I am sure that you—as much as (Kindly turn to page five, now) one else . . . must be able to enlighten me; very soon, my good old friend . . . Behavioral Disorders Many patients with schizophrenia show a quantitative change in their activity, most commonly manifested as a reduction in energy, spontaneity, and initiative. In acute stages patients may become excited and show increased activity but usually only in the early phases of the illness. In a qualitative sense their behavior is often poorly coordinated, unpredictable, eccentric, and inappropriate. Even before the development of antipsychotic drugs patients conveyed an awkwardness and stiffness of movement. The great dancer Nijinsky lost his natural gracefulness with the onset of his schizophrenia. Mannerisms Many patients with schizophrenia exhibit mannerisms of speech and movement. Grimacing is noticeable to varying degrees and at times may appear almost as a tic, particularly in the perioral regions. These perioral movements were reported and described by Kraepelin long before the use of neuroleptic drugs. He considered it a pathognomonic sign for poor prognosis in schizophrenia. Stuporous States Stuporous states used to be common in the catatonic subtype of schizophrenia. Today they are quite rare and respond quite quickly to modern treatment when they are found. Similarly, catalepsy or waxy flexibility is almost unknown today, whereas 40 years ago it was common. It consists of a waxlike yielding of the movable parts of the body to any effort made to place them in certain positions. Once placed in the position, the patient remains in that position for a long time—even if the position is physically uncomfortable ( Fig. 12.7-9). While these extreme examples of stupor and waxy flexibility have essentially disappeared, many chronic patients show a lack of spontaneity and movement that bears an attenuated resemblance to the more severe conditions described above.

FIGURE 12.7-9 A patient exhibiting catatonic posturing. (Reprinted with permission from Davison GC, Neale JM: Abnormal Psychology: An Experimental Clinical Approach. Wiley, New York, 1974.)

Echopraxia The motor symptom echopraxia is analogous to echolalia in the verbal sphere. It is the imitation of movements and gestures of the person the patient is observing. Negativism Negativism refers to a patient's unwillingness to cooperate without any apparent reason for that lack of cooperation. It does not appear to be related to fatigue, depression, suspicion, or anger. Negativism may even take the form of unwillingness to follow a request for a physical movement. It can become so severe that the patient will do the opposite of what is asked. For example, when asked to raise an arm, they may lower it. Stereotyped Behavior Stereotyped behavior is primarily seen in patients with chronic schizophrenia, including those in the community. At times it may take a motoric form and be expressed in a repetitive pattern of walking or pacing. It may also be demonstrated in repetitive strange gestures, which may or may not have a magical meaning to the patient. Finally, in language one can have the repetition of phrases or comments for long periods. This is separate from preservation and distinct from verbigeration. Interestingly, when schizophrenia patients are engaged psychosocially, this symptom tends to diminish. It appears to be a consequence of psychosocial isolation. Deteriorated Appearance and Manners Patients with schizophrenia tend to neglect their appearance. This extends not only to elements of personal hygiene such as bathing, but even to changing their clothing. They can appear indifferent to the social amenities, such as returning a greeting. Frequently, they exhibit bad table manners despite the fact that in their premorbid condition they did not do so. Prior to the advent of antipsychotic drugs, regressed patients with schizophrenia could frequently be seen masturbating openly in hospital wards without apparent concern about the public nature of their act. Affective Features Both quantitative and qualitative changes in affect may occur in patients with schizophrenia. Reduced Emotional Responses Most commonly, patients show a quantitative change in the intensity of their emotional responses. Many patients with schizophrenia appear indifferent and apathetic. Others show diminished emotional intensity, described as emotional restriction or blunting. This quantitative aspect, which has been emphasized by Bleuler, is common in schizophrenia. In judging emotional depth, one must consider the cultural background of the patient. A normal emotional expression in one culture may appear to be a reduced emotional response in another. Cultures differ dramatically in their willingness to accept a public display of emotion; therefore, the examiner should have some knowledge of the cultural background of the patient being assessed. Often the patient and family are the best informants; they may be able to describe changes from the premorbid emotional state before they become obvious to even an experienced clinician. Anhedonia Anhedonia is a particularly distressing symptom. Sandor Rado considered anhedonia to be a cardinal feature of schizophrenia. There is frequently a diminution in the patient's ability to experience pleasure and, in some severe cases, even to imagine a pleasant feeling. Patients may not meet the criteria for the diagnosis of clinical depression but will describe an emotional emptiness or barrenness. Anhedonia can become unbearable enough to contribute to a suicide attempt. Inappropriate Responses A common finding in schizophrenia is a failure of congruence between an emotional expression and the ideational content. A patient with schizophrenia may talk about the death of a family member with a broad smile. This loss of harmony between the affective display and the ideational content is more common in chronic patients. Loss of congruence creates marked discomfort in the observer and contributes to the tendency of family and friends to remove themselves from contact with the patient. Psychological testing has demonstrated that patients with schizophrenia frequently cannot recognize the emotional state expressed in photographs of faces. This inability to recognize emotional cues in others may be expressed in the patient's inability to show their own emotional experiences in ways that are understood by others. The degree of emotional blunting and inappropriateness of emotional responses are excellent measures of the extent to which the illness has invaded the person's personality and contributed to its deterioration. Severe blunting and inappropriateness are associated with chronic schizophrenia. Unusual Emotions Schizophrenia is characterized frequently by alterations in emotional reactions to external stimuli and often demonstrates peculiarities of emotions infrequently seen in normal states. Particularly during acute decompensations, patients may describe states of exaltation with feelings of omnipotence, oceanic feelings of oneness with the universe, religious ecstasies, and terrifying apprehensions about the disintegration of their own personality or body. It is not unusual to see intense anxiety about the impending end of the universe. These experiences are rare in normal individuals, except when under the influence of psychotomimetic drugs. Emotional Sensitivity Many individuals who eventually develop schizophrenia premorbidly demonstrate a hypersensitivity to rejection. Much of the premorbid tendency toward social isolation can be understood as an avoidance mechanism to reduce the risk of rejection. After the onset of the disorder most patients continue to display extreme sensitivity to criticism and rejection. They may react to the tone or content of the therapist's intervention with a marked exacerbation of positive symptoms. An intelligent, well-mannered young woman suffering from chronic schizophrenia, who had improved to the point where she could live autonomously in her own apartment, had invited some friends to dinner. The dinner was well prepared and the evening enjoyable, until the friends invaded the patient's kitchen with forceful enthusiasm, and insisted on washing the dishes. Their hostess became enraged and ordered all guests to leave her home immediately. She later explained to her therapist that she felt humiliated and hurt by what she felt was a rude demonstration of her guests' conviction that she would never be able to make order in her own kitchen by herself. Those who have worked extensively with patients with schizophrenia know that they are extremely sensitive. They are easily hurt by even slightly aggressive or rejecting behavior by others—behavior that in most cases would hardly be noticed by a person of normal sensitivity or, if noticed, would not lead to traumatic experiences. For example, a father's refusal to let his son with schizophrenia watch a particular program on television caused the son, who was not known to be a violent or impulsive person, to knife his father to death. In another case a psychiatrist's refusal to see a patient with schizophrenia at the moment the patient requested it (the patient was told he would be seen 3 hours later) caused the patient to commit suicide. Another patient with schizophrenia in remission committed suicide when his parents refused to include him on a 2-week trip to Florida. Perceptual Disorders Various perceptual disorders occur in schizophrenia. It may be hypothesized that those disorders result from the patient's constant exposure to an overwhelming influx of sensory stimuli. Although normal persons have a fundamental, pervasive feeling of familiarity with the environment to which they have become accustomed and adapted—a necessary background for all normal perception—patients with schizophrenia may experience a haunting unfamiliarity with their environment. That unfamiliarity sometimes comes over them with a sudden jolt; at other times they experience a continuous feeling of strange remoteness, alienation,

and lack of contact (Fig. 12.7-10).

FIGURE 12.7-10 A symbolic representation of alienation that may be very severe in schizophrenia. (Courtesy of Erich Hartmann.)

Spontaneously reported sensory disturbances, mostly optical but also acoustic, olfactory, and gustatory, were observed in 15 percent of a large sample of patients with schizophrenia. The disturbances included hypersensitivity to light, changes in the perception of other people's faces and figures, misperception of movement, hypersensitivity to sound or smell or taste, and other changes in those senses. Because of the unpredictable variability of the patient's experiences, the gestalt of the visual world are broken into disjointed parts. These patients frequently see objects and people change their dimensions, outlines, and brightness from minute to minute or even from second to second before their eyes. Déjà vu experiences may intrude and produce an uneasy feeling of spurious familiarity. Time may lose any structure or meaning, and the experience of passing time may extend or contract. These changes can be shown in experimental investigations on size and brightness constancy, on critical flicker-fusion frequency, on time estimation, and on many other perceptual functions (Fig. 12.7-11).

FIGURE 12.7-11 Drawings of a house made by a young man during an acute schizophrenic illness. A was drawn on admission to the hospital. B was drawn after 1 week of phenothiazine treatment. The percept house in the first drawing is fragmented. The windows are displaced, the roof is lying on the ground, beside the walls. In the second drawing, the structure and the perspective of the house are restored. (Courtesy of Heinz E. Lehmann.)

Hallucinations Sensory experiences or perceptions without corresponding external stimuli are common symptoms of schizophrenia. Most common are auditory hallucinations, the hearing of voices. Sometimes the voices are those of God or the devil; sometimes they are the voices of relatives or neighbors. Frequently, the patient can neither recognize nor understand them. Most characteristically, two or more voices discuss the patient in the third person. Frequently, the voices address the patient, comment on the patient's activities and surroundings, or are threatening or obscene and very disturbing to the patient. They may represent some evil outside power over which the patient has no control. Many patients with schizophrenia hear their own thoughts. When they are reading silently, for example, they may be quite disturbed by hearing every word clearly spoken to them. Patients with schizophrenia experience visual hallucinations less frequently than auditory hallucinations, but they are not rare. Patients suffering from medically caused visual hallucinations experience them primarily at night or during limited periods of the day. They get relief only in sleep. Visual hallucinations that occur in schizophrenia are usually seen nearby, clearly defined, in color, life size, in three dimensions, and moving ( Fig. 12.7-12). Visual hallucinations almost never occur by themselves but in combination with hallucinations in one of the other sensory modalities. Tactile, olfactory, and gustatory hallucinations are less common than visual hallucinations. Patients with schizophrenia often experience cenesthetic somatic hallucinations, sensations of altered states in body organs without any special receptor apparatus to explain the sensations (e.g., a burning sensation in the brain, a pushing sensation in the abdominal blood vessels, or a cutting sensation in the bone marrow. Hallucinations may absorb all or much of the patients' attention and may control their behavior to a considerable extent. While they are listening to voices, they may be preoccupied and oblivious to the environment. They may react with laughter or anger or terror and may carry on lengthy conversations with the voices.

FIGURE 12.7-12 This photograph may symbolize the fantasy world of the schizophrenic. Not all psychiatrists are willing or able to attempt to empathize with that world, which can be a valuable therapeutic technique in some cases. (Courtesy of Arthur Tress.)

Modern treatment methods, particularly pharmacotherapy and social therapies that engage patients in various activities all day, have robbed hallucinations of much of their vividness and persistence. Also, many patients today know what hallucinations are and realize that hearing voices may be considered pathological and they will be considered crazy. Thus, present-day schizophrenia patients are much less likely to discuss their hallucinations openly than they were only 20 years ago. Dream Content Studies of the dream content of patients with schizophrenia have shown that their dreams are less coherent, less complex, and less bizarre than those of normal persons. The incidence of dreams with color is apparently somewhat higher in patients with schizophrenia than in normal persons. Family members appear more often in dreams, and friends less often. The incidence of pleasant emotions in dreams of patients is similar to that for normal persons, but unpleasant

emotions are more common in the dreams of patients with schizophrenia than in the dreams of normal persons. Thought Disorders Delusions By definition, delusions are false ideas that cannot be corrected by reasoning and that are idiosyncratic for the patient (i.e., not part of the patient's cultural environment). They are common symptoms of schizophrenia. Most frequent are delusions of persecution, which are a key symptom in the paranoid type of schizophrenia. The conviction of being controlled by some unseen mysterious power that exercises its influence from a distance is almost pathognomonic for schizophrenia ( Fig. 12.7-13). It occurs at one time or another, in most, if not all, patients with schizophrenia, and for many it is a daily experience. Patients who are convinced that they are being persecuted by powerful agencies often harbor delusions of grandeur; they must be very important if so much effort is spent on their persecution. In connection with their experiences of being physically controlled by unseen forces, many patients with schizophrenia have elaborate delusions that their minds are controlled by telepathy or hypnotism. Modern patients whose delusions have kept up with the scientific times may be preoccupied with atomic power, X-rays, or spaceships that take control over their mind and body. Many patients with schizophrenia have delusional fantasies about the destruction of the world. The radio waves of the 1930s have been replaced by the alien creatures of the new millennium.

FIGURE 12.7-13 In schizophrenia, irrational and idiosyncratic ideas create a fearful world that is difficult for others to experience or understand, as symbolized above. (Courtesy of Arthur Tress.)

Further to my investigation and research . . .. I would like to inform you that the tadpole in the eyes moves or floats around with the movement of the iris . . .. The tadpole reveals the photographic and its spirit the parabiological matter. From experience the Spirit is more deadly than the vision—the vision could bring on a person a berserk or manic attitude if he is unaware of its tricks—it could also be a danger to schizoid, alcoholic, and neurotic personalities. Further to the tadpole, it is luminous in the dark at times and flashes rings of light when both eyes are closed. Have you any idea if science could produce a solution that could cover the iris and eradicate the tadpole and the luminous matter? I repeat again, this is a diabolical science deliberately done to destroy human nature. Yours sincerely, J.M. A delusional idea may occur with extraordinary rapidity. The patient may experience it as an illumination of the intellect in which the meaning of certain matters suddenly becomes clear. The total certainty is diagnostic of the delusional nature of the belief. There is a variation over time in the degree of certainty about the belief. At times the patient believes but is not absolutely certain, and at other times the patient cannot entertain any doubt in the belief system. Phases of Cognitive Disturbance K. Conrad studied the development of delusions in patients with schizophrenia. In the first phase of the schizophrenic process, which he called “trema” (German for stage fright), patients become aware that something ominous is happening to them. Somehow, the world around them is changing, and they feel locked in, harassed, and powerless. They may make desperate attempts to regain control through elaborate schemes of body and character building. Table 12.7-6 contains the schedule that a young man, aged 19, set for himself in a desperate last attempt to achieve a sense of security 3 months before he was admitted to a mental hospital in an acute catatonic stupor.

Table 12.7-6 Schedule of a Person with Catatonic Schizophrenia

During the trema phase patients are anxious, irritable, and often depressed. That phase may last for only a few days, but it sometimes lasts for weeks or months. In the latter stages of the trema phase, patients may be in a delusional mood that makes them see their environment in a new and strange light, appearances are changed and familiarity is lost. A description of such an experience is given in the following excerpt from a patient's account, after recovery, of his schizophrenic attack. I suddenly realized that I just didn't have a clue where I was. I came to consciousness still driving along 401 highway but I had a vague suspicion that I might be nearing Montreal. I made a real effort to stay alert, but I seemed to keep drifting back to my former thoughts. Why had Edith said that I should believe in fairy tales? Was Joan really not dead but in a mental institution? Why had I been so cold that night in my car (the thermostat broke) and what was the significance of coldness, magnetism, and love? I imagine what I have recorded represents about 10 percent of my thoughts. They flashed through my mind so rapidly and with such turmoil that I became aware my thoughts were running out of control. And I felt that I wanted to see Dr. Wilson . . . Again on the same stretch of Highway 401 I lost the knowledge of location. The trigger again was through theories of cosmic matter in the aurora borealis—the Northern Lights; and the meaning of the Southern Cross.

The trema phase is followed by the epiphany phase, a Greek expression suggesting sudden revelation. Conrad postulated two phases after the apophanous: the apocalyptic fragmented phase and the terminal phase, in which the patient becomes vegetable-like. In the apophanous phase the patient suddenly becomes sure of certain new “facts.” A taxi driver this morning touched his cap with his right hand; this meant that he knew where the patient had been last night. A newspaper was lying on the stairs; this meant that his reputation would be ruined before nightfall. A man was feeding two squirrels in the park, indicating that the patient's future would be decided in 2 weeks. A television announcer makes a verbal slip; this broadcasts that the patient is stupid. Conrad called such delusions autochthonous, meaning that they are primary and irreducible. They appear de novo and seem to have little or no connection with the patient's life history or specific stresses and conflicts. Why do patients believe in the reality of these delusions? What evidence supports the farfetched connections they make? Patients always give the same answer, “I know it.” That direct, immediate, total certainty is the irrational, pathological aspect of the primary delusional experience. That certainty—“I know it”—cannot be explained by analyzing the patient's conscious psychic content. Many leading German psychiatrists, such as Jaspers, have stressed the difference between the primary pathological possibility of having delusions and the contents of delusions, which may have distinct, analyzable meaning based on the patient's psychological conflicts, drives, and needs. Disturbances of Thinking Disturbances of thinking and conceptualization are one of the most characteristic features of schizophrenia. The feature common to all manifestations of schizophrenia thought disorder is that patients think and reason on their autistic terms according to their own intricate private rules of logic. Schizophrenic patients may be highly intelligent, certainly not confused, and they may be painstaking in their abstractions and deductions. But their thought processes are strange and do not lead to conclusions based on reality or universal logic ( Fig. 12.7-14). The first author found that about 70 percent of patients with schizophrenia showed a typical schizophrenic thought disorder, and those who did usually had a withdrawn personality. He hypothesized that premorbid withdrawal characteristics already contained the thought disorder that emerged later.

FIGURE 12.7-14 Schizophrenic patient's schema illustrates his fragmented, abstract, and overly inclusive thinking and preoccupation with religious ideologies and mathematical proofs. (Courtesy of Heinz E. Lehmann.)

One study emphasized the fact that the patient with schizophrenia may consider two things identical merely because they have identical predicates or properties. By contrast, in normal logical thought, identity is based on identical subjects and not on identical predicates. The patient with schizophrenia may reason (to quote Silvano Ariete), “The Virgin Mary was a virgin; I'm a virgin; therefore, I'm the Virgin Mary.” However, this particular fallacy is not specific for schizophrenia and is commonly committed by college students who are distracted or fatigued. Arieti believed that schizophrenic cognition uses isolated segments and parts, rather than the whole of the concept. Patients with schizophrenia may reason: “John is Peter's father; therefore, Peter is John's father.” Such symmetrical reasoning is sometimes justified (e.g., John is Peter's brother, therefore, Peter is John's brother), but at other times such symmetrical conclusions are not justified, and patients not seem to know when they may apply them and when they may not. Patients with schizophrenia use archaic modes of mystical or magical thinking. Such primitive modes of thinking are closely related to the psychoanalytic concept of primary thought processes that are at work in normal dreaming and allow condensation, reversal, substitution, displacement, and other distortions of conceptual relations impossible in rationally controlled thought. Jung, in fact, compared the psychic processes of schizophrenic patients who are awake to those of normal persons who are dreaming with their eyes open. Kurt Goldstein described a concretization of thought and a loss of the abstract attitude as typical of schizophrenic thinking. Patients lose their ability to generalize correctly and exhibit in the ordering of their concepts a defect similar to a loss of the figure-ground relation in perceptual performance. That defect is often brought out by the simple clinical test of asking a patient to interpret a well-known proverb. One patient interpreted the saying “A stitch in time saves nine” as “I should sew nine buttons on my coat,” an overly personalized and concrete explanation. Norman Cameron identified overinclusion as a typical feature of schizophrenic thought disorder. In contrast to patients whose mental functions are impaired by an organic brain lesion and who tend to omit important items in thought and speech, patients with schizophrenia tend to include many irrelevant items in their ideational and verbal behavior. That tendency seems to result from a loosening of associations in the schizophrenia patient. Studies have shown that overinclusive thinking is not a learning defect but an impairment of a central filtering process that normally inhibits external sensations and internal thoughts that are irrelevant to a given focus of attention. Only a well-functioning filtering-inhibiting process makes rational thinking possible. Overinclusive thinking usually develops within the setting of a delusional mood, when things look different, sensations are more intense, and everything seems to have some strange special significance ( Fig. 12.7-15).

FIGURE 12.7-15 This drawing, carefully executed by a schizophrenic woman, graphically expresses her incoherent thinking and her tendency to perseveration of ideas, combined with an ability to accomplish quite complex drafting. Similar drawings may be produced when normal people doodle while their attention is not focused on what they are doing. (Courtesy of Heinz E. Lehmann.)

David Shakow demonstrated in a series of experiments that patients with schizophrenia cannot hold a set as well as a normal person can. That inability becomes

evident when patients are tested for their reaction time in responding to a stimulus preceded by a ready signal. Introduction of a ready signal shortens the reaction time of a normal person to the stimulus that may follow the signal within 10 to 15 seconds. The patients' reaction time remains the same, whether or not they are warned of the coming stimulus. Somatic Findings Physiological Testing A significant proportion of the patients who carry the diagnosis of schizophrenia exhibit neurological test abnormalities. The neurological findings that can be identified in approximately half the population tend to be soft signs. A careful history will also reveal that a significant percentage of patients with the diagnosis of schizophrenia experienced difficult labors and various obstetrical complications at birth. The patient's childhood developmental milestones tend to be delayed. School and work performance tends to be less adequate than that of their siblings. One of the earliest signs of a developing schizophrenic illness is the loss of the normal gracefulness of body movements. This was reported before the advent of antipsychotic drugs, and it should not be confused with the dystonias seen secondary to medication. Perioral tremors were reported long before the use of dopamine receptor antagonists and should not be confused with tardive dyskinesia. All of these signs are associated with poor prognosis. During the onset of an acute schizophrenic episode patients show increased autonomic tone, manifested in dilated pupils, moist palms, and moderate tachycardia. Systolic blood pressure tends to be elevated. Interestingly enough, there are few sleep disturbances after the acute stage of illness, although schizophrenic sleep is characterized by a tendency towards reduction of stage 4 sleep. Water Intoxication Routine laboratory tests of patients sometimes find a low specific gravity of urine and a low sodium concentration in serum. Retrospectively, it may be noted that the patient seems always to be at the water fountain. The syndrome of self-induced water intoxication should then be considered, particularly in the differential diagnosis of seizures in schizophrenic patients. As many as 20 percent of patients with a diagnosis of chronic schizophrenia drink excessive amounts of water, and 4 percent of the chronic population suffer from chronic hyponatremia and episodic water intoxication. The workup for increased water intake should include repeated daily weighing and tests for inappropriate secretion of antidiuretic hormone, whose secretion is sometimes altered by treatment with antipsychotic agents, carbamazepine (Tegretol), lithium (Eskalith), or other drugs. Constitutional Characteristics The relationship between body build and personality structure has been studied intensively for many years. Early studies showed that the diagnosis of schizophrenia occurred more frequently in persons of asthenic, athletic, and dysplastic body types than in the pyknic type. The pyknic type was believed to be more likely to develop manic-depressive psychosis. Although these observations may seem peculiar today, this perspective was prevalent in the 1930s. In the United States workers such as William Sheldon made extensive studies of the relationship between body type and mental illness. Using more-precise methods for measuring body types, he reclassified people into ectomorphic, mesomorphic, and endomorphic ( Fig. 12.7-16 ). In this classification schizophrenics were more likely to be ectomorphs or mesomorphs.

FIGURE 12.7-16 Sheldon's method of dividing people into distinct body types. A, Endomorphic, characterized by roundness and excess subcutaneous fat deposits. B, Mesomorphic, characterized by excess muscular tissue. C, Ectomorphic, characterized by minimal muscular and subcutaneous tissues.

In urban areas today a high percentage of patients diagnosed with schizophrenia also suffer from concomitant substance abuse—alcohol, drugs, or both. The substance abuse appears to be a form of self-medication, which unfortunately leads to additional problems for the patients. Two major eye abnormalities occur in schizophrenia. The first is a tendency toward frequent blinking, which is reduced with neuroleptic medication. This increased blink rate may reflect increased dopaminergic tone in the nervous system. The second is that in attempting to follow a moving object smoothly, abnormal saccades occur in approximately one-half to three-quarters of patients studied. Abnormal smooth pursuit may be a neurophysiologic marker for certain aspects of the pathophysiology of some patients with schizophrenia. Abnormalities of prosody are quite common in patients with schizophrenia. This can be conceptualized as a neurological disorder of the parietal lobe. Considerable evidence from imaging studies indicates that the temporoparietal region is important in the pathophysiology of these disorders. Imaging studies, including quantitative electroencephalography, reveal problems in having different brain areas work together in a synchronized fashion. This failure of coherent and integrated activity of different cell ensembles may well be the cardinal pathophysiologic finding of this group of disorders. Suicide and Violence Suicide is surprisingly common in this population. The frequency of attempts varies to up to 40 percent of the population. About 10 percent of people diagnosed with schizophrenia commit suicide during the first 10 years of the illness. The risk of suicide is higher in men, particularly those with the paranoid type. The sudden, otherwise unexplained suicides of university students may be related to their experiencing cognitive dysfunction and positive symptoms that they fear to mention to anyone and that go undiagnosed and untreated. Suicide of an individual with a diagnosis of schizophrenia is much less predictable than it is for someone with depression. A 32-year-old man with chronic schizophrenia who lived at the home of his parents and was compliant with treatment committed suicide in a bizarre way while his parents were on a 2-week trip to Florida. The parents had taken such trips previously on several occasions. In a rambling suicide note the patient indicated that he resented not having been asked to accompany them. Suicide is a significant danger for patients with schizophrenia. Probably more patients with schizophrenia than with bipolar I disorder commit suicide, although the immediate risk of suicide is relatively greater among the latter. Patients with schizophrenia may commit suicide because they are deeply depressed or they may kill themselves in response to the relentless commands they receive from hallucinatory voices. A patient with schizophrenia who had jumped to the street from a third-floor balcony sustained several fractures but lived to say that for many days a man's voice had told him persistently to jump out of a window. He did not want to die, and he resisted the voice for as long as he could, but he finally had to yield to its demands. Patients with schizophrenia are more violent as a group than the general population. This is particularly a problem with patients with the paranoid type who may act quite suddenly and impulsively on a delusional idea. Patients with paranoia tend to be intelligent and capable of forming plans; therefore, they represent a much greater risk than individuals who are disorganized and cannot plan an effective attack. Despite earlier beliefs, command hallucinations do not appear to play a particularly important role in violence. Violence between patients in hospitals frequently results from the attacking patient's mistaken belief that another patient is behaving in a threatening way or getting physically too close. Studies have revealed that violence in a hospital setting can result from undiagnosed neuroleptic-induced acute akathisia. Persistently violent inpatients often do well on special treatment units that provide a more structured program and a less-crowded

environment. The patients who fail to respond to this kind of care usually show neurological signs in addition to their diagnosis. Unfortunately, it is exceedingly difficult to prevent most schizophrenic homicides, since there is usually no clear warning. Most of the homicides come as a horrifying surprise. Patients who are known to be paranoid with homicidal tendencies should not, as a rule, be allowed to move about freely as long as they retain their delusions and their aggressive tension. But, like the patient who hanged himself without previously manifesting any observable depression, the homicidal schizophrenia patient may appear to be relaxed, even apathetic, and then, within a day or two, kill somebody. The number of homicides committed by patients with schizophrenia may increase during the next few years. As a result of the gradual reduction in the hospital confinement of patients with schizophrenia, many of them are treated with modern methods of therapy in the community, where it is often impossible to control and supervise their pharmacotherapy and to prevent recurrences of paranoid homicidal behavior. A man with schizophrenia who had been going home on weekends for many months was told by his sister that she would no longer ask permission to take him out of the hospital if he would not do his part of the housework—for instance, help with the dishes. On the next weekend visit, the patient killed his sister and his mother. He had shown no signs of disturbance whatsoever during the preceding week, had been sleeping well, and had been attending occupational therapy classes as usual. A 19-year-old boy was discharged from a mental hospital in what seemed to be a residual state of chronic schizophrenia of the undifferentiated type. He stabbed his father to death when the father, during a state of intoxication, told the patient that he was too much of a bother around the house and that he might as well return to the hospital. A man with schizophrenia, whose condition had not yet been diagnosed, complained to a general practitioner about various physical ailments. When the physician finally told him that he should not come anymore because there was nothing else he could do for him, the patient quietly left the office. He returned a few hours later and killed the doctor. Rejection Careful analysis of these unpredictable suicides and homicides leads to the conclusion that the most significant single factor in most of them was a traumatic experience of rejection. The pathological sensitivity of persons with schizophrenia makes them extraordinarily vulnerable to all common life stresses. Rejection, particularly by members of their own family, seems to be more traumatic for them than most other stresses. The act of rejection may seem trivial, and it is often not deliberate on the part of those who reject the patient. In fact, they are practically never aware of it, and the patient may not show any immediate reaction to the rejection at the time. It may be significant that four of the second author's patients with schizophrenia who committed homicide harbored the delusion that their parents were adoptive parents rather than real parents. That delusion in itself seems to reflect a deep-seated feeling of being rejected by the parents. Prepsychotic Personality A clinical evaluation must always consider the patient's prepsychotic personality. The clinical, but not typical, history is that of a schizoid personality—quiet, passive children with few friends; daydreaming, introverted, and shut-in adolescents and adults. They are often reported as having been especially good children because they were always obedient and never in any mischief. In school they were good in spelling but poor in arithmetic. They made few friends as children and their deficient friendship was particularly noticeable in adolescence. Typical schizoid adolescents have few dates, do not usually learn to dance, and have no close boyfriends or girlfriends. They are not interested in petting or other heterosexual or homosexual activities but are often disturbed about masturbation. They avoid competitive sports but like to go to the movies, watch television, or listen to music. They may be avid readers of books on philosophy and psychology. Less than 25 percent of patients with schizophrenia have a history of the type of schizoid personality described above. The former assumption that schizophrenia is genetically transmitted either as the disease proper or as a schizoid character structure is now changing to the concept of genetic transmission of schizophrenic spectrum diseases (including various personality and neurotic disorders) and a variety of conditions—even valuable traits, such as creative ability. About 90 percent of patients diagnosed with schizophrenia have no known family history of the disease. Precox Feeling Some clinicians believe they can diagnose a precox feeling. That feeling consists of an intuitive experience by the examiner that determines whether or not it is possible to empathize with the patient. Patients whose emotional distance makes it impossible to establish an empathic rapport are classified as having schizophrenia, providing other criteria are met. The reliability of this approach is questionable and even though important, the use of the examiner's feeling as a diagnostic criteria should be discouraged. Positive-Negative Distinction The distinction between manifestations of schizophrenia that appear to represent a loss of function (e.g., emotional blunting, poverty of speech) and such symptoms as delusions and hallucinations has been part of the diagnostic process at least since Kraepelin, whose concept of an avolitional syndrome was the predecessor of the concept. Bleuler's division of symptoms into fundamental and accessory types may be seen as supporting that separation, with certain of the negative symptoms assigned diagnostic primacy. However, Kraepelin agreed in principle with Bleuler on the distinction between fundamental and accessory symptoms. In 1913 Kraepelin stated the former [fundamental symptoms] constitute the real characteristics of the clinical state and can be demonstrated in each individual case more or less distinctly; the latter [accessory symptoms] may be present but may also be absent; they are not caused by the character of the morbid process but by circumstances which are in loose connection with it . . . [F]rom this point of view the weakening of judgment, of mental activity and of creative ability, the dulling of emotional interest and the loss of energy, lastly, the loosening of the inner unity of the psychic life would have to be reckoned among the fundamental disorders of dementia praecox, while the remaining morbid symptoms, especially hallucinations and delusions . . .. would be regarded more as secondary accompanying phenomena . . .. As psychiatric nosology has been modified over the past decades, largely in the service of greater reliability, the positive symptoms (designated accessory symptoms by Bleuler) have assumed principal importance in the diagnostic criteria used internationally and in the United States from DSM-III onward. Two distinct psychopathological processes were postulated in 1980. Type I schizophrenia was characterized by predominantly positive symptoms, good premorbid functioning, sudden onset, normal brain structures by computed tomography (CT), good response to treatment, and a better long-term course. Type II schizophrenia was characterized mainly by negative symptoms, an insidious onset, poor premorbid functioning, abnormalities on CT scans, a tendency to drug resistance, and a poorer long-term course and outcome, often resulting in behavioral deterioration. Other similar groupings include negative and positive schizophrenia ( Table 12.7-7) and deficit and nondeficit forms of schizophrenia. The past decade saw a large number of investigations into possible relations between those syndromes and a variety of issues, including course and outcome, neurotransmitter hypotheses, brain imaging findings, and family studies.

Table 12.7-7 Percentage of Patients With Negative and Positive Symptoms (111 Consecutively Admitted Schizophrenic Patients)

Scales have been developed to measure negative symptoms that have acceptable interrater reliability. Those scales invariably designate flat affect and poverty of speech among the negative symptoms and generally also include anhedonia, apathy, and avolition. Thought disorder, bizarre behavior, and inappropriate affect are more variable in such classifications. A recent review summarized and compared findings in patients with negative and positive symptoms. Those with negative symptoms experienced an earlier onset of schizophrenia, tended to be male and unmarried, had worse premorbid functioning, had more motor abnormalities, and were more likely to be concordant for illness if an identical twin. In view of those findings, negative symptoms have been reintroduced into the diagnostic classifications as one of the characteristic symptom complexes necessary for the diagnosis of schizophrenia. Certain manifestations simulate negative symptoms but are a consequence of medication, depression, institutionalization, or other life circumstances. These manifestations must be distinguished from the core negative symptoms of schizophrenia. Moreover, most patients present with a mixture of positive and negative symptoms, which vary in degree over time.

DIFFERENTIAL DIAGNOSIS Hallucinations and Delusions Another reason for the greater tendency to diagnose schizophrenia in North America than in other countries is that many North American psychiatrists take it for granted that a patient who is hallucinating or who expresses paranoid delusions must be schizophrenic if no organic brain disease can be detected. For example, in a survey of psychiatrists in the United States delusions ranked second of the top 10 symptoms indicating schizophrenia and hallucinations fifth; psychiatrists in Great Britain list delusions in eighth place and hallucinations are not among the first 10 symptoms. The clinician must not forget that the presence of delusions and hallucinations confirms only the presence of psychosis, not that of schizophrenia. Between 10 and 15 percent of bipolar I disorder patients have hallucinations or delusions. These symptoms indicate a serious loss of contact with reality, a principal criterion for the diagnosis of a psychotic condition, which may or may not be schizophrenic. At times schizophrenia-like symptoms frequently occur in cyclothymic disorder, and delusions and hallucinations may occur in other nonschizophrenic psychiatric conditions (e.g., delusional disorder, psychotic disorder, brief hysterical twilight states, toxic conditions, and mental disorders due to a medical general condition). Diagnosing schizophrenia simply because delusions and hallucinations are present is like making the diagnosis of a coronary occlusion solely on the basis of pain in the chest or the diagnosis of typhoid fever only on the presence of sustained pyrexia. Single symptoms should certainly suggest conditions in which such symptoms frequently occur, but unless specific, conclusive tests exist for disease processes, a final differential diagnosis must always be based on the complete clinical picture. Sensory and perceptual disorders, such as hallucinations, may indeed give good diagnostic clues. However, not all types of hallucinations point toward schizophrenia. There are important qualifications regarding the modality, the time, and the content of the hallucinations. Experiences of being controlled by outside forces or having strange, continuous, somatic (cenesthetic) hallucinations or auditory, verbal hallucinations (particularly if the voices are coming from God or the devil or address the patient in the second person or talk about him) may support a diagnosis of schizophrenia. Perceptual distortions of time or objects in space point toward a diagnosis of schizophrenia, but only if they have been present at least several days; otherwise, they may have a toxic origin. The time factor also applies to loss of ego boundaries and the experience of having one's thoughts spread to others. The presence of delusions provides strong presumptive evidence for schizophrenia only if those delusions have strange, magical, esoteric, or bizarre content. A person who is convinced that he is deliberately discriminated against by his foreman at the factory, that his wife is running around with other men, or that his wife is trying to poison him may have paranoid delusions, but they are not necessarily due to schizophrenia. On the other hand, a man who is convinced that he is the victim of a Pentagon-directed plot to destroy his brain by special death rays beamed at him from space satellites or that he is the Virgin Mary expresses delusions that, by their very bizarre character, point definitely in the direction of schizophrenia. The diagnosis of schizophrenia cannot be made entirely on the basis of observation, logical reasoning, or objective measurement. It still requires a careful and comprehensive clinical evaluation. Such an evaluation must take into account the presence or absence of certain key schizophrenic symptoms, the patient's prepsychotic personality, the physical findings, the family genetic history, the social environment, the various aspects a good clinical anamnesis may reveal about the natural history of the disease, and any possible precipitating factors. Catatonia Several investigators have emphasized that catatonia is not a disease entity or exclusively a subtype of schizophrenia but is instead a nonspecific syndrome that occurs quite frequently in other psychiatric conditions such as mania. In one study of 123 patients who satisfied the criteria for manic episode, following catatonic signs were present: sterotypy, echopraxia, and stupor. Others have reported the presence of a typical catatonic syndrome in organic brain diseases (e.g., cerebral aneurysm). Anxiety Disorders Hysterical symptoms are common in schizophrenic breakdown; thus, the presence of hysterical, dissociative, or even conversion symptoms does not rule out a diagnosis of schizophrenia. Schizophrenic breakdown is preceded by a period of marked tension and anxiety, which may last only a few days or extend over many months. During the acute and subacute stages of a schizophrenic attack, anxiety and depression may color the clinical picture significantly, again without excluding the overruling diagnosis of schizophrenia, which in some cases has not yet diminished the patient's emotional reaction to the onslaught of the psychotic attack. Obsessive symptoms are common in schizophrenia, and what appears to be obsessive-compulsive disorder can develop into schizophrenia. Bipolar I Disorder The differential diagnosis between schizophrenia and bipolar I disorder should not present many difficulties. The behavior of excited catatonic persons is directed primarily by their own qualitatively disordered mental process. Their actions are unpredictable and appear senseless, affect is difficult to understand, and verbal productions may be irrational and incoherent. Patients with mania, on the other hand, are distractible, and most of their actions are determined by their immediate environment. Their activity resembles that of an excessively busy person, rushing from one superficial job to another. Their affect is clearly one of playful euphoria or angry irritability but always outgoing and expansive. Their verbal productions are accelerated and increased in number, and they reveal a quantitative disorder of association processes, rather than the intrinsic, qualitative thought disorder of the patient with schizophrenia. Nevertheless, several investigators have raised the question, mainly on the basis of a favorable outcome, of whether schizophrenic episodes of relatively short duration are associated with mood disorders. Depressive conditions should not be diagnosed as schizophrenic unless some unmistakably schizophrenic symptoms are present. In schizoaffective disorders (which may resemble bipolar disorders), the presence of clearly schizophrenic symptoms, such as schizophrenic thought disorder, places the reactions in the diagnostic category of schizophrenia. Delusional Disorders Since delusions of persecution or grandeur are essential symptoms in both the paranoid type of schizophrenia and in the paranoid type of delusional disorders, the differential diagnosis between the two conditions must be carefully considered when paranoid symptoms prevail. The diagnostic decision must be based on the presence or absence of the essential features of schizophrenia and its paranoid type. Adolescent Disorders Any psychiatric disorder that occurs during adolescence assumes a certain schizophrenic coloring, since many of the features characteristic of nonschizophrenic adolescent turbulence—exaltation, intense preoccupation with abstract ideas, unpredictable variations of mood, daydreaming, introspection, shyness—are often seen in schizophrenia. Therefore, it is not unusual to misdiagnose a manic or depressive phase of a bipolar disorder as schizophrenia if the patient's first attack occurs in late adolescence. The rule that bipolar disorders do not occur in late adolescence is not always true; later recurrences of that mental disorder may cease to display symptoms resembling schizophrenia, and the correct diagnosis can then be made.

PSYCHOLOGICAL TESTS There are no psychological tests for schizophrenia comparable to the definitive biological or immunological tests for pregnancy and syphilis. There are only psychological tests that are more or less compatible with a diagnosis of schizophrenia and make the diagnosis more or less probable. Tests can rarely establish a diagnosis by themselves, divorced from the clinical findings.

The clinical psychologist's tests differ from clinical observation and interview; the method of test administration is uniform and the final evaluation of the test findings is based on comparisons with statistical norms, at least with psychometric test instruments. In most clinical centers certain psychological test batteries are routinely used to indicate, confirm, or rule out a diagnosis of schizophrenia. These test batteries are usually composed of projective tests, psychometric tests, and personality inventories. The most frequently used projective tests are the Rorschach test, some drawing tests, and the Thematic Apperception Test (TAT). The most commonly used psychometric tests are the Wechsler Adult Intelligence Scale (WAIS) and some tests that probe concept formation and the organization of thought processes. The most widely used personality inventory is the Minnesota Multiphasic Personality Inventory-(MMP-2), a self-report questionnaire that renders profiles of psychopathology or response styles. Effects of Medications Many patients with schizophrenia today have received some form of pharmacotherapy before they are seen by a psychiatrist. If they were given adequate dosages of antipsychotic drugs in the early stages of a schizophrenic attack, important key symptoms (e.g. the experience of being controlled, thought hearing, delusions, hallucinations, and inappropriate behavior) may have subsided within 2 or 3 days, and the disorder the psychiatrist now faces may lack all or most of its more specific distinguishing features. The dilemma is similar to that of making an accurate diagnosis of an acute abdominal condition after opioids have been administered or of diagnosing a septicemia after administration of antibiotics. The possible effect of previous antipsychotic pharmacotherapy on key schizophrenic symptoms must always be taken into account when making a differential diagnosis. Substance-Related Disorders Another drug factor that may render a differential diagnosis of schizophrenia more difficult today is the widespread nonmedical use of amphetamines, crack cocaine, hallucinogens, and drugs with similar effects. Many young people who develop psychotic symptoms have a history of using these drugs. Amphetamines, amphetamine-like drugs, and cocaine in high doses can produce psychotic (usually paranoid) conditions that mimic schizophrenia in their symptoms and course so closely that a differential diagnosis may be impossible in some cases. Fortunately, treatment is the same for amphetamine-induced psychotic disorder and for paranoid schizophrenia. With hallucinogens, the psychotic symptoms may have more of a toxic character, with vivid nonauditory hallucinations and sometimes clouding of consciousness. Differentiating drug-induced psychosis from schizophrenic psychosis may sometimes be difficult. Schizophrenic symptoms seem to develop about 4 years earlier in drug users than in nonusers; thus, drugs may play a precipitating role in the onset of schizophrenia. Cultural Factors An entirely new set of differential diagnostic problems has been generated by special lifestyles and philosophies, such as beliefs borrowed from Eastern cultures. A 20-year-old college dropout was arrested in front of a gas station, where he was meditating and blocking traffic. (Inappropriate and bizarre behavior?) When he was arrested, he responded by laughing. (Inappropriate emotional reaction?) At the police station he expressed his need to “laugh or fuck” to “prevent thinking.” (Bizarre and irrelevant, probably autistic, reasoning?) The police concluded that he was clearly insane and delivered him to a mental hospital. The young man told the psychiatrist who examined him that he was a Zen Buddhist and that thinking and analyzing things inhibited true growth of personality, according to his philosophy. He was convinced that the two best ways of preventing himself from getting lost in thinking were “laughing and fucking,” because both were incompatible with thinking. “Sort of reciprocal inhibition, if you believe in that stuff.” Under certain circumstances (e.g., in the police station) he could use only the laughing method. He tried to make things “buddhaful;” his smile indicated that that was a pun and not a neologism. Why had he chosen the gas station as a place to meditate? “Well, that's where the winds of Karma blew me.” After 30 minutes he terminated the interview by walking out of the room, remarking that he was becoming upset by the “very bad vibrations” he was getting from the psychiatrist. After a few day's observation the man was discharged. The psychiatrist suspected that he might develop schizophrenia eventually, but there were no grounds for making the diagnosis at the time.

COURSE AND PROGNOSIS Course Natural History Using the term natural history is almost arbitrary in describing a heterogeneous group of disorders with differences in cause, onset, pathogenesis, course, and outcome. It is possible, however, to describe the more common clinical patterns, even though they do not attain the frequency necessary to serve as absolute diagnostic criteria. Mode of Onset Onset of the schizophrenic disorders ranges from acute to subacute to insidious. Onset usually occurs in late adolescence or early adulthood, somewhat earlier in men and later in women. Commonly following a prolonged period of increasing social withdrawal and turning inward to philosophical or religious interests or both, is the onset of psychotic illness. These individuals frequently show a childhood developmental pattern in which they tend to play by themselves, have few playmates, avoid eye contact, and be somewhat awkward in their motor activities. They tend to achieve developmental milestones later and frequently show poorer school performance than their siblings. About the time of onset of illness there is frequently social deterioriation as well as a loss of interest in personal grooming and hygiene. The prodromal period may continue for weeks and up to several years before the symptoms suffice to make a diagnosis. When properly recognized this long prodromal period offers an opportunity for early intervention. Studies are under way to evaluate the use of low-dosage antipsychotic treatment in high-risk individuals showing prodromal signs. However, some individuals have very short prodromal periods before the onset of a psychotic state. In these latter individuals the progression to psychosis is more obvious, while in the former cases the progression is almost imperceptible. Nevertheless, despite the variability the first psychotic episode is frequently associated with a stressful life event such as going off to college. Characteristic of most psychotic states is the loss of reality testing and insight. As a consequence, a psychotic episode is often heralded by an increasing dissonance between persons and their social environment. As the members of the social environment become increasingly concerned it is not unusual for them to use some form of coercion to bring the patient to medical attention. Episodic Course Some patients with schizophrenia may have five or more psychotic attacks, usually of the catatonic type, without suffering any obvious personality damage, but because the risk of developing a schizophrenic defect increases after each additional schizophrenic attack, today's therapeutic challenge is to use all available measures to prevent relapses. In Russia, psychiatrists place special diagnostic importance on the occurrence of relapse and base their criteria for the differentiation of various types of schizophrenia on the character of the course of the illness. Three main types of schizophrenia are distinguished in Russia: (1) continuous, with subtypes of sluggish, progressive, and malignant schizophrenia; (2) periodic, not progressive; and (3) shiftlike progressive, again with subtypes mild, progressive, and malignant. Russian psychiatrists assume that these differences in the course of schizophrenia are also related to differences in cause, symptom formation, and response to treatment.

PROGNOSIS Table 12.7-8 lists features of schizophrenia that weigh toward a good or poor prognosis. It has been clinical knowledge since Kraepelin and Bleuler that the hebephrenic and simple types of schizophrenia have the poorest prognoses, that paranoid reactions have an intermediate prognosis, and that acute catatonic reactions have the best prognosis but that catatonic patients who go on to chronicity usually continue to regress and may become markedly deteriorated.

Table 12.7-8 Features Weighing Toward Good to Poor Prognosis in Schizophrenia

Modern pharmacotherapy has changed many of the old prognostic patterns. Today, a paranoid type schizophrenia patient's chances of making a good recovery are at least equal to those with the catatonic type. Even patients with the disorganized type often have good remissions after a few months of pharmacotherapy. The simple deteriorative disorder patient is still the least responsive to modern biological therapies. The more sudden the onset of a schizophrenic attack, the better are the chances for a good remission or complete recovery. If a precipitating event has clearly triggered the breakdown, the chances for a favorable outcome are also relatively better. As a rule, the younger a patient is at the onset of schizophrenic psychosis, the worse is the prognosis. Patients with onset in childhood or early puberty seldom recover completely. Some investigators believe that there may be two major groups of people with schizophrenia: those with difficulties in childhood before the onset of schizophrenic symptoms and those with a history of normal childhood. The first group is characterized by lower I.Q.s, a higher incidence of difficulties in school, poor peer group adjustment, an earlier age of first psychiatric contact, evidence of possible minimal brain damage, and a poor prognosis. A history of good adjustment in the important areas of social, sexual, and occupational functioning before the breakdown also indicated a favorable prognosis. Married men with schizophrenia have a better prognosis than do single, divorced, or widowed patients; the fact that they are married is evidence that interpersonal bonds may serve as a bridge for a return to the community. Patients who relate easily to people in their environment and who are capable of emotional warmth and natural emotional reactions have a good chance for reintegration. The presence of depression as in schizophrenia also improves the prognosis. Conversely, sustained emotional withdrawal and aloofness or shallow and inappropriate affective responses are ominous prognostic signs. In 1968 this first author and Felix Sugerman drew attention to the significance of formal thought disorder and of reaction time performance for the prognosis in patients with schizophrenia. They found that a combination of test results for thought disorder and motor reaction time, combined with the presence or absence of depression and marital status, gave the most important clues to the final outcome in their sample of schizophrenia patients. In 1973 a report concluded from an extended follow-up study of patients with schizophrenia that most of them seemed to reach a plateau about 5 years after their first breakdown and that those who had not remitted after 2 to 3 years faced a guarded outlook. However, one must not assume that the prognostic indicators that are relatively well established for schizophrenia patients in Western culture are universally valid. A different cultural setting may produce different results. For example, one study examined admission data and 12-year outcomes for Moslem Indian, Hindu Indian, and African schizophrenia patients on the island of Mauritius and found that only for the small Moslem Indian sample were prognostic criteria comparable to those of a British sample. In the Hindu Indian and non-Indian groups, the results were no better than chance. Depression was not associated with recovery; sudden onset was a favorable factor in the Indian group but not in the others; flatness of affect was not highly associated with chronicity. Only the absence of a good work history gave the expected results. But two features that are not known to have prognostic significance in the West, psychosomatic symptoms and somatic disease, had a strong association with chronicity in the Hindu Indian and African groups of the Mauritius schizophrenia patients. Family The family plays an important role in a patient's prognosis. A number of studies in recent years have shown that many patients with schizophrenia come from deeply disturbed families. Before making a prognosis one should determine whether the patient is accepted by the family and whether the dynamic pattern of communication within the family is adequate or characterized by irrationality, deficient sharing of foci of attentions, or the production of double-bind messages. Relapses A new prognostic factor has emerged in the past few years, the patient's cooperation and conscientiousness in following prescribed drug maintenance therapy. Many patients with schizophrenia can be rendered relatively symptom free within a few weeks or months, but about 60 percent of them can be maintained in that condition only with continued drug therapy after they have been discharged into the community. Placebo-controlled maintenance studies have established this point well. The more often patients neglect taking their maintenance medications (i.e., the worse their compliance), the more likely they are to suffer relapse. Several important observations have been made about the factors that determine whether a patient in remission will suffer a relapse. The most important protective factor is undoubtedly maintenance therapy with antipsychotic drugs. One study noted a history of sudden social or psychological traumas (e.g., the death of a parent, moving from one apartment to another) during the 3 weeks preceeding schizophrenic relapses in about 60 percent of cases. The type of home in which the patient in remission resides plays a vital role. In one American study patients with schizophrenia fared better in conjugal homes than in parental homes, but some British investigators made the opposite observation in their sample. Most importantly, clear correlations exist between exposure to expressed negative critical emotions in the household of a patient with schizophrenia in remission and the likelihood of relapse. The critical time limit seemed to be about 35 hours of such exposure a week. When that time limit was exceeded, even maintenance drug therapy was often inadequate in preventing relapse. Deterioration The risk of personality deterioration increases with each schizophrenic relapse. Schizophrenic recoveries are often called remissions because many of the patients later relapse. Although patients may remit again, each schizophrenic attack carries a greater probability of some permanent personality damage. Risk of personality deterioration increases rapidly after the second relapse. However, chronic schizophrenia does not inevitably lead to intellectual deterioration. In fact, in one sample, patients with chronic schizophrenia retained or improved their mean intelligence scores in spite of old age and prolonged institutionalization over a period of 14 years. In a group of schizophrenia patients who were followed over a 10-year period, schizophrenic symptoms decreased by 15 percent. Final Outcome A schizophrenia patient's chances for a favorable outcome of the psychosis are estimated today to be about 4 to 5 times better than they were before World War 1. Kraepelin reported in 1913 that nearly 13 percent of his patients with dementia precox recovered from their first attack, but most of them later relapsed. Altogether, only about 15 percent ultimately had passable social remissions, usually with slight-to-moderate personality damage. Today, with good follow-up therapy and well-controlled maintenance drug treatment, only some 10 to 15 percent of patients in remission relapse within a year, compared with about 65 to 70 percent who relapse during the same period without such follow-up treatment. There are five possible outcomes for the patient with schizophrenia: full and permanent recovery; full remission, with one or more future relapses; social remission with personality defect and with the patient either capable of self-care and self-support or dependent on protection and supervision; stable chronicity; and deterioration to a terminal stage. Deterioration to a Terminal Stage A vegetable-like existence is rare among patients with schizophrenia who have become ill during the past 25 years. Modern biological and social therapies are generally successful in preventing at least the terminal stage of deterioration, which was the most probable outcome of schizophrenia in Kraepelin's time and which was probably due to the ravages of institutionalization more than to schizophrenia. The modern mental hospital has few patients who illustrate this terminal stage of schizophrenia. Almost all patients with the symptoms and signs of extreme regression of behavior, affect, and ideation were admitted 30 or more years ago. Stable Chronicity Despite all intensive therapeutic efforts, many patients with schizophrenia remain in a state of stable chronicity, although they do not regress to a terminal stage of deterioration. Their psychotic symptoms may make it necessary to keep them hospitalized or, if the symptoms are not severe, they may reside outside the mental hospital. They remain definitely incapacitated, with clearly visible signs and symptoms of active mental disease. In a study of schizophrenia patients from 1913 to 1923, when virtually no treatment was available for chronic schizophrenia, clinicians reported that some patients who had been chronically ill for almost 10 years occasionally had spontaneous remissions that lasted for years. The combination of institutionalism and poverty frequently works to the detriment of the patient, and it is often difficult to determine how much of the patient's defective

functioning is due to each of these factors. However, many patients do not seem to be much better off in the community than in the hospital. It has been estimated that unemployed patients with chronic schizophrenia living outside the hospital spend about 30 percent of their time doing nothing, which is approximately what one observes in chronic schizophrenic patients residing in a modern hospital. The casual observer in big cities (not only in the poor districts) encounters many of those formerly hospitalized schizophrenic patients along the sidewalks, talking to themselves and passers by, gesticulating, preaching, or just sitting around. It is difficult to estimate how many patients with schizophrenia today will end up in this category of stable chronicity, but under good therapeutic conditions, the percentage almost certainly will not exceed 30 to 40 percent. The remainder of the patients will either remit or recover. Remission and Social Recovery Many patients with schizophrenia today fall into the categories of stable remission with personality defect and full remission with relapse. Schizophrenic personality defects and schizophrenic residual states are characterized by a reduction of ambition, initiative, available energy, and emotional responsiveness. Persons in that state may be more withdrawn, more aloof, and more selfish than they were before the onset of illness. They may neglect their personal appearance, and they almost certainly go down on the occupational ladder. Professional persons may, at first, still hold professional positions, but positions with reduced responsibility and less scope for personal initiative. They may eventually end up doing menial work well below their educational level. Persons with schizophrenic personality defect cannot readily assume responsibility. They cannot cope with competitive pressures and cannot tolerate time pressure. They are best suited for quite, routine work they can perform independently from others and at their own pace. Some former schizophrenia patients, therefore, prefer to do night-shift work, because it is less demanding and often permits them to work alone. The personality defect may be so pronounced that patients cannot take charge of their own affairs and require continuous protective supervision and sheltered work conditions. If the personality defect is less pronounced, patients may be capable of acting independently and supporting themselves, although usually at a lower occupational level than before the illness. Sometimes the personality defect is so slight that only the patient's family and close friends recognize the subtle changes that have taken place—a diminished capacity for enthusiasm, lessened spontaneity, decreased initiative, and a decline in creative imagination. In most daily life situations the patient may even function socially at an apparently normal level. Full and Permanent Recovery The prospect for full and permanent recovery from a schizophrenic episode is probably considerably brighter today than it was a half century ago, when the chances for such complete recovery were only 2 to 4 percent. Under careful supervision, antipsychotic drugs can now prevent relapse that could not have been prevented before the advent of those drugs. Only with maintenance drug therapy has it become possible to prevent relapses and thereby greatly reduce the risk of personality deterioration in many patients. Nevertheless, the introduction of modern treatment methods over the years has not yet significantly increased the actual number of full, permanent recoveries. Occupational Rehabilitation Studies found that about 60 percent of schizophrenia patients were employed 75 percent of the time over a 5-year period. A follow-up study of a sample of 108 schizophrenia first-admission patients for 5 years revealed that they had been working for 65 percent of that period. Of a series of 188 discharged patients, 67 percent were employed for more than half of the 1-year follow-up period. Other studies found that more than half of a group of male schizophrenia patients had been employed more than half of the 5-year follow-up period. Among 100 hospitalized patients with schizophrenia followed for 5 years after discharge, 18 percent of the patients had not been employed at all during the follow-up period, but the other patients had been employed, on average, for 57 percent of the follow-up period.

FUTURE DIRECTIONS Schizophrenia as currently diagnosed does not inevitably lead to severe deterioration but it is usually chronic and psychologically disabling to a significant degree. The better the premorbid social adjustment, the better the prognosis. Individuals who had good interpersonal skills and good psychosocial adaptation premorbidly do better than those who showed premorbid withdrawal. The outcome of schizophrenia tends to be worse in terms of functional level than it is in the affective disorders. Like the mood disorders, it is associated with an increased risk of suicide but a much shorter life expectancy, because suicide tends to occur in young adulthood. While the disorder tends to plateau clinically after about 5 years, it does not tend to remit in symptomatology until after the age of 50. Evidence suggests that patients do better in a rural and less demanding environment than they do in a complex urban culture. While it is possible to be more reassuring today than it was in the preneuroleptic era, the prognosis for full psychosocial recovery is still guarded, and families must be informed honestly of what can be expected.

SUGGESTED CROSS-REFERENCES The other sections in this chapter on schizophrenia have a bearing on this section. A general discussion of clinical manifestations of psychiatric disorders appears in Chapter 8. Perception and cognition are discussed in Section 3.1. Psychological tests are discussed in Section 7.4 and Section 7.5. DSM-IV is discussed in Section 9.1. Delusional disorders are discussed in Section 13.2, schizoaffective disorders in Section 13.1, mood disorders in Chapter 14, cognitive disorders in Chapter 10, and somatoform disorders in Chapter 16. Personality disorders are discussed in Chapter 24, impulse-control disorders in Chapter 22, and unusual acute and transient psychotic disorders in Section 13.3. Suicide is discussed in Section 29.1. Antipsychotic drugs are covered in Section 31.17 and Section 31.26. SECTION REFERENCES Addington J, Addington D: Premorbid functioning, cognitive functioning, symptoms and outcome in schizophrenia. J Psychiatry Neurosci 18:18, 1993. *Amador XF, Kirkpatrick B, Buchanan RW, Carpenter WT, Marcinko L, Yale SA: Stability of the diagnosis of deficit syndrome in schizophrenia. Am J Psychiatry 156:637, 1999. Andreasen NC, Arndt S. Alliger R, Miller D, Flaum M: Symptoms of schizophrenia: Methods, meanings, and mechanisms. Arch Gen Psychiatry 52:341, 1995. Andreasen NC, Flaum M. Arndt S: The Comprehensive Assessment of Symptoms and History (CASH): An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 49:615, 1992. Andreasen NC, Olsen S: Negative versus positive schizophrenia: Definition and validation. Arch Gen Psychiatry 39:789, 1982. Andreasen NC, Roy M-A, Flaum MA: Positive and negative symptoms. In Schizophrenia, SR Hirsch, DR Weinberger, editors. Blackwell Science, Cambridge, England, 1995. Anpermeyer MC, Katsehning H: Psychotropic medication and quality of life: a conceptual framework for assessing their relationship In Quality of Life in Mental Disorders. H Katschnig, HL Freeman, N Sortorious, editors. Wiley, New York, 1997. Arieti S: Interpretation of Schizophrenia. Brunner, New York, 1955. Bailer J, Brauer W, Rey ER: Premorbid adjustment as predictor of outcome in schizophrenia: Results of a prospective study. Acta Psychiatr Scand 93:368, 1995. *Bleuler E: Dementia Praecox, or, The Group of Schizophrenias, H Zinkin, translator. International Universities Press, New York, 1950. Crow TJ: Molecular pathology of schizophrenia: More than one disease process? Br Med J 280:66, 1980. Fenton WS, McGlashan TH: Natural history of schizophrenia subtypes. Arch Gen Psychiatry 48:969, 1991. Freud S: Standard Edition of the Complete Psychological Works of Sigmund Freud. Hogarth Press, London, 1953–1966. *Friedman JI, Temporini H, Davis KL. Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biol Psychiatry 45:1, 1999. Gureje O, Aderibigbe YA, Obikoya O: Three syndromes in schizophrenia: Validity in young patients with recent onset of illness. Psychol Med 25:715, 1995. Hwu HG, Tan H. Chen CC, Yeh LL: Negative symptoms at discharge and outcome in schizophrenia. Br J Psychiatry 166:61, 1995. Jaspers K: The phenomenological approach in psychopathology. Br J Psychiatry 114:1313, 1968. Katshnig H: How useful is the concept of quality of life in psychiatry? In Quality of Life in Mental Disorders, H Katschnig, HL Freeman, N Sartorious, editors. Wiley, New York, 1997. *Kraepelin E: Dementia praecox and paraphrenia. In The 8th German Edition of the Textbook of Psychiatry , vol III, part 2, Endogenous Dementias, RM Barclay, translator. Livingstone, Edinburgh,

1919. Maurice G, Stephen B, Abbie L, Waddington JL, Larkin C, O'Callaghan E: Spontaneous abnormal involuntary movements in first-episode schizophrenia and schizophreniform disorder: Baseline rate in a group of patients from an Irish catchment area. Am J Psychiatry 155:9, 1998. Schneider K: Clinical Psychopathology, MW Hamilton, translator. Grune & Stratton, New York, 1959. *Solomon LD, Goldman-Rateic PS: The reduced neuropil hypothesis: A circuit based model of schizophrenic. Biol Psychiatry 45:17, 1999. Thara R, Eaton WW: Outcome of schizophrenia: The Madras longitudinal study. Aust NZ J Psychiatry 30:516, 1996. Wieselgren IM, Lindstrom E, Lindstrom LH: Symptoms at index admission as predictor for 1–5 year outcome in schizophrenia. Acta Psychiatr Scand 94:311, 1996.

Textbook of Psychiatry

12.8 SCHIZOPHRENIA: SOMATIC TREATMENT Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.8 SCHIZOPHRENIA: SOMATIC TREATMENT STEPHEN R. MARDER, M.D. History Phases of Treatment in Schizophrenia Focus of Treatment Effectiveness of Antipsychotic Medications Effectiveness of ect in Schizophrenia Treatment of Acute Episodes Managing Adverse Effects Negative and Cognitive Symptoms Strategies for Poor Responders Maintenance Therapy Integrating Pharmacotherapy and Psychosocial Treatment Suggested Cross-References

The somatic treatment of schizophrenia has changed substantially during the 1990s. Until 1990 when clozapine (Clozaril) was introduced in the United States, all available antipsychotic drugs had a similar range of efficacy and were associated with neurological side effects that seriously interfered with their effectiveness. Clozapine was the first of a new generation of antipsychotics that are associated with far fewer extrapyramidal side effects than older drugs and perhaps have better efficacy. Although clozapine's association with agranulocytosis has limited the number of patients who receive it, this agent plays an important role in the treatment of severe psychosis. The introduction of risperidone (Risperdal) in 1994, olanzapine (Zyprexa) in 1996, quetiapine (Seroquel) in 1997, and ziprasidone (Zeldex) in 1998 have given clinicians new alternatives for treating a large number of patients with schizophrenia. The overall impact of these changes on the course of schizophrenia remains to be seen.

HISTORY The history of somatic therapies in schizophrenia can be divided into two eras: before the discovery of chlorpromazine (Thorazine), the first clearly effective antipsychotic drug, and after. Prior to the introduction of antipsychotics in the early 1950s, several treatments had been administered to individuals with psychotic illness, with results that are difficult to interpret because careful research methods in psychiatry had not been developed. During the late nineteenth and early twentieth century schizophrenia was believed to deteriorate inevitably into dementia. As a result, patients were frequently hospitalized for long periods. Somatic treatments were used to help control the most severe symptoms of the disorder and to make hospitals safer. Sedating agents such as bromides and barbiturates were used to control agitation, and physical treatments such as hydrotherapy and wet sheet packs were also used for their calming effects. In the early 1920s sleep treatment with barbiturates was introduced. This treatment was based on the observation that symptoms tended to improve following an overdose of barbiturates. The method involved maintaining patients in a highly sedated state for days, during which they would awaken only for necessary activities such as eating and personal hygiene. Insulin coma treatment was introduced during the 1930s. Patients were administered gradually increasing doses of insulin until a coma occurred. After being monitored for an hour the patient was administered glucose, which terminated the coma. Patients were commonly administered as many as 20 comas. Insulin coma was widely used in the treatment of psychosis, suggesting that it may have been somewhat effective. Unfortunately, it never received adequate research trials, and it remains unclear if the treatment was effective. It was abandoned when antipsychotics were introduced. Prefrontal lobotomy was proposed as a treatment for serious mental illnesses by Egas Moniz in 1935. The support for this treatment came from animal studies in which frontal lobe extirpations in monkeys resulted in an animal that appeared less easily frustrated. The use of frontal lobotomy was common prior to the introduction of effective antipsychotics, although there is a remarkable lack of controlled studies comparing psychosurgery with other treatments. Although reports suggest that lobotomy may have been effective in reducing severe psychotic symptoms, they also resulted in deteriorations in other areas. Following lobotomies patients frequently demonstrated personality deterioration with impulsive and psychopathic behaviors as well as impaired concept formation and ability to plan. Psychosurgery was abandoned as a treatment for schizophrenia after the introduction of effective antipsychotic medications. Convulsive therapies were developed after it was observed that some patients improved after a seizure. Drugs such as camphor and metrazol were used initially to induce seizures but were abandoned after Ugo Cerletti and Lucio Bini proposed the use of electrically induced convulsions. In its early days electroconvulsive therapy (ECT) was administered without anesthetics or muscle relaxants. The lack of anesthetics inspired fear in many patients, and the lack of muscle relaxants led to injuries from forceful muscle contractions. ECT administered with anesthesia and muscle relaxants continues to have a role in certain types of schizophrenia. The first effective antipsychotic medications were probably derived from extracts of the rauwolfia plant. Publications from the 1930s and 1940s suggest that these agents were effective for both hypertension and psychosis. Reserpine (Serpasil) the most potent of the rauwolfia alkaloids, was introduced in the early 1950s and was widely prescribed in the United States and elsewhere for schizophrenia and other psychotic illnesses. Studies comparing reserpine with dopamine receptor antagonists suggested that their efficacies were similar. However, reserpine's adverse effects, particularly depression, led most clinicians to prefer the dopamine receptor antagonists. Thus, reserpine is only rarely used for managing psychosis. The discovery of the phenothiazine chlorpromazine in the early 1950s may be the most important single contribution to the treatment of psychiatric illness. Laborit, a surgeon in Paris, noticed that administering chlorpromazine to patients prior to surgery resulted in an unusual state in which they seemed less anxious regarding the procedure. In 1952 he convinced Jean Delay and Pierre Deniker and other psychiatrists to administer chlorpromazine to psychotic and excited patients—the effects were extraordinary. Chlorpromazine was effective in reducing hallucinations and delusions as well as excitement. It also caused adverse effects that resembled parkinsonism. The use of chlorpromazine spread rapidly through the psychiatric hospitals in Paris and eventually to the rest of the world. Since chlorpromazine was relatively easy to administer to large numbers of patients, it was partially responsible for a substantial reduction in the number of patients in psychiatric hospitals. Thioridazine and fluphenazine (Permitil, Proloxin) as well as other classes of drugs such as the butyrophenones (e.g., haloperidol [Haldol]) and the thioxanthenes (e.g., thiothixene [Navan]) were developed after the introduction of chlorpromazine. Although these newer agents differed in their potency and their adverse effect profiles, all had similar effectiveness. Clozapine, the first effective antipsychotic with negligible extrapyramidal effects was discovered in 1958 and first studied in the 1960s. However, in 1976 it was found to be associated with a substantial risk of agranulocytosis, which resulted in delays in its introduction. In 1990 clozapine finally became available in the United States, but its use was restricted to patients who responded poorly to other agents. Risperidone, olanzapine, quetiapine, ziprasidone, and other agents with affinity for both dopamine and serotonin receptors cause minimal extrapyramidal side effects and are not associated with a risk of agranulocytosis. These newer agents are replacing older drugs as the standard treatments for schizophrenia.

PHASES OF TREATMENT IN SCHIZOPHRENIA Somatic treatment varies depending on the phase of a patient's illness. The acute stage is usually characterized by psychotic symptoms that require immediate clinical attention. These symptoms may represent a first psychotic episode or, more commonly, a relapse in an individual who has experienced multiple episodes. Treatment during this phase focuses on alleviating the most-severe psychotic symptoms. Following the acute phase, which usually lasts from 4 to 8 weeks, patients usually enter a stabilization phase in which acute symptoms have been controlled, but patients remain at risk for relapse if treatment is interrupted or if they are exposed to stress. During this phase, treatment focuses on consolidating therapeutic gains with treatments similar to those used in the acute stage. This phase may last as long as 6 months following recovery from acute symptoms. The third stage is the stable, or maintenance, phase when the illness is in relative remission. The goals during this phase are to prevent psychotic relapse and to assist patients in improving their level of functioning.

FOCUS OF TREATMENT Patients with schizophrenia can demonstrate large differences in the severity of their psychopathology as well as in the type of symptoms they demonstrate. As a result, treatment strategies should be individualized to the characteristics of each patient's illness. Recent studies indicate that psychopathology in schizophrenia can

be classified into three dimensions: psychotic, negative, and disorganized. Psychotic symptoms include hallucinations, ideas of reference, and delusions. These are symptoms that tend to result in hospitalization and to disrupt the lives of patients. Negative symptoms include decreased motivation, emotional blunting, and impoverished speech and thought; these symptoms are associated with the social and vocational impairments of schizophrenia. Disorganized symptoms include disorganized speech and behavior as well as impairments in attention and information processing; these symptoms are also associated with the social and vocational impairments of schizophrenia. Antipsychotic drugs are most effective in treating the psychotic dimension. As a result, clinicians adjusted their expectations about the goals of pharmacotherapy in schizophrenia. Although some improvement in the other dimensions often occurred with drug treatment, clinicians were usually satisfied when psychotic symptoms were minimized. These expectations changed following the introduction of clozapine. A proportion of patients who improved with clozapine demonstrated changes in other dimensions as well, including better social and vocational adjustments. Similar improvements have been reported on other serotonin-dopamine antagonists. In addition, other studies (discussed later) suggested that both negative and cognitive symptoms improved with these newer medications.

EFFECTIVENESS OF ANTIPSYCHOTIC MEDICATIONS A large body of evidence supports the effectiveness of antipsychotics for schizophrenia. Many of these studies were carried out in the 1960s when there was skepticism that these agents were truly antipsychotic rather than more effective tranquilizers. An evaluation of these studies by the 1995 Schizophrenia Patient Outcomes Research Team (PORT) found that about 70 percent of patients treated with an antipsychotic achieved remission. In contrast, only about 25 percent of patients treated with placebo remitted. Most studies compared one or more antipsychotic with either a placebo or an agent such as phenobarbital that served as a control; antipsychotic drugs were found to be more effective than either placebo or tranquilizers.

EFFECTIVENESS OF ECT IN SCHIZOPHRENIA ECT has been studied in both acute and chronic schizophrenia. Studies in patients with recent-onset schizophrenia indicate that ECT is about as effective as antipsychotic medications and more effective than psychotherapy. Other studies suggest that supplementing antipsychotic medications with ECT is more effective than antipsychotic medications alone. Studies of ECT in chronic schizophrenia have been less promising. Anecdotal reports indicate that ECT is effective in patients who respond poorly to antipsychotic medications. Overall these results suggest that ECT probably has a limited role in schizophrenia. Patients should first receive trials of antipsychotic medications; if these medications are ineffective, acutely ill patients can be treated with ECT. Antipsychotic medications should be administered during and following ECT treatment.

TREATMENT OF ACUTE EPISODES Indications for Somatic Treatment Nearly all patients with acute psychotic symptoms benefit from an antipsychotic medication. Aside from relieving symptoms, evidence indicates that lengthy delays in initiating drug treatment may alter the long-term course of schizophrenia. This evidence is summarized in a scholarly review by Richard J. Wyatt, who found that treatment delays—usually of 6 months or more—were associated with a greater need for hospital treatment and a worse social and vocational outcome. Many of the studies reviewed by Wyatt have important limitations such as lack of randomization and comparing individuals treated during different decades. However, for ethical reasons a definitive study will never be carried out to determine if withholding treatment worsens the long-term course of schizophrenia so it is probably prudent for clinicians to consider the possibility that untreated psychosis can result in a type of permanent damage. These data do not mean that all patients need to be treated immediately. In some circumstances the management of a patient may be better if drug treatment is delayed for several days. A brief delay may permit clinicians to make a more thorough diagnostic evaluation and rule out causes of abnormal behavior such as substance abuse, extreme stress, medical illnesses, and other psychiatric illnesses. Assessment Whenever possible, patients should receive a physical examination with a neurological examination, a mental status examination, and a laboratory evaluation before medications are started. A urine screen for drugs of abuse and blood tests for complete blood count (CBC) electrolytes, glucose, and liver, renal, and thyroid function should be ordered. Other evaluations that should be considered are pregnancy tests in women, electrocardiograms (ECGs) when cardiac disease or age is a factor, and human immunodeficiency virus (HIV) and syphilis tests when relevant. The presence of movement disorders—particularly preexisting tardive dyskinesia—should be assessed because they may influence the selection of an antipsychotic. Antipsychotics are relatively safe drugs so treatment can usually begin before the results of laboratory tests are known. An exception is clozapine treatment, which should only begin after the patient is known to have a normal CBC. Under emergent conditions—for example, when patients refuse to cooperate with an evaluation—antipsychotics can be administered prior to a medical evaluation. Selection of an Antipsychotic Drug The introduction of new antipsychotic agents has made the selection of an antipsychotic much more complicated. Prior to the development of the new antipsychotics, all the drugs were equally effective for schizophrenia. Many clinicians believed that different subtypes of schizophrenia responded differently to different antipsychotics. For example, it was proposed that more agitated patients responded better to more-sedating drugs whereas more withdrawn patients responded better to less-sedating agents; however, controlled trials failed to support this. The differences among antipsychotics were confined to their side effects, the available formulations, and, to some extent, their cost. The newer antipsychotics challenged this view, suggesting that certain populations of individuals with schizophrenia were likely to do better on a newer antipsychotic. Antipsychotic drugs can be categorized into two main groups: the older conventional ones, which have also been called dopamine receptor antagonists and the newer second-generation drugs which have been called serotonin-dopamine antagonists (SDAs), or more broadly, atypical antipsychotics. This textbook uses the terms dopamine receptor antagonist and SDA, which refer to the theory that the antipsychotic effects of dopamine receptor antagonists result from the blockade of dopamine type 2 (D2) receptors. The SDAs differ in having effects related to their ratio of D 2 and serotonin (5-hydroxytrptamine [5-HT]) type 2A (5-HT 2A) antagonism. The dopamine receptor antagonists are further categorized as being low-, mid- or high-potency, with the higher-potency drugs having a greater affinity for D 2 receptors and a greater tendency to cause extrapyramidal side effects. Low-potency drugs are less likely to cause extrapyramidal side effects, but more likely to cause postural hypotension, sedation, and anticholinergic effects. A number of factors should be considered in selecting an antipsychotic medication. Perhaps the most important consideration should be the patient's prior experience with drug treatment. This includes both the patient's clinical and subjective response. Regarding the subjective response, studies by Theodore Van Putten and others found that a patient's early response to a query such as “How does this medication agree with you?” was a powerful predictor of whether that patient would comply with taking that particular medication. In other words, if the patient has uncomfortable side effects on a medication, compliance is likely to be poor if that medication is prescribed. Prior to the introduction of the SDAs few options were available for patients who developed extrapyramidal effects. At times, dosage reduction or changing the patient to a lower-potency dopamine receptor antagonist may be helpful. Unfortunately, many patients experience extrapyramidal or other adverse effects at the lowest effective dosage that is clinically effective. The introduction of the SDAs provides an opportunity for treating these individuals with agents that seldom cause extrapyramidal side effects at their effective dosage. With these factors in mind, clinicians should consider the factors included in Table 12.8-1. In some cases these recommendations are based on incomplete data. For example, it remains unproven that patients with prominent negative or cognitive symptoms will respond better to an SDA than to a dopamine receptor antagonist. Haloperidol is recommended for pregnant patients because more data support its safety and not because it has proved safer than other drugs.

Table 12.8-1 Factors Influencing Antipsychotic Drug Selection

An important nonclinical factor is the cost of the drug; the SDAs are much more expensive. However, evidence indicates that the higher drug costs of these agents may be offset by other factors. Studies from the Department of Veterans Affairs and State Hospitals in Connecticut found that patients treated with clozapine required fewer hospital days than patients treated with a conventional dopamine receptor antagonist. As a result, the reduction in hospital days compensated for the higher drug cost associated with clozapine treatment. Similar results from other studies suggest that the higher costs of risperidone and olanzapine may also be partially offset by a reduced need for hospitalization. In selecting a drug for first-episode patients, clinicians should give a high priority to minimizing adverse effects. Many of these individuals are ambivalent about drug treatment and may discontinue antipsychotics when they experience relatively mild adverse effects. Unpleasant experiences with medications during this initial episode may be frightening to these individuals and may influence their future attitudes toward pharmacotherapy. These considerations may lead to the selection of an SDA or a relatively low dosage of a high-potency dopamine receptor antagonist. A number of studies indicate that both olanzapine and risperidone are effective for first-episode patients. Route of Administration The decision regarding route of administration is usually straightforward. Under most conditions, patients should be treated with an oral antipsychotic agent. Most antipsychotic drugs have half-lives that permit a single daily dose. Short-acting intramuscular drugs are useful when the patient refuses oral dosing and when a rapid onset is helpful. Intramuscular administration of most antipsychotics results in peak plasma concentrations in about 30 minutes, with clinical effects emerging within 15 to 30 minutes. Most orally administered dopamine receptor antagonists yield a peak plasma concentration 1 to 4 hours following administration. Antipsychotic medications can also be administered as long-acting injectable compounds. These drugs differ from short-acting compounds in that they have a very gradual onset of action and are eliminated very slowly. This route of administration is helpful for long-term maintenance therapy, but not for acute treatment because clinicians cannot titrate dosage against adverse effects or clinical effects when the onset of clinical effects may occur weeks or months after a drug or dosage change. Prescribing Antipsychotics Prior to prescribing an antipsychotic drug, clinicians should describe the medication, its target symptoms, and its possible side effects. It is particularly important to describe adverse effects such as akathisia, which can be misinterpreted as agitation under some circumstances. Patients who are severely disturbed may be unable to participate meaningfully in this discussion. However, most patients benefit from information about the goals of treatment and important risks associated with antipsychotic medication. Patients with schizophrenia may be suspicious so it is particularly important to emphasize that they can participate in interpreting medication effects. Because psychotic individuals may be dependent on the help and support of their families, it is frequently helpful to involve one or more family members in decisions about drug treatment. In some settings and locations patients must give written or verbal consent prior to receiving an antipsychotic medication. This can be a dilemma for patients who are conceptually disorganized and find it difficult to understand the risks and benefits of drug treatment. Under these circumstances, clinicians should adjust the complexity of the discussion to the patient's state of mind. Thus, it may be appropriate to provide a limited amount of information that focuses on the most common acute adverse effects of the medication when the patient is most seriously impaired. As the patient improves, clinicians may then elaborate on the costs and benefits of medication. For example, detailed discussions about tardive dyskinesia, an adverse effect associated with chronic treatment, may be deferred until the patient has improved and long-term maintenance is being considered. Psychiatrists must also evaluate whether acutely disturbed patients can participate meaningfully in decisions about their medication. Clinicians should become familiar with local and state laws that affect a patient's right to refuse or accept drug treatment. The most difficult situation is when a patient who desperately needs medication refuses it. Under some conditions, family members who have been educated about schizophrenia may be helpful in convincing patients to accept medication. Every locality has provisions for treating patients against their will under emergency conditions; some areas permit involuntary treatment when certain conditions are met. As patients improve, the great majority eventually accept their own need for medication. Dosage Selection Finding the best dosage of an antipsychotic is both difficult and important. It is important because these agents, particularly the dopamine receptor antagonists, may cause adverse effects at their effective dosages. Often the clinician must weigh the therapeutic advantages of a particular dosage against uncomfortable or disabling side effects. Figure 12.8-1, from a study by Theodore Van Putten and his colleagues, displays dose-response curves for fluphenazine for both clinical improvement and disabling side effects. These two curves are close together, which indicates that it may be difficult for the clinician to find a dosage that results in clinical improvement without substantial adverse effects.

FIGURE 12.8-1 Improvement and disabling side effects as a function of plasma fluphenazine concentration.

Finding the right dosage is difficult because the physician cannot titrate dosage against clinical effects because of the delay between a clinical intervention and the patient's clinical response. Some individuals experience a delay of days or even weeks between the time treatment is started and when the patient eventually responds. These studies are supported by findings indicating that the neurochemical response to an antipsychotic agent is complex and includes an initial blockade of central dopamine receptors, followed by delayed decrease in dopamine turnover. Although high doses of dopamine receptor antagonists can be associated with extrapyramidal side effects, some patients can tolerate antipsychotics at very high dosages. This is particularly true of nonsedating, high-potency drugs, which has led clinicians to raise the prescribed dosage in hope that higher dosages will lead to greater improvement than moderate dosages. This belief resulted in a substantial increase in the average dosage of antipsychotic drugs prescribed in the United States during the 1970s and 1980s. Many psychiatrists during this period routinely prescribed dosages above 1000 mg a day of chlorpromazine equivalents (20 mg of

haloperidol), whereas others reserved high-dosage treatment for patients who remained symptomatic on lower dosages of medication. A number of dosage comparison studies have failed to support the routine use of higher doses; that is, when groups of patients are assigned to higher dosages (e.g., more than 2000 mg a day of chlorpromazine or 40 mg a day of haloperidol), the rate of improvement and the amount of improvement are no greater than for those assigned to more moderate dosages. Clinicians are sometimes impressed by individuals who require these higher dosages, suggesting that there is a small group of patients who should be treated with high dosages. However, most patients who receive these high dosages are only partial responders to an antipsychotic and have endured dosage increases that were not associated with improvement. Dosage comparison studies indicate that dosages below 300 mg a day of chlorpromazine (or 5 mg a day of fluphenazine or haloperidol) are likely to be too low for many psychotic patients. At the same time doses above 1000 mg a day of chlorpromazine (or 20 mg a day of fluphenazine or haloperidol) are seldom necessary and may lead to substantial adverse effects. Only limited data from controlled trials exist to assist clinicians in finding the best dose of clozapine. The mean dose of clozapine prescribed differs between Europe and the United States, with European physicians commonly prescribing less than 300 mg of clozapine daily and clinicians in the United States often prescribing 500 mg or more. These experiences support the practice of treating most clozapine patients with doses in the range of 300 to 500 mg daily. However, adverse effects, particularly sedation and orthostatic hypotension, are often limiting factors that prevent clinicians from reaching a targeted dosage. Although some patients have an optimal response at dosages between 600 and 900 mg daily, the risk of seizures increases substantially in this dosage range. More-recent studies suggest that patients are more likely to respond to clozapine when plasma concentrations are 350 ng/mL or higher, suggesting that measuring plasma concentrations may be useful for poor responders. Large multicenter trials indicate that risperidone is most effective at 4 to 8 mg daily. Higher doses may lead to extrapyramidal effects without increased effectiveness. In the United States, the average dosage of risperidone prescribed for schizophrenia is slightly more than 4 mg daily. This suggests that a reasonable practice would be to manage patients with schizophrenia with 4 mg of risperidone and increase the dosage if they fail to respond after 4 to 6 weeks. Most patients with acute schizophrenia can be managed on dosages between 15 and 25 mg daily of olanzapine. Some individuals respond well to as little as 5 or 10 mg daily. Quetiapine is usually effective when dosages are between 150 and 600 mg daily. Ziprasidone is effective at dosages of 80 to 160 mg daily. A number of recent findings suggest a reasonable strategy for treating acute schizophrenia. The dose of an antipsychotic that is likely to be effective is the dose that occupies an appropriate number of D 2 receptors. For dopamine receptor antagonists this is approximately 80 percent of receptors. The therapeutic response depends upon processes that occur after these receptors have been occupied for a period of time. This observation is supported by findings from both position emission tomography (PET) scanning and the measurement of plasma homovanillic acid, which suggest that clinical improvement is not associated with the immediate effects of the drug on dopamine receptors, but on processes that occur later. Therefore, the goal in the first days of treatment is to prescribe a drug dosage that occupies an adequate proportion of dopamine receptors and to keep the patient comfortable until the drug is effective. If a patient does not respond in the first week or two, this does not indicate that the current treatment is inadequate. Since most patients on antipsychotic drugs improve during the first 6 weeks, patients should be observed for this interval before a drug is changed. Also, the strategy of using medications on an as-needed basis as a guide to finding the optimal dosage makes very little sense because the immediate and delayed responses to the drug are very different. A comparison of some antipsychotic drugs is presented in Table 12.8-2.

Table 12.8-2 Selected Antipsychotic Drugs

Managing Agitation in Acute Psychosis Agitation in acute schizophrenia can result from disturbing psychotic symptoms such as frightening delusions or suspiciousness or from other causes, including stimulant abuse or extrapyramidal side effects, particularly akathisia. Patients with akathisia can appear agitated when they experience a subjective feeling of motor restlessness. Differentiating akathisia from psychotic agitation can be difficult, particularly when patients cannot describe their internal experience. A trial with an anticholinergic antiparkinson medication or propranolol may be helpful in making the discrimination. Clinicians have a number of options for managing agitation that results from psychosis. Antipsychotic drugs and benzodiazepines can result in relatively rapid calming when psychotic patients are agitated. An advantage of an antipsychotic agent is that a single intramuscular injection of a high-potency drug such as haloperidol or fluphenazine can result in calming without excess sedation. Low-potency antipsychotics are often associated with sedation and postural hypotension, particularly when they are administered intramuscularly. The disadvantage of high-potency drugs is that extrapyramidal effects can result from a single injection or, more often, from repeated injections. In younger patients, excessive amounts of injected high-potency drugs can lead to dystonia, which may increase the patient's agitation. A reasonable intervention for the agitated patient is to treat the agitation with either an intramuscular or oral antipsychotic. If the situation is urgent, intravenous or intramuscular drug administration will lead to more rapid calming. The patient should be started on a regimen of oral antipsychotic the same day. If further treatment of agitation is necessary, benzodiazepines may be administered. Lorazepam (Ativan) has the advantage of reliable absorption when it is administered either orally or intramuscularly. The combination of lorazepam with a high-potency antipsychotic agent has been found to be safer and more effective than large doses of antipsychotics in controlling excitement and motor agitation. Moreover, the use of benzodiazepines may reduce the amount of antipsychotic medication that is needed to control psychotic patients.

MANAGING ADVERSE EFFECTS Patients frequently experience the adverse effects of an antipsychotic agent before they experience clinical improvement. Whereas a clinical response may be delayed for days or weeks after drugs are started, adverse effects often begin almost immediately. For low-potency drugs, these adverse effects are likely to include sedation, postural hypotension, and anticholinergic effects, whereas high-potency drugs are likely to cause extrapyramidal side effects. This early onset of adverse effects is important because a patient's interpretation of a drug's effectiveness is often associated with how that drug makes them feel. Moreover, one of the challenges of treating the acutely psychotic is maintaining the trust of individuals who may misinterpret experiences and become suspicious. Warning patients about the potential side effects of medication can lead to prompt management and often improves the trust between patient and clinician. Moreover, minimizing the adverse effects may do long-lasting damage to the patient-clinician relationship because one of the powerful predictors of drug reluctance or drug refusal is an earlier experience of adverse effects. Extrapyramidal Side Effects The most common form of extrapyramidal side effect is neuroleptic-induced acute akathisia, an adverse effect consisting of a subjective feeling of restlessness along with restless movements, usually in the legs or feet. Patients who experience severe akathisia often pace continuously or move their feet restlessly while they are sitting. Some complain that they are unable to feel comfortable, regardless of what they do. Severe akathisia can make patients feel anxious or irritable, and some reports suggest that severe akathisia can result in aggressive or suicidal acts. Researchers have estimated that 25 to 75 percent of patients treated with a high-potency dopamine receptor antagonist experience akathisia. This adverse effect can be difficult to assess and is frequently misdiagnosed as

anxiety or agitation. Akathisia is also thought to be a correlate of poor antipsychotic drug response. Because patients may experience akathisia as irritability or agitation, asking patients whether they are restless or if they have difficulty sitting still can be helpful in early stages of treatment. At this point, a dosage adjustment, a b-adrenergic receptor antagonist, or an anticholinergic drug may provide considerable relief. Also, patients who have a history of developing severe akathisia that responds poorly to these treatments are likely to do better if they are treated with a new antipsychotic such as clozapine, risperidone, or sertindole. Neuroleptic-induced acute dystonia is probably the most frightening extrapyramidal side effect. It consists of intermittent or sustained muscular spasms and abnormal postures affecting mainly the musculature of the head and neck, but sometimes the trunk and lower extremities. Common forms of dystonia include abnormal positioning of the neck, impaired swallowing (dysphagia), hypertonic or enlarged tongue, and deviations of the eyes (oculogyric crisis). These reactions usually appear within the first few days of therapy. Dystonias are more likely to occur in younger patients, particularly males in their teens or 20s. Neuroleptic-induced parkinsonism consists of tremor, muscular rigidity, and a decrease in spontaneous movements, features that resemble the movement disorder in idiopathic parkinsonism. Examination usually reveals a positive glabella tap. This motor disturbance affects about 30 percent of patients who are chronically treated with traditional antipsychotics. The first evidence of drug-induced parkinsonism may be a diminished arm swing or decreased facial expressiveness. Risk factors for antipsychotic-induced parkinsonism include increasing age, dosage, a history of parkinsonism, and underlying basal ganglia damage. When patients develop neuroleptic-induced parkinsonism, clinicians have a number of alternatives. These include reducing the dosage of the antipsychotic (which is most commonly a dopamine receptor agonist), adding an antiparkinsonism medication, or changing the patient to an SDA that is less likely to cause extrapyramidal adverse effects. The most effective antiparkinsonism medications are the anticholinergic drugs. Although these medications are frequently effective, they also cause their own adverse effects including dry mouth, constipation, blurred vision, and often memory loss. Also, these drugs are often only partially effective, leaving patients with substantial lingering extrapyramidal side effects. Centrally acting b-adrenergic receptor antagonists such as propranolol (Inderal) are frequently effective for treating akathisia; most patients respond to daily dosages between 30 and 90 mg. Clinicians may consider prescribing prophylactic antiparkinsonism medications for patients who are likely to experience disturbing extrapyramidal effects. These include patients who have a history of extrapyramidal sensitivity or those who are being treated with relatively high dosages of high-potency drugs. Prophylactic antiparkinsonism medications may also be indicated when high-potency drugs are prescribed for young men who tend to have an increased vulnerability for developing dystonias; these patients may also be candidates for the newer drugs. Some individuals are highly sensitive to extrapyramidal adverse effects at doses that are necessary to control their psychosis. For many of these patients, the adverse effects of the medication may seem worse than the illness itself. These patients should routinely be treated with an SDA because these agents result in substantially fewer extrapyramidal adverse effects than the dopamine receptor antagonists do. These highly sensitive individuals may actually experience extrapyramidal side effects on an SDA. Risperidone may cause extrapyramidal effects at higher dosages, (e.g., above 6 mg) and olanzapine, quetiapine, and ziprasidone may cause akathisia at their higher dosages. Tardive Dyskinesia and Other Tardive Syndromes Chronic treatment with an antipsychotic—usually for 6 months or more—can result in movement disorders including neuroleptic-induced tardive dyskinesia and other tardive disorders. Tardive dyskinesias commonly consist of abnormal, involuntary movements of the mouth, tongue, trunk, and extremities. The oral-facial movements occur in about three-fourths of patients with tardive dyskinesia and may include lip smacking, sucking, and puckering as well as facial grimacing. Other movements may include irregular movements of the limbs, particularly choreoathetoid-like movements of the fingers and toes and slow, writhing movements of the trunk. Younger patients with tardive dyskinesia tend to develop slower athetoid movements of the trunk, extremities, and neck. The abnormal movements of tardive dyskinesia are usually reduced by voluntary movements of the affected areas and are increased by voluntary movements of unaffected areas. The abnormal movements of tardive dyskinesia are usually increased with emotional arousal and absent when the individual is asleep. According to the research criteria in DSM-IV the abnormal movements should be present for at least 4 weeks and patients should have been exposed to an antipsychotic agent for at least 3 months (see Table 31.4-5). The onset of the abnormal movements should occur either while the patient is receiving an antipsychotic agent, within 4 weeks of discontinuing an oral agent, or 8 weeks after the withdrawal of a depot antipsychotic drug. Prevalence surveys indicate that 20 to 30 percent of patients who are chronically treated with a dopamine receptor antagonist exhibit symptoms of tardive dyskinesia. Three to 5 percent of young patients receiving a dopamine receptor antagonist develop tardive dyskinesia each year. The risk in elderly patients is much higher. Although seriously disabling dyskinesia is uncommon, a small proportion of patients have trouble walking, breathing, eating, and talking. Individuals who are more sensitive to acute extrapyramidal effects appear to be more vulnerable to developing tardive dyskinesia. Patients with cognitive disorders and mood disorders may also be more vulnerable to developing tardive dyskinesia than those with schizophrenia. All dopamine receptor antagonists are associated with a risk of tardive dyskinesia. Evidence from prospective studies indicates that clozapine is associated with a substantially lower risk than dopamine receptor antagonists. Anecdotal evidence indicates that clozapine can decrease abnormal movements in some patients with tardive dyskinesia. At this time it is unclear if the other SDAs are also associated with a lower risk than the dopamine receptor antagonists. The argument has been made that because these drugs are less likely to cause extrapyramidal side effects, they are less likely to cause tardive dyskinesia. For risperidone and olanzapine, prospective studies indicate new cases of tardive dyskinesia develop at a lower rate on these agents than on haloperidol. However, these studies are relatively small and include few cases of tardive dyskinesia. Until these findings are replicated with these agents or other SDAs, clozapine is the drug of choice for individuals who suffer from disabling tardive dyskinesia. A Task Force on Tardive Dyskinesia of the American Psychiatric Association recently made a number of recommendations for preventing and managing tardive dyskinesia. These include (1) establishing objective evidence that antipsychotic medications are effective for an individual; (2) using the lowest effective dosage of an antipsychotic drug; (3) prescribing cautiously with children, elderly patients, and patients with mood disorders; (4) examining patients on a regular basis for evidence of tardive dyskinesia; (5) considering alternatives to antipsychotic agents, obtaining informed consent, and also considering dosage reduction in patients who develop tardive dyskinesia; (6) if the tardive dyskinesia worsens consider a number of options, including discontinuing the antipsychotic drug, switching to a different drug, or a trial of clozapine. Regular monitoring for tardive dyskinesia should be a component of management strategies with antipsychotic drugs. The monitoring should be particularly careful for patients who have an increased risk for tardive dyskinesia, including elderly patients, patients who are sensitive to extrapyramidal side effects, and individuals with affective illness. Routine monitoring should include examination every 3 to 6 months, and high-risk groups should be monitored every 3 months. A summary of extrapyramidal syndromes is presented in Table 12.8-3.

Table 12.8-3 The Drug-Induced Extrapyramidal Syndromes

Other Adverse Effects Sedation and postural hypotension can be important adverse effects for patients who are being treated with low-potency DRAs, such as chlorpromazine and thioridazine, and clozapine. These effects are often most severe during the initial dosing with these medications, so it may be weeks before patients treated with these medications—particularly clozapine—reach a therapeutic dosage. Although most patients develop tolerance to sedation and postural hypotension, sedation may continue to be a problem. Daytime drowsiness may interfere with such patients attempts to return to community life. All of the dopamine receptor antagonists as well as risperidone increase prolactin concentrations, which can result in galactorrhea and irregular menses. Evidence suggests that prolactin elevation may impair libido in men and women. Fortunately, clozapine, olanzapine, quetiapine, and ziprasidone do not appear to elevate prolactin above normal concentrations. As a result, patients who demonstrate these symptoms on a dopamine receptor antagonist or risperidone and have high prolactin concentration should instead be given an agent that does not increase prolactin concentration. Many antipsychotic drugs cause disturbances in sexual function including ejaculatory or erectile disturbances in men and decreased libido in women; these effects result in a substantial amount of noncompliance in men. Thus clinicians should discuss issues of sexual functioning with patients and intervene when possible. It is unclear if any of the SDAs are associated with a reduced or greater risk of sexual dysfunction than the dopamine receptor antagonists. Adverse Effects of Clozapine Clozapine has a number of adverse effects that make it a difficult drug to administer. The most serious adverse effect is a risk of agranulocytosis, a potentially fatal condition that occurs in approximately 1 percent of patients treated with clozapine. As a result, patients who receive clozapine in the United States are required to be in a program of weekly blood monitoring for as long as they receive the drug. Clozapine is also associated with a higher risk of seizures than other antipsychotics. The risk reaches nearly 5 percent at doses over 600 mg. Patients who develop seizures while on clozapine can usually be managed by reducing the dosage and adding an anticonvulsant, usually a form of valproic acid (Depakene) or divalproex (Depakote). Other adverse effects with clozapine include hypersalivation, sedation, tachycardia, weight gain, fever, and postural hypotension.

NEGATIVE AND COGNITIVE SYMPTOMS Negative symptoms and cognitive impairment are associated with a substantial number of the social and vocational impairments of schizophrenia. This observation has resulted in a reappraisal of the goals of treatment, with a greater emphasis being placed on treatment strategies for decreasing the severity of these impairments. Most of the attention has focused on negative symptoms. Carpenter has made an important contribution to this area by classifying negative symptoms into primary and secondary categories. Secondary negative symptoms are those that may result from other conditions, such as depression or extrapyramidal side effects. The latter are a common cause of secondary negative symptoms, particularly when patients are experiencing akinesia, an adverse effect that can be manifest in decreased speech, decreased motivation, and decreased spontaneous gestures. In addition, positive or psychotic symptoms may result in secondary negative symptoms. A common example is the patient who is withdrawn or uncommunicative as a result of suspiciousness. The management of secondary negative symptoms begins with the management of the condition that caused these symptoms. For depression this may include the addition of an antidepressant medication; for extrapyramidal effects this may involve the addition of an antiparkinson medication, a dose reduction, or a change to an antipsychotic—usually an SDA—that is associated with less extrapyramidal adverse effects. If the previously mentioned causes of secondary negative symptoms have been ruled out, the patient is likely to be demonstrating a type of enduring primary negative symptom. Some evidence suggests that the SDAs are more effective in treating negative symptoms than conventional agents. However, it is unclear if these effects are related to a reduction in secondary negative symptoms. Until this issue is decided by adequate controlled studies, it is reasonable for clinicians to consider prescribing an SDA to patients who have substantial negative symptoms. Patients with schizophrenia frequently suffer from impairments in attention and information processing. These cognitive impairments can also interfere with their social and vocational rehabilitation, even when their psychotic symptoms have been well controlled. As with negative symptoms, cognitive impairments can be due to other causes such as substance abuse or drug effects of medications. The anticholinergic effects of either an antipsychotic or an antiparkinsonism medication such as biperiden (Akineton) or benztropine (Cogentin) can cause cognitive impairments that are difficult to distinguish from symptoms that are part of the schizophrenia. Decreasing the use of anticholinergic medication by changing to drugs that do not require antiparkinsonism medications—particularly SDAs—may be helpful. Evidence also suggests that clozapine, risperidone, olanzapine and other SDAs may be more effective at treating cognitive impairments than dopamine receptor antagonists. For example, a recent study found risperidone effective in improving verbal working memory. Others have reported that clozapine is effective for improving verbal fluency. Olanzapine has resulted in improvements in a number of cognitive measures. If confirmed, these findings will support the practice of treating cognitively impaired patients with schizophrenia with an SDA.

STRATEGIES FOR POOR RESPONDERS When patients with acute schizophrenia receive an antipsychotic medication approximately 60 percent improve to the extent that they will achieve a complete remission or experience only mild symptoms; the remaining 40 percent of patients improve, but still demonstrate variable levels of positive symptoms that are resistant to the medications. Rather than categorizing patients into responders and nonresponders, it is more accurate to consider the degree to which the illness is improved by medication. Some resistant patients are so severely ill that they require chronic institutionalization; others respond to an antipsychotic drug with substantial suppression of their psychotic symptoms but demonstrate persistent hallucinations or delusions. Before considering a patient a poor responder to a particular drug one must be certain that they received an adequate trial of the medication. A 6-week rial on an adequate dosage of an antipsychotic agent is considered reasonable for most patients. If patients demonstrate even mild improvement during this period, it may be reasonable to wait because data indicate that patients may improve at a steady rate for 3 to 6 months. It may be also be helpful to confirm that the patient is receiving an adequate amount of the drug by monitoring the plasma concentration. Information about therapeutic plasma concentrations is available for a number of antipsychotic drugs including haloperidol, clozapine, fluphenazine, trifluoperazine (Stelazine), and perphenazine (Trilafon). A very low plasma concentration may indicate that a patient has been noncompliant or, more commonly, only partially compliant. It may also suggest that the patient is a rapid metabolizer of the drug or that the drug is not being adequately absorbed. Under these conditions increasing the dose may be helpful. If the level is already relatively high, clinicians should consider whether adverse effects may be interfering with therapeutic response. If the patient is responding poorly, many clinicians will consider raising the dosage above the usual therapeutic level. The use of high dosage in poor medication responders has been studied under a number of circumstances. Nearly all studies found that higher dosages were not associated with greater improvement than conventional dosages, which suggests that changing to another drug is more likely to be helpful than increasing the dosage. A patient who has responded poorly to a conventional dopamine receptor antagonist is unlikely to do well on another dopamine receptor antagonist. Studies suggest that a poor response to one dopamine receptor antagonist is likely to be followed by a poor response to another; thus, changing to an SDA is more likely to be helpful. Substantial evidence indicates that clozapine is effective for patients who respond poorly to dopamine receptor antagonists. Double-blind studies comparing clozapine to other antipsychotic agents indicated that clozapine had the clearest advantages over conventional drugs in patients with the most severe psychotic symptoms as well as those who had previously responded poorly to other antipsychotic drugs. The most definitive evidence of clozapine's advantages in this population comes from a multicenter trial reported by John Kane in which clozapine was compared with chlorpromazine. This study was conducted on severely psychotic patients who had failed in trials with at least three antipsychotic drugs. Clozapine was significantly more effective than chlorpromazine in nearly every dimension of psychopathology, including both positive and negative symptoms. This study found that 30 percent of patients treated with clozapine met improvement criteria by the end of the 6-week trial. Studies of longer duration indicate that 60 percent of patients are likely to meet these same improvement criteria when patients are maintained on clozapine for 6 months. There is also evidence suggesting that risperidone and olanzapine may be helpful when a dopamine receptor antagonist is only partially effective. A Swiss study found that clozapine and risperidone were equally effective in a treatment-resistant population, but risperidone's side effects were more easily tolerated. Another study found that risperidone was somewhat more effective than haloperidol in a similar population and that risperidone was better tolerated. A multicenter comparison of olanzapine and haloperidol in a largely treatment-resistant group of patients found that olanzapine was more effective for both positive and negative symptoms. Taken

together these studies support the practice of trying patients on risperidone or olanzapine when they have responded poorly to a dopamine receptor antagonist. When switching patients from one antipsychotic to another clinicians should be aware that abrupt changes in drugs and dosage can have serious adverse effects in some individuals. For example, abrupt discontinuation or rapid dosage reduction of low-potency antipsychotics such as clozapine or chlorpromazine can lead to withdrawal adverse effects such as nausea or diarrhea. Anecdotal reports indicate that rapid discontinuation of clozapine can lead to severe psychotic relapse. When treatment is started with some antipsychotics such as clozapine or quetiapine, dosage titration often requires days or even weeks. For individuals who are being changed to treatment with one of these agents, the best strategy usually entails continuing the first agent until the patient is receiving a clinically effective dosage of the second drug. For these reasons, the best methods for switching drugs usually involve a cross-titration in which the patient is gradually changed from one antipsychotic to the other.

MAINTENANCE THERAPY During the stable or maintenance phase, patients are usually in a relative state of remission, with only minimal psychotic symptoms. The goals during this stage are to prevent patients from suffering psychotic relapse and to assist them to improve their level of functioning. Pharmacotherapy plays an important part in both of these goals. Medications are effective in preventing or delaying psychotic relapse and may also be an important adjunct in managing functional impairments that may interfere with rehabilitation; unfortunately, the adverse effects of medications can undermine these goals. Drug and Route of Administration for Maintenance Therapy Stable patients maintained on an antipsychotic drug have a much lower relapse rate than patients whose medications are discontinued. Although studies differ, most suggest that 16 to 23 percent of patients a year experience a relapse while receiving medications and 53 to 72 percent relapse without medications. Clinicians are often tempted to discontinue medications in patients who have een well and stable for prolonged periods; unfortunately, these patients also have high relapse rates when their medications are discontinued. Other evidence indicates that patients who experience relapses while they are receiving an antipsychotic drug have milder episodes than patients who relapse on no medication. Donald Johnson has reported that patients whose medications are discontinued are more likely to show dangerous behavior and are more likely to be admitted involuntarily. These observations about the effectiveness of continuing antipsychotic medication in stable patients have led to the recommendation that most patients with schizophrenia should receive an antipsychotic to prevent relapse. In 1989 the duration of maintenance was considered at an international consensus conference. This consensus group recommended 1 to 2 years of maintenance for patients following a first episode. Although this may be somewhat longer than current practice in many settings, it was recommended because individuals at this stage of their illness may have the most to gain if relapse can be prevented or delayed. First-episode patients may be working or involved in educational programs, both of which can be jeopardized by a second psychotic episode. The consensus conference also recommended that multiepisode patients receive maintenance antipsychotic for at least 5 years. For patients with a history of serious suicide attempts or violent, aggressive behavior, maintenance treatment with neuroleptics may be indicated for longer periods—perhaps indefinitely. The first 3 to 6 months following an acute episode was considered a period of stabilization when patients may not demonstrate acute symptoms but may nevertheless remain more vulnerable to relapse. The consensus conference recommended that following this stabilization period gradual dosage reduction should be implemented at the rate of approximately 20 percent every 6 months until a minimal maintenance dosage level is reached. There is also evidence that long-acting depot antipsychotic drugs may be the most effective agents for preventing relapse. A number of double-blind and uncontrolled trials have compared oral and depot treatment. The uncontrolled trials usually compared individuals who were assigned to a depot with those assigned to oral medications; patients assigned to depot medication usually demonstrated much lower rates of relapse. The results are less clear for well-designed double-blind studies. However, these studies tended to use highly selected groups of cooperative patients who were carefully monitored, which would tend to undermine the advantages of depot medications by excluding the patients who were most likely to benefit from this form of treatment: that is, patients with compliance problems. Nevertheless, even under these conditions, in a meta-analysis of six studies Janicak found an advantage in favor of depot treatment. Dosage Reduction Strategies Concerns about the long-term adverse effects of antipsychotic medications—particularly extrapyramidal effects and tardive dyskinesia—have led to a search for methods of treating patients with the lowest effective dose of medication. One strategy proposes using substantially lower antipsychotic dosages during maintenance treatment than those prescribed for initial short-term treatment. Studies indicate that many patients do well when they are treated with dosages that are approximately 20 percent of an initial treatment dosage. The low dosages were in the range of 4 to 10 mg of fluphenazine decanoate administered every 2 weeks. In 1997 Nina Schooler and her coworkers published the results from the Treatment Strategies in Schizophrenia multicenter study. Their 2-year comparison of low and conventional dosages found that low dosages in this range resulted in relapse rates that were slightly higher than those with conventional dosages but within an acceptable range. Moreover, other studies suggest that lower dosages are associated with milder side effects and better patient compliance. Another strategy, termed targeted or intermittent therapy, proposes gradually reducing and finally discontinuing the medications in stable patients. Patients are then monitored carefully, and medications are reintroduced if early signs of relapse appear. Controlled trials with this strategy have mostly shown discouraging results. Relapse rates were relatively high as were rates of rehospitalization. These results were confirmed in the Treatment Strategies Study in which rates of rehospitalization were significantly elevated in the targeted treatment group. Still another strategy combines the features of low- and targeted-dose strategies. In this method patients are treated with the same low doses of a depot drug that were used in the low-dose studies. Patients are monitored for early prodromal signs of relapse, and if these symptoms appear, patients are treated with oral medication. Results suggest that this is an effective strategy for making low-dose treatment safer. Although the SDAs may be excellent drugs for maintenance treatment, few controlled long-term trials have evaluated their effectiveness. Nevertheless, risperidone, olanzapine, quetiapine, and ziprasidone appear to have important advantages. Concern about adverse effects should be substantially less, which would allow clinicians to treat patients with dosages that should be associated with very low relapse rates. If findings suggesting that SDAs are associated with a reduced risk of tardive dyskinesia are confirmed, this advantage will provide a compelling reason to select these newer agents. Also, the improved side-effect profile may result in better medication compliance. The SDAs also have serious adverse effects that are likely to be important concerns during long-term treatment. Some of the newer agents—particularly olanzapine and clozapine—can result in substantial weight gain. Risperidone can cause some extrapyramidal effects and may cause problems related to increased prolactin concentrations such as irregular menstrual periods and galactorrhea. An important disadvantage of the SDAs is the lack of availability of long-acting formulations that are useful for patients who are unreliable pill takers.

INTEGRATING PHARMACOTHERAPY AND PSYCHOSOCIAL TREATMENT Most patients with schizophrenia will benefit from a combination of pharmacotherapy and psychosocial treatments. Recent improvements in both domains suggest that the overall outcome of this disorder can be improved if patients receive the optimal forms of both treatments at the appropriate stage of their illness. Research studies and clinical experience suggest that psychosocial treatments are probably most effective when patients have recovered from severe psychotic episodes. During the acute psychotic phase clinical management should emphasize maintaining patient cooperativeness and trust. This is particularly important when there is overt suspiciousness or a tendency to misinterpret the intentions of the treatment team. A successful strategy is likely to include clear explanations of the rationale for treatment and possible drug adverse effects. Family members may be important allies in ensuring cooperation, and family psychoeducation programs have been demonstrated to be helpful during this phase. It is difficult to generalize about the interactions of drugs and psychosocial treatments for stable patients because psychosocial treatments can vary greatly in terms of content and goals. Nevertheless, a number of important treatment principles can be drawn from the literature on combining treatments. The first is that psychosocial treatments are most likely to be effective when patients have been effectively stabilized on drugs. Early studies by Hogarty ndicated that psychosocial treatments could actually lead to a worse outcome when outpatients with schizophrenia were treated with a placebo. Other studies indicate that patients are most likely to respond to psychosocial treatments when their condition is stable. For example, a recent study with social skills training found that patients who received pharmacotherapy that minimized the proportion of time that they were in a psychotic state also demonstrated the greatest improvements in social adjustment. Psychosocial treatments may also improve patient response to pharmacotherapy by improving medication compliance. This was suggested in a study in which patients received a form of family treatment that also encouraged medication compliance. Other studies have indicated that psychosocial treatments—particularly family treatment—may decrease the amount of stress that the patient experiences within the family and that this, in turn, decreases the amount of antipsychotic

medication required by the patient. The introduction of the newer antipsychotics may result in much greater interest in psychosocial interventions. Patients who receive the newer agents may be better candidates for psychosocial treatments when treatment with these agents is associated with improvements in negative and cognitive symptoms as well as reduced adverse effects. Also, patients who improve on clozapine, risperidone, olanzapine, or other drugs may initially appear ready to return to community life. However, these individuals then experience a series of frustrating failures at work, school, or social relationships, which indicate that drug therapy alone may not suffice to prepare them for their new roles.

SUGGESTED CROSS-REFERENCES For further information related to assessment of the patient with schizophrenia see Section 7.3 on typical signs and symptoms of psychiatric illness and Section 7.8 on psychiatric rating scales. Chapter 12 on schizophrenia is important for a full understanding of the syndrome. To appreciate the antipsychotic medications see Section 31.17 and Section 31.26 on antipsychotic drugs. As other medicines are used to augment antipsychotic medications, see the other sections of Chapter 31 on biological therapies. SECTION REFERENCES American Psychiatric Association: Practice Guideline for the treatment of patients with schizophrenia. Am J Psychiatry 154(Suppl):1, 1997. Baldessarini RJ, Cohen BM, Teicher MH: Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 45:79, 1988. Baldessarini RJ, Frankenburg FR: Clozapine: A novel antipsychotic agent. N Engl J Med 324:745, 1991. Bollini P, Pampallona S, Orza MJ: Antipsychotic drugs: Is more worse? A meta-analysis of the published randomized control trials. Psychol Med 24:307, 1994. Carpenter WT Jr, Heinrichs DW, Wagman AMI: Deficit and nondeficit forms of schizophrenia: The concept. Am J Psychiatry 145:578, 1988. Conley RR, Carpenter WT Jr, Tamminga CA: Time to clozapine response in a standardized trial. Am J Psychiatry 154:1243, 1997. Falloon IRH, Liberman RP: Behavioral family interventions in the management of chronic schizophrenia. In Family Therapy in Schizophrenia, WR McFarlane, editor. Guilford Press, New York, 1983. Goldstein MJ, Rodnick EH, Evans JR: Drugs and family therapy in the aftercare of acute schizophrenics. Arch Gen Psychiatry 32:1169, 1978. Hogarty GE, Anderson CM, Reiss DJ, Kornblith SJ, Greenwald DP, Jabna CD, Medonia MJ: Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia: I. One year effects of a controlled study on relapse and expressed emotion. Arch Gen Psychiatry 43:633, 1986. Hogarty GE, Anderson CM, Reiss DJ, Kornblith SJ, Greenwald DP, Ulrich RF, Carter M: Family psychoeducation, social skills training, and maintenance chemotherapy in the after-care treatment of schizophrenia: II. Two-year effects of a controlled study on relapse and adjustment. Arch Gen Psychiatry 48:340, 1991. Janicak PG, Davis JM, Preskorn SH, Ayd FJ: Principles and Practice of Psychopharmacology. Williams & Wilkins, Baltimore, 1993. Kane JM, Honigfeld G, Singer J, Meltzer H, the Clozaril Collaborative Study Group: Clozapine for the treatment-resistant schizophrenic: A double-blind comparison versus chlorpromazine/benztropine. Arch Gen Psychiatry 45:789, 1988. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: Combined results of the North American trials. J Clin Psychiatry 58:538, 1997. Marder SR, Hubbard JW, Van Putten T, Midha KK: The pharmacokinetics of long-acting injectable neuroleptic drugs: Clinical implications. Psychopharmacology 98:433, 1989. Marder SR, Wirshing WC, Mintz J, McKenzie J, Johnson K, Eckman T, Lebell M, Zimmerman KZ, Liberman RP: Behavioral skills training versus group psychotherapy for outpatients with schizophrenia: Two-year outcome. Am J Psychiatry 153:1585, 1996. *Robinson DG, Woerner MG, Alvir JJ, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieberman JA: Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 156:544, 1999. Rosenheck R, Cramer J, Xu W. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 337:809, 1997. Schooler NR, Keith SJ, Severe JB, Matthews SM, Bellack AS, Glick ID, Hargreaves WA, Kane JM, Ninan PT, Frances A, Jacobs M, Lieberman JA, Mance R, Simpson GM, Woerner MG: Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment. Arch Gen Psychiatry 54:453, 1997. Tollefson GD, Beasley CM Jr, Tamura RN, Tran PV, Potvin JH: Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 154:1248, 1997.

Textbook of Psychiatry

12.9 SCHIZOPHRENIA: PSYCHOSOCIAL TREATMENT Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.9 SCHIZOPHRENIA: PSYCHOSOCIAL TREATMENT JUAN BUSTILLO, M.D., SAMUEL J. KEITH, M.D. AND JOHN LAURIELLO, M.D. General Considerations Individual Psychotherapy Group Therapy Family Therapy Psychiatric Rehabilitation Social Skills Training Services Delivery Systems Case Management Residential Treatment and Housing Programs Suggested Cross-References

Central to the enthusiasm for psychosocial treatments has been the question of whether applying psychosocial treatment to an illness like schizophrenia implies a belief in a psychosocial origin or causality of the disorder. For the era of the 1960s the belief systems of the time posited such causality as schizophrenogenic mothers, double-binds, and familial pathogenesis. Elements observed in families with a schizophrenic member were linked to causality in a post hoc or propter hoc manner. While few hold tenaciously to such concepts now, the pain and suffering inflicted on families during that period of thought still resonates through the professional community. It was a time when families were accused of causing schizophrenia, excluded from the treatment process, and forced to pay the financial and psychological price for both. As an almost predictable result of such accusations and attributions, the families of the severely mentally ill joined forces to fight the remnants of such thinking. However, by 1979, when the National Alliance for Mentally Ill was founded, much of this thinking had receded and the theory that such illnesses were biologically determined and should be biologically treated was proposed. Proposals even surfaced to move research on illnesses like schizophrenia from the National Institute of Mental Health to the National Institute of Neurologic Diseases and Stroke because this would be a more appropriate place for a neurobiological illness to be treated. Psychosocial treatments were frequently seen as merely a means to increase medication compliance and were looked at by some family advocates as psychiatry's new means of blaming the family for causing this illness. Fortunately, this was also an era of rapid growth in research studies on psychosocial treatments, and it would eventually be the data that preserved and advanced the knowledge and utilization of psychosocial treatments. Psychiatry has been fortunate in possessing one of the richest and most extensive data bases in all of medical science. The role of clinical trials in establishing which treatments are effective for which populations has become one that mental health professionals have thoroughly embraced. The field has moved away from blind belief systems and the great-person hypothesis (i.e., if a great person said to do it a certain way, that was the way it was done) toward testable and tested hypotheses.

GENERAL CONSIDERATIONS The assumption that psychosocial treatments have the ability to effect change carries with it the possibility that the change can go in either a positive or negative direction. It is important to examine the potential for gains and losses for specific modalities. Intensive individual psychotherapy brought about a level of intensity that may have been too high for people suffering from severe psychosis. The intensity of the environment is a critical factor in modulating treatment impact. There is substantial literature from England that has tried to link an overinvolved, intense, hostile, critical environment (i.e., expressed emotion) with poor outcome in schizophrenia. Originally this type of environment was associated with families of origin and was correctly perceived by families as disguised finger pointing. Additional studies were able to point out that others, including care providers, were certainly able to produce similar environments iatrogenically. One leading British investigator has noted that in a total push rehabilitation program in which treatment is very intensive with high expectations, he was able to produce dramatic relapse rates in an otherwise well-stabilized population. From the other side of intensity, however, comes the clear demonstration that institutional environments lacking almost completely in stimulation will produce rather striking negative symptoms of schizophrenia. The psychosocial treatment of schizophrenia includes the role of individual, group, and family therapies; the forms of vocational rehabilitation; and the various service delivery models available.

INDIVIDUAL PSYCHOTHERAPY It is important to note that psychiatric research has always questioned the efficacy of the treatments for mental illness. The 1960s began with intensive individual psychotherapy serving as the main treatment for schizophrenia with little faith placed in other possible treatments. The first major study to question this belief was conducted at Camarillo State Hospital, California, and involved five modalities: antipsychotic medication alone, antipsychotic medication plus individual psychotherapy, individual psychotherapy alone, electroconvulsive therapy (ECT), and milieu alone. The results of this study showed that modalities that contained the antipsychotic medication did best; the effect of ECT was intermediate; and the modalities that did not use antipsychotic medication (individual psychotherapy alone and milieu alone) did the poorest. Traditional psychodynamic advocates criticized the study for using inexperienced therapists, setting it in a state hospital, not continuing the pharmacology into the community, and because the psychotherapy was not intensive enough (twice a week). A study was conducted to answer these criticisms in the 1980s in Boston at McLean Hospital and Boston University using therapists with more than 3 years of experience with intensive psychotherapy with schizophrenia patients; the pharmacology was continued into the community and the intensive therapy was conducted three times a week. The results of this study, which compared the intensive form of psychotherapy with a supportive form given 60 minutes each week, were quite striking: the more severely ill patients dropped out of the intensive psychotherapy, but not out of the supportive version; despite this differential attrition, in only one outcome measure—ego functioning—intensive treatment had an advantage. Overall any advantages at all favored the supportive group. Intensive individual psychotherapy for schizophrenia would continue to be practiced (for a small group of functional patients who were relatively stable and could afford it), but not based on evidence that it was effective for the general population of schizophrenia patients. This research on psychosocial treatments moved the field away from the idea that greater intensity was better. Moreover, with the rise of biological psychiatry the field could no longer assume pure psychological causes for schizophrenia. This was now an era that looked toward genetic linkage, enlarged lateral ventricles, and hypofrontality of cerebral functioning. However, in the daily struggles with life, persons suffering from schizophrenia think little of these biological variables but rather about their relationships, their ability to be financially self-supporting, and the skills needed to navigate the complex society they live in. Treatments need to be used that first eliminate symptoms and prevent relapse, after which the skills of daily living and relating need to be achieved. Researchers at the University of Pittsburgh have recently published the results of a 3-year randomized trial of individual interpersonal therapy for schizophrenia compared to family therapy, combined treatment and supportive therapy. Personal therapy was conducted weekly following an incremental approach individualized for the patients' stage of recovery: The initial phase focused on the relationship between stress and symptoms; the intermediate phase emphasized learning to use relaxation and cognitive reframing techniques when stressed; the advanced phase (which generally started 18 months into treatment) focused on seeking social and vocational initiatives in the community and applying what was learned in interpersonal therapy. Social adjustment (a composite measure including work performance, leisure, and interpersonal relationships) clearly favored the interpersonal therapy group. The greatest differential improvement took place in the last two years of treatment, however there were no advantages in relapse for interpersonal therapy. Relapse rates were low, only 29 percent in 3 years.

GROUP THERAPY The systematic provision of care for persons with schizophrenia in a group setting has followed the general principles of both psychodynamic and behavioral (learning) theories. The behavioral approach has resulted in well-structured interventions (social skills training, social problem-solving, and cognitive remediation) that are often delivered in a group setting. The psychodynamic group therapies, like the individually based approaches, exist along a continuum between intensive and supportive forms. There have been no studies to date comparable to the Boston Psychotherapy Study on individual therapy of schizophrenia in methodological rigor that test the efficacy of intensive versus supportive group therapy. A few studies have evaluated the effects of adding group therapy (mostly supportive form) to standard antipsychotic medication in a controlled design. For inpatients, the advantage of adding group therapy appears almost negligible. In one of the better-designed studies, investigators evaluated insight-oriented group therapy during the first 3 weeks of hospitalization. The comparison conditions were a task-oriented group and an unstructured control group. Patients with psychosis in the

insight-oriented group did particularly poorly, with an actual worsening in symptoms ratings. Addition of group therapy to medication for outpatients also suggests very limited effects. The one outpatient study with a large sample ( N = 100) that actually compared group with individual therapy for the treatment of schizophrenia found advantages in psychopathology and social adjustment ratings for group treatment after 2 years. Nevertheless, this study was more a naturalistic evaluation of effectiveness in a clinic setting than a true efficacy study. There was no attempt to standardize both interventions or to ensure that the patients received optimal and equivalent pharmacotherapy. In summary, there is little empirical evidence and no compelling theoretical reason to justify submitting an acutely psychotic inpatient to a potentially intrusive and overstimulating group intervention. Similarly, the evidence for a specific psychodynamic effect of group treatment in schizophrenia is quite limited. Supportive outpatient group therapy most likely has a modest effect and will probably continue to be used as a practical setting to monitor symptoms and medication compliance and to provide ongoing education for the person with schizophrenia.

FAMILY THERAPY The role of the family in the treatment of schizophrenia has gone through a number of changes. The present context sees the family as very important clinically. First, it has been clearly demonstrated that even as passive participants, family members are extraordinarily important in providing the clinical treatment team with accurate information on how the patient is doing. It is clear that families identify impending signs of relapse much earlier in the illness than do patients, who tend to lack insight into the onset of the psychotic process. The scientific investigations on family therapy since the 1970s, however, have gone much further than passive participation in the treatment process; families have been invited to become active members of the clinical treatment team. Families are perhaps the most consistent factor in a patient's life. Over 60 percent of patients discharged from a psychiatric facility return to their families of origin. Early in the course of the illness, this figure is much higher. Further, even patients who do not reside with their parents frequently remain in close contact with them. With today's shrinking resources for psychiatric care, the family represents a resource that could not be easily replaced. Many families are interested in participating in a treatment program, particularly early in the treatment process and particularly if they are welcomed and valued. There must, however, be a series of caveats in regard to the involvement of the family in the treatment process. First, mental health systems have looked to many types of facilities to house the mentally ill. It should not be a part of a family's role to turn their home into a psychiatric ward. Many families will want to have their family member at home; some will not. Both positions should be given equal respect. Further, the family should not be seen as the long-term caregiver; their energies and good will should be used in the development of transitional strategies or burnout will occur with rapid demoralization and an increasing likelihood of patient relapse. Third, it cannot be emphasized enough how sensitive families are to criticism. The historical context in which they were disparaged has made them justifiably suspicious of their role vis-a-vis psychiatry; this is compounded by their natural feelings of guilt and responsibility. All efforts must be directed initially at reducing this guilt to its lowest possible level. The treatment focus should be on what families can do positively. The negative factors that need to change must do so in the context of an accepting clinical alliance. It was first noted in a landmark study in Ventura, California, how the addition of a family component over a brief 6-week period provided significant protection against relapse regardless of the medication status of the patient. The effect of this family involvement was present at the end of 6 months despite the brevity of the therapy. This particular family therapy focused on clarity of communication and limited problemsolving. The next contribution to establishing the importance of the role of the family in the treatment of schizophrenia came from studies conducted in the United Kingdom. Expressed emotion describes a critical, overinvolved environment that led to relapse rates exceeding 50 percent in its presence and 20 percent in its absence. These findings have now been replicated across many cultures and countries worldwide and a number of strategies were developed to take advantage of this new information. These strategies differed in where the treatment was delivered (inpatient setting, clinic, or home), whether the patient was acutely ill or stabilized, whether the patient and family were seen as an individual unit or in groups, and what the family treatment was compared to. The first generation of studies produced remarkably homogeneous results. Studies were done that added family therapy to energetic social treatments, to medication programs, and to other forms of common treatments. Each of these was able to find a major benefit from the addition of family therapy. The one study done on an inpatient unit with the family therapy added to a well-conducted inpatient program also found significant positive results from this addition. There have also been studies that compared family therapy to individual therapy. One that was conducted in Los Angeles compared individual psychotherapy to a form of behavioral family therapy conducted in the home. The results of this study in terms of symptom exacerbation and relapse were strikingly in favor of the family therapy. Further, although it did not reach significance, there was a strong suggestion that this strategy of in-home sessions was responsible for the use of less medication in those treated with family therapy. These studies were all of a first-generation type, that is, they were done by people who designed the treatment and were heavily involved in its delivery. A second-generation study in which the developers of the treatment taught others how to deliver it but did not treat patients themselves has now been completed by the National Institute of Mental Health (NIMH) in a five-site collaborative study. The importance of such second-generation studies for public health purposes is critical: the methodology must be transferable or it can never be used in any sort of general manner. The NIMH study compared an in-home (weekly for the first 3 months, biweekly for the next 6 months, and monthly to complete the first year) intensive behavioral family therapy in conjunction with a monthly multiple family and patient group meeting to monthly family and patient group meetings alone. The study was able to demonstrate a number of issues: first, that the family home-based treatment could be taught to clinicians; second, that families and patients would participate; and third, that those families who did participate in the initial component of the treatment (a 4-hour psychoeducational workshop) had better initial outcomes. The overall outcome of the study, however, showed no differences between the intensive, in-home treatment plus the monthly group meeting and the monthly group meeting by itself. One possible interpretation of these results is that there is a general positive outcome from involving families in a therapy program that respects their needs and that provides them with useful clinical information, but that the ultimate refining of the procedure does not appear to add significantly to the outcome. Consistent in the principles of family therapy is the establishment of a positive alliance with the family. Families should be provided psychoeducational material about schizophrenia that includes basic, clinically useful information such as identification of early signs of relapse, the role of medication, and anticipated adverse effects of these medications. Families and patients need to learn simple communication skills (e.g., how to make a positive request, how to make a negative request, how to use “I” statements). In addition, simple problem-solving skills (e.g., identification of a problem, listing of possible solutions, selecting the solution, practicing the solution, implementing it, and reviewing the outcome) should also be taught. Finally, helping the family expand its social network is extremely important. Each of these components can be delivered in a neutral context of caring and the results achieved are incontrovertible.

PSYCHIATRIC REHABILITATION Because the majority of persons with schizophrenia, even those with a favorable response to antipsychotic medications, will have residual symptoms, cognitive impairments, and limited social skills, psychosocial interventions aimed at the functional rehabilitation of the patient have been designed and systematically studied since the 1980s. Largely following the work on persons with physical disabilities, psychiatric rehabilitation uses principles of learning and social systems theories to effect three types of changes: (1) direct improvement of the disability, (2) development of a new skill that circumvents the original impairment, and (3) targeted manipulations of the environment to make it more supportive and to improve functioning. The common goal of these interventions is to improve the person's social competence in self-care, work, leisure, relationships, and parenting. Improvement in any of these areas contributes to more autonomous functioning in the community. Two broad types of clinical studies have looked at the effects of psychiatric rehabilitation: studies of social skills training and studies of particular systems of delivery of mental health services. Both these have been evaluated in several randomized controlled studies, but the studies differ in their methodological rigor and potential for applicability in the community. The clear advantage for the studies of social skills training is the ability to more clearly interpret the findings in terms of the specific teaching techniques used. Studies of social skills training are limited by questions of its generalization to more naturalistic settings. Conversely, studies of systems of delivery of services offer a better opportunity of rapid applicability in the community, although their specific reason for working is difficult to identify. In the current era of managed care and financial restraint it is particularly important to determine which elements of a package of care are essential and which are superfluous. Therefore studies that use specific learning technologies, which have the potential to be assembled in different systems of delivery depending on the needs of particular patients and the resources available, offer the greatest potential.

SOCIAL SKILLS TRAINING Social skills have been described as those specific response capabilities necessary for effective social performance. By definition all patients with schizophrenia are, at least during a considerable period of time, impaired in one or more social skills. To what extent these limitations are secondary to the positive symptoms, negative symptoms, and cognitive impairments of schizophrenia is still debated. The severity and persistence of symptoms and cognitive deficits undoubtedly contribute to the

poor social competence. The ‘lost opportunities' to acquire the skills, especially during the crucial developmental years of adolescence and early adulthood when the illness first manifests, could also importantly determine the impaired social competence. Social skills training should be distinguished from the activities in other rehabilitation programs in which the acquisition of skills occur incidentally. Three important social skills models are the basic social skills model, the social problem-solving model, and the cognitive remediation model. Basic Social Skills Model Also known as the motor skills model, the basic social skills model was developed in the 1970s and has been studied in controlled-randomized clinical trials with schizophrenia patients since the 1980s. Typically, dysfunctional complex social behaviors are identified and broken down into more elementary tasks, which are learned through repeated performance; then the elements are combined into a more complete functional repertoire. A socially withdrawn patient may be taught the set of skills necessary to start a casual conversation with a stranger. The patient may first be videotaped while role-playing a conversation with a confederate; then the therapist provides feedback with the videotape focusing on elementary behaviors: Is there avoidance of eye contact or too intense gazing? Are the answers too short and the speech barely audible? Does the patient ask follow-up questions that denote interest and promote the flow of the conversation? Each elementary behaviors (e.g., contact, speech volume, length of response, questions) are repeated until learned. The therapist may model the behavior. Next, the patient role-plays the integrated social repertoire and finally practices it in a natural setting. The literature is consistent in that patients with schizophrenia can be taught various social skills that can be retained for up to 12 months. The data on whether the social skills learned will lead to an improvement in other important clinical measures, such as symptom severity and relapse rate, are mixed. In one of the most rigorous clinical trials of social skills training to date, researchers at the University of Pittsburgh compared relapse rates for outpatients with schizophrenia assigned to an individually administered program of social skills training plus antipsychotic medications with a group that only received pharmacotherapy. At 1 year of follow-up, there was a 46 percent rate of relapse in the control group compared to 30 percent in the social skills training group. The difference remained statistically significant in favor of social skills training for up to 21 months but not at the end of the study (24 months). The limited durability of a therapeutic effect in schizophrenia is not unique to social skills training and it should be viewed in the context of the total period of time during which the intervention is applied. For antipsychotic medications too, relapse prevention is closely related to length of exposure to treatment. For psychosocial interventions in general and social skills training in particular, booster sessions or continuous treatment may be required in order to maintain a favorable effect on relapse rates. Even if schizophrenia patients learn social skills, the extent to which these skills generalize in the patients' natural environment and result in improved social competence is a crucial measure of outcome. Generalization has not been clearly demonstrated for the motor skills model. In part to deal with this limitation, problem-solving techniques have been integrated with the more traditional social skills training model. Social Problem-Solving Model Developed by researchers at the University of California at Los Angeles, this model uses social learning principles and assumes that impairments in information processing underlie the limited social competence present in the patient with schizophrenia. Like traditional social skills training, complex problem behaviors are identified. Patients can then be assigned to each of five target modules for improvement: (1) medication management, (2) symptom management, (3) recreation, (4) basic conversation, and (5) self-care. For each of these modules an emphasis is placed on learning, receiving, processing, and sending skills, in the hope that these will increase flexibility, durability, and generalization of the module learned. Receiving skills are those skills necessary to appropriately identify social cues. Processing skills deal with the context-appropriate interpretation of input information and the generation of the various potential responses. Sending skills correspond to the behaviors targeted by the traditional motor skills model. A recent study reported the results of a 2-year study comparing problem-solving group therapy with supportive group therapy for relapse prevention and social adjustment in outpatients with schizophrenia. Each group received the same intensity, frequency, and overall length of psychosocial treatment. There was a small but statistically significant advantage for the experimental intervention in two out of six measures of social adjustment after 2 years. There were no differences in relapse rate. Therefore the benefits of the problem-solving therapy were modest at best. It has been argued that for many patients with schizophrenia deliberately evaluating a social situation in terms of information-processing skills may be particularly difficult and could actually limit the acquisition of social skills. The traditional strategy of simple practice so that overlearned responses can be emitted automatically may be more advantageous. The social problem-solving model will require further evaluation but it offers advantages resulting from its potential for applicability: the modules are clearly structured, manuals are available for patients and therapists, and each module stands independently and can be implemented according to the individual patient's needs. A recent report on this model found it to be more effective in a measure of independent living skills than in a control condition. This effect was maintained even 18 months after completing the intervention. Cognitive Remediation That patients with schizophrenia have a multiplicity of cognitive impairments is well established. These are most likely not just epiphenomena of symptom severity or medication adverse effects because they are present in various subclinical populations (children at high risk for schizophrenia, nonpsychiatric relatives of schizophrenia patients, and persons with schizophrenia-spectrum [Cluster A] personality disorders). The cognitive impairments are usually generalized, but specific functions like attention, memory, and planning may be more impaired than others. The use of cognitive remediation of schizophrenia is relatively new, and the impaired functions that underlie the generalized deficit, as well as the failure in social competence, have yet to be fully established. Researchers have reasoned that the limitations on the durability and generalization of social skills training may be overcome by improving the impairments in basic cognitive functions before teaching social skills. Studies on cognitive remediation of schizophrenia are few in number. There is some evidence that patients can improve their performance through practice in measures of vigilance and planning. Nevertheless, transfer of learning to another test has not been documented, even within the same cognitive domain (vigilance or planning), let alone showing any evidence of generalization to particular social skills. Probably the most comprehensive hierarchical program, which attempts to teach social skills by building upon learning on elementary cognitive functions, is the integrated psychological treatment for schizophrenia devised by researchers in Switzerland. Patients are seen in a group setting three times a week over 3 months and begin training in card sorting and concept formation using computer games (cognitive differentiation subprogram). This is followed by exercises fostering social problem-solving (social perception and verbal communication subprograms). The final subprograms (social skills and interpersonal problem-solving) resemble the more traditional motor skills model. Although the few controlled studies of integrated psychological treatment in schizophrenia show some modest gains in elementary cognitive functions and some learning in social skills, this preliminary literature is not supportive of the view that improved basic cognitive performance will predict acquisition of social skills. The generalization of integrated psychological treatment to measures of symptomatology and social competence in the community remains to be assessed. It has been argued that until more is known about the specific cognitive dysfunctions in schizophrenia and the way these might determine higher-order problems in social competence, cognitive remediation may be more successful by focusing on cognitive schemas more closely linked to relevant patterns of psychopathology. Schizophrenia is most likely a heterogeneous disorder. Studies of cognitive psychopathology suggest three clinical syndromes within the disorder: psychomotor poverty, disorganization, and reality-distortion, each with an underlying faulty cognitive style. The psychomotor poverty syndrome may be characterized by a failure to initiate a cognitive set, leading to mental poverty and apathy. The disorganization syndrome is a failure to maintain a cognitive set, leading to distraction and disorganized thinking. Finally, the reality-distortion syndrome is an inability to change cognitive sets, resulting in fixed beliefs and misinterpretation of internal stimuli. It has been suggested that initial training in these cognitive styles for patients selected on the basis of their symptomatology may be more fruitful than remediation of nonspecific elementary cognition and may lead to greater flexibility than traditional social skills training. These techniques focus on improving faulty cognitive processes. Recently there has been an interest in cognitive-behavioral therapy of schizophrenia, which focuses on the content of the symptoms. Researchers in United Kingdom have applied coping strategy enhancement for residual psychotic symptoms. The goal is to teach coping mechanisms that will distract patients and help them ignore their symptoms, hopefully decreasing their distress. Initial reports suggest a beneficial effect on delusions with loss of effect at 6 months and limited generalizability to other symptoms or social functioning. A different approach, and closer to the original cognitive-behavioral therapy for depression, this modality consists of a gentle but systematic verbal challenge of the delusional belief. This is followed by a behavioral experiment that does not support the delusional belief. The outcome of the experiment (reality testing) reinforces the verbal challenge. This technique may help decrease the severity of delusions. Persistent hallucinations seem particularly resistant to cognitive-behavioral therapy, perhaps because of the recurrence of internally generated stimuli that the patient misattributes to an external source. A recent approach attempts to help patients reattribute the voices to themselves through focusing on the meaning and other characteristics of the hallucinations. These content approaches may offer hope for some patients with persistent delusions or hallucinations. Nevertheless, these studies should be viewed as preliminary and awaiting replication in well-controlled studies with larger samples. Social skills training has been shown to improve social competence in the laboratory and the clinic. The extent to which this learning translates into better role functioning in the community has yet to be determined. Therapeutic effects have been demonstrated for social skills training in clinical measures like relapse rate, but because of the limited durability, booster or follow-up sessions may be required.

SERVICES DELIVERY SYSTEMS The period of deinstitutionalization of care for the mentally ill in the United States began in the 1950s and peaked in the 1970s. This massive relocation of patients from state hospitals to the community implied but frequently did not deliver a parallel shifting in delivery of services on a long-term basis. These services not only

included the continued provision of psychiatric treatment to prevent rehospitalization, but the availability of stable and secure housing and systematic efforts to rehabilitate and reintegrate patients into the workplace. Vocational Rehabilitation Work has been viewed as an important element of the treatment of schizophrenia dating back to the era of the large asylums, which often had farms or other protected settings for patients to work in. With the modern goal of maintaining patients to be as functional and autonomous as possible in the community, various programs to help patients find and maintain jobs have been implemented. Despite these efforts, rates of competitive employment for chronically mentally ill persons have been estimated to be less than 20 percent and are more likely to be lower for patients with schizophrenia. With the current average hospital stay being shorter than 2 weeks, there are practically no hospital-based workshop programs and most vocational rehabilitation takes place in the community. These programs are very heterogeneous but can be subsumed under four models: (1) job clubs, (2) Boston University model, (3) transitional employment, (4) and supported employment. Job clubs were originally used to help unemployed nonpsychiatric persons to find jobs. This approach focuses on teaching individuals how to look for a job and how to apply for it; there is no actual teaching of job skills. Because past history of competitive employment is the best predictor of future employment, this approach is probably not useful for the majority of patients with schizophrenia who never learned particular job skills. The Boston University Model is an intensive and individualized program. A patient and a counselor first identify a specific paid job that the patient would like to obtain. Then they both proceed through a systematic review of the skills needed for the job, the skills the patient has, and the resources available to improve these skills. A plan is defined that usually takes, 1 or 2 years to implement. This model may be most helpful for younger, less disabled patients who have a prospect for long-term career choices. The transitional employment program (the train-and-place model) is exemplified by Fountain House, one of the oldest rehabilitation programs in the United States. Initially, the patient's work aptitudes and preferences are assessed. Next, patients are taught general work habits (e.g., appropriate appearance, keeping hours, asking for clarification, following through). Then patients start working in a sheltered program that is usually owned by the rehabilitation agency, learning more specific skills like typing, filing, janitorial work, or maintenance routines. Once a certain level of competency has been consistently maintained for a period of time, they are placed in a regular job. Many of the most severely disabled patients with schizophrenia are incapable of moving beyond the sheltered workshop level. The transitional process of training, sheltered work, and placement appears to reduce stress related to the demands of employment. Supported employment is the most recent approach. It attempts to improve the opportunities for competitive employment by referring the patient to a regular job that is intended to be permanent. Unlike in the transitional model, the job identified for the patient is not owned by the rehabilitation agency. The patient's skills and a job that matches these skills are identified and the patient begins to work. The goal is for the patient to develop the necessary skills while working, getting on-site support and training from a work coach. This on-site job training was developed for developmentally disabled individuals who require initial high-intensity services that are later phased out. For persons with schizophrenia some form of continuous long-term on-the-job training may be needed. Outcome research for these vocational rehabilitation programs is particularly limited by the lack of standardization of the experimental intervention and the difficulty in implementing adequate control treatments. Another limitation is that in these studies patients are not usually differentiated diagnostically, but lumped as chronically mentally ill or psychiatrically disabled. Also, the adequacy of pharmacological treatment is generally assumed. Various vocational outcome measures are used: job performance and satisfaction, earnings, percentage of time employed, and maintenance of a full-time or part-time job or competitive employment. Full-time competitive employment is the most desirable outcome measure. A meta-analysis on 19 controlled studies of various vocational rehabilitation interventions found a 51 percent rate of paid employment in the experimental group compared to 29 percent for the control group, a significant difference. There were additional advantages for vocational rehabilitation in terms of job starts and longer duration of employment. In none of the studies did the outcomes favor the control interventions. Nevertheless there were no differences in terms of competitive employment in any of the studies after the patients were discharged from the programs. The success of these interventions has been mostly to help patients to adapt to a specific transitional or sheltered employment, but they have failed to prepare them for future regular employment. Results from two recent studies involving supported employment provide a more hopeful outlook. In a quasiexperimental study in New Hampshire researchers compared vocational outcomes in two groups: patients involved in a traditional partial hospitalization program and those assigned to an integrated program of supported employment and intensive case management. During the follow-up year the experimental group significantly increased its rate of competitive employment by 14 percent while there was no improvement in the control group. In another study, researchers in Indiana compared two forms of supported employment programs: one with gradual entry and the other with accelerated involvement in the job. The accelerated-entry patients showed significantly superior outcomes in competitive employment at 1-year follow-up (56 versus 29 percent). Several vocational rehabilitation studies have also measured other clinically relevant outcomes, like rate of hospitalization, medication compliance, and substance abuse; most of these studies find advantages for the experimental treatment. Nevertheless, a causal relationship cannot be inferred from these studies because they all fail to describe other important clinical interventions and patient characteristics. In summary, vocational rehabilitation programs by definition enhance job-related activities in chronically mentally ill patients (including persons with schizophrenia), but they do not have significant effects on competitive employment once the patient leaves the program. However, there is reason for optimism with some forms of supported employment.

CASE MANAGEMENT Patients with schizophrenia are often ill prepared to find and maintain proper use of the multiple services they need in order to function in the community. The providers of these services include psychiatrists, nurses, pharmacists, general practitioners, dentists, psychologists, social workers, vocational and recreational therapists, home supervisors, patient advocates, lawyers, and benefits officers. Case managers function at two ends of a continuum: the broker approach and the intensive case management approach. At a minimum, case managers function as brokers of services and are contacted by other professionals. Case managers identify a new need for the patient and referring the patient to the provider able to deliver these services. This approach may be sufficient for patients with physical disabilities and for some patients with mental illness of moderate severity. Unfortunately, many patients with schizophrenia lack the level of cognitive and social competence to consistently follow through and get their needs met. The polar opposite of the case-manager-as-broker is exemplified by the Assertive Community Treatment (ACT) program. Originally developed by researchers in Madison, Wisconsin, in the 1970s, this is the most carefully defined, well-documented, and successful program for the delivery of services for persons with chronic mental illness. Patients are assigned to one multidisciplinary team (case manager, psychiatrist, nurse, general physician, etc.). The team has a fixed case load of patients and delivers all services when and where needed by the patient, 24 hours a day, 7 days a week. This is a mobile and intensive intervention that provides treatment, rehabilitation, and support activities. These include home delivery of medications, monitoring of mental and physical health, in vivo social skills training, and frequent contact with family members. There is a high staff-to-patient ratio (1:12, compared to 1:30 in traditional case management models). The original study from Wisconsin followed chronically mentally ill patients assigned to the ACT program and compared them with a group discharged from the hospital to standard community care. After 14 months the ACT group showed significant advantages in rates of hospitalization, sheltered employment, independent living, family burden, with essentially no difference in costs. Unfortunately, the advantages were lost after the patients were discharged from the experimental program; there is no present data on the minimum intensity needed for the program to maintain gains or which special population of patients may require continuous services. There have been several replications of the effectiveness of the ACT program in reducing total number of days in the hospital and increasing patient and family satisfaction. Nevertheless, most studies have failed to document improvement in employment, social functioning, and other measures of quality of life. Because of the comprehensive services provided by the ACT program and the lack of adequate controls, it is unknown whether the reduction in hospitalization is due to improved medication compliance, continuity of caregivers, 24-hour coverage, site of service, intensity of services, therapeutic alliance, or a combination of any of these elements. Neither is it known whether ACT is more cost effective than another high-intensity system that does not use multidisciplinary teams with constant availability. Preliminary results are available from a randomized study from Connecticut that compared the ACT program with a program of high-quality brokered case management (two-thirds of the patients were diagnosed with schizophrenia or schizoaffective disorder). In the control intervention, patients had access to mobile crisis services, supported housing, respite services, vocational programs, clubhouses, and outpatient psychiatric clinics. Case managers were responsible for brokering instead of directly providing any of these services. Results show that after 18 months the control group spent twice as much time in the hospital (14.3 percent versus 7.6 percent) as the ACT group. There was also a significant advantage for the ACT group in terms of percentage of time spent in an unstable living situation (11.6 versus 16.9 percent); data on cost effectiveness is not currently available.

In summary, ACT programs can effectively decrease the risk of rehospitalization for chronically mentally ill patients in general and persons with schizophrenia in particular but the beneficial effects do not extend to measures of social functioning. The issue of cost effectiveness will not be settled until a systematic effort is undertaken to identify the essential elements of the ACT program.

RESIDENTIAL TREATMENT AND HOUSING PROGRAMS Patients with schizophrenia often need supportive housing. They can sometimes reside with their families, but eventually most patients will need other forms of permanent housing. Since deinstitutionalization, housing options for the chronically mentally ill have used a linear continuum paradigm. According to this view, patients are placed in different housing programs following hospitalization, beginning with the most controlled, supervised, and hospital-like setting, and moving down in a progressive fashion to the least restrictive, regular–household-like settings. These housing programs have received numerous names, but they basically vary depending on the level of staff supervision, the length of stay, number of residents, and whether other services in addition to housing are provided (e.g., vocational rehabilitation or recreational activities). For patients who are at imminent risk of relapse or in the initial stage of decompensation, crisis care centers may be particularly helpful. These have a 24-hour nursing staff and are supervised by a psychiatrist. Patients are in a more controlled environment where symptom progression and risks can be assessed and medications delivered; no vocational or other rehabilitative services are provided. Length of stay is usually limited to 30 days and disposition is either to a hospital or to a nonclinical residential type of program. Transitional half-way houses provide a supportive environment for patients recently discharged from the hospital who require some limited level of clinical supervision, such as dispensation of medication. By definition, length of stay is limited to a few months and patients are then placed in some form of long-term housing. Persons with schizophrenia who have pervasive disruptive symptoms that interfere with daily living skills or are associated with potentially dangerous behavior may require long-term group residencies. These often have 24-hour-a-day on-site supervision, usually with minimal clinical services. Their length of stay is between several months and years and no rehabilitative services are provided. Cooperative apartments typically house a small number of patients who do not require on-site supervision. Nursing homes are a long-term housing and clinical care option for severely disabled individuals who require daily nursing care. Boarding homes are usually remodeled apartment buildings that only provide room and board for persons with some form of disability; there are no clinical or rehabilitative services but there is often some minimal supervision. Foster care homes are owned by private citizens who agree to house psychiatricaly disabled persons for a fee; the match between patient and provider is particularly important. Two other well-known centralized programs which provide housing in addition to various rehabilitative services are the Fairweather Lodge and Fountain House. The Fairweather Lodge was conceived in California in the 1960s with the goal of reducing the revolving-door cycle of chronically mentally ill patients who improved while hospitalized but were unable to remain in the community for long periods of time. As originally conceived, a small group of hospitalized patients is taught a variety of skills for daily living. They are encouraged to work together and are eventually discharged to live in a community lodge that serves the functions of housing, socialization, and work; the lodge frequently operates its own business. The basic philosophy is that patients will help rehabilitate themselves while functioning as a family. Although initial controlled studies found advantages in rehospitalization and employment, these have not been replicated—partly due to the difficulties in implementing the original model. With the current limitations on length of hospital stay, this model may be an option only for a minority of patients. Fountain House was started in New York in the late 1940s not just as a housing option but as a full rehabilitative program in which patient involvement and self-help are emphasized, with support from staff as needed. One component of the program is the clubhouse, which provides opportunities for socialization while functioning as a transitional workshop; the patients learn clerical, maintenance, and food preparation skills while working. There are no controlled randomized studies on the effectiveness of this approach but some uncontrolled studies have found beneficial effects on employment. A new paradigm on housing for the chronically mentally ill, supported housing, aims toward further patient reintegration in the community while minimizing stigmatization. This approach is analogous to the concept of supported employment. Patients are encouraged to live in small groups in regular homes in the community. The basic concept is of housing as a normal living environment, not as a setting for services administered by an agency. Patients are not placed but are encouraged to choose a particular home that suits their needs. Long-term support by staff is available but not on site. It is not yet clear for what group of patients and at which point in the course of the illness supported housing will be most beneficial.

SUGGESTED CROSS-REFERENCES Psychotherapies are covered in Chapter 30. Various aspects of schizophrenia are covered in the other sections of Chapter 12. SECTION REFERENCES *Bellack AS, Mueser KT: Psychosocial treatment of schizophrenia. Schizophr Bull 19:317, 1993. Bond GR, Drake RE, Mueser KT, Becker DR: An update on supported employment for people with severe mental illness. Psychiatr Serv 48:335, 1997. Brown GW, Birlley JLT, Wing JK: Influence of family life on the course of schizophrenic disorders: A replication. Br J Psychiatry 112:241, 1972. *Bustillo JR, Lauriello J, Keith SJ: Schizophrenia: Improving outcome. Harv Rev Psychiatry 6:229, 1999. Essock SM, Kontos N: Implementing assertive community treatment teams. Psychiatr Serv 46:679, 1995. *Falloon IRH, Boyd JL, McGill CW: Family management in the prevention of exacerbations of schizophrenia. N Engl J Med 306:1437, 1982. Glick ID, Spencer JH, Clarkin JF, Haas GL, Lewis AB, Peyser J, DeMane N, Good-Ellis M, Harris E, Lestelle V: A randomized clinical trial of inpatient family intervention. IV. Follow-up results for subjects with schizophrenia. Schizophr Res 3:187, 1990. Goldstein MJ, Rodnick EH, Evans JR, May PRA, Steinberg MR: Drug and family therapy in the aftercare of acute schizophrenics. Arch Gen Psychiatry 35:1169, 1978. *Gunderson JG, Frank AF, Vannicelli JL: Effects of psychotherapy in schizophrenia. II. Comparative outcome of two forms of treatment. Schizophr Bull 10:564, 1984. *Hogarty GE, Anderson CM, Reiss D, Kornblith SJ, Geenwald DP, Ulrich RF, Carter M, and the Environmental-Personal Indicators in the Course of Schizophrenia (EPICS) Research Group: Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia, II. Two-year effects of a controlled trial on relapse and adjustment. Arch Gen Psychiatry 48:340, 1991. Hogarty GE, Kornblith SJ, Greenwald D, DiBarry AL, Cooley S, Ulrich RF, Carter M, Flesher S: Three-year trials of personal therapy among schizophrenic patients living with or independent of family, I. Description of study and effects on relapse rates. Am J Psychiatry 154:1504, 1997. Hogarty GE, Greenwald D, Ulrich RF, Kornblith SJ, DiBarry AL, Cooley S, Carter M, Flesher S: Three-year trials of personal therapy among schizophrenic patients living with or independent of family, II. Effects on adjustment of patients. Am J Psychiatry 154:1514, 1997. Lehman AF: Vocational rehabilitation in schizophrenia. Schizophr Bull 21:645, 1995. Lehman AF, Dixon L, Kerman E, DeForge BR, Postrado LT: A randomized trial of assertive community treatment for homeless persons with severe mental illness. Arch Gen Psychiatry 54:1038, 1997. Lieberman RP, Wallace CJ, Blackwell G, Kopelowicz A, Vaccaro JV, Mintz J: Skills training versus psychosocial occupational therapy for persons with persistent schizophrenia. Am J Psychiatry 155:1087, 1998. Marder SR, Wirshing WC, Mintz J, McKenzie J, Johnston K, Eckman T, Lebell M, Zimmerman K, Lieberman RP: Two-year outcome of social skills training and group therapy for outpatients with schizophrenia. Am J Psychiatry 153:1585, 1996. May PRA: Treatment of Schizophrenia: A Cooperative Study of Five Treatment Methods. Science House, New York, 1968. *Schooler NR, Keith SJ, Severe JB, Matthews SM, Bellack A, Hargreaves WA, Kane JM, Ninan PT, Frances A, Jacobs M, Mance R, Simpson GM, Woerner MG: Relapse and rehospitalization during maintenance treatment in schizophrenia. The effects of dose reduction and family treatment. Arch Gen Psychiatry 54:453, 1997. Stanton AH, Gunderson JG, Knapp PH, Frank AF, Vannicelli ML, Schnitzer R, Rosenthal R: Effects of psychotherapy in schizophrenia, I. Designed implementation of a controlled study. Schizophr Bull 10:520, 1984. Wing JK, editor: Schizophrenia: Towards a New Synthesis. Academic Press, London, 1978.

Textbook of Psychiatry

12.10 SCHIZOPHRENIA: INDIVIDUAL PSYCHOTHERAPY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 12. SCHIZOPHRENIA

12.10 SCHIZOPHRENIA: INDIVIDUAL PSYCHOTHERAPY WAYNE S. FENTON, M.D. AND THOMAS H. MCGLASHAN, M.D. History Investigative Psychotherapy Investigative Psychotherapy Supportive Psychotherapy Flexible Psychotherapy Suggested Cross-References

No single treatment can ameliorate the myriad symptoms and disabilities associated with schizophrenia. As articulated in the American Psychiatric Association's Practice Guidelines for the Treatment of Patients with Schizophrenia, therapeutic efforts must be comprehensive, multimodal, and empirically titrated to the individual patient's response and progress. While there is at present no cure for schizophrenia, the skillful application of pharmacological, psychotherapeutic, rehabilitative, and community support interventions can limit illness morbidity and mortality, improve patient outcome, and enhance quality of life. As with individuals with other long-term medical disorders, many patients with schizophrenia will need comprehensive and continuous care over prolonged periods. To the extent that both biological and psychosocial factors are crucial determinants of the course and outcome of schizophrenia, a psychiatrist may be in the best position to coordinate and integrate the various treatments required and provide continuity of care over time. Each component of a comprehensive treatment plan for a patient with schizophrenia targets specific aspects of the disorder and its common sequelae. Pharmacological interventions target positive, negative, and disorganized symptom domains; mood symptoms; and cognition. Rehabilitation efforts target deficits in self-care, social or vocational skills, and provide structure in the form of someplace to be and something productive to do. Access to appropriate entitlements, treatment services, housing, and social support are the goals of community support programs. Individual psychotherapy addresses the human aspects of adaptation to a serious psychiatric disorder and targets problems such as denial, demoralization, treatment compliance, personal relationships, and self-esteem. Its focus is on understanding the patient's beliefs, attitudes, aspirations, and experiences. The coordination, timing, and titration of all specific treatment elements is informed by this understanding and by an ongoing assessment of individual patient needs that can often best be achieved within a long-term physician-patient relationship. Individual psychotherapy is defined most broadly as a professional relationship in which the technical expertise of the physician is directed toward promoting the patient's recovery or toward relieving suffering. At a minimum this physician-patient relationship provides the context in which symptoms and disabilities are assessed, consent and collaboration for treatment obtained, and the effects of interventions are evaluated. More ambitious goals, appropriate for selected patients in settings where time and resources allow, can include the exploration of maladaptive patterns of living through careful scrutiny of relationships with others and the therapeutic relationship itself. Most psychotherapy, as actually practiced, falls somewhere in between, requiring from the therapist a broad base of medical and psychological skills. A psychiatrist providing psychotherapy for schizophrenia patients should probably be prepared to give an intramuscular injection one day, interpret transference the next, and give a patient a ride to work on the third. Some form of individual psychotherapy in combination with pharmacological treatment is the most common care offered to patients with schizophrenia. Psychodynamic and biological conceptions of schizophrenia have yielded the two distinct therapeutic traditions of investigative and supportive psychotherapy. Current practice represents an amalgamation of these approaches that is best described by flexible psychotherapy. This approach draws upon perspectives and techniques derived from each of these traditions to accommodate the heterogeneity of schizophrenia and the individuals who suffer from it.

HISTORY In the early decades of the twentieth century schizophrenia was viewed as an irreversible and untreatable process. “Organic” psychiatry as represented by Emil Kraeplin saw schizophrenic personality disintegration as an inevitable product of neurological deterioration. Sigmund Freud, representing the mainstream of psychoanalysis, considered dementia precox to be a “narcissistic neurosis” where “libido” was directed inward, away from others. As a result, transference and hence analytic treatment was considered impossible. In this context, the diagnosis of dementia precox most often led to therapeutic nihilism and the recommendation of life-long institutional care. Despite the misgivings of classical adherents to Freud, individual psychotherapy for schizophrenia in the United States originated as a modification of psychoanalysis. Early psychoanalysts such as A.A. Brill advocated an active effort to promote “rapport” and arouse patients' interest in their own malady. He described providing direct advice about work and relationships, visiting a patient at home, providing didactic reading material, and at times frankly labeling false beliefs as delusions. In time, he observed that confidence in and a “passive attachment” to the physician can develop so that the latter might become a bridge between the patient and reality. Between 1922 and 1930 Harry Stack Sullivan ran a small treatment unit for male schizophrenia patients at Sheppard and Enoch Pratt Hospital in Towson, Maryland. He was influenced by the early psychobiological perspectives of Adolph Meyer and William Allison White, who emphasized that personality was influenced by life events not only in childhood, but over the entire course of development. Based on his intuition that like cures like, Sullivan staffed his unit with sensitive, shy, and introverted male attendants who possessed a natural proclivity and ease of rapport with withdrawn patients. Stressing that patients' difficulties were similar to those of so-called normals, Sullivan promoted the development of closeness or benevolent intimacy in this milieu. He observed that providing an experience of reciprocal trust—which he hypothesized many patients had lacked during important periods of development—could be beneficial by allowing a “validation of all components of personal worth.” Careful observation of the difficulties his patients had in maintaining relationships led Sullivan to formulate the paradigm of interpersonal psychiatry. He de-emphasized the prevailing psychoanalytic view that personality was formed and behavior motivated by drives pressing for expression from within. Instead, he recast psychopathology as difficulties in living arising largely from personal and social relations, and as personality warps thought to be the lasting residue of earlier unsatisfactory interpersonal experiences. Over a period of years Sullivan elaborated these ideas in a series of seminars at Chestnut Lodge Hospital in Rockville, Maryland, where, under the leadership of Dexter Bullard, a group of psychoanalysts and social scientists interested in the intensive study of schizophrenia assembled during the 1940s. There the influence of interpersonal patterns among patients and between patients and staff were observed to have a powerful impact on patients' psychopathology. Covert tension and disagreement among staff, for example, often appeared to be associated with worsening of patients' psychotic symptoms; likewise, improvement followed when those tensions were resolved. Such observations drew attention to the influence of psychosocial factors on schizophrenia and raised the notion that the disorder might be caused and potentially cured by psychosocial means. Drawing upon her European psychoanalytic background, her mentorship with Sullivan, and her clinical work with psychotic patients at Chestnut Lodge, Frieda Fromm-Reichmann integrated the available knowledge concerning the intensive psychotherapy of schizophrenia into a relatively comprehensive body of theory and technique. Her seminal work, Principles of Intensive Psychotherapy, articulated a modified form of psychoanalysis that was applicable to patients with severe mental illness, including schizophrenia. The ideas embodied in her writings and clinical work also represent the first elaboration of what became known as intensive psychodynamic psychotherapy. The predecessors of ego and self psychology, interpersonal psychiatry and psychodynamic psychotherapy became dominant paradigms in American psychiatry in the 1940s and 1950s and beyond. Their hopeful and humanistic perspectives were adopted by many influential psychiatric treatment centers. Intensive individual psychotherapy came to be viewed as the treatment of choice and at times the only effective treatment for schizophrenia. Its practitioners kept the field's interest focused on severely ill patients during the decades prior to the widespread availability of effective pharmacological treatments. Exposure to a second generation of charismatic teachers and clinicians (e.g., Otto Will, Steve Fleck, Elvin Semrad, and Harold Searles) kindled interest in treating and studying schizophrenia among countless psychiatric residents and trainees throughout the country.

INVESTIGATIVE PSYCHOTHERAPY

Perspectives derived from the tradition of investigative psychotherapy are of value in understanding the psychological aspects of the disorder and in managing commonly encountered difficulties in forming and maintaining a therapeutic relationship. A review of the voluminous clinical literature in this area suggests that differences in language and terminology notwithstanding, a consistent orientation and approach has been articulated. This can be outlined in terms of the nature of investigative psychotherapy, the nature of schizophrenia from the psychotherapist's point of view, elements of the psychotherapeutic situation, general technical interventions, and general technical attitudes.

INVESTIGATIVE PSYCHOTHERAPY Sullivan defined the psychiatric interview as a two-person transaction, more or less voluntarily initiated on a progressively unfolding expert-client basis. Its purpose is to elucidate the patient's characteristic patterns of living, the revealing of which is assumed to be useful. The psychotherapeutic encounter is an actual interpersonal experience in which the doctor and patient are both participant observers. According to Fromm-Reichmann, the goal of intensive psychotherapy is alleviation of the patient's emotional difficulties and elimination of symptoms. This is accomplished by undertaking a thorough scrutiny of the patient's life history (especially the history of interpersonal relationships), reviewing in close detail the realities of the patient's current relationships and life situation, and understanding the genetic (historical) roots and current ramifications of maladaptive interpersonal patterns as reflected in the doctor-patient relationship and in daily life. Important emotional experiences related to the patient's difficulties are assumed to have been forgotten and their recovery during the therapeutic process is expected. This process is expected to result in the modification of maladaptive interpersonal patterns and personality growth. Schizophrenia The literature on intensive psychotherapy emphasizes the influence of the environment and learning in the etiology of schizophrenia. Characteristic difficulties in interpersonal relations among schizophrenia patients are said to include a basic mistrust of and expectation of harm from others, marked ambivalence in relationships with endless oscillations between longing for merger based on intolerance of loneliness and withdrawal and isolation based on terror of closeness, weak or absent ego boundaries with resulting difficulty differentiating one's own thoughts and impulses from those of others, the absence of a sense of self often compensated for by an effort to ascertain the expectations of others and mold oneself accordingly (false self) or alternatively to organize in fixed opposition to the wishes of others, a pervasive posture of passivity (things happen to one and others are the cause of all difficulties), fear that strong emotional arousal of any sort (anger, pleasure, wants, desires) will escalate uncontrollably and lead to panic or catastrophe (with compensating constriction and repression of drives or affects and resultant inability to express affects or desires to others), fragmented or idiosyncratic thinking, frequent misinterpretation of the motivation of others, and an antipathy towards reality with intolerance of frustration and withdrawal into fantasy. Extrapolating from these aspects of schizophrenic psychopathology, most early proponents of intensive psychotherapy postulated real or fantasized negative first experiences between the infant patient and primary caregivers. This was thought to result in a central unconscious conflict described as “that of a small child dependent on a person by whom he feels persecuted and who is, in his opinion, unstable and uncertain,” as described by Lewis Hill. This position represents the patient's conviction concerning the nature of human relationships and it dominates all thoughts, feelings, and behaviors. Regrettably, psychodynamic theorizing regarding the cause of schizophrenia often devolved into blaming the parents for causing their child's illness. Despite the lack of any credible scientific evidence to support these theories, for a period they were widely and uncritically accepted. Now rejected as invalid, psychodynamic etiological explanations of schizophrenia have left a legacy of mistrust between families, patients, and psychiatry. Clinical descriptions deriving from that era, however, continue to be of value in enriching clinicians' understanding of schizophrenia patients' subjective experience, and may allow clinicians to anticipate the impact of life events and important relationships on the patient's course of illness. A developmental perspective and hierarchical model of the mind is implicit in the clinical theory underlying intensive psychotherapy. Although a variety of specific developmental schemes has been offered, most suggest some version of the following phases in emotional development: (1) autistic phase during the first weeks of life in which the presence of others is not recognized, satisfaction of biological needs is hallucinated, and only undifferentiated states of anxiety or activation and satiation are present; (2) symbiotic phase in which a boundaryless state of bliss is present with an empathic caregiver who can anticipate and fulfill all needs—successful completion of this phase is thought to form the substrate of basic trust; (3) separation-individuation phase beginning with the ability to ambulate, when the image of the good-enough caregiver becomes progressively internalized, allowing a feeling of security during physical separations. Early in this phase experiences of frustration with the caregiver are emotionally separate from experiences of satisfaction and the respective good object and bad object seem like different people. Aggression and anger deriving from frustrations are projected onto and attributed to the bad object. The good-enough caregiver accepts these projections without responding with excessive retaliatory anger or anxiety and thus contains and soothes the frustrated child. These experiences of containment or holding form the basis for children's later capacity to soothe themselves, modulate affect, and become comfortable with emotional arousal. By the end of this phase cognitive and emotional development allow for recognition that the frustrating and satisfying caregiver are indeed the same person (libidinal object constancy), a recognition that forms the basis of seeing others as separate and complex individuals; (4) Oedipal phase, which is the major focus of psychoanalysis with patients who have neuroses. This involves the mastering of triadic relationships, competitive urges, and identifications with the same-gender parent. Although no writers about intensive psychotherapy consider the schizophrenia patient's mental functioning as equivalent to that of an infant, more primitive adaptive levels of functioning derived from early phases of development are considered to be ever present, hierarchically underlying more sophisticated adaptive levels acquired later in development. During states of psychotic regression, developmentally primitive states of mind are thought of as gaining ascendancy while higher capacities are temporarily lost. Nonetheless, the retention of some nonpsychotic functioning is assumed, however sick the patient is. Psychotherapeutic Situation: Participants Although the characteristic difficulties of schizophrenia patients have been elaborated at length in the literature, attributes of the optimal psychotherapist are less well defined. Among those cited as important are an interest in and capacity to tolerate intense affect, dependency, confusion, and ambiguous communication. Basic respect for the patient is a prerequisite, especially respect that stems from a conviction that the patient's problems are not too different from one's own. Aloofness, rigidity, and critical pomposity are especially discouraged. Psychotherapists should be flexible, creative, and willing to admit when they are wrong. The match between patient and therapist is thought to be central, but defies easy categorization. Many authors emphasize that a physician working with schizophrenia patients must possess sufficient self-esteem and sources of satisfaction in his or her nonprofessional life to avoid using the patient to meet personal needs for admiration or prestige. Setting Intensive psychotherapy must be conducted in a setting of mutual safety. Within an organized care setting, the milieu must be ideologically supportive. Frequency of visits can range from one to five per week. Use of the couch and free associations as in psychoanalysis are discouraged as aggravating disorganization and thought disorder. As part of creating the setting for individual psychotherapy, the therapist endeavors to achieve an early consensus with the patient regarding the nature of the latter's problems, the treatment required, and the rules governing therapy. Process Process elements in the psychotherapy of schizophrenia refer to expectable developments in the doctor-patient relationship as it evolves over time, including transference and countertransference. The management of these is considered central to the therapeutic endeavor. Transference broadly refers to the manner in which the perception of others in the present is shaded or distorted by important past relationships. It is thought of as a natural but often unconscious aspect of all human relationships. Examining transference as it develops and unfolds in the doctor-patient relationship is a major task in investigative (as opposed to supportive) psychotherapy—this examination is expected to be useful in allowing patients to better understand their current difficulties and respond more realistically and productively to people in their current life. It should also facilitate the recall of memories that may be accessible only through their recreation in the transference relationship. In nonpsychotic transferences the patient perceives or responds to the therapist as if the latter resembled some other important figure from the patient's past. The patient retains the capacity to recognize these as misperceptions, to separate real aspects of the therapist from distorted aspects, and to trace the distortions back to their origin in past experiences.

James, a shy and isolated young man with schizophrenia treated as an outpatient with intensive psychotherapy and medication, was able to begin classes at a local college. Many years earlier he had first become ill and was hospitalized a few days after leaving home to attend college far from his family. An avid reader, he had long dreamed of returning to school to study English literature. As the semester progressed James became increasingly self-conscious and despite a good midterm grade began talking about dropping the course. Wishing to see his patient succeed, James' young male therapist agreed to drive him to class first once, then three times a week. To the therapist's surprise, after several weeks John's resentment erupted in a tirade about not wanting to be forced to go to class so his therapist could look good. Discussion led to recollections of the daily struggles James had had when he became afraid to attend class in junior high—at that time his resentment and school refusal had led to physical altercations with his parents at the front door. The therapist pointed out the similarity between John's past and current reactions and noted that while all parents take pride in their children's success, it was doubtful that this was his parent's principal motivation in pushing him to attend school. Patient and therapist realized that at present it had been James' idea to go to class, and that he would have to decide whether or not to continue. The capacity to recognize earlier experiences as the source of current distortions is often absent or lost in schizophrenia, leading to transference psychosis in which the patient believes or behaves as if the therapist actually is, or is like, some figure from the past. Frances, a woman in her 20s with paranoid schizophrenia, had been raised in a neighborhood that she claimed was kept safe and orderly by organized criminals. Furious at her family for having committed her several months earlier she claimed to have no psychiatric problems whatsoever, adamantly refused antipsychotic medications, and complained that her family had bribed the police to lock her up. Despite her extensive denial, she attended scheduled outpatient appointments with complete reliability. After several months, however, Frances began accusing the therapist of spreading the rumor that she was a prostitute and having the police follow and harass her. She called the Mayor's office to report that the therapist was taking bribes and, expecting retaliation, left the therapist's office threatening to harm herself. The therapist, who for weeks had adamantly tried to reassure the patient that he was not having the police follow her, found himself needing to obtain their assistance to arrange for the patient's detention and emergency assessment. Transference is at times an inevitable and unavoidable development in intensive psychotherapy, including transference psychosis. Nonpsychotic transference can usually be resolved with time, support, and interpretation. Psychotic transference is more difficult to remove and a therapeutic relationship must often be developed that can accommodate this distortion while remaining useful to the patient. Countertransference refers to all the therapist's thoughts and feelings about the patient. Some of these are distortions arising from the therapist's personal past, but others derive largely from current interaction with the patient. Feelings that arise in work with schizophrenia patients can be particularly intense and uncomfortable, and may include discouragement, fear, worthlessness, hatred, contempt, guilt, rage, envy, or lust. In view of this, awareness of countertransference and the ability through introspection to understand its sources are crucial functions for the psychotherapist. Countertransference can often serve as an important source of information about the patient's state of mind, particularly in patients who are unable to talk. John was a recently hospitalized, mute, schizophrenia patient. Moments after seating him for an initial psychotherapeutic interview, the therapist found himself feeling trapped and terrified by the sudden recognition that John, with a paranoid glare, was on the verge of assault. After ruling out a run for the door as too risky, the therapist looked at John and asked: “Are you afraid of me?” “Yes,” indicated a perceptibly relieved patient, “I think something bad is going to happen and you're part of it.” “Well, you're scaring the hell out of me,” said the therapist. Now appreciably calmer John said, “I'm sorry,” and a conversation ensued. Some time later John explained that on the day of his arrival he felt he had been brought to the hospital to be executed and expected at any moment to be shot in the head. Parenthetically, the therapist learned to conduct initial assessments of hospitalized patients in a place where help could be more readily obtained if needed. The therapist's reaction may also serve as a good barometer for understanding how others typically react and respond to the patient: Mary, a woman in her 30s, complained bitterly to her female therapist about weakness, fatigue, and an inability to function that she steadfastly attributed to her medications. Try as she might, the therapist's efforts to respond to these complaints, by changing medications, offering advice (such as exercise), and reframing the complaints amounted to nothing. Fed up with complaints that she “didn't understand,” the therapist was herself left feeling useless, angry, and very tempted to tell the patient to quit complaining and take some responsibility for herself. The therapist remembered, however, that for the past year Mary had had no contact whatsoever with her sister after the latter told Mary to quit complaining and try to make something of her life. Many of Mary's relationships with friends had ended with recriminations about their lack of sympathy and understanding. Finally, successful management of countertransference allows the therapist to create a holding or containing relationship with the patient that is postulated to be central to the mutative action of psychotherapy. Frank, a schizophrenia patient in his early 30s who lived in the community, had enormously ambivalent feelings about his 20-hours-per-week job as a dishwasher at a nearby hotel. Frank often found his interaction with co-workers stressful and was prone to avoid work; he was also plagued by unrelenting guilt about his inability to move up to full-time work on any sustained basis. Frank's father often reinforced this view by telling him that his illness amounted to little more than laziness, and that with will power and a strong character Frank should certainly be able to handle a full-time job. Over a period of years a clear pattern in Frank's illness was detectable: Frank would work part-time and be stable for a period. Driven by his guilt, he would increase his work hours. The stress and overstimulation of the heavier work schedule would lead to an exacerbation of symptoms and finally a fullblown relapse. He would have to quit work altogether for a period, seek a new part-time job, and the cycle would begin anew. During Frank's relapses, his primary symptom was the delusional fear that he would be “damned” and persecuted for his moral weaknesses. Over years of outpatient psychotherapy, Frank's interactions with his therapist about work (the therapist himself being something of a workaholic) were of great interest. Whenever Frank contemplated missing a day's work (and there were many such times) he would call the therapist at home the evening before for permission, often presenting the flimsiest of excuses and rationales about why he should not work the next day. Receiving these calls late in the evening (when he himself was still working) the therapist often felt the intense urge to tell Frank to shape up, be a man, show some character, and quit acting like a little work would kill him. Recognizing this urge as countertransference (derived in part from Frank's seemingly unconscious effort to recreate his relationship with his father with the therapist, the therapist was largely able to refrain from such moralistic admonishments, discuss matters calmly, and allow Frank to decide on his own about work the next day. Over a period of years Frank came to realize that his illness was something real rather than a moral weakness. With this realization he was able to accept the fact that for him, full-time work was probably not going to be possible. The frequent relapses ceased and Frank was able to sustain longer periods of stability. The therapist felt that his recognition of countertransference allowed him to “hold” Frank's self-loathing about his work disability and reflect this back to Frank in a more benign manner—without being overly accusatory or moralistic. To the therapist this seemed to be an important factor leading to Frank's more benign and accepting view of his own disabilities. Transference and countertransference tend to mirror each other at any given time, and over the course of treatment a range of transference and countertransference configurations are traversed. These may recreate earlier developmental epochs. For example, typical configurations can include (1) an autistic relationship in which the patient does not express the slightest interest or even recognize the existence of the therapist—the therapist in turn feels devalued as a nonhuman object; (2) the idealizing, symbiotic interaction in which the therapist is perceived by the patient as an omnipotent, protective, and loving figure and negative feelings are projected onto others outside the dyad; here the therapist is likely to feel that he or she alone can truly understand this patient, whose problems clearly stem from the insensitivities of others; (3) the hostile, paranoid relationship in which the therapist is perceived as a bad object, untrustworthy, engulfing, and intent on harming the patient; here the therapist often feels hatred and rage at the patient's accusations and is tempted to become defensive or retaliatory, thus fulfilling the patient's expectation of others as untrustworthy. General Technical Interventions The literature on intensive psychotherapy describes categories of interventions that roughly correspond to different phases of therapy. Although these tasks and strategies may be relevant at any point in treatment, they are often ordered sequentially: (1) establishing a relationship with the patient, (2) elucidating the patient's experience in the here and now, (3) tolerating the mobilized transference and countertransference, (4) integrating the patient's experiences into an expanded perspective of the self, and (5) working through. If therapy progresses, the accomplishment of earlier tasks allows greater attention to

be paid to subsequent ones. Establishing a Relationship With the Patient Because of suspiciousness, disorganization, indifference, or ambivalence about human attachments, establishing a relationship with the schizophrenia patient can be challenging. Analytic strategies of passive neutrality and anonymity can easily be misinterpreted as disinterest or dislike and are generally discouraged. Consistency, straightforwardness, and an active effort to establish rapport are advocated. Within bounds, a reasonable degree of self-disclosure on the therapist's part can help to counter distortions by allowing the patient to get a fix on the therapist as a person. A relationship should be sought on the patient's terms. If the patient initially wants the therapist only to meet some immediate need (e.g., to secure discharge from a hospital or intervene with the patient with family) this is taken as the starting point and viewed positively as a sign that the therapist is seen as potentially useful. At times, engaging in activity (walking or playing a game), finding a neutral topic of common interest (sports, music), or placidly accepting periods of silence will further promote establishing a relationship. Creativity and patience are the only rules. If the initial encounters are traversed successfully, a background feeling of security and predictability will increasingly characterize the therapy. After summoning the police to have Frances detained and committed, her therapist decided that transfer to a new doctor would probably be best: after all, how could this patient ever trust a therapist who, confirming her worst fears, had her picked up by the police? Wanting some closure before transferring the case, the therapist drove to the state hospital where Frances had been committed to visit her. To his surprise, the patient greeted him warmly and thanked the therapist for going out of his way to visit her. With second thoughts about transferring the patient, the therapist agreed that they would meet at his office after Frances's discharge. Discharged from the hospital on long-acting antipsychotic medication, Frances arrived as scheduled for her outpatient appointment. The therapist acknowledged the awkwardness of meeting again at the site of their last acrimonious encounter. Both patient and therapist agreed that avoiding future hospitalizations would be a common goal. Although, if asked, Frances still denied any psychiatric difficulties, she agreed to continue medication to keep her family and the doctors “off her back.” At times, a more engaging style can promote the establishment of a relationship. Some have advocated active participation or playing with a patient's communications or symptoms as a means of capturing their attention. Despite trials of a variety of treatments Tim, a patient in his mid-30s, often contended that he was in continuous and intensive training by “security forces” to unite world nationalities under one government. His therapist suggested he call a summit of world leaders to further this plan. After an extensive discussion that included consideration of the site of such a meeting, logistics, security, and arrangements for translators, Tim cracked a smile; although he continued to be preoccupied with messages he received from “security forces” the world summit became an inside joke between doctor and patient. Intellectual conversation can obscure important emotional reactions, but may be promoted to further the goal of establishing a relationship; it can also provide a patient whose self esteem has been damaged the opportunity to exercise areas of competence. Donna, a 27-year-old woman, experienced an acute psychotic episode during her second year as a graduate student in comparative religion at a first-rate university. While hesitant to discuss the events leading to her hospitalization, she easily discussed the papers she had to complete to secure readmission to the program. Impressed by Donna's vital engagement with the subject and her ability to present it in a compelling manner, for several weeks the therapist took on the role of a uninformed student glad to receive a survey of comparative religion from such a competent teacher. The therapist felt that acknowledging the patient's intellectual ability and expertise in comparative religion made it considerably easier for the patient to later accept the therapist's expertise in medicine and psychiatry. Elucidating the Patient's Experience Elvin Semrad viewed the three core tasks of psychotherapy as helping the patient acknowledge, bear, and put into perspective feelings and painful life experiences. Acknowledging the patient's feelings and painful experiences in the present becomes particularly pertinent once a relationship has been established. Acknowledging first requires elucidating affects. Strategies for elucidating include listening, narrowing the focus, seeking concrete detail, acknowledging feelings (especially of loss, anger, sadness), and naming or labeling affects. The therapist may act as a comforter, inquisitor, or teacher, conveying to the patient that experiencing feelings will neither overwhelm the patient nor hurt others. Psychotic symptoms, when expressed, are considered to signal an affective reaction to some actual event that patient and doctor do not yet understand. Examining the patient's day-to-day life in detail will allow the therapist to develop a more vivid picture of the patient's difficulties, frustrations, and characteristic reactions to others. The aim is to help the patient better organize and communicate, to guide the patient into sharpened conceptualizations, and to promote tolerance of life experience as it is. If successful, therapist and patient will share a common language with which to communicate about the latter's difficulties and increasingly the patient will independently report important life events and emotional reactions to them. During a therapy hour, John, a patient in his 20s with treatment-resistant schizophrenia reported that under his control, a nuclear attack had just been launched in Europe and that as he and the therapist sat, millions of people were being killed. With single-minded persistence, despite John's evasive disorganization, the therapist attempted to find out what John had been doing that morning before his therapy appointment. The therapist was able to piece together that immediately preceding the “nuclear attack” John had been listening to the radio and another patient on his unit had changed the station without asking. The therapist suggested, and John acknowledged, that this had made John a bit irritated. The therapist suggested that perhaps there was a connection between John's anger at his peer and his current concern with millions being killed. The therapist wondered whether next time something like that happened it would be possible for John to temperately register his protest to his peer. John indicated this was out of the question—he did not want to be tried for murder. The therapist indicated that in his view, a mild protest was quite different from murder. Tolerating the Mobilized Transferences and Countertransferences Tolerating affects, transference, and countertransference corresponds to Semrad's concept of “bearing” painful feelings that have been acknowledged. Tolerance is achieved first by the therapist and then, through example, by the patient. Here the concept of “holding” or “containment” is relevant and is thought to be central to the mutative effect of psychotherapy. By means of projective identification the patient is thought of as putting negatively valenced affects and self-representations into the therapist who, by processing these feelings in a more mature way, contains, holds, or metabolizes them and makes them palliatively available for reinternalization by the patient. More simply stated, patients experience themselves being accepted, negative emotions and all, and learn from the therapist's example to become better able to accept unwanted aspects of themselves. Thus, patients' identification with the therapist and their functioning is seen as a major factor in the therapeutic action of psychotherapy. Having exhausted her ability to respond constructively to Mary's unending complaints, the therapist found herself viewing Mary with contempt and derision, comparing her unfavorably to patients with severe physical disabilities who had struggled courageously to accomplish goals despite their disability. Upon reflection, the therapist became vividly aware of the manner in which Mary's view of herself as the victim of other people's insensitivity had become a self-fulfilling prophesy. Mary's inconsolable complaining was so irritating that these accusations, if not true today, would be true tomorrow: the therapist or anyone else who had to deal with Mary would soon find themselves irritated and would run out of patience. Concluding that Mary's own feelings of incompetence and self-hatred had been projected onto her, the therapist found her contempt for Mary tempered by a better understanding of Mary's suffering. The therapist hoped that if this could be conveyed to Mary, the vicious cycle of Mary's turning nearly everyone against her might be interrupted. Integrating the Patient's Experience into an Expanded Perspective of Self Broadening patients' understanding of themselves and their situation corresponds to the third part of Semrad's triad: helping patients put into perspective their painful affects, life experiences, and maladaptive solutions. According to Sullivan “No one has grave difficulties in living if he has a very good grasp of what is happening to him.” Thus, providing insight is another way in which psychotherapy is thought to be useful, complementing identification with the therapist. Integrating the patient's experience entails a change in therapeutic relationship and enlists interpretation as its major technical tool. At this phase in therapy the nature and tenor of the therapeutic relationship changes such that the therapist becomes more demanding, frustrating, and insistent on adaptation, reality testing, and health. While remaining supportive, the therapist increasingly confronts defenses, frustrates wishes, and interprets transference. The major task is to accept the patient but to reject the patient's psychosis and maladaptive interpersonal maneuvers. Insight in this context can occur at several depths: (1) as simple recognition of the fact of illness, (2) as knowledge about the nature of the illness (e.g., that hallucinations come from one's own mind, (3) as recognition of the dynamics of the illness (i.e., that symptoms occur in relation to personal difficulties), and (4) as recognition that symptoms solve problems and conflicts. Emotional insight, gained by direct experience in the doctor-patient relationship, is emphasized. These derive from interpretations pointing out the transferential

nature of the patient's feeling towards the doctor, including their origin in the patient's past experience and their inappropriate application in the patient's current everyday life. The what, how, and when of interpretation stems from an empathic attunement to the patient's tolerance, although certain recommendations recur repeatedly. Most psychotherapists are reluctant to interpret content (particularly sexual) since patients are often flooded with unwanted thoughts and impulses. Rather, interpretations focus on defensive operations, resistances to therapy, and the link between symptoms and everyday stresses. Especially targeted for interpretation are negative transference, aggressive impulses, depressive concerns, and dependency issues, which are often warded away from consciousness because of the patient's fear that their emergence would be overwhelming. Interpretations are presented in a way that is aimed at helping patients learn to formulate interpretations on their own. They are presented as tentative observations in the spirit of mutual inquiry. Short, simple, nontechnical language should be used and the patient is considered the final judge of an interpretation's validity and usefulness. If traversed successfully, this phase of therapy will leave patients with a more accepting and complex view of themselves as a people capable of experiencing the full range of human emotions. Patients will no longer view all their difficulties as the product of mistreatment at the hands of others, and will assume more responsibility for their own treatment and health. Passivity and indecision will be seen as an active choice, and patients will recognize that continued progress depends on their willingness to attempt new solutions, both inside and outside of treatment. Working Through With improvement in psychosis and maturation of the patient's nonpsychotic personality, the phase of integrating evolves into the last phase of working through. Patients become better able to help therapists perform their functions and eventually become capable of performing these functions themselves. Patients see their therapists as real, different, and imperfect in their empathy. Each step towards greater independence and autonomy generates separation anxiety and a “two steps forward and one step back” trajectory can be anticipated. Regressions or symptomatic exacerbations recur but should be shorter, less intense, and more readily influenced by interpretation. The end of treatment may be negotiated, but many authors have noted that not uncommonly patients remain attached and may contact the therapist during crucial junctures many years after therapy has ended.

SUPPORTIVE PSYCHOTHERAPY Goals Supportive psychotherapy has historically been favored by biologically and pharmacologically oriented clinicians. It is firmly grounded in the medical model in which the patient is seen as suffering from an organically based illness that requires treatment from a physician. As described by Talcot Parsons nearly 50 years ago, the medical model implies essential elements of expected behavior for both the physician and patient. These elements define the physician's and patient's respective roles, relationship, and responsibilities. The physician's role is characterized by four key qualities: it is (1) universalistic, (2) functionally specific, (3) affectively neutral, and (4) collectivity oriented. The universalistic norm requires the physician to treat all patients alike according to scientific and medical standards. The role is functionally specific in that the physician is seen as a specialist in health and disease who is expected to limit attention to circumscribed areas involving medical matters. Affective neutrality prevents the doctor from entering too sympathetically into the patient's situation, allowing for steadfastness of judgment and the exercise of emotional control. Finally, collectivity-orientation, as opposed to self-orientation, demands that the doctor treat the patient according to the patient's needs and the health standards of the community. Like the role of the physician, the role of the patient is defined by expected behavior that involves both rights and obligations. First, the person who is ill is exempt from normal social responsibilities and excused from customary obligations so as to attend to the process of getting well. A second right is exemption from responsibility for illness—the illness is not considered the patient's fault and the patient has the right to receive care. At the same time, the patient has the obligation to want to get well, obtain technically competent help, and cooperate with treatment. In contrast to the ambitious aim of personality change associated with the intensive therapy tradition, the short- and long-term goals of supportive psychotherapy are comparatively modest. These include (1) relief from the immediate crisis or direct reduction of acute disequilibrium, (2) removal of symptoms to premorbid levels, (3) re-establishment of psychic homeostasis through a strengthening of defenses, (4) sealing over psychotic experiences and conflicts, (5) the circumscribed fostering of adaptation, and (6) mobilization and preservation of healthy aspects of the patient to enable optimal functioning and minimize the impact of persistent deficits. Supportive therapy uses the physician-patient relationship to create a background of adequate clinical care that supports the prescription of effective pharmacological interventions. Functional or social recovery, rather than personality change, is the primary aim of treatment. Techniques The overall technical approach of supportive psychotherapy is one of pragmatism and management in which based on medical and psychiatric expertise, the physician helps the patient interpret and adapt to reality. As such, the therapist employs techniques that include defining reality, offering direct reassurance, giving advice on current problems of living, urging modification of expectations, and actively organizing the environment for patients who cannot do so themselves. To help stabilize the patient's environment the therapist often maintains close contact with the patient's family or other treaters and may intervene on the patient's behalf with family, employers, and social agencies. Eliciting and tracking symptomatology and targeting symptoms for psychopharmacological intervention is a major focus for the supportive psychotherapist. Psychopathology is interpreted in a medical context as the unwanted emergence of signs of illness. The basic content of psychotherapy focuses on teaching and relearning—the patient is educated regarding the nature of the illness, taught to monitor symptoms, and act promptly to suppress their exacerbation. The therapist fosters positive transference as a benign authority; positive feelings are treated as real and negative transference is avoided. The therapist may become very active in helping the patient learn new ways of adapting and may use or prescribe cognitive, behavioral or social skill training techniques. Empirical Studies Efficacy of Individual Psychotherapy In the decades following the introduction of phenothiazines psychiatry became increasingly divided into adherents of the psychodynamic and biological paradigms. Disagreement concerning the value of intensive psychotherapy became a focal point of often acrimonious ideological and scientific debates. Randomized clinical trial methodology unambiguously demonstrated the value of pharmacological interventions in schizophrenia and came to be seen as the optimal standard for evaluating all treatments. In this context, five studies conducted during the 1960s and 1970s attempted to assess the efficacy of various forms of individual psychotherapy compared to treatment programs that did not specifically feature psychotherapy. Although criticized by proponents of intensive psychotherapy on a number of methodological grounds, together the results of these randomized clinical trials provided little or no evidence for the efficacy of psychotherapy as the sole treatment for schizophrenia. Supporting this conclusion were the results of long-term follow-up studies both at Chestnut Lodge, where many of the techniques of intensive individual psychotherapy were developed, and at Columbia's Psychiatric Institute. Exceptions notwithstanding, these studies found that the majority of patients treated with intensive psychotherapy alone remained seriously and chronically ill. Reflecting the then-extant ideological rivalry between psychodynamically and biologically oriented clinicians, the Boston Psychotherapy Study was designed in the 1970s to address the methodological weaknesses of earlier clinical trials. This study aimed to evaluate the comparative effectiveness of expressive, insight-oriented individual psychotherapy and reality-adaptive, supportive psychotherapy against a backdrop of high-quality inpatient, outpatient, and pharmacological treatment provided to both patient groups. Contrary to the investigator's expectations, neither treatment emerged as clearly superior, although differential effects across outcome domains were noted: reality-adaptive, supportive therapy was preferentially effective in the areas of recidivism and role performance while expressive, insight-oriented therapy exerted a modest preferential effect on ego functions and cognition. The disappointing results of randomized clinical trials and follow-up studies contributed substantially to a decline in prestige and influence of the psychodynamic paradigm generally, and intensive individual psychotherapy of schizophrenia in particular. An additional challenge came from infant observational research that indicated that infants were far more active, stimulus seeking, and socially oriented from birth than was suggested by earlier psychodynamic theory. Similarly, stages such as the autistic and symbiotic were not observed and the infants' plasticity, resilience, and capacity for adaptation appeared far greater than earlier thought. These findings challenged the validity of psychosocial theories of etiology, at least as articulated by psychodynamic thinkers. Because of these and other factors, individual psychotherapy research and psychological theorizing concerning schizophrenia slowed to a near halt. The biological paradigm decisively gained ascendancy as the most influential in the field. Reappraisal of Individual Psychotherapy Significant among the findings from the Boston Psychotherapy Study was the degree to which, despite theoretical differences, the actual techniques employed by the expressive, insight-oriented therapy and reality-adaptive, supportive therapists tended to converge. For example,

both theories were found to employ substantial supportive elements. Sobering but significant were the substantial attrition rates for both types of therapy. Although those who remained in therapy continued to accrue benefits, by the end of 1 year more than half (56 percent) and by the end of 2 years more than two-thirds (69 percent) of all patients had unilaterally dropped out of treatment. Having found few differences in overall outcome between patients treated with expressive, insight-oriented therapy and reality-adaptive supportive therapy, investigators from the Boston Psychotherapy Study searched for common factors in the treatments associated with positive therapeutic change and good outcome. Results indicated that independent of severity of psychopathology, patients able to form a good alliance with the therapist within the first 6 months of treatment were more likely to remain in therapy and to comply with medication. These patients achieved better outcomes at 2 years and used less medication than those who did not form a therapeutic alliance. Looking at therapist activity, these investigators found across both therapies a strong positive correlation between reductions in patient denial of illness and retardation-apathy, and the therapists' demonstration of a sound dynamic understanding and accurate attunement to the patients' underlying concerns. Directive activity was associated with reductions in anxiety and depression. Rancorous debates concerning the relative value of drugs versus psychotherapy collapsed in the 1980s under the weight of data in opposition to the view that any single treatment is definitive for schizophrenia. Lack of efficacy weighed against a sole reliance on investigative psychotherapy whereas high rates of medication noncompliance, relapse, and persistent dysfunction defined the limits of a narrow medically oriented approach. The historical distinction between supportive and exploratory therapy was no longer salient.

FLEXIBLE PSYCHOTHERAPY Flexible psychotherapy refers to a broad and pragmatic approach to psychotherapy that relies on a variety of strategies applied flexibly depending on the individual patient's type of schizophrenia and phase of illness. Such an approach might at various times include supportive, directive, educational, investigative, and insight-oriented activity, provided in the context of an ongoing and stable doctor-patient relationship. The quality of this relationship should be characterized by empathy and a sound dynamic understanding of schizophrenia on the part of the physician. Dogmatic or rigid adherence to a single approach applied to all patients is probably the least likely to be of value. As described here in terms of assumptions, clinical tasks, and interventions, flexible psychotherapy approximates how most patients are treated in current practice. A specific form of flexible psychotherapy, personal therapy, has recently been sufficiently operationalized to allow for rigorous empirical evaluations. Flexible Psychotherapy: Assumptions A flexible approach to psychotherapy is based on a revised set of assumptions about the nature of schizophrenia that recognizes the joint contributions of biological, psychological, and social or environmental factors: 1. The stress-diathesis or vulnerability-stress model represents the best available integration of data pertinent to the etiology, course, and outcome of schizophrenia. The model postulates that schizophrenia results from a dynamic interaction between environmental or experiential stress in a person who is vulnerable to react to this stress with schizophrenic symptom formation. The vulnerabilities to schizophrenia are likely to be multiple and heterogeneous. Family and twin studies unambiguously indicate a genetic contribution to vulnerability, although a simple Mendelian mode of inheritance is not evident. Epidemiological investigations point to the contribution of acquired, biologically based environmental risk factors such as maternal influenza, Rh incompatibility, maternal starvation, and obstetrical complications. Although a variety of specific vulnerabilities have been identified, none has been shown to be ubiquitous. Biologically based vulnerability may be expressed as relatively enduring psychophysiological, cognitive, or behavioral difficulties among subgroups of patients. Most common findings include (1) deficits in information processing and maintaining a steady focus of attention; (2) dysfunctions in psychophysiology suggesting deficits in sensory inhibition and autonomic responsivity; (3) impairments in social competence; and (4) general coping deficits such as overvaluing threat, underappraising abilities, and extensive use of denial. The vulnerability to schizophrenia is seen as a relatively enduring proclivity to developing overt clinical symptoms; vulnerability is likely to be manifest as a set of stable traits present premorbidly, at onset, during acute episodes, and remissions. However, vulnerability is not static but is shaped epigenetically over time by environmental influences; a stress sufficient to precipitate relapse at one time, for example, may be less likely to do so at a later point when new coping strategies or better supports have been acquired. 2. The stress side of the vulnerability-stress model postulates that a variety of stressors (internal or external events requiring adaptation) can precipitate the emergence of symptoms in a vulnerable individual. Given biologically based vulnerability, the onset, course, and outcome of an individual's disorder may be shaped largely by interactions between the person and the environment. Among psychosocial factors, stressful life events, cultural milieu (egocentric versus sociocentric), social class, social network size and density, and emotional quality of the living environment have been demonstrated to be associated with the onset or course of schizophrenia. The vicissitudes of illness are best understood as a dynamic product of the affected individual's adaptive assets and vulnerabilities interacting over time with various stresses. In a highly vulnerable individual, sufficient stress can precipitate intermediate (prodromal) states of dysfunction that amplify preexisting cognitive, affective-autonomic, and social coping deficits. In the absence of adaptive strategies or environmental supports these interact negatively with the existing stressors to magnify their effect in a downwardly spiraling process that ends in a full-blown clinical syndrome. Clinical experience indicates that the stresses associated with illness onset or exacerbation may be highly individualized, rendering generalization about the typical nature of such stresses difficult. Stresses may be primarily biochemical (as in substance abuse), environmental (as in leaving for college, joining the armed services, breaking up with a girlfriend), or social (poverty, unemployment). 3. Schizophrenia is heterogeneous, as are individuals afflicted with it. The clinical diversity of schizophrenia in relation to vulnerabilities and risk factors, age and type of onset, manifest signs and symptoms, longitudinal course, and long-term outcome suggest that the disorder may be heterogeneous in regard to underlying etiology. This heterogeneity may be partially captured by currently available subtyping systems. Paranoid schizophrenia, for example, is associated with good premorbid functioning, late age of onset, many positive symptoms, intermittent illness over the first several years, and a comparatively high likelihood of good outcome despite a higher risk of suicide; the deficit form of schizophrenia is characterized by poor premorbid functioning, earlier onset, severe and enduring negative symptoms, a low risk of suicide, and often persistent life-long disability. However, an etiology-based subtyping that allows for precise longitudinal prediction for individual patients is not available. At a minimum, schizophrenic illnesses of greater and lesser severity and virulence can be identified and the biological vulnerability of individuals may differ. Like the illness itself, individuals afflicted with schizophrenia differ substantially in adaptive capacities, intelligence, and instrumental and verbal competence. Furthermore, the degree of social support available to them varies greatly. In general, the greater the level of instrumental skills acquired prior to the onset of illness (work or educational experience, experience with relationships, experience living independently), the better positioned the individual will be to recover or maintain functioning once the illness has become established. For some patients the failure to acquire much in the way of adaptive skills may represent the product of the life-long vulnerability underlying the tendency to the illness. For other patients a particularly virulent form of schizophrenia may catastrophically erode adequate premorbid skills, resulting in substantial permanent disability. Other patients with good premorbid abilities may be left with their skills and competence largely intact after an acute episode. 4. Schizophrenia is often phasic in course. Systematic investigation of longitudinal course has only recently begun and the understanding of illness phases is preliminary. Phases may include (1) prodromal periods, during which a highly individualized constellation of symptoms that represent early manifestation of clinical decompensation emerges; (2) acute or active phases, often associated with the full-blown emergence of positive symptoms superimposed onto pre-existing deficits; (3) subacute, convalescent, or stabilization phases characterized by gradual restoration of some functioning perhaps associated with postpsychotic depression; (4) moratoriums or adaptive plateaus, characterized by a gradual reconstitution of identity, gathering of support, and strengthening of skills; (5) change points or shifts in functioning over a relatively brief period of time, initiated by the patient's own desires or pressure from others and associated with the potential for either quantum improvement or decompensation; (6) end-state or stable plateaus, relatively enduring periods of stability characterized by greater or lesser fixed deficits or chronic levels of positive symptoms. Flexible Psychotherapy: Clinical Tasks and Technical Strategies To treat schizophrenia the therapist must use a variety of interventions and strategies. The crucial question is which interventions are of potential value for a particular individual at a particular phase of illness. All interventions aim to minimize the effect of vulnerabilities, bolster adaptive capacities, and reduce the extent and impact of stress. The range of therapeutic tasks and associated goals and interventions can be ordered hierarchically. As outlined in Table 12.10-1, different therapeutic tasks are of particular importance during different illness phases. In addition, although some

tasks are clearly relevant for all patients receiving individual treatment; other tasks, particularly those relating to the goals of intensive psychotherapy, are pertinent for only a small subgroup of patients. The strategic rosetta stone here is the therapist's capacity to shift gears, be flexible, and change roles with all patients based on changing circumstances, always keeping in mind the goal of helping the patient accept, learn about, and self-manage what may often be a chronic and devastating illness.

Table 12.10-1 Flexible Psychotherapy: Therapeutic Tasks, Interventions, and Goals

Consideration of the patient's schizophrenia subtype, current and premorbid functioning, and self-defined treatment goals are all relevant to the determination of appropriate treatment tasks. For patients with severe disorganized or deficit forms of schizophrenia, for example, the most humane and practical goal may be establishing a supportive ongoing treatment within a sheltered setting that minimizes stress and provides for basic human needs for an indefinite period. For the majority of patients who reside in the community amidst varying supportive structures, some degree of psychoeducation and rehabilitative tasks should be planned with the aim of minimizing acute relapses and promoting maximal functioning and quality of life. A primary focus on investigative tasks should be reserved for motivated patients who have established a good working relationship with the therapist and exhibit an interest in and ability to make constructive use of such techniques. These patients are likely to have demonstrated good premorbid functioning, intermittent and less severe forms of schizophrenia, minimal residual deficits, and retention of some capacity for self-observation, curiosity, tolerance of frustration, and humor. Attunement to psychological concerns may be particularly important for patients who have a dramatic response to new medications. The use of multiple treatment modalities creates the need for someone to orchestrate and coordinate them. In many instances a psychiatrist is best at providing individual therapy and continuity of care over a prolonged period. As is true in medicine generally, the quality of the individual doctor-patient relationship is a major factor in the success of the therapeutic endeavor. Thus, a focus on the skillful use of this relationship usefully informs all tasks at all levels. Here, removed from its outmoded etiological assumptions and overly ambitious aims, the substantial clinical knowledge derived from the tradition of investigative psychotherapy can be applied pragmatically in a contemporary context. Many of the tasks overlap with the concerns and expertise of other service providers; however, all the tasks should be the concern of the individual psychotherapist and a focus for individual psychotherapy. A common mistake made by trainees is to focus on higher-level psychological tasks while ignoring overwhelming difficulties at the level of basic human services. Thus, the necessary first goal of psychotherapy with a homeless person may be direct assistance in finding housing. Although other professionals may be relied upon to accomplish specific tasks, physician-therapists should consider themselves responsible for ensuring the results of these efforts. The following general treatment strategies are common to all the specific therapeutic tasks outlined: 1. Evaluation.A thorough evaluation of the patient initiates the treatment process. During medical assessment and stabilization this includes ruling out identifiable physical conditions, assessing competence to consent to treatment and risk, and determining the response of symptoms to short-term pharmacological intervention. Psychosocial assessment inventories available supports and aims to measure the degree to which the patient's adaptive capacities measure up against the stresses and demands of their living environment. Efforts to establish a supportive ongoing treatment test the patient's capacity to trust and rely upon another human being for support and guidance. When applicable, psychoeducational, rehabilitative, and investigative interventions are preceded by an assessment of the patient's cognitive strengths and deficits, allowing interventions to be formulated that match the patient's talents. 2. Continuous reevaluation. The fluid nature of schizophrenia and an individual's adaptation to it over time demands periodic reassessment of course, prognosis, phase of illness, and target problems; as these change, so do treatment goals. Providing concrete support in the form of a ride to work may be helpful early in the effort to promote vocational rehabilitation, but later may promote unwarranted dependency and prolong disability. 3. Timing. The phasic natural history of schizophrenia requires attention to the timing of particular therapeutic tasks. For many patients, in order to minimize stress and forestall relapse, relatively little beyond assessment, stabilization with medication, and establishment of a supportive ongoing treatment should be attempted during the first 6 to 12 months following an acute episode. Once the patient is asymptomatic and shows signs of revitalization, rehabilitation and more complex psychoeducational elements may be gradually introduced. 4. Titration.Treatment interventions should be applied with graded increases of intensity and complexity. Higher-level therapeutic tasks should be attempted and higher levels of work or social functioning expected only after completion and consolidation of earlier gains. Substantial rehabilitation, for example, will rarely be possible until progress has been made in attaining a stable supportive treatment relationship. Similarly, there is evidence that early, active, and ambitious psychologically oriented treatment may be disorganizing or toxic for certain patients. In general, treatment changes should be pursued cautiously, with only one element being modified at a time. 5. Integration with psychopharmacology. Each of these tasks take acute and prophylactic antipsychotic drugs as given for most patients. Control and prevention of psychotic symptoms using the lowest effective dosage of medication is the overall treatment goal. Decisions regarding pharmacological management are often linked to the relative success or failure of accomplishing various psychotherapeutic tasks. Considerable psychoeducation, for example, should be accomplished before attempting maintenance medication dose reduction or the initiation of a targeted (intermittent) medication strategy. Long-acting injectable antipsychotic agents may be useful for patients who are unable to tolerate the daily reminder of illness associated with oral medication or for patients who are unable to maintain a reliable treatment relationship. Personal Psychotherapy While reflecting clinical practice, flexible psychotherapy has not been formally assessed. Similar in overall outlook to flexible psychotherapy, however, personal therapy has recently been developed by Gerry Hogarty and his colleagues at the University of Pittsburgh as a form of individual treatment that is sufficiently operationalized to allow empirical testing. Personal therapy is designed for recently discharged outpatients with chronic or subchronic schizophrenia. Its objective is to enhance personal and social adjustment and forestall late (third-year) relapse. A disorder-specific treatment, it accommodates neuropsychological aspects of schizophrenia and attempts to avoid the adverse effect of poorly timed interventions. Within a stress-vulnerability model individual-specific stress, often interpersonal, is seen as precipitating affective dysregulation. This loss of control over mood is seen as resulting in poorly reasoned dysfunctional behavior that negatively influences the reciprocal behavior of others in a cycle that may end in relapse. Based on individual patients' needs, personal psychotherapy uses a range of interventions to promote patients' self-awareness and foresight and to equip patients with adaptive strategies that facilitate self-monitoring and self-control of affect. Personal psychotherapy includes three phases, each with explicitly defined goals and corresponding interventions. The achievement of these goals is carefully assessed before the patient advances to the next level of treatment. Phases of treatment, goals, and operational criteria defining readiness to move to more advanced phases are summarized in Table 12.10-2. Within each phase, the exposure of patients to specific interventions is varied based on individual need. While the therapy was designed to be given over a 3-year time span, patients spend as much time at each level as required to meet advancement criteria and not all patients progress through all three phases. Personal therapy is administered against a backdrop of psychopharmacological treatment that aims to minimize adverse effects by using the lowest medication dose needed to prevent symptom exacerbation.

Table 12.10-2 Personal Therapy: Goals, Techniques, and Criteria for Advancement

Investigators at the University of Pittsburgh have recently completed two 3-year randomized controlled trials of personal therapy for newly discharged patients with schizophrenia and schizoaffective disorders. Patients residing with their families were assigned to supportive therapy, personal therapy, families psychoeducation or management, or a combination of the latter two treatments. Patients living alone, who were generally more disabled, were assigned to personal therapy or supportive therapy. Results indicated that personal therapy was remarkably well accepted by patients participating in the trials. Over 3 years only 8 percent of patients receiving personal therapy and 23 percent of patients in contrasting treatments, were dropped for noncompliance or administrative reasons. The efficacy of personal therapy in relapse reduction was tied to residential status. Patients receiving personal therapy who were living with family experienced fewer relapses. The more impaired group of patients receiving personal therapy who were living alone experienced a greater relapse rate. Consistent with the clinical dictum that psychologically oriented treatments can be futile or harmful when applied before basic human service needs are addressed, personal therapy patients who relapsed were more likely to have unstable housing and difficulty securing food and clothing. Independent of relapse reduction, personal therapy produced substantial differential improvements in social adjustment and role performance. Whereas improvements in social adjustment among patients receiving supportive and family therapy reached a plateau at 12 months, the personal adjustment of personal therapy patients continued to improve in the second and third postdischarge years with no evidence of a plateau. Relative to supportive and family therapy, individual psychotherapy was superior in promoting a progressive improvement in psychosocial adjustment. Results from the Pittsburgh clinical trial of personal psychotherapy provide the first rigorous empirical support for the efficacy of disorder-specific and flexible form of individual psychotherapy as part of an overall treatment plan that includes psychopharmacology, attention to social service needs, and rehabilitation. Although research psychotherapies often have a limited impact on clinical practice, personal therapy is not tightly prescriptive. Rather, it provides a general strategy for ordering clinical work that leaves considerable room for individualization. Some form of individual psychotherapy combined with medication is the most common treatment provided to outpatients with schizophrenia. Personal therapy provides a previously lacking empirically supported framework to guide the provision of usual care. Targeted Individual Psychotherapies Working within an overall clinical framework that takes the necessity of multidisciplinary and individualized treatment as a starting point, several new individual psychotherapies that target specific problems or subgroups of patients have been developed and tested. These psychotherapies have generally been time-limited and administered as an adjunct to usual long-term care that includes medical management and medication. These illness-phase–specific treatments use circumscribed and measurable goals to target improvements in medication-resistant positive symptoms or treatment compliance. Elizabeth Kuipers and her colleagues at London's Institute of Psychiatry described the result of a randomized trial of cognitive-behavioral therapy for stabilized schizophrenia outpatients with at least one persistent medication-resistant positive psychotic symptom. The cognitive-behavioral intervention began with active efforts to promote engagement and a therapeutic alliance and later used individually tailored skills training, relaxation, and psychoeducational and exploratory techniques. Over a 9-month trial period, individual therapy recipients had a low dropout rate, expressed high levels of satisfaction with treatment and compared to a standard treatment control group showed a 25 percent reduction in symptom severity as measured by the Brief Psychiatric Rating Scale. Patients rated at baseline as showing some cognitive flexibility about delusions were most likely to benefit from this psychotherapeutic intervention. Nicholas Tarrier and his colleagues at University of Manchester conducted a randomized trial of intensive cognitive-behavioral therapy twice a week for 10 weeks (20 sessions) as an adjunct to usual care for compliant outpatients with medication-resistant positive psychotic symptoms at a residual phase of illness. To control for nonspecific factors, comparison groups included a generic supportive counseling with routine care and routine care–only group. Compared with routine care alone and routine care with supportive counseling, significant improvement in the severity and number of positive symptoms was found in those treated with cognitive therapy 3 months after treatment. Compared with both treatment groups, patients receiving usual care alone experienced more relapses and days hospitalized. A brief individual psychotherapy termed compliance therapy has been designed for acutely psychotic patients with chronic illness who have recently been readmitted for an illness relapse. This intervention consists of 4 to 6 cognitive-behaviorally oriented sessions lasting 20 to 60 minutes twice a week administered prior to hospital discharge. The sessions focus on (1) a review of symptoms and treatment adverse effects, (2) the patient's actions and beliefs regarding treatment, and (3) reducing stigma comparing pharmacotherapy to the need for medicine in other physical illnesses and defining drug treatment as a freely chosen strategy to enhance quality of life. In a randomized, controlled trial, Anthony David and his colleagues at the Maudsley Hospital reported that inpatients receiving compliance therapy showed greater postdischarge insight and more observer-rated treatment compliance compared with nonspecific counseling. In addition, survival in the community and social functioning were significantly better in the treatment group over an 18-month follow-up period. Prodromal Phase Intervention Many investigators have noted in recent studies of first-episode schizophrenia that patients typically experience active psychosis for 12 to 24 months before obtaining treatment. The observation that a longer duration of untreated psychosis is associated with a poorer initial pharmacological treatment response and more severe, chronic disability has rekindled interest in early detection and intervention as potential means to prevent the onset of severe symptoms or positively modify the long-term course of schizophrenia. Specialized early intervention programs have been developed in several countries and include individual therapy and case management techniques modified to meet the needs of patients who may be in the prodromal phase. Although no approach to early intervention has undergone rigorous empirical testing, a cognitive-behavioral focus on assisting the person to adapt to the onset of psychotic illness and its effects on self-concept, identity, and self-esteem has been described by Patrick McGorry. Limiting the damage to personal identity, social networks, and role functioning and promoting recovery and adaptation are treatment goals. Providing treatment in a less stigmatizing general youth center, and targeted use of low-dosage antipsychotic medication is a feature of this treatment. In addition, recognizing that many young people who recover from a prodromal state experience a flight into health and a determination to discontinue medication, therapists remain willing to maintain clinical contact without enforcing medication adherence. In this way medication can be quickly reinstituted if required. Practical Considerations in Outpatient Assessment When scheduling an initial outpatient visit for a patient with schizophrenia the therapist should set aside sufficient time (11/2 to 2 hours) to conduct a thorough preliminary assessment. If the referral is initiated over the phone by someone other than the patient, it is useful to use the phone contact to obtain a cursory outline of the patient's history and current mental status. Information about symptom severity, current medications, and current and past suicidality and aggression should be sought with the aim of determining whether outpatient evaluation can proceed safely. If preliminary contacts suggest the possibility of a need for hospitalization or other immediate short-term care, specific information about what such care resources the patient is eligible to access should be obtained. It is common for patients with schizophrenia to arrive for a first appointment accompanied by a family member, case manager, or other caregiver. Following introduction to the patient and those arriving with him or her, an initial assessment interview can be conducted with the patient alone. In this interview the therapist may need to make an active effort to promote the patient's comfort. This can be done by, for example, offering coffee, pointing out the specific place to sit, outlining what will be discussed, and if necessary conducting the assessment interview with a specific set of questions. With the patient's permission, it is then often useful to spend some time alone with the accompanying family member or other caregiver. This interview allows the person accompanying the patient to express specific

concerns or worries in private and can provide important additional information about the patient's situation. Ideally, the outcome of the initial visit will be a mutually agreed upon plan for further assessment or treatment. This plan should include the frequency and duration of visits, payment, medication regime, and arrangements for the patient and caregivers to reach a physician (or other team member) in the event of a crisis between scheduled appointments. Attention should also be given to practical considerations such as transportation to appointments and how and where prescriptions will be filled. If psychotherapy is recommended, a general statement of its methods and goals may be useful (“We will meet so that we can talk together, better understand your difficulties, and work with you on your medications to improve your situation”). In addition, defining some mutually agreed upon area (problem, concern, goal, medication adverse effects) in which the therapist can be seen as potentially useful to the patient will set the stage for a positive therapeutic relationship. The frequency and duration of psychotherapy are individualized. Weekly psychotherapy for 45 to 50 minutes is most common in an outpatient setting, but the frequency of visits may be increased during periods of clinical instability or if insight-oriented psychotherapy is prescribed. Less frequent visits of shortened duration (15 to 20 minutes) may be negotiated during periods of stability, for patients who have learned to self-manage their illness, or for those who find contact with a physician aversive, disorganizing, or irrelevant. In addition to setting the stage for establishing a working relationship with the patient, the physician's management of the initial interview should promote collaboration with the patient's family member, case manager, or other caregiver. Both the patient and the caregiver can be told that the patient's confidentiality will be respected, but should the therapist at any time believe a relapse or other dangerous situation is developing, the help of family and other caregivers will be solicited. The family can be encouraged to contact the physician should they develop concerns and the frequency of future family contacts should be agreed upon. Family or caregiver support is crucial to the outcome of treatment and will most likely be extended to a clinician who is felt to be empathic, responsive to concerns, and available. Therapists should be cognizant of the fact that suicide is the most common cause of premature death in schizophrenia and that patients with schizophrenia are less prone to spontaneously report suicidality. As a result, the therapist should be active in eliciting suicidal ideation; if not directly asked, patients may not reveal their intent. Several studies have shown that two-thirds or more of schizophrenia patients who commit suicide have seen an apparently unsuspecting clinician within 72 hours of death. Research indicates that less-disabled patients with few negative symptoms who retain the capacity to experience painful affects and can reflect on the seriousness of their situation are at greatest risk of suicide. Periods following discharge from a hospitalization and loss of an important relationship have been identified as high-risk periods. Providing additional therapeutic support for patients during high-risk periods and monitoring for the emergence of potentially treatable syndromal depression may be reasonable strategies to reduce suicide risk. Medication Compliance Noncompliance with effective psychopharmacological treatments during both short-term and maintenance therapy is a major cause of morbidity among patients with schizophrenia. When prolonged or repeated, noncompliance contributes to a downwardly spiraling cycle of relapse, recidivism, and deterioration of social and instrumental functioning. Empirical correlates of noncompliance include (1) patient-related factors (greater illness severity or grandiosity, lack of insight, substance abuse comorbidity); (2) medication-related factors (dysphoric medication adverse effects, ineffective or excessively high dosages); (3) environmental factors (inadequate support of supervision, practical barriers); and (4) clinician-related factors (poor therapeutic alliance). Available research underscores the multiplicity of explanations for reduced compliance and highlights the necessity of an individualized assessment. Of particular relevance to psychotherapy are patients' health beliefs and the psychological meanings attached to their illness and its treatment. Among the psychological meanings associated with medication noncompliance, the following have been described: (1) pervasive denial about having an illness and needing treatment; (2) reactive efforts to regain control of one's life and maintain a sense of self-cohesion by organizing in opposition to the will of others; (3) the concrete equation of taking medication with being ill (“If I need drugs, I must be sick; The higher the dose, the sicker I am; I'll stop being ill if I stop taking drugs”); (4) lack of knowledge or incorrect beliefs about medications (taking drugs is a sign of weakness); (5) paranoid views of medication as being poisonous, controlling, or damaging; (6) secondary gain from psychosis—grandiose delusional gratification, escape from normal expectations and responsibilities; (7) pain and anguish accompanying symptom reduction with its attendant recognition that one has been ill and that the illness is severe; (8) displacement from transference—for example, discontinuing medication as an expression of anger towards one's therapist or family; and (9) an expression of unconscious ambivalence or fear of autonomy—as in discontinuing medication immediately before beginning a new job or rehabilitation program. The variety of possible factors related to noncompliance point to the need for a broad and flexible approach that applies a range of interventions based on current knowledge of psychopharmacology and sound dynamic understanding of the individual patient. General recommendations for improving compliance in the context of psychotherapy have included: (1) conveying interest and concern about medication by asking specific questions about how much medication is being taken, effects, and adverse effects; (2) assuming many patients will at times take more or less medication and creating a therapeutic environment where such experiments are legitimized and can be talked about; (3) involving patients to the greatest extent possible in their own medication treatment—for example, allowing self-regulation of dosage within limits; (4) arranging for the taking of medication under the supervision of family, friends, or others and enlisting their support for medication; (5) direct praise and support for medication compliance; (6) education in the areas of medication adverse effects, relapse prevention, and the biological basis of major mental illness; (7) promoting self-monitoring through record keeping and other behavioral interventions; (8) attending to and building the therapeutic relationship as a lever to change; and (9) helping the patient experience activities that promote self-esteem and compete with psychosis as sources of gratification. The choice of specific interventions should be based on a differential diagnosis that generates hypotheses regarding which specific factors are operative in the individual patient. When lack of knowledge and cognitive deficit are a major factor in noncompliance, specific cognitive and behavioral procedures have been developed to enhance cognitive mastery and skills attainment. When noncompliance represents the unconscious wish to regress or to act out transference, dynamic exploration and interpretation are required. When severe disorganization is a major factor, arrangements for supervised medication administration may be necessary. Finally, it must be recognized that some patients who appear to be clear candidates for benefiting from medication will continue to refuse this treatment, despite all efforts. These circumstances typically arouse countertransference reactions that require attention, such as telling the patient to seek treatment elsewhere out of anger or wishing to hurt the patient through abandonment. Another unproductive countertransference is withholding advice or support that might be of use to patients in order to see them learn their lesson by experiencing a full-blown relapse. Allowing the noncompliant patient who leaves treatment against medical advice to do so with dignity can set the stage for greater collaboration should the patient return in the future. Circumstances requiring the therapist to initiate commitment or involuntary administration of medication also typically evoke powerful countertransference. Following such coercive interventions, the psychotherapist may experience considerable guilt about and fear of the patient. At such a time the therapist is tempted to discontinue all contact and turn the patient over to another clinician, rationalizing that a therapeutic alliance will never again be possible after such heavy-handed acts. Experience demonstrates that such an assessment is usually a distortion that more often serves the needs of the therapist than the patient. Following resolution of such an episode, many patients may express gratitude for the therapist's action, and in hindsight recognize that they were in need of treatment. The results of empirical research have catalyzed a reformulation of psychotherapeutic techniques. An approach to individual therapy that includes appropriate attention to pharmacological, psychotherapeutic, psychosocial, and rehabilitative interventions titrated to the individual patient's response and progress has been articulated in clinical literature. The introduction of new antipsychotic agents with greater efficacy and fewer adverse effects will raise the functional ceiling previously imposed on many patients who experienced persistent symptoms or disabling adverse effects with first-generation agents. The greater efficacy of new medications creates new opportunities to realize the potential therapeutic synergy of blending multiple interventions into an integrated treatment approach.

SUGGESTED CROSS-REFERENCES General discussions of the psychotherapies appear in Chapter 30. Various aspects of schizophrenia and its treatments are discussed in the other sections of Chapter 12. SECTION REFERENCES Alanen YO: Schizophrenia: Its Origins and Need-Adapted Treatment. Karnac Books, London, 1997. American Psychiatric Association: Practice guidelines for the treatment of patients with schizophrenia. Am J Psychiatry 154(Suppl):1, 1997. Book HE: Some psychodynamics of non-compliance. Can J Psychiatry 32:115, 1987.

Brill AA: Schizophrenia and psychotherapy. Am J Psychiatry 9:519, 1929. Corrigan PW, Liberman RP, Engel JD: From noncompliance to collaboration in the treatment of schizophrenia. Hosp Community Psychiatry 41:1203, 1990. Coursey RD: Psychotherapy with persons suffering from schizophrenia: The need for a new agenda. Schizophr Bull 15:349, 1989. Diamond RJ: Enhancing medication use in schizophrenic patients. J Clin Psychiatry 44:8, 1983. *Dingman CW, McGlashan TH: Psychotherapy. In A Clinical Guide for the Treatment of Schizophrenia, AS Bellack, editor. Plenum, New York, 1989. Duckworth K, Nair V, Patel JK, Goldfinger SM: Lost time, found hope and sorrow: The search for self, connection, and purpose during “awakenings” on the new antipsychotics. Harv Rev Psychiatry 5:277, 1997. Eckman TA, Liberman RP, Phipps CC, Blair KE: Teaching medication management skills to schizophrenic patients. J Clin Psychopharmacol 10:33, 1990. Fenton WS, McGlashan TH: We can talk: Individual psychotherapy for schizophrenia. Am J Psychiatry 154:1493, 1997. Fenton WS, Blyler CR, Heinssen RK: Determinants of medication compliance in schizophrenia: Clinical and empirical correlates. Schizophr Bull 23:637, 1997. Frank AF, Gunderson JG: The role of the therapeutic alliance in the treatment of schizophrenia: Relationship to course and outcome. Arch Gen Psychiatry 47:228, 1990. *Fromm-Reichmann F: Principles of Intensive Psychotherapy. University of Chicago Press, Chicago, 1950. Gilbert S, Ugelstad E: Patient's own contributions to long-term supportive psychotherapy in schizophrenia disorders. Br J Psychiatry 164 (Suppl):84, 1994. Glass LL, Katz HM, Schnitzer RD, Knapp PH, Frank AF, Gunderson JG: Psychotherapy of schizophrenia: An empirical investigation of the relationship of process to outcome. Am J Psychiatry 146:603, 1989. *Greenfeld D: The Psychotic Patient: Medication and Psychotherapy. The Free Press, New York, 1985. Gunderson JG, Frank AF, Katz HM, Vannicelli ML, Frosch JP, Knapp PH: Effects of psychotherapy in schizophrenia, II. Comparative outcome of two forms of treatment. Schizophr Bull

10:564, 1984.

Hogarty GE, Kornblith SJ, Greenwald D, DiBarry AL, Cooley S, Flesher S, Reiss D, Carter M, Ulrich R: Personal therapy: A disorder-relevant psychotherapy for schizophrenia. Schizophr Bull 21:379, 1995. Hogarty GE, Kornblith SJ, Greenwald D, DiBarry AL, Cooley S, Ulrich RF, Carter M, Flesher S: Three-year trials of personal therapy among schizophrenic patients living with or independent of family, I. Description of study and effects on relapse rates. Am J Psychiatry 154:1504, 1997. Hogarty GE, Greenwald D, Ulrich RF, Kornblith SJ, DiBarry AL, Cooley S, Carter M, Flesher S: Three-year trials of personal therapy among schizophrenic patients living with or independent of family, II. Effects on adjustment of patients. Am J Psychiatry 154:1514, 1997. Kane JM, McGlashan TH: Treatment of schizophrenia. Lancet 346:820, 1995. Kemp R, Kirov B, Everitt B, Hayward P, David A: Randomised controlled trial of compliance therapy. 18-month follow-up. Br J Psychiatry 172:413, 1998. *Kendler KS: Long-term care of an individual with schizophrenia: Pharmacologic, psychological, and social factors. Am J Psychiatry 156:124, 1999. Kuipers E, Garety P, Fowler D, Dunn G, Bebbington P, Freeman D, Hadley C: London-East Anglica randomised controlled trial of cognitive-behavioral therapy for psychosis. Br J Psychiatry 171:319, 1997. Levine IL, Wilson A: Dynamic interpersonal processes and the inpatient holding environment. Psychiatry 48:341, 1985. Liberman RP: Psychosocial treatments for schizophrenia. Psychiatry 157:104, 1994. McGlashan TH, Keats CJ: Schizophrenia: Treatment Process and Outcome. American Psychiatric Press, Washington, DC, 1989. McGlashan TH: Schizophrenia: Psychosocial treatments and the role of psychosocial factors in its etiology and pathogenesis. In Annual Review of Psychiatry, vol 5, A Frances, R Hales, editors. American Psychiatric Press, Washington, DC, 1986. McGorry PD, Edwards J, Mihalopoulos C, Harrigan SM, Jackson HJ: EPPIC: An evolving system of early detection and optimal management. Schizophr Bull 22:305, 1996. *Meehl PE: Schizotaxia, schizotypy, schizophrenia. Am Psychol 17:827, 1962. Nuechterlein KH, Dawson ME: Vulnerability and stress factors in the developmental course of schizophrenic disorders. Schizophr Bull 10:158, 1984. Parsons T: The Social System. Free Press, Glencoe, IL, 1951. Rako S, Mazer H, editors: Semrad: The Heart of a Therapist . Jason Aronson, New York, 1980. A Recovering Patient: “Can we talk?” The schizophrenic patient in psychotherapy. Am J Psychiatry 143:68, 1986. Scott JE, Dixon LB: Psychological interventions for schizophrenia. Schizophr Bull 21:621, 1995. Searles HF: Countertransference. International Universities Press, New York, 1979. Stanton AH, Gunderson JG, Knapp PH, Frank AF, Vannicelli ML, Schnitzer R, Rosenthal R: Effects of psychotherapy in schizophrenia, I. Design and implementation of a controlled study. Schizophr Bull 10:520, 1984. Strauss JS, Hafez H, Lieberman P, Harding CM: The course of psychiatric disorder, III. Longitudinal principles. Am J Psychiatry 142:289, 1985. *Sullivan HS: The Psychiatric Interview. Norton, New York, 1970. Tarrier N, Yusupoff L, Kinney C, McCarthy E, Gledhill A, Haddlock G, Morris J: Randomised controlled trial of intensive cognitive behaviour therapy for patients with chronic schizophrenia. Br Med J 317:303, 1998. Weiden P, Havens L: Psychotherapeutic management techniques in the treatment of outpatients with schizophrenia. Hosp Community Psychiatry 45:549, 1994.

Textbook of Psychiatry

13.1 SCHIZOAFFECTIVE DISORDER, SCHIZOPHRENIFORM DISORDER, AND BRIEF PSYCHOTIC DISORDER Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 13. OTHER PSYCHOTIC DISORDERS

13.1 SCHIZOAFFECTIVE DISORDER, SCHIZOPHRENIFORM DISORDER, AND BRIEF PSYCHOTIC DISORDER JOHN LAURIELLO, M.D., BRENDA R. ERICKSON, M.D., AND SAMUEL J. KEITH, M.D. Schizoaffective Disorder Schizophreniform Disorder Brief Psychotic Disorder Suggested Cross-References

There are three disorders in addition to schizophrenia listed in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) in the section “Schizophrenia and Other Psychotic Disorders.” The first, schizoaffective disorder, is a complex illness that has changed significantly over time. In its simplest definition, it is presently conceived as an illness with coexisting, but independent, schizophrenic (psychotic) and mood components. Schizoaffective disorder is seen primarily as part of a schizophrenia spectrum rather than an equal hybrid of mood and schizophrenia disorders. Schizophreniform disorder is a diagnosis that assumes another will replace it after 6 months. Most cases of schizophreniform disorder progress to either schizophrenia or schizoaffective disorder, with some cases rediagnosed as a non–schizophrenia spectrum illness (i.e., schizotypal or schizoid personality disorders), while a few resolve completely. Finally, the diagnosis brief psychotic disorder describes an impairment in reality testing that lasts at least 1 day, but less than 1 month. All three disorders have a psychotic component, are often misunderstood, are incorrectly applied, and are not as well studied as schizophrenia, bipolar I disorder, or major depressive disorder.

SCHIZOAFFECTIVE DISORDER As the end of the century nears great strides have been made in clarifying the diagnostic criteria for many psychiatric illnesses. However, patients often do not fall neatly into set illness criteria. There are several approaches to dealing with such patients. One is to diagnose the patient with two distinct illnesses and treat those illnesses as separate problems. Another possibility is to consider that the patient has a primary illness and symptoms of a second illness that are not as important and might even resolve when the primary illness is treated. A third approach considers that the patient suffers from a distinct blended illness with its own history, diagnosis, and treatment. This last approach best represents the current orthodoxy in the diagnosis and treatment of patients with the DSM-IV diagnosis of schizoaffective disorder. Unfortunately, this approach is not easily applied, often making the diagnosis confusing and convoluted. History At the beginning of this century, patients with mental illness were grouped together as suffering from the common illness insanity. With the work of Emil Kraepelin, and Eugene Bleuler, distinct diagnostic groups began to emerge. Kraepelin was able to distinguish an unremitting, dementing illness in young patients that became known as schizophrenia, which he contrasted with an episodic illness of affect now known as bipolar I disorder. However, there were patients who did not fit neatly into either category. Bleuler believed that the presence of any symptoms of schizophrenia even when there was an affective component was still schizophrenia. Patients with mixed features of schizophrenia and affective (mood) disorder were first described by George Kirby and August Hoch in the early part of the century. In 1933, Jacob Kasanin introduced the term “schizoaffective psychosis” to describe a group of patients who had symptoms of both affective and schizophrenic illnesses. While he is credited with introducing the term, on subsequent review of these patients, all would now meet the diagnosis of a pure mood disorder. Nevertheless, the term schizoaffective disorder has survived albeit in several different contexts. Comparative Nosology One of the difficulties in using a diagnosis that depends on not being another diagnosis is that both depend on changes in the other. Schizoaffective disorder is affected by any changes in the diagnostic criteria of schizophrenia, affective disorder, or both. As psychotic affective disorders and schizophrenia have been better distinguished, those who fall through the “diagnostic cracks” have become clearer. In the second edition of DSM (DSM-II) schizoaffective disorder was a subtype of schizophrenia and denoted patients who had any mood symptoms while meeting the criteria for schizophrenia. In contrast, the Research Diagnostic Criteria (RDC) for schizoaffective disorder allowed as few as one symptom of schizophrenia in a patient who met the criteria for a full affective disorder. The third edition of DSM (DSM-III), influenced by studies in the United States and Great Britain, narrowed the diagnosis of schizophrenia and expanded the diagnosis of bipolar disorder. It allowed symptoms of schizophrenia to coexist with a mood disorder as long as these schizophrenic symptoms did not remain when the mood disorder resolved. Moreover, mood-incongruent psychotic symptoms could now exist in bipolar disorder. Finally, schizoaffective disorder moved from its schizophrenia subtype place to stand alone as a “psychotic disorder not elsewhere classified.” The revised third edition of DSM (DSM-III-R) expanded this notion by inserting the criterion that a patient with schizoaffective disorder must meet the criteria for schizophrenia for at least 2 weeks independent of any mood syndrome. DSM-IV has retained most of the DSM-III-R criteria but has stricter diagnostic criteria for schizophrenia. Patients must meet the symptoms of schizophrenia for at least 1 month as opposed to the previous 1-week criterion. Schizoaffective disorder is now listed in the section “Schizophrenia and Other Psychotic Disorders.” The 10th revision of International Statistical Classification of Diseases and Related Problems (ICD-10) essentially describes the same disorder. The ICD-10 schizoaffective disorders describe single as well as recurrent episodes. Subtypes include manic, depressed, and mixed types. Mixed type includes a cyclic schizophrenia and a mixed schizophrenic-mood psychosis. Epidemiology There is no psychiatric epidemiological study of the incidence or prevalence of schizoaffective disorder in a general population. Even if there were such studies, older reports might not be useful, because the diagnosis (and therefore the incidence and prevalence) would have changed over time. Prevalence rates for consecutive patients diagnosed in a psychiatric treatment setting are available. These numbers range from 2 to 29 percent, a potentially significant cohort requiring treatment. Several lines of evidence support the idea that one might expect an increased prevalence of schizoaffective disorder in women. Women have a higher prevalence of major depressive disorder than men do, and women with schizophrenia express more affective symptoms than men with schizophrenia do. In family studies of patients with schizoaffective disorder, relatives of females with schizoaffective disorder have a higher rate of schizophrenia and depressive disorders than do relatives of males with schizoaffective disorder. Etiology It is difficult to determine a cause of a disease that has changed so much over time. One might conjecture that the etiology of schizoaffective disorder as currently defined might be similar to the etiology of schizophrenia. Thus etiological theories of schizoaffective disorder would include some genetic and environmental causation. Molecular genetic studies of schizoaffective disorder have lagged behind recent studies of the genetics of schizophrenia and bipolar I disorder. Available family studies have reported that families of schizoaffective probands have significantly higher rates of relatives with mood disorder than families of schizophrenia probands. Similarly, these schizoaffective probands have more psychotic symptoms than families of mood disorder probands. The results of these family studies have argued that schizoaffective disorder is a unique disorder, separate from schizophrenia and mood disorders. Possible environmental causes of schizoaffective disorder are similar to those of schizophrenia, including in utero insult (including malnutrition and viral causes) and obstetrical complications. One hypothesis considers schizophrenia to be a developmental and progressing disorder that can be seen in the development of brain dysmorphology. This includes less cortical gray matter and more fluid and fluid-filled spaces; however, no definitive study of patients with DSM-IV schizoaffective disorder has been done. One might assume that schizoaffective patients would have similar brain abnormalities, because the disorder mimics many aspects of schizophrenia. For nearly a half century the prevailing etiologic theory of schizophrenia was the dopamine hypothesis. In its simplest description it postulates that the underlying abnormality is excess dopamine in areas of the brain, leading to psychosis. Thus, successful treatment with antipsychotics is due to their dopamine-blocking properties. With the successful use of clozapine (Clozaril) and other serotonin-dopamine antagonists, the dopamine hypothesis has been amended. Currently, a critical balance between the neurotransmitters dopamine and serotonin is believed to be important for treating schizophrenia. At the same time it is accepted that there are abnormalities of serotonin and norepinephrine in mood disorders. These theories are particularly interesting when considering underlying causes of schizoaffective disorder. Possibly this balance of dopamine and serotonin is particularly affected in schizoaffective disorder, leading to chronic psychosis and intermittent but substantial mood alterations. Diagnostic and Clinical Features DSM-IV diagnostic criteria are provided in Table 13.1-1.

Table 13.1-1 DSM-IV Diagnostic Criteria for Schizoaffective Disorder

These criteria are a product of several revisions that have sought to clarify several diagnoses including schizophrenia, bipolar disorder, and major depressive disorder. It was hoped that improving these diagnoses would make schizoaffective disorder begin to stand out apart from them. However, the diagnostic criteria still leave much to interpretation. The diagnostician must accurately diagnose the affective illness, making sure it meets the criteria of either a manic or depressive episode but also determining the exact length of each episode (not always an easy or possible task). The length of each episode is critical for two reasons. First, to meet the B criterion (psychotic symptoms in the absence of the mood syndrome) one has to know when the affective episode ends and the psychosis continues. Second, to meet criterion C the length of all mood episodes must be combined and compared with the total length of the illness. If the mood component is present for a substantial portion of the total illness, then that criterion is met. Calculating the total length of the episodes can be difficult, and it does not help that the term “substantial portion” is not defined. In practice, most clinicians look for the mood component to be 15 to 20 percent of the total illness. Patients who have one full manic episode lasting 2 months but who have suffered from symptoms of schizophrenia for 10 years do not meet the criteria for schizoaffective disorder. Instead, the diagnosis would be a mood episode superimposed on schizophrenia. It is unclear whether the bipolar or depressive type specifiers are helpful, although they may direct treatment options. These subtypes are often confused with earlier subtypes (schizophrenic versus affective type) thought to have implications in course and prognosis. As with most psychiatric diagnoses, schizoaffective disorder should not be used if the symptoms are caused by substance abuse or a secondary medical condition. The ICD-10 diagnostic criteria for schizoaffective disorder are listed in Table 13.1-2.

Table 13.1-2 ICD-10 Diagnostic Criteria for Schizoaffective Disorders

Ms. A.D. was a 29-year-old white unmarried woman, with a 10-year history of schizoaffective disorder bipolar type. She was first hospitalized after child protection took her son away for alleged child abuse. When the patient was interviewed at that time, she was described as dressed like a “gypsy” with heavy makeup and pressured speech. She told the treatment team her son had been abused by his father, a well-known rock star. During this time she was stabilized on lithium (Eskalith) and haloperidol (Haldol). A.D.'s manic symptoms resolved, but her belief that she was a rock star's girlfriend remained. Since that first hospitalization she has lost custody of her son. She remains delusional about the child's famous father, and in addition, she believes people are out to get her. She has had three distinct episodes of mania during which she needs little sleep and has racing thoughts and pressured speech. She has been intermittently compliant with medications and is currently receiving haloperidol in a long-acting form. In the 10 years of her illness she has never been free of her delusions. She has not been able to work and receives federal disability assistance. Differential Diagnosis The psychiatric differential diagnosis includes all the possibilities usually considered for mood disorders and for schizophrenia In any differential diagnosis of psychotic disorders a complete medical workup should be performed to rule out organic causes of the symptoms. A history of substance use with or without a positive toxicology screening test may indicate a substance-induced disorder. Preexisting medical conditions, their treatment, or both may cause psychotic and mood disorders. Any suspicion of a neurological abnormality warrants consideration of a brain scan to rule out anatomical pathology and an electroencephalogram (EEG) to determine any possible seizure disorders (e.g., temporal lobe epilepsy). Psychotic disorder due to seizure disorder is more common than that seen in the general population. It tends to be characterized by paranoia, hallucinations, and ideas of reference. Epileptic patients with psychosis are believed to have a better level of function than patients with schizophrenic spectrum disorders. Better control of the seizures can reduce the psychosis. The same hypothetical case is used in the 3 cases below with different outcomes to illustrate the diagnostic decision. Mrs. B. was a 32-year-old married woman with three children. She reported being relatively happy and free of illness until the birth of her third child. She had the usual “baby blues” that resolved after the first month. When her third child was 14 months old, she began to have trouble sleeping, and her husband noticed that she was sometimes irritable and at other times euphoric. She began to talk rapidly and call family members at all hours of the night. One night her husband received a phone call that his wife was in the county jail. She had secretly left the house, gone to a local bar, and instigated a fight with a female patron. The police thought she was acting wildly and suspected some sort of intoxicant. She was taken to the local psychiatric clinic where a urine toxicology screen was negative. She was admitted to the hospital and treated with the benzodiazepine, lorazepam (Ativan), and the mood stabilizer lithium, and after 2 weeks was completely asymptomatic. Her diagnosis is bipolar I disorder, manic type. Discussion The patient suffered from an elevated and euphoric mood alone. She did not exhibit any symptoms of schizophrenia and was appropriately treated with a benzodiazepine, lorazepam, to calm her and long-term treatment with a mood stabilizer, lithium. This patient might have future episodes with hallucinations, delusions, or both. These psychotic symptoms may or may not be congruent with her mood state (e.g., a patient who is depressed and has the delusion of being a terrible person who has committed a crime and deserves to suffer and be punished). However, the psychotic symptom might also be very incongruent with the mood. The critical distinction for this patient was that the psychotic symptom existed only during the mood episode. Conceptually, the psychosis was fueled by the mood. Correct the mood and there is no fuel for the psychosis and it also disappears.

Mrs. S. was a 32-year-old married woman with three children. She reports that she has been relatively happy and free of illness until the birth of her third child. She had the usual “baby blues” that resolved after the first month. When her third child was 14 months old she began to have trouble sleeping and her husband noticed that she was becoming increasingly isolated and not able to take care of her children. One night her husband received a phone call that his wife was in the county jail. She had secretly left the house, gone to a local bar and instigated a fight with a female patron. The police thought she was acting wildly and suspected some sort of intoxicant. She was taken to the local psychiatric clinic where a urine toxicology screen was negative. At that time she told the staff that she was sure someone was using her social security number and consuming the benefits she would need when she was older. She had gone to the bar because a man's voice had told her that the person who was using her benefits was there. This voice had been talking to her for over a year and often commented on her looks and actions. The patient was admitted to the hospital, treated with the antipsychotic risperidone (Risperdal), and after 2 weeks of treatment was completely asymptomatic. Her diagnosis is schizophrenia, paranoid type. Discussion The patient's primary symptoms were delusions and hallucinations without any accompanying mood abnormality. They were of sufficient severity and duration to give her a diagnosis of the paranoid type of schizophrenia, and she was appropriately treated with an antipsychotic agent. Patients suffering from schizophrenia often have both depressive and euphoric symptoms. A common mistake is assuming that a schizophrenic patient presenting with a full range of affect is a patient with schizoaffective disorder. The presence of euphoria or demoralization alone does not meet the criteria for diagnosis of schizoaffective disorder. Patients must both meet the appropriate criteria for the affective disorder and have the affective disorder for a substantial portion of their chronic illness. That said, a patient with schizophrenia suffering from subsyndromal demoralization or disinhibited behavior might benefit from an antidepressant or mood stabilizer, respectively. Mrs. S.A. was a 32-year-old married woman with three children. She reports that she has been relatively happy and free of illness until the birth of her third child. She had the usual “baby blues” that resolved after the first month. When her third child was 14 months old she began to have trouble sleeping and her husband noticed that she was becoming increasingly irritable, euphoric, isolated and not able to take care of her children. One night her husband received a phone call that his wife was in the county jail. She had secretly left the house, gone to a local bar and instigated a fight with a female patron. The police thought she was acting wildly and suspected some sort of intoxicant. She was taken to the local psychiatric clinic where a urine toxicology screen was negative. At that time she told the staff that she was sure there was someone using her social security number and consuming the benefits she would need when she was older. She also described herself as being one of the 10 smartest people in the world and was sure that the treatment team did not understand her because of their incompetence and she asked to be seen by the head of the hospital. The patient was treated with the antipsychotic risperidone and the mood stabilizer lithium and was completely asymptomatic after 2 weeks of treatment. A year later her husband brought her back to the psychiatric hospital. He reported she had been doing well and was compliant with her medication, which was now lithium carbonate alone. Her mood has been unremarkable, but in the last month she again began to say that someone had stolen her social security benefits. On interview she was calm and cooperative although a little guarded. She reluctantly admitted that the man's voice had returned recently. Risperidone was added back to her regimen, and after 2 weeks she returned to her usual self. Her diagnosis is schizoaffective disorder, bipolar type. Discussion The third case (above) displayed symptoms of both a mania and a delusion. She was appropriately treated with an antipsychotic agent and a mood stabilizer. If the vignette had ended there, one might conclude that she had a manic episode with psychotic features. However, she had an exacerbation a year later. This time her mood was totally normal but her delusions and hallucinations returned. She is restarted on the antipsychotic since it appears the mood stabilizer alone was insufficient. It was very appropriate in this circumstance to first taper the patient off the antipsychotic and try the patient on a mood stabilizer alone, aware of the long-term risks of antipsychotics. However, having had the delusional episode while on the mood stabilizer most likely portends a need for intermittent or maintenance antipsychotic treatment. These 3 women, while having historical details in common, illustrate the differences between a pure mood disorder, schizophrenia, and schizoaffective disorder. Course and Prognosis Considering the uncertainty and evolving diagnosis of schizoaffective disorder, determining the long-term course and prognosis is difficult. Given the definition of the diagnosis, one might expect patients with schizoaffective disorder to have either a course similar to an episodic mood disorder, a chronic schizophrenic course, or some intermediate outcome. It has been presumed that an increasing presence of schizophrenic symptoms predicted worse prognosis. Studies using RDC criteria showed that after 1 year patients with schizoaffective disorder had different outcomes depending on whether their predominant symptoms were affective (better prognosis) or schizophrenic (worse prognosis). With the narrower definition of DSM-III-R and DSM-IV, all patients had to have an independent schizophrenic component to meet the diagnosis of schizoaffective disorder. One study that followed patients diagnosed with DSM-III-R schizoaffective disorder for 8 years found that the outcomes of these patients more closely resembled schizophrenia than a mood disorder with psychotic features. Treatment There are several extensive reviews of the treatment of schizoaffective disorder, but critical evaluation of the results of these studies is not easy. Because the operational definition of schizoaffective disorder has shifted over the last 30 years, comparing or pooling studies is impossible. The efficacy and selection of treatment for a patient under the broader (more mood disorder inclusive) DSM-II criteria may differ from that of the patient diagnosed with the narrower DSM-III-R criteria. However, there are some general recommendations for treatment. The principle rule is to treat the patient's symptoms, not the diagnostic label. Mood Stabilizers Mood stabilizers are a mainstay of treatment for bipolar disorders and would be expected to be important in the treatment of patients with schizoaffective disorder. Few studies have examined the efficacy of mood stabilizers in schizoaffective disorder, in contrast to the extensive studies of lithium, valproate (Depakote), and to a lesser extent carbamazepine (Tegretol) in bipolar I disorder. A recent study that compared lithium with carbamazepine showed superiority for carbamazepine for schizoaffective disorder, depressive type, but no difference in the two agents for the bipolar type. In practice however, these medications are used extensively alone, in combination with each other, or with an antipsychotic agent. In manic episodes, schizoaffective patients should be treated aggresively with dosages of a mood stabilizer in the middle to high therapeutic blood concentration range. As the patient enters a maintenance phase the dosage can be reduced to low to middle range to avoid adverse effects and potential effects on organ systems (e.g., thyroid and kidney) and to improve ease of use and compliance. Laboratory monitoring of plasma drug concentrations and periodic screening of thyroid, kidney, and hematological functioning should be performed. As in all cases of intractable mania, the use of electroconvulsive therapy (ECT) should be considered. Psychosis or akathisia must be distinguished from a manic episode. For a psychotic agitation, an antipsychotic agent (often with a benzodiazepine) is indicated. In akathisia, numerous studies have shown that reducing the antipsychotic agent dosage or using benzodiazepine or a b-adrenergic receptor antagonist are helpful. Antidepressants By definition many schizoaffective patients suffer from major depressive episodes. Treatment with antidepressants mirrors treatment of bipolar depression. Care should be taken not to precipitate a cycle of rapid switches from depression to mania with the antidepressant. The choice of antidepressant should take into account previous antidepressant successes or failures. Selective serotonin reuptake inhibitors (e.g., fluoxetine [Prozac] and sertraline [Zoloft]) are often used as first-line agents because they have less effect on cardiac status and have a favorable overdose profile. However, agitated or insomniac patients may benefit from a tricyclic antidepressant. As in all cases of depression, use of ECT should be considered. It is very important to try to distinguish psychosis, akinetic syndromes, and primary negative symptoms from depression. Again, psychosis should be adequately treated with an antipsychotic agent. Suspected akinetic treatment can be improved by lowering the dosage of antipsychotic agent, treating with an anticholinergic agent, or switching to a serotonin-dopamine antagonist like clozapine (Clozaril), risperidone, olanzapine (Zyprexa), or quetiapine (Seroquel). Negative symptoms are often difficult to tease out. While there are no definitive studies, these symptoms may improve with the use of serotonin-dopamine antagonists. Antipsychotic Agents As mentioned above, antipsychotic agents are important in the treatment of schizoaffective disorder. The introduction of chlorpromazine in the 1950s showed antipsychotic agents that block the action of the neurotransmitter dopamine are effective in the treatment of psychosis. Therefore it is not surprising that these compounds are effective in treating the psychotic symptoms that plague patients with schizoaffective disorder. What is not as clear is whether they alone can control both the schizophrenic and the affective symptoms. Because of the complexity and mixed nature of the illness pharmaceutical companies have generally avoided separate studies of antipsychotic agents, with schizoaffective patients. As medications were approved for use in schizophrenia, they were almost immediately used for patients with schizoaffective disorder. With the advent of combined serotonin-dopamine blocking agents, more schizoaffective patients are being recruited for efficacy and safety trials of new antipsychotic agents. The introduction of the serotonin-dopamine antagonist holds promise for patients with schizophrenia and schizoaffective disorder. While much more data exist on clozapine efficacy in patients with schizophrenia, a few studies have described either comparable or greater efficacy with schizoaffective patients. There may be

several reasons why patients diagnosed with schizoaffective disorder respond favorably to clozapine. First, clozapine has been shown to be superior in treating positive symptoms of schizophrenia and therefore the positive symptoms of schizoaffective disorder. Second, akinetic syndromes that can mimic depressive syndromes are greatly reduced with clozapine use. Third, some evidence indicates that clozapine may have mood-stabilizing properties. This hypothesis is based on several studies showing good results using clozapine in patients with difficult cases of bipolar disorder. Data for risperidone, olanzapine, and quetiapine in treating schizoaffective disorder are minimal. One such study showed superiority of haloperidol and amitriptyline over risperidone in a group of psychotic patients (including schizoaffective disorder patients) with depressive symptoms. Psychosocial Treatment Considering the present notion that schizoaffective disorder as specified in DSM-IV closely resembles schizophrenia, one can assume that psychosocial treatment of schizoaffective disorder should mimic that of psychosocial treatment of schizophrenia. Therefore, patients should benefit from a combination of family therapy, social skills training, and cognitive rehabilitation. Because the psychiatric field has had difficulty deciding the exact diagnosis and prognosis of schizoaffective disorder, this uncertainty must be explained to the patient. Historically, patients and families have been told that schizoaffective illness has a better prognosis than schizophrenia, but this may no longer be true. Patients and their families must contend with an evolving diagnosis; they may be told the patient is suffering from a treatable mood disorder at first and later told that it is a severe psychotic disorder. The range of symptoms can be quite large as patients contend with both ongoing psychosis and varying mood states. It can be very difficult for family members to keep up with the changing nature and needs of these patients. Medication regimens can be more complicated, with multiple medications frequent, and psychopharmacological education is important. However it is often difficult to explain to patients and their families that new medication treatments have been tested in affective and schizophrenic disorders but not schizoaffective disorder.

SCHIZOPHRENIFORM DISORDER History Gabriel Langfeldt, first used the term schizophreniform in 1939, at the University Psychiatric Clinic in Oslo, Norway. As originally used, this diagnosis relied on a tradition of Scandinavian psychiatry, which had identified a condition that had relatively brief and self-contained psychotic intervals. Patients recovered well and had affective and sometimes hysterical components to their illness, and the diagnosis was used to distinguish a group considered to have little relation to true schizophrenia. Comparative Nosology In contrast to this rather specific role for schizophreniform disorder, the current DSM-IV diagnosis has relatively little to do with the origin of the term and much more to do with the tradition of Kraepelinian schizophrenia as a chronic illness. Prior to the DSM-IV revision of this diagnostic entity, DSM-III and DSM-III-R had used this diagnosis as a “schizophrenia-in-waiting” diagnosis, with the only difference between the two diagnoses being whether the illness had lasted a total of 6 months including psychotic, prodromal, and residual symptoms. Under the DSM-III and DSM-III-R systems, the psychotic phase of the illness needed to last only 1 week, and less if treated successfully. The remainder of the 6-month-duration criteria for schizophrenia comprised residual or prodromal symptoms. Patients who had an insidious onset with prodromal symptoms preceding the onset of psychotic symptoms by at least 6 months would be given a diagnosis of schizophrenia as soon as the psychotic symptoms lasted 1 week. Those who had limited prodromal symptoms or who had sudden onset of psychosis as the first sign of illness, however, would not be diagnosed as having schizophrenia until the total period of illness reached 6 months. During what for many was a waiting period, the diagnosis of schizophreniform disorder would be used. Because of the relatively brief period of psychosis required (1 week) on the one hand and the similarity with schizophrenia on the other, this category formerly consisted of patients with potentially many types of psychoses—brief reactive psychosis, “schizophrenia-in-waiting,” and true schizophreniform disorder. Unfortunately, the true schizophreniform disorder would be difficult to sort out from this diagnostic system, and relative to the other categories it is probably quite rare, although potentially important as a time-limited psychotic illness that returns to baseline functioning without residual symptoms. The revisions of DSM-IV have made one of the above overlaps less likely—the one with brief reactive psychosis. To separate these two disorders diagnostically, the DSM-IV diagnosis for schizophreniform disorder requires a month of psychotic symptoms rather than 1 week. Further, brief reactive psychosis has changed to brief psychotic disorder because the diagnostic criteria reaction-to-a-stressor was considered too ubiquitous—but DSM-IV includes the concept as a specifier. From the other side, the diagnosis of schizophreniform has moved much closer to its parent diagnosis of schizophrenia with the requirement for 1 month of psychotic symptoms. Although no data are currently available on the course of schizophreniform illness, the requirement for a greater duration of psychotic illness will probably make it less likely that a given patient will recover before 6 months of total illness comprising both psychotic symptoms and residual or prodromal symptoms (now referred to as attenuated symptoms) is reached. This category now looks exactly like schizophrenia with an unanticipated full recovery before 6 months. Some data suggest that those who indeed do recover before 6 months have better 5- and 10-year outcomes. Whether this represents a separate disorder category or merely one end of a distribution of outcomes in schizophrenia is yet to be determined. There will always be the unusual patient who appears to have schizophrenia but recovers completely. They are exceedingly rare. Further, this category of illness continues to be severely hampered by a lack of research, and indeed the changing criteria for diagnosis makes it difficult to focus on this “moving target.” Most data will continue to be anecdotal. ICD-10 does not have a designated schizophreniform disorder, although the concept is included in several categories. The diagnosis acute schizophrenia-like psychotic disorder describes a disorder that would otherwise be considered schizophrenia but with symptoms lasting less than 1 month. If the symptoms persist past the month, the ICD-10 diagnosis of schizophrenia should be used. There is also a subclassification for a schizophreniform psychosis manic or depressed type under “schizoaffective disorders”; however, according to DSM-IV, schizophreniform disorder is subsumed order ICD-10's category of other schizophrenia. Another reason for having this diagnostic category is that it avoids having to use the term schizophrenia with all of its negative connotations early in the diagnostic formulation. Many families require considerable time to reconcile the future of their family member. A gradual introduction to the concept of schizophreniform disorder, with a waiting period during which the family can more realistically orient itself and learn about the illnesses in the schizophrenia spectrum may prove helpful to some. Further, because of the negative connotation of schizophrenia and the stigma currently attached to it, a diagnostic system that avoids a false-positive diagnosis of schizophrenia is desirable. A 6-month duration of illness prior to making the diagnosis of schizophrenia will eliminate virtually all false-positive diagnoses. As noted above, schizophreniform disorder shares an overlap with schizophrenia with two exceptions: the duration of illness is from 1 to 6 months and social or occupational dysfunction is not required to meet the diagnosis, although it may occur at some point in the illness. Given the requirement of 1 month of psychotic symptoms, however, it seems quite unlikely that a person's social and occupational functioning would not be disrupted. DSM-IV describes two possible conditions for this diagnosis: (1) when a person has recovered within the 6-month period (the “pure” form of schizophreniform disorder) and (2) when a person has not had the illness long enough (6 months) to meet the diagnosis of schizophrenia. For this latter condition, the term “provisional” is used. A guide for clinicians is given as a part of the diagnosis, which should be qualified by the presence or absence of good prognostic signs. The following are listed, and two are required for the qualifier of good prognosis: (1) rapid onset of psychotic symptoms, (2) confusion at the peak of psychotic symptomatology, (3) good premorbid social and occupational functioning, and (4) maintenance of a range of affect. As with most psychiatric diagnoses, schizophreniform disorder should not be used if substance abuse or a secondary medical condition causes the symptoms. Epidemiology Because of the significant change in the diagnostic criteria for schizophreniform disorder in DSM-IV, there are currently no epidemiological data from community samples. The risks of drawing from treatment samples are well known in terms of the variability introduced by clinic type, socioeducational variables, urban/rural factors, and even treatment philosophy. The elegance of the Epidemiologic Catchment Area (ECA) study with its five sites, using census track data collection, is not likely to be repeated in the near future, and its data were derived using DSM-III criteria. The significant changes from that period would include changing from 1 week of psychotic symptoms to 1 month, adding the concept of “provisional” diagnosis, and adding the good prognostic signs. Clearly, lengthening the requirement for psychotic symptoms was the most significant change, because it eliminated what most certainly were many cases of brief psychotic disorder. The data from the ECA study indicate a lifetime prevalence of 0.2 percent and a 1-year prevalence of 0.1 percent. Even with inclusion of cases of brief psychosis, this is a relatively small category. One could extrapolate that with the further stringency of DSM-IV, the category would become even smaller. Etiology Because of the change in the duration of illness, most persons who fall in this category will have underlying pathologies similar to those with schizophrenia. This will certainly be true for those who carry this diagnosis provisionally while waiting for the 6-month time period to elapse before changing the diagnosis to schizophrenia. There has been ample speculation about whether “acute” schizophrenia (rapid onset, good premorbid functioning) differs from insidious-onset schizophrenia in anything more than severity of such factors as negative symptoms. A rapid and complete response to a treatment intervention may eventually help to differentiate those in this category from standard antipsychotic nonresponders. The concept that the heterogeneity of the underlying biology may be responsible for differential treatment response is not new, but it has been given increasing credibility with the advent of the serotonin-dopamine antagonists (clozapine, risperidone, olanzapine, and quetiapine). It is now probably safe to say that any set of biological, neurophysiological, psychologic or other tests will find this group of patients looking much more closely like schizophrenia than any other category. In fact, the abnormalities consistent with schizophrenia may already be present in schizophreniform disorder. One such abnormality, decreased gray matter volume, has been seen in MRI studies but to a lesser extent than in patients with chronic

schizophrenia. The cause of pure schizophreniform disorder will probably not be known for a long time, because a patient group that small will be hard to study. Diagnostic and Clinical Features The DSM-IV criteria for schizophreniform are listed in Table 13.1-3. Schizophreniform disorder in its typical presentation is a rapid-onset psychotic disorder without a significant prodrome. Hallucinations, delusions, or both will be present; negative symptoms of alogia and avolition may be present. Affect may be flattened, which is seen as a poor prognostic sign. Speech may be grossly disorganized and confused, and behavior may be disorganized or catatonic. The symptoms of psychosis, the negative symptoms, and those affecting speech and behavior will last at least 1 month but may last longer. The patient's degree of perplexity about what is happening should be assessed, as this is a differentiating prognostic sign.

Table 13.1-3 DSM-IV Diagnostic Criteria for Schizophreniform Disorder

Although the above is the typical presentation, a picture exactly resembling that of schizophrenia may also occur. In that case, the onset may be insidious, premorbid functioning may have been poor, and affect is quite blunted. The only differentiation from schizophrenia for this type of presentation will be duration of the total episode of illness. When it has lasted 6 months, the diagnosis becomes schizophrenia. In making the diagnosis in the case with insidious onset, the “attenuated symptoms” of the acute episode may have lasted for some time. If they have been present for at least 5 months and then the acute episode lasts 1 month, the diagnosis of schizophrenia is appropriate, without a prior diagnosis of schizophreniform disorder. In the typical form of the disorder, the patient returns to baseline functioning by the end of 6 months. Theoretically, repeated episodes of schizophreniform illness are possible, each lasting less than 6 months, but rarely is functioning not lost with repeated episodes of this severe illness, and schizophrenia is a more likely consideration. Ms. L.J. was a 29-year-old Hispanic second daughter of an intact and stable family. She completed high school without problems and was described as outgoing and friendly. She considered college but opted to work. She spent several years as factory worker and had decided to go back to school and become a teacher. Five months ago she had a sudden “awareness” that God was present and filling the souls of people around her. She became acutely distressed when she realized God was not going to “touch her.” Her family was quite surprised and alarmed by her sudden change in behavior. She was brought to the local emergency room. While she occasionally drank alcohol and had smoked marijuana in the past, the family did not suspect a substance abuse problem. Toxicology screening in the emergency room was negative for substances. She was admitted to the hospital for evaluation. She told the psychiatrist that she felt she had done something wrong and that was why God had abandoned her. She also reported that she felt people on the ward were reading her mind. She was particularly concerned that her critical thoughts about others could be heard and then these angry people would attack her. L.J. was stabilized on haloperidol then switched to risperidone because of side effects. A family meeting was held to discuss her problems. At that time, the psychiatrist recommended a wait-and-see approach. The psychiatrist told the family and patient to follow up with an outpatient doctor and remain on the medication if the outpatient psychiatrist recommended it. Two months after her admission she no longer was distressed by her religious concerns. However, she still felt people could read her mind. Three months after her admission she no longer felt that people could read her mind, and she had returned to her community college. A month later, she stopped taking her antipsychotic agent because she felt she didn't need it. Two weeks ago her family brought her to the emergency room because she was again talking about God and “hiding” from people who could read her thoughts. She initially refused medications but resumed taking them, with some improvement of her psychosis. A family meeting was held to discuss the return of her psychosis and the fact that she may eventually be diagnosed with schizophrenia. Differential Diagnosis Although the major differential diagnoses are with brief psychotic disorder and schizophrenia, the rapid onset of acute psychosis may be the most important diagnostic point in a patient's course of illness. The clinician should focus on the prior 6 months, taking a detailed history of occupational and social functioning, the pattern of onset, the presence or absence of mood changes, alcohol and substance abuse, and other illness and prescriptive medication. Of special interest will be any family history of psychiatric illness, mood disorders or schizophrenia-like illnesses in particular. A recent study showed a high prevalence of personality disorders after recovery from the psychosis. One could hypothesize that the personality disorder predisposes one to psychosis especially when under stress. A complete physical examination is always indicated with the presentation of a psychotic illness. Suggestions of endocrinologic involvement, such as thyroid functioning, should be followed up with laboratory studies. If substance abuse is suspected, however remote a possibility, a toxicology screening test should be performed. Changes in sensorium and the rapid onset of symptoms should raise clinical suspicion of substance toxicity. Alcohol may be involved in a number of ways. Certainly, alcohol withdrawal and the onset of delirium may be associated with psychotic symptoms. Further, alcohol abuse leads to unreliable medication taking, even of prescribed medications, which can lead to psychotic features. The separation of mood disorders with psychotic features from a rapid-onset schizophreniform disorder may be difficult and tests the clinician's skills. Negative symptoms such as alogia, avolition, and blunted affect may be difficult to distinguish from the loss of interest and pleasure seen with major depressive episodes. Appetite, sleep, and other neurovegetative symptoms may also occur with both. The presence of the psychotic features of the illness, in the absence of these mood features, will assist the clinician in making the diagnosis of schizophreniform disorder, but this may take time to evolve. To differentiate from brief psychotic disorder, a time cutoff has been established, more than 1 day but less than 1 month. During this period, the diagnosis must be brief psychotic disorder. In diagnostic systems prior to DSM-IV, the presence or absence of a stressor was used to differentiate these two conditions further, but it is no longer used in the nosology, except as a descriptor or modifier. Differentiation is based solely on the time line. Course and Prognosis The course of schizophreniform disorder is for the most part defined in the criteria. It is a psychotic illness lasting more than 1 month and less than 6 months. The real issue is what happens to persons with this illness over time. Most estimates of progression to schizophrenia range between 60 and 80 percent. What happens to the other 20 to 40 percent is currently not known. Some will have a second or third episode during which they will deteriorate into a more chronic condition of schizophrenia. A few, however, may have only this single episode and then are able to continue on with their lives. While this is clearly the outcome desired by all clinicians and family members, it is probably a rare occurrence and should not be held out as likely. The prognostic features used to characterize the illness are listed above. Their presence will, indeed, be useful in suggesting some likelihood of a favorable outcome. Clinical experience, however, tempers the confidence in these predictors, as many patients with all four of the descriptors have a deteriorating course and outcome. Treatment Although no available studies have directly addressed the treatment of schizophreniform disorder, the approach should be that for any psychotic disorder of recent onset. The most important initial evaluation is safety, both for the patient and the patient's environment. Safety Assessment of safety or danger is a complex series of probabilities, not certainties. The best predictor is, of course, past behavior. Someone suffering from the sudden onset of psychosis may not have any past history if this is the first episode. If so, any evidence of prior violence must be seriously considered in forming the initial treatment plan. The evaluation of predictability and hostile affect becomes critical in deciding whether hospitalization is necessary. With someone suffering from an acute psychotic disorder who shows any signs of hostility, anger, and confusion or has a history of explosive or violent activity, hospitalization should be an important consideration. In the absence of these features, hospitalization may be a consideration if the environment itself, usually the family, cannot comfortably

ensure that the treatment plan can be carried out in a safe, stress-reducing manner. For most families this will not be possible. Inpatient Treatment Plan The inpatient unit is usually a significant part of the initial treatment plan. In addition to pharmacological management, the unit program and philosophy are critical ingredients in helping to stabilize the patient as rapidly as possible. An environment that is critical, intrusive, and overinvolved, with a multistimulus approach to the patient has negative impact on psychosis-prone patients. With this in mind, the patient should not necessarily be required to attend group meetings, therapeutic community, or orientation but should rather be approached in a one-on-one manner with time-limited interactions. Communication should be direct and simple, and the program should be structured with relatively little free time. Visitors should be oriented to this same principle and should be encouraged to visit one at a time. Outpatient Treatment Plan The patient who has begun to recover from an acute psychotic episode will continue to need a comfortable environment with considerable structured activity. Complex communications and interactions should be kept to a minimum early, although introduction of some simple group work in an attempt to normalize socialization may be carefully planned. Gradual resumption of activities should be attempted one at a time, with mastery achieved before the introduction of new activities. In the case of a student, for example, it would be much better to begin with one course and succeed than with a full course load that would most likely lead to failure. Incremental progress is the goal, and it should extend well beyond the 6 months required for diagnosis. Role of the Family There is no more significant factor in the successful outcome of a patient with acute onset psychosis than family involvement in the treatment. As reviewed elsewhere, the data are compelling that a clinical treatment program that enlists the family in a positive clinical alliance does better than one that does not, regardless of the other treatment modalities being used. There is no more consistent finding in outcome studies of the late 1980s and 1990s than the positive outcomes found in programs that work with families. In general, most of these programs begin with some form of educational program about schizophrenia, the importance of medication, the expectations of families, and the identification of early signs of impending relapse. Some of the programs have worked elaborately with patients and their families with behavioral paradigms, others have worked with monthly group interactions involving multiple patients and their families. For many of these families this introduction to working as a member of the treatment team enlists them into a long-term positive relationship with the treatment program. For others, it gives them the skills needed to participate in the rehabilitation process. This positive alliance will serve the program, the patient, and the family well. It opens lines of communication and takes a major step toward ensuring that the patient will receive the best monitoring and most appropriate treatment available. Active involvement of a family support group, such as the local chapter of the Alliance for the Mentally Ill, is often quite useful as well. Frequently, however, families experiencing their first episode of psychosis in a family member find association with a group of people who have family members with chronic illnesses to be too threatening. They may wish to believe that their family member will recover, and certainly for those who have true schizophreniform disorder, this will be true. Pharmacological Therapy The pharmacological approach to the acutely psychotic patient is one of the most challenging and difficult in all of psychiatry. There was an era in psychiatry when there was time to observe the patient to determine whether there was a transient condition that would be self-limiting. The economic forces of today's psychiatry do not permit such an observation period and demand vigorous pharmacological intervention. Perhaps the sole remaining condition in which it would be reasonable to wait before vigorous pharmacological intervention is one that elicits a high index of suspicion of chronic amphetamine abuse, with a positive toxicology screening test result. With these patients it is probably better to wait and treat the agitation with benzodiazepines; the psychosis will usually resolve. Even among these patients will be a small but significant group who will continue with what looks like a schizophreniform or schizophrenia-like illness. Whether this group represent a subgroup of patients who were already at risk for schizophrenia or whether chronic amphetamine abuse sensitizes dopamine receptors in some patients is not known. Given that it is not economically feasible to wait before initiating treatment, selection of the most appropriate medication becomes a critical decision. The choices basically come down to selection of an antipsychotic agent. For many years this decision involved selecting the antipsychotic agent whose side-effect profile fit the needs of the patient best. If the patient was agitated, a more sedating antipsychotic agent (e.g., chlorpromazine [Thorazine], thioridazine [Mellaril]) would be selected. If not, a less sedating, high-potency compound would be used (e.g., haloperidol, fluphenazine [Prolixin]). Both strategies, however, exposed the patient to extrapyramidal adverse effects initially and to tardive dyskinesia if long-term continuation was needed. With the use of anticholinergic medications, some of the extrapyramidal symptoms could be reduced. However, anticholinergic medications themselves have been associated with decrements in memory, executive functioning, and new learning. Therefore they are used much less frequently than previously and certainly not used routinely unless adverse effects are present. There are now other choices with the advent of the novel serotonin-dopamine antagonists. These antipsychotic agents, while considerably more expensive, hold out the advantage of fewer extrapyramidal adverse effects. They may rapidly become the medications of first choice for psychosis, because they are much better tolerated by the patient and are thus more likely to be taken over a period of time, eliminating the potential for relapse from noncompliance. The expense of readmission of a patient more than makes up for the difference in cost. Dosage of any antipsychotic agent should be at the lowest possible level, both for adverse effect prevention and for cost. There is a tendency for medication dosages to climb in an effort to shorten the length of the psychosis. Originally, the concept of “rapid neuroleptization was a method of treatment in which a patient was given antipsychotic medication every hour until sedated. Thorough evaluation of this strategy revealed no therapeutic advantages and considerably increased risk for acute dystonic reaction. It is now widely accepted that the full resolution of a psychotic episode may take anywhere from 3 to 6 weeks. Pressure to discharge a patient well before this time certainly places considerable psychological pressure on the physician to increase the medication dosage. It is not clear that there is any advantage to doing this, and maintaining a lower dosage keeps the patient considerably less uncomfortable with adverse effects. If agitation is a problem, addition of a medium- to long-acting benzodiazepine will usually produce the desired results. Benzodiazepines are much better at sedation than are antipsychotic agents. Data suggest that use of a benzodiazepine reduces the amount of an antipsychotic agent that must be used. A small subgroup of patients present with an acute psychotic episode that rapidly resolves. The more rapid the resolution, the more likely it is that they have a self-limited disorder. These patients will probably not meet the DSM-IV diagnosis of schizophreniform disorder with its requirement of 1 month of symptomatology. For those whose symptoms do last 1 month or longer and who meet the criteria for schizophreniform disorder, there is a question of how long do they need to be on medication. Although no study has directly addressed this question with patients who met DSM-IV criteria for schizophreniform disorder, strategies have been tested on patients with schizophrenia who have been recruited in an acute episode. Patients who were taken off medication in the first 6 months did much worse than those who were maintained at standard dosages or those who had an 80 percent reduction of dosage. Currently, the low-dosage strategy for maintenance should be considered with the standard antipsychotic agents and probably with the serotonin-dopamine antagonists as well. With the standard antipsychotic agents, a completely resolved psychotic episode, and full return to premorbid functioning, the usual decision point has been 6 months. This time frame was driven by the finding that almost no cases of tardive dyskinesia occur before 6 months of continuous medication. Going beyond 6 months does increase this risk. With the serotonin-dopamine antagonists, tardive dyskinesia is presumed to be a much lower risk if at all, and thus clinical judgment is needed. If a gradual tapering strategy is selected, the dosage should not be lowered more frequently than every 3 to 4 months if the physician wishes to see the effect of one dosage lowering before initiating the next. Unlike antibiotic use, for example, the infection may well return quickly after premature discontinuation of the medication, psychosis does not immediately reappear even if the medication is completely eliminated. Relapse curves from dosage-discontinuation studies are quite compelling in this regard.

BRIEF PSYCHOTIC DISORDER History Brief psychotic disorder is a new diagnosis in DSM-IV that subsumes the former diagnostic category of brief reactive psychosis, which first appeared in DSM-II. Brief psychotic disorder is one of the least understood and least studied types of functional psychosis; most research has had methodological flaws and unclear diagnostic criteria. Historically, Karl Jaspers described the concept of a reactive psychosis in 1913. Jaspers described the essential features, which include presence of an identifiable traumatic stressor, close temporal relation between stressor and psychosis, and generally benign course of the psychotic episode. Jaspers also believed that the content of the psychosis was related to the trauma and served some therapeutic purpose. Comparative Nosology Over the past century myriad terms have been used to describe psychotic episodes precipitated by stressful events, including good-prognosis schizophrenia, but brief reactive psychosis had gained prominence until the DSM-IV. Compared with the DSM-III and DSM-III-R criteria that required a precipitating stressor and confusion or emotional turmoil during the episode, the new diagnosis of brief psychotic disorder is less restrictive. With its broader definition, brief psychotic disorder will presumably reduce the use of the classification “psychotic disorder not otherwise specified.” Because stressors and reactions to stressors are so ubiquitous and ill defined, reactivity to a stressor is no longer necessary for the diagnosis and is used instead as a descriptor. Scandinavian researchers have been integral in delineating this disorder, which has been gradually gaining international recognition. Conceptual generalization of the disorder is both supported and challenged by culture-bound syndromes such as koro and amok, which demonstrate significant differences while still falling under the rubric of

brief psychotic disorder. The ICD-10 classifies these symptoms as “acute and transient psychotic disorders” (see Table 13.3-1). Subtypes include “acute polymorphic psychotic disorder without symptoms of schizophrenia,” which has an overall picture of unstable, highly emotional symptoms with psychotic features that would not justify a diagnosis of schizophrenia. In contrast, the diagnosis acute polymorphic psychotic disorder with symptoms of schizophrenia also describes an unstable clinical picture, but symptoms of schizophrenia are also present for a major part of the time. If the acute picture is marked by delusions, only a diagnosis of “other acute predominately delusional psychotic disorders” can be used. Finally, any unspecified transient psychotic disorder can be designated as other or unspecified acute and transient psychotic disorders. Epidemiology Relatively uncommon in DSM field trials, brief psychotic disorder has large discrepancies in reported incidence and prevalence rates because of methodological flaws and diagnostic variability in the literature. Its age of onset is most commonly reported to be in the late 20s or early 30s. Although reliable data on sex and sociocultural determinants are limited, preliminary data suggest a higher incidence in women and persons in developing countries. Such epidemiological patterns are sharply distinct from those of schizophrenia. Etiology Little is known about the etiology of brief psychotic disorder. The existence of one or many events becomes the identified causative agent in psychotic disorder with marked stressor (brief reactive psychosis). Both the magnitude and the multiplicity of such stressors are posited to be important, but no well-controlled studies assessing the causal role of various types of stressors are available. Severe intrapsychic conflict (an internal stressor) may be the etiological agent for brief psychotic disorder without a marked stressor. Preexisting characterological psychopathology of either cluster A or B variety may predispose a person to development of the disorder. Many explanatory models of this increased vulnerability exist, but most are based on immature defenses and ego development as major contributors. Family studies support a genetic vulnerability to brief reactive psychosis but do not support a genetic link between this disorder and schizophrenia. Diagnostic and Clinical Features The DSM-IV diagnostic criteria are listed in Table 13.1-4. DSM-IV defines brief psychotic disorder as impairment in reality testing lasting at least 1 day but not more than 1 month. An eventual full return to premorbid levels of functioning is required; if the diagnosis is made without waiting for the anticipated recovery, then the qualifier provision must be added. At least one of the following symptoms is present during the circumscribed illness: delusions, hallucinations, disorganized speech, disorganized behavior, or catatonia. Exclusionary criteria include the presence of a mood disorder with psychotic features, schizoaffective disorder, schizophrenia, and any psychotic disorder secondary to the direct physiological effects of a substance or a general medical condition. If symptoms occur in response to one or more events that would be markedly stressful to almost anyone in similar circumstances and within the same cultural context, then the illness bears the specifier with marked stressor (formerly referred to as brief psychotic disorder). Conversely, if symptoms are not in response to such an event, the specifier without marked stressor is applied. An additional specifier, with postpartum onset, indicates the onset of psychotic symptoms within 4 weeks postpartum.

Table 13.1-4 DSM-IV Diagnostic Criteria for Brief Psychotic Disorder

Patients with brief psychotic disorder typically have rapid-onset psychotic symptomatology and often demonstrate emotional turmoil, confusion, or both. Prompt recovery with a full return to premorbid level of functioning within a month is dictated by definition. It is imperative to assess the impact of culture on symptom presentation prior to making the diagnosis. In the case of brief reactive psychosis, the precipitant may be one or a series of life stressors, such as the loss of an important relationship, familial disruption, or combat-related trauma. In such cases, environmental adversity combines with cultural expectations and support systems to manifest symptoms distinctly. R.S. was a 44-year-old Haitian male admitted for observation at the local emergency room. He was agitated and combative, requiring restraints and several intramuscular doses of droperidol and lorazepam. The psychiatrist could not interview him under these acute circumstances. His mother arrived soon after and was able to give corroborative history. According to his mother the patient had just learned that his wife and two children had died in a natural disaster in Haiti. Several hours after his first evaluation, the patient was calmer. He told staff that he was hearing his wife talking to him and he wished to “join her.” He also believed the Haitian secret police were coming to arrest him. He was admitted to the inpatient ward and began a course of an antipsychotic agent. By the third day of his hospitalization there was no evidence of the previous psychosis. He was discharged from the hospital and given a follow-up appointment in 1 month. When he returned the next month he had been medication free for that time. He was grieving the loss of his family but was not psychotic. He was referred to a grief group, which he attended for the next 6 months. In that time he remained sad, but there were no other episodes of paranoia or hallucinations. Differential Diagnosis Sharing rapid onset of symptoms, brief psychotic disorder must be differentiated from substance-induced psychotic disorders and psychotic disorders due to a general medical condition. A thorough medical evaluation including a physical examination, laboratory studies, and brain imaging will help rule out many of those conditions. With only cross-sectional information, brief psychotic disorder is difficult to differentiate from other types of functional psychosis. The relationship between brief psychotic disorder and both schizophrenia and affective disorders remains uncertain. As noted above, DSM-IV has made the distinction between brief psychotic disorder and schizophreniform disorder clearer by now requiring a full month of psychotic symptoms for the latter. If psychotic symptoms are present longer than 1 month, the diagnoses of schizophreniform disorder, schizoaffective disorder, schizophrenia, mood disorders with psychotic features, delusional disorder, and psychotic disorder not otherwise specified need to be entertained. If psychotic symptoms of sudden onset are present for less than a month in response to an obvious stressor, the diagnosis of brief psychotic disorder is strongly suggested. Other diagnoses to differentiate include factitious disorder, malingering, and severe personality disorders, with consequent transient psychosis possible. Course and Prognosis The course of brief psychotic disorder is found in the diagnostic criteria of DSM-IV. It is a psychotic episode that lasts more than 1 day but less than 1 month, with eventual return to premorbid level of functioning. Approximately half of patients diagnosed with brief psychotic disorder retain this diagnosis; the other half will evolve into either schizophrenia or a major affective disorder. There are no apparent distinguishing features between brief psychotic disorder, acute-onset schizophrenia, and mood disorders with psychotic features on initial presentation. Several prognostic features have been proposed to characterize the illness, but they are inconsistent across studies. The good prognostic features are similar to those found in schizophreniform disorder: acute onset of psychotic symptoms, confusion or emotional turmoil at the height of the psychotic episode, good premorbid functioning, the presence of affective symptoms, and short duration of symptoms. There is a relative dearth of information on the recurrence of brief psychotic episodes, however, so the course and prognosis of this disorder have not been well characterized. Treatment Although no available studies directly address the treatment of brief psychotic disorder, the treatment approach should focus on the acute onset of psychotic symptoms. In particular, patient safety is of paramount importance. Depending on the danger the patient represents to self and others, psychiatric hospitalization is often warranted. A patient demonstrating acute psychotic symptoms who also displays a hostile affect or has a history of violence is particularly likely to require hospitalization. In addition to providing a safe and structured environment, hospitalization permits observational monitoring and a medical examination investigating potential etiological factors. If medication is necessary, a high-potency antipsychotic agent in low dosage is typically recommended. An antiparkinsonism agent may be added if extrapyramidal adverse effects occur. A benzodiazepine used in combination with an antipsychotic agent can act synergistically, thereby lowering the necessary doses of each and reducing the risk of side effects. Benzodiazepines can also be used as monotherapy to reduce agitation without obscuring the clinical picture. The role of other

psychotropic medications such as mood stabilizers and antidepressants is not yet clear. After the acute episode has subsided, long-term treatment is required. An individualized treatment strategy based on increasing problem-solving skills while strengthening the ego structure through psychotherapy, appears to be the most efficacious. Involvement of the family in the treatment process is crucial to a successful outcome and is reviewed elsewhere in this chapter. There is no role for maintenance antipsychotic treatment in brief psychotic disorder; if such treatment is required, the diagnostic assumptions must be questioned.

SUGGESTED CROSS-REFERENCES A more detailed review of schizophrenia is presented in Chapter 12; acute and transient psychotic disorders are presented in Section 13.3. Mood disorders are covered in Chapter 14. Personality disorders are discussed in Chapter 24. SECTION REFERENCES Blacker D, Tsuang MT: Contested boundaries of bipolar disorder and the limits of categorical diagnosis in psychiatry. Am J Psychiatry 149:1473, 1992. Goldstein JM, Faraone SV, Chen WJ, Tsuang MT: The role of gender in understanding the familial transmission of schizoaffective disorder. Br J Psychiatry 163:763, 1993. Greil W, Ludwig-Mayerhofer W, Erazo N, Engel RR, Czernik A, Giedke H, Muller-Oerlinghausen B, Osterheider M, Rudolf GA, Sauer H, Tegeler J, Wetterling T: Lithium vs. carbamazepine in the maintenance treatment of schizoaffective disorder: a randomized study. European Archives of Psychiatry and Clinical Neurosciences 247: 42, 1997. Jorgensen P, Bennedsen B, Christensen J, Hyllested A: Acute and transient psychotic disorder: Comorbidity with personality disorder: Acta Psychiatrica Scandainavica 94:460, 1996. Keck PE, McElroy SL, Strakowski SM: New developments in the pharmacological treatment of schizoaffective disorder. J Clin Psychiatry 57:41, 1996. Keck PE, McElroy SL, Strakowski SM, West SA: Pharmacological treatment of schizoaffective disorder. Psychopharmacology 114:529, 1994. Kendler KS, McGuire M, Gruenberg AM, Walsh D: Examining the validity of DSM-III-R schizoaffective disorder and its putative subtypes in the Roscommon family study. Am J Psychiatry 1995.

152:755,

Lapensee MA: A review of schizoaffective disorder, I. Current concepts. Can J Psychiatry 37:335, 1992. *Lapensee MA: A review of schizoaffective disorder, II. Somatic treatment. Can J Psychiatry 37:347, 1992. Lapierre YD: Schizophrenia and manic-depression: Separate illnesses or a continuum? Can J Psychiatry 39(Suppl):S59, 1994. Levitt JJ, Tsuang MT: The heterogenity of schizoaffective disorder: Implication for treatment. Am J Psychiatry 145:20, 1988. Maier W, Lichtermann D, Minges J, Heun R, Hallmayer J, Benkert O. Schizoaffective disorder and affective disorders with mood-incongruent psychotic features: Keep separate or combine? Evidence from a family study. Am J Psychiatry 149:1666, 1992. Migliorini G, Lazzarin E: Acute psychosis: Clinical contribution. Minerva Psychiatr 34:231, 1993. Muller-Siechender F, Muller MJ, Hillert A, Szegedi A, Wetzel H, Benkert O, Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. J Clin Psychopharmacol 18:111, 1998. *Robinson DG, Woerner MG, Ma J, Alivir J, Geisler S, Doreen AM, Sheitman B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieberman J: Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 156:544, 1999. Rubin P: Neurobiological findings in first admission patients with schizophrenia or schizophreniform disorder. Danish Medical Bulletin 44:140, 1997. Smith GN, MacEwan W, Ancill RJ, Honer WG, Ehmann TS: Diagnostic confusion in treatment-refractory psychotic patients. J Clin Psychiatry 53:197, 1992. *Susser E, Fennig S, Jandorf L, Amador A, Bromet E: Epidemiology, diagnosis and course of brief psychoses. Am J Psychiatry 152:20, 1995. Susser E, Wanderling J: Epidemiology of nonaffective acute remitting psychosis vs. schizophrenia. Arch Gen Psychiatry 51:20, 1994. Taylor MA, Amir N: Are schizophrenia and affective disorder related? The problem of schizoaffective disorder and the discrimination of the psychoses by signs and symptoms. Compr Psychiatry 35:420, 1994. *Thweatt R: European interest in transient psychotic episodes. Am J Psychiatry 143:557, 1986. Tsuang D, Coryell W: An 8-year followup of patients with DSM-III-R psychotic depression, schizoaffective disorder and schizophrenia. Am J Psychiatry 150:1182, 1993. *Winokur G, Monahan P, Coryell W, Zimmerman M: Schizophrenia and affective disorder—distinct entities or continuum? An analysis based on a prospective 6-year follow-up. Compr Psychiatry 37:77, 1996. *Zipursky RB, Lambe EK, Kapur S, Mikulis DJ: Cerebral gray matter volume deficits in first episode psychosis. Arch Gen Psychiatry 55:540, 1998.

© 2000 Lippincott Williams &#_003_8; Wilkins Harold I. Kaplan, M.D, Benjamin J. Sadock, M.D and Virginia A. Sadock, M.D. Kaplan &#_003_8; Sadock's Comprehensive Textbook of Psychiatry

13.2 DELUSIONAL DISORDER AND SHARED PSYCHOTIC DISORDER Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 13. OTHER PSYCHOTIC DISORDERS

13.2 DELUSIONAL DISORDER AND SHARED PSYCHOTIC DISORDER THEO C. MANSCHRECK, M.D., M.P.H. Definition History Paranoid Concept Comparative osology Epidemiology Etiology Pathogenesis Pathogenesis Diagnosis and Clinical Features Pathology and Laboratory Examination Differential Diagnosis Course and Prognosis Treatment Suggested Cross-References

Once viewed as too rare to warrant a separate classification, delusional disorder has emerged in recent years as a focus of clinical research and treatment innovation. Better definition and a growing literature have revitalized the efforts to characterize, understand, and treat these conditions. Limited but growing evidence supports not only its occurrence, but its distinctiveness from schizophrenia and mood disorder as well as its treatability. Delusional disorder refers to a group of disorders, the chief feature of which is the presence of a nonbizarre delusion. It is the delusion and the relative absence of other psychopathology that unifies these disorders in terms of natural history and impact on functioning. Once called paranoia, this condition as defined in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) is easier to recognize and less subject to misdiagnosis. Despite such advances, clinicians are relatively ill-informed about delusional disorders and many have only seen an occasional example. There are several possible reasons why this is so. Persons with this condition do not regard themselves as mentally ill and actively oppose psychiatric referral. Because they may experience little impairment, they generally remain outside hospital settings, appearing reclusive, eccentric, or odd, rather than ill. If they do have contact with professionals, it is more likely to be with lawyers regarding litigious concerns; with medical specialists regarding health concerns; or with the police regarding complaints of trespass, persecution, or threat, rather than with psychiatric clinicians regarding complaints of emotional disorder. A hallmark of these disorders is that the patient does not believe that he or she is deluded or in need of psychiatric assistance. In the infrequent psychiatric encounter, clinicians tend to diagnose these disorders as other conditions, often as schizophrenia or mood disorders. Although delusional disorders are uncommon, they are probably not as rare as previously thought. While many individuals with such disorders seek assistance from other medical specialists, judges, or the police, they are increasingly being recognized as psychiatrically ill. The relationship of these disorders to other psychoses remains unclear, and much about them is puzzling. The DSM-IV requirement of excluding other conditions is prudent given the special importance of differential diagnosis. Armed with newer and better criteria, clinical research is ongoing in areas such as natural history, pathogenesis, neuropsychology, neuroimaging, treatment, and even genetics. Although the DSM-IV criteria are not definitive, they have provided a sound basis for clinical and research investigation. Systematic studies based on larger samples of these disorders are needed to anchor classification with sound information; however, such studies may be difficult to conduct because of the large numbers of patients required and their reluctance to participate in research. A biological basis for these disorders is proposed on many grounds, but its definition remains elusive. The study of misidentification syndromes (e.g., the Capgras's syndrome) has led to interesting hypotheses and methods that draw on neuropsychological and clinical insights that may inspire progress in delusional disorders. Treatment remains an obstacle, although recent reports suggest that favorable responses to psychopharmacologic and psychotherapeutic interventions are more common than previously thought.

DEFINITION Delusional disorder is the current classification for a group of disorders of unknown cause, the chief feature of which is the delusion ( Table 13.2-1). Although the specific content of the delusion may vary from one case to the next, it is the occurrence of the delusion, its persistence, its impact on behavior, and its prognosis that unifies these seemingly different disorders. In considerable agreement with Emil Kraepelin's concept of paranoia, the revised third edition of DSM-III-R provides reliable criteria for identifying cases and collecting systematic information about these conditions. This development in classification helped to reestablish the clinical importance of this group of disorders and may have reversed a trend of infrequent diagnosis. The criteria use the term delusional to avoid the ambiguity of the term paranoid used earlier in the third edition of DSM (DSM-III) classification, paranoid disorders, as well as to emphasize that the category includes disorders in which delusions other than those of the persecutory or jealous type are present. Although these changes were initially confusing, especially in terms of comparisons to diagnostic approaches elsewhere, they have gained acceptance and have created a more level playing field for further empirical contributions.

Table 13.2-1 DSM-IV Definition of Delusion and Certain Common Types Associated With Delusional Disorders

In 1994 DSM-IV refined the definition and the boundaries with other disorders, including substance-induced disorders, mental disorders due to general medical conditions, mood disorders, and schizophrenia. No laboratory test exists to assist in diagnosis. The DSM-IV definition, like its predecessors, hinges on the presence of a nonbizarre delusion. DSM-IV acknowledges the difficulty of judging whether a delusion is bizarre, meaning clearly implausible, not understandable, and not derived from ordinary life experiences. In contrast, the nonbizarre delusion involves situations or circumstances that can occur in real life (e.g., being followed, infected, or deceived by a lover). DSM-IV also emphasizes the differential diagnoses of schizophrenia, mood disorders, substance-induced disorders, and mental disorders due to a general medical condition before the diagnosis of delusional disorders can be made. These conceptual refinements and demarcations from other conditions have increased the usefulness of the criteria for delusional disorder. Delusional Disorder According to DSM-IV, the diagnosis of delusional disorder can be made when a person exhibits nonbizarre delusions of at least 1 month's duration that cannot be attributed to other psychiatric disorders. Definitions of the term delusion and types relevant to delusional disorders are presented in Table 13.2-1. Nonbizarre means that the delusions must be about situations that can occur in real life, such as being followed, infected, loved at a distance, and so on; that is, they usually have to do with phenomena that, although not real, are nonetheless possible. There are several types of delusions, and the predominant type is specified when the diagnosis is made. In general, the patient's delusions are well systematized and have been logically developed. The person may experience auditory or visual hallucinations, but these are not prominent features. Tactile or olfactory hallucinations may be present and prominent if they are related to the delusional content or theme, examples are the

sensation of being infested by bugs or parasites, associated with delusions of infestation, and the belief that one's body odor is foul, associated with somatic delusions. The person's behavioral and emotional responses to the delusion appear to be appropriate. Impairment of functioning is not marked and personality deterioration is minimal, if it occurs at all. General behavior is neither obviously odd nor bizarre. Shared Psychotic Disorder This unusual condition has also been called folie à deux and induced or shared psychotic disorder. It develops in an individual in the context of a close relationship with another person who has an established delusion that he or she also believes, and requires an absence of psychotic disorder prior to the onset of the induced delusion; it is usually classified with paranoid disorders.

HISTORY Nineteenth-century psychiatry devoted much attention to the description of paranoid disorders, in which delusions are a cardinal feature. Karl Ludwig Kahlbaum's description of paranoia in 1863 was the first in a series of contributions that culminated in the classification of paranoia, and inspired that of folie à deux, morbid jealousy, the better-known schizophrenias, and mania. His work also led to a recognition that paranoid features are nonspecific characteristics of many medical diseases. Subsequent work has led to refined criteria for paranoid and related disorders and has reestablished awareness of less common paranoid presentations such as delusional disorder. Many clinicians remember being taught that paranoia is so rare that most would not see a single such patient during an entire career. This widespread belief has compromised interest in paranoid disorders. The fact that most persons with delusional disorder live in the community and do not generally seek psychiatric care has made it difficult to carry out systematic case studies. Indeed, knowledge of these conditions has grown slowly. However, case series such as those of Alistair Munro (for delusional disorder, somatic type) or those of Nils Retterstol have been influential in shaping understanding and awareness. What they reveal is that there are persons with these disorders, that the disorders are complex forms of psychiatric illness, and that much remains to be learned. A major change in the classification of delusional disorders in DSM-III-R and DSM-IV has been to emphasize the central role of delusions in those disorders and to steer away from the vague label of paranoid, which has become synonymous with suspicious and has come to apply largely to a personality disorder. Indeed, suspiciousness occurs in only some of these disorders. The history of the concept of paranoia indicates that lack of clarity in its use is not new. The word paranoia was coined by the ancient Greeks from roots meaning beside and self. Hippocrates applied this term to delirium associated with high fever, but other writers used it to describe demented conditions and madness. It sometimes meant thinking amiss, folly, and the like; hence, its meaning was unclear. For centuries the term fell into disuse until a revival of interest in the nineteenth century. In 1863 Karl Kahlbaum classified paranoia as a separate mental illness: “a form of partial insanity, which throughout the course of the disease, principally affected the sphere of the intellect.” Influenced by the new scientific methods of empirical medicine, Kahlbaum emphasized the importance of natural history in mental illness and restricted the use of the term paranoia to a persistent delusional illness that remained largely unchanged throughout its course. He noted that delusions could occur in other medical and psychiatric conditions. Emil Kraepelin found the paranoid concept troublesome and altered his thinking on it with each edition of his influential textbook. His final view advocated three types of paranoid disorder. Like Kahlbaum, Kraepelin based his conclusions on an analysis of the natural history of mental disorders, particularly on outcome, because etiology was obscure. He restricted the definition of paranoia to an uncommon, insidious, chronic illness (he saw 19 cases) characterized by a fixed delusional system, an absence of hallucinations, and a lack of deterioration of the personality. The types of delusions included persecutory, grandiose, jealous, and possibly hypochondriacal. He considered this illness to derive from defects in judgment, a disorder of personality caused by constitutional factors and environmental stress. Paraphrenia was a second paranoid disorder that developed later than dementia precox and was milder. Hallucinations (auditory in particular) occurred, but there was no mental deterioration (dementia). Finally, there was dementia paranoides, an illness that initially resembled paranoia but had an earlier onset and showed a deteriorating course. Because of this latter feature, Kraepelin considered dementia paranoides a form of dementia precox that arose from disorders of thought, cognition, and emotion. Kurt Mayer's follow-up of Kraepelin's 78 paraphrenia cases challenged the validity of this category because the vast majority of patients showed an outcome indistinguishable from that of dementia precox, casting doubt on the separability of this group. Karl Kolle's follow-up of Kraepelin's paranoia cases indicated some overlap with dementia precox. Kraepelin also emphasized that isolated paranoid symptoms occurred in a variety of psychiatric and medical illnesses. Eugen Bleuler also recognized paranoia; he broadened its definition to include cases with hallucinations—a paranoid form of dementia precox for which he coined the term schizophrenia—and an intermediate group. However, he thought that the paranoia described by Kraepelin was so rare that it did not warrant a separate classification. Further, he argued that schizophrenic symptoms must be suspected and carefully sought even in those cases. He believed that paraphrenia and intermediate conditions were forms of schizophrenia linked by “much that was identical,” and particularly by a common disturbance in associative processes. He also emphasized that paranoid symptoms occurred in other conditions and that to label the symptoms schizophrenic required at least one of the fundamental symptoms: loosened associations, ambivalence, inappropriate affect, and autism. Bleuler's contributions reinforced a trend toward the diagnosis of paranoid illness as a form of schizophrenia. Sigmund Freud used the autobiographical writings of Judge Daniel Schreber to illustrate the role of psychological defense mechanisms in the development of paranoid symptoms. He proposed that Schreber's illness involved a process of denial or contradiction of repressed homosexual impulses toward his father. Persecutory and other delusions result from projecting these denied yearnings onto the environment. Freud did not differentiate subtypes of paranoid disorder, and confused the issue somewhat by proposing that the term paraphrenia be substituted for the term dementia precox or schizophrenia. The major impact of Freud's work was to suggest hypotheses that indicated the relationship between certain delusions and personality. Ernst Kretschmer's work on the theory of paranoia emphasized that certain sensitive personalities, characterized by depressive, pessimistic, and narcissistic traits, developed paranoid features acutely when key or precipitating experiences occurred at critical moments in their lives. He observed that these individuals did not develop schizophrenia and had a favorable prognosis. A number of other observations, predominantly but not exclusively emanating from European clinicians (e.g., the American concept of hysterical psychosis), proposed connections between personality and delusion development. Those efforts, based on various theories of the cause of paranoid disturbance, have persisted despite modest empirical support. Out of such work have come terms, such as reactive and psychogenic psychosis, which have figured in various classification schemes, undermining the effort to bring international consistency in definition. Many barriers remain to international agreement on definition. For example, the term paraphrenia, unlike paranoia, has slipped into near obscurity in North America. In the United Kingdom, however, the diagnosis of late paraphrenia is often used and it is occasionally used in the United States. This term refers to cases of late-onset paranoid symptomatology not characterized by the presence of dementia, confusion, or mood disorder. Interestingly, Kraepelin did not identify a late age of onset in his cases. The potential overlap with late-onset cases of schizophrenia has been a focus of investigation and controversy. With the removal of the DSM-III age criterion for schizophrenia (upper limit of age of onset at 45) in DSM-III-R, cases of late-onset symptoms have tended to be diagnosed as schizophrenia in the United States. Nevertheless, clinical research continues to address the puzzle of whether late-onset cases, despite considerable overlap in clinical features, arise from a variety of causes. Current controversy is based on these historical antecedents and contemporary practices. DSM-III introduced greater rigor in the assessment by requiring clearer criteria boundaries among the varied disorders with delusions. Increased awareness that delusions result from numerous conditions has had a positive influence on the diagnostic process. Yet much of current clinical and research writing on paranoid conditions has characteristically avoided defining the terms paranoid and delusion, apparently because everyone was assumed to know what these terms mean. In popular and literary usage the term paranoid has come to mean insane, angrily suspicious, distrustful, or irrationally irritable. However vague the concept may be, it continues to be used in clinical work. Because it is necessary to differentiate conditions with paranoid features, a useful concept of the term is fundamental. However, the nature and definition of delusions upon which modern psychopathology and psychiatry are built remain unclear. Shared Psychotic Disorder Jules Baillarger first described the syndrome in 1860, calling it folie à communiquée, although the first description is commonly attributed to Ernest Charles Lasègue and Jules Falret, who described the condition in 1877 and gave it the name of folie à deux. The syndrome has also been called communicated insanity, contagious insanity, infectious insanity, psychosis of association, and double insanity. Marandon de Montyel divided folie à deux into three groups (folie imposée, folie simultanée, and folie communiquée), and Heinz Lehmann added a fourth group, folie induite.

PARANOID CONCEPT

Paranoid signs and symptoms are among the most dramatic and serious disturbances in psychiatry and medicine but the term paranoid refers to a variety of behaviors that may not be psychopathological nor indicative of schizophrenia; hence, the meaning of the term has become obscure. Some clinicians label ordinary suspiciousness paranoid; others restrict use of the term to persecutory delusions; still others apply the term only to grandiose, litigious, hostile, and jealous behavior, despite the fact that those behaviors may be within the normal spectrum. To make the paranoid concept useful and less vague requires consideration of several points: 1. The term paranoid is a clinical construct used to interpret observations, and in order to apply this construct effectively, the clinician must know its meaning and be able to make accurate observations of potentially paranoid behavior. 2. Use of the term paranoid means the clinician has judged that the person's behavior is psychopathological. This judgment is usually based on the discovery that the person who displays such features is either disturbed or disturbing to others. 3. Although many contributions to understanding paranoid phenomena have focused on conditions in which paranoid features are central (e.g., schizophrenia for Bleuler, paranoia and dementia paranoides for Kraepelin), those features are not necessarily associated with schizophrenia and can appear in other psychiatric and medical disorders. Hence, paranoid features indicate psychopathology, but no specific cause or outcome ( Table 13.2-2)

Table 13.2-2 Conditions and Agents Associated With Delusions and Other Paranoid Features

4. The observations that form the basis for judging behavior to be paranoid are of two kinds: subjective (part of the private mental experience of the patient, e.g., a delusion) and objective (observable as a manifest form of behavior, such as litigiousness, guardedness, and grandiosity). Table 13.2-3 is a list of the subjective and objective features that have traditionally been labeled paranoid and that are frequently found in association; some of these features can be manifestations of normal behavior. The judgment that such features are paranoid may rest on how extreme or inappropriate they are, their presence in combination or association with other behaviors on the list, and the presence of delusions.

Table 13.2-3 Paranoid Features

5. The term paranoid delusion has traditionally referred to a wide variety of delusions, not simply those of grandeur, persecution, or jealousy. Because of recent confusion that term probably should not be used. The term paranoid and related terms are defined in Table 13.2-4.

Table 13.2-4 Terminology Connected with Paranoia

Delusions When Karl Jaspers formulated the concept of delusion widely used today, he suggested three criteria: (1) subjective certainty, (2) incorrigibility, and (3) falsity of content. He viewed these criteria as tentative, preferring to consider them as approximations to a definition in that they provided practical suggestions for detecting delusions rather than actually defining them. This and later contributions emphasized a certain humility about the delusion concept that has not been sustained in contemporary formulations of this psychopathological feature. Numerous, often ignored, problems compromise the clinical research utility of the delusion concept. For example, according to DSM-III-R and DSM-IV, delusion is “an incorrect inference about external reality.” This definition has certain implicit and complicating features: (1) there is a process of inference separable from the belief that the process produces, (2) this same process is used by normal persons to generate beliefs about the world, and (3) this process is impaired in delusional patients. As pointed out later in this chapter, the validity of the latter two assertions is questionable. Also, central to the concept of delusional disorder is the distinction between bizarre (impossible) and nonbizarre (possible) delusions. This distinction has been difficult to apply reliably in clinical assessment, yet on it rests considerable weight in making the diagnosis of delusional disorder. Further examples of difficulties concerning the definition of delusion have been discussed by Manfred Spitzer, who has traced the movement from philosophy to empirical science in the evolution of the definition of delusion. Awareness of the vagaries and imprecise nature of the definition of delusion is essential to clinical and research efforts. Since the early nineteenth century delusions have been classified by content or theme. Other descriptive dimensions have gained acceptance through clinical use and some empirical research: understandability, degree of certainty, systemization, complexity, relevance to patient's life, plausibility, onset, associated psychopathology, and time course. These features are used to grasp the nature of the delusional experience, translate clinical observations into diagnostic and treatment interventions, and design research. In clinical encounters delusions are usually easy to detect. Certain features ( Table 13.2-3) of the patient's behavior may suggest the presence of delusions or help confirm the impression that the beliefs are delusional. In subtle cases, however, this task is more challenging. The clinician must make a judgment, based on the behavior and reported private mental experience of the patient, of whether or not delusional beliefs are present. Attempts to present counterevidence and argument may be useful to determine whether the patient's views can be influenced by evidence that is usually sufficient to alter the belief of a normal person. This judgment often depends on deciding whether a threshold indicative of psychopathological disorder has been passed, possibly reflected in the inappropriateness or extreme

nature of the patient's behavior, rather than the simple truth or falsity of the belief. In practice, the only effective approach to assessing delusions is to put together as comprehensive a picture as possible regarding the nature of the patient's condition. Lacking laboratory tests for delusions, clinical judgment will be required to some degree in virtually all cases. At the theoretical level, the definition of delusions is moving gradually away from its roots in philosophy and phenomenological description toward a more empirically derived set of features. This process will take considerable time to achieve a satisfactory resolution of the many issues plaguing this aspect of psychopathology.

COMPARATIVE NOSOLOGY Certain advances have been made in the nosology of delusional disorders, but the variety of current definitions illustrates that consensus has not yet been achieved. The reasons for such differences are multiple: the principal reason is the lack of relevant data—delusional disorders occur infrequently. Typically, patients continue to function and live in the community without ever seeking clinical intervention. When they do, the condition is easily misdiagnosed because patients may have minimal overt identifying characteristics. Limited knowledge, based largely on case reports, exists; systematic, larger-scale studies are uncommon. Most of these studies are European and have employed varied classifications. Also, the fundamental concept that these disorders are distinct from schizophrenia and mood disorders has until recently been unrecognized by many psychiatrists. Kahlbaum was the first to use the term paranoia to designate a diagnostically separate group of disorders. Kraepelin developed this diagnostic concept further by emphasizing the chronic and unremitting nature of paranoia and the lack of other features such as hallucinations that distinguished it from schizophrenia. In 1952 the first edition of DSM (DSM-I) defined paranoid reactions as conditions in which there are persecutory or grandiose delusions, with emotional responses and behavior consistent with the delusions, but generally lacking hallucinations. The subtypes were paranoia (a chronic disorder with systematized delusions) and paranoid state (a more acute, less persistent condition with less systematized delusions). In 1968 DSM-II largely preserved these concepts. DSM-III Although new definitions were established in DSM-III in 1980, earlier concepts are still evident. The essential features of paranoid disorders according to DSM-III were persistent persecutory delusions or delusional jealousy not due to any other mental disorder. Included in the group of paranoid disorders were paranoia, shared paranoid disorder, acute paranoid disorder, and a residual category called atypical paranoid disorder. The boundaries between these conditions and other disorders, such as paranoid personality disorder or paranoid schizophrenia, were noted to be vague. Different types of paranoid disorders were classified on the basis of chronicity. The criteria narrowed the bounds of previous classifications by not including cases with marked hallucinations or certain delusions (e.g., hypochondriacal, erotomanic, and others). DSM-III-R In 1987 DSM-III-R simplified the DSM-III definition, attempted to minimize the confusion associated with the term paranoid, and highlighted the view that the formation of delusions in the absence of schizophrenia, mood disorder, or organic disorder is the essential feature of these conditions. In contrast to DSM-III, diagnosis in DSM-III-R and DSM IV requires a month-long duration of symptoms. Subtyping is based on the predominant type of delusion, which is specified (such as jealous, erotomanic, or somatic). This latter feature broadens the category to include a variety of unusual delusions as well as the more common persecutory type. In many respects these criteria are virtually identical to Kraepelin's definition of paranoia. The two exceptions were Kraepelin's reluctance to endorse a subtype of somatic or hypochondriacal paranoia or to permit cases with hallucinations to fall within this diagnosis. Kraepelin believed that cases with hypochondriacal delusions rarely occurred in this pattern. Shared paranoid disorder was renamed induced psychotic disorder in DSM-III-R and was placed in the category of psychotic disorders not elsewhere classified, along with schizophreniform, schizoaffective disorders, and brief reactive psychosis. This represents a fundamental departure from DSM-III, which classified this disorder among the paranoid disorders. The delusional content of patients with this disorder may concern not only persecution or jealousy but virtually any form of delusion, hence the change in terminology. The term induced may better describe the nature of the condition, but hardly resolves the puzzle of causation. DSM-IV In 1994 a revised classification made modest changes in the DSM-III-R criteria in an attempt to refine the definition of delusional disorders. In DSM-III-R the distinction between schizophrenia and delusional disorders had been unclear and controversial. In DSM-III-R this boundary was defined by the nonbizarre qualities of delusions in delusional disorder and the absence of other active-phase symptoms of schizophrenia. Also important was the required absence of other odd or bizarre behavior apart from the delusion. Because the distinction between bizzare and nonbizarre is difficult to define and therefore to apply reliably, other terms such as systematized and prominent were suggested. In practice, however, those terms also have limitations. This problem has helped to promote the case for modifying the criteria in another way: specifically, to use the level of impaired functioning as a means of characterizing the distinction between schizophrenia (considerable impairment) and delusional disorders (relatively less impairment). However, the variability of outcomes in both disorders undermines this strategy somewhat. DSM-IV suggests that when poor functioning occurs in delusional disorder, it is the result of the delusional beliefs themselves. For example, a person quits a job because he or she believes that the fumes in the workplace are causing a cancerous growth. That person's financial situation worsens and preoccupation with repeated medical consultations enhances a downward spiral. In contrast, poor functioning in schizophrenia usually results from cognitive compromise and positive and negative symptoms, especially avolition. The resolution of how to make modifications, however, depends on the effectiveness of the criteria in defining homogeneous and valid subsets of psychotic disordered patients. For this purpose, field trials and data analyses have been used to inform the decision scientifically. Although the DSM-IV criteria reflect progress, their validity remains only partly established. Another unsettled issue that DSM-IV attempts to resolve is the classification of delusional variants of somatoform disorder, specifically body dysmorphic disorder. In this condition the patient suffers from preoccupation with imagined or slight defects in appearance (such as skin blemishes, the size of one or more body parts); it is accompanied by impairment in social and occupational functioning, shame, and repetitive, often ritualistic behaviors. These may include skin picking, mirror checking, requests for reassurance, and attempts to camouflage the supposed deformity. In some cases, the preoccupation appears to be delusional. However, the relationship between nondelusional and delusional variants is unclear; whether the disorders are distinct or overlapping remains unknown. DSM-IV permits dual diagnosis of body dysmorphic disorder and delusional disorder when a delusional belief is present in the former condition. This resolution, in which the same symptoms are given two diagnoses, accurately reflects the available research data on the relationship of these two disorders and also underlines the need for further research to clarify these distinctions. A similar problem arises with respect to delusional variants of hypochondriasis and of obsessive-compulsive disorder, and a similar solution is applied: obsessive-compulsive disorder patients may also be diagnosed as delusional disorder. Shared Psychotic Disorder DSM-IV renamed the DSM-III-R category induced psychotic disorder, calling it shared psychotic disorder. This change reflects the attempt to avoid the term paranoid and to identify the condition without reference to any presumed cause or mechanism. The goal is to define the boundaries between this condition and more common ones, such as other psychotic disorders, mood disorders with psychotic features, substance-induced psychotic disorders, and psychotic disorders due to a general medical condition. ICD The ninth revision of International Statistical Classification of Diseases (ICD-9) contained more categories for paranoid disorder than the American schemes. Most paranoid disorders fall under the rubric paranoid state, including simple paranoid state, paranoia, paraphrenia, and induced psychosis. Additional subcategories include other and unspecified paranoid states. Acute paranoid reactions and psychogenic paranoid psychosis are classified separately. DSM-III, DSM-III-R, and DSM-IV generally reflect an atheoretical position with respect to the causes of these disorders whereas ICD-9 was less neutral. For example, psychogenic paranoid psychosis implies a kind of causal mechanism. The categories of paranoid disorder according to these classifications are summarized in Tables 13.2-5.

Table 13.2-5 Comparative Nosology of Delusional Disorder

ICD-10 pays more attention to creating classifications similar to DSM-III-R and DSM-IV. Paraphrenia, for example, is subsumed under persistent delusional disorder but delusions must be present for about 3 months in order to diagnose delusional disorder. The subtypes of the disorder overlap with DSM-IV subtypes. For those conditions of less duration, acute and transient psychotic disorder is diagnosed. Induced (shared) delusional disorder is considered a separate designation with a phenomenology similar to persistent delusional disorder.

EPIDEMIOLOGY Delusional disorder has been considered an uncommon if not rare condition from its earliest descriptions even though epidemiological information is meager. Recent demographic evidence covering a period from 1912 to the 1970s provides an estimate of incidence, prevalence, and related statistics ( Table 13.2-6). However, this evidence was assembled using definitions that are not the same as those of DSM-III, DSM-III-R, or DSM-IV. Subsequent data will in all likelihood be somewhat different using the newer criteria. It is clear that the estimates are merely indications, but can be useful guidelines to future appraisals.

Table 13.2-6 Epidemiological Features of Delusional Disorder

However, certain features of the data are remarkable. For example, the stability of estimated incidence has been striking over extended periods of time in this century. The prevalence of these disorders substantiates the widely held clinical impression that they are uncommon conditions (compared with mood disorders and schizophrenia) but are not rare. Some studies indicate that delusional disorder accounts for a surprising 2 to 8 percent of inpatient psychiatric admission for “functional psychosis.” Patients with delusional disorders are somewhat more likely to be women (but this is an inconsistent feature), and to be more socially and educationally disadvantaged as compared to patients with mood disorders. Women tend to be older than men at the time of diagnosis. While the onset age range is wide (18 to 80), most patients are middle-aged. There is suggestive evidence that immigrant status, celibacy among men, and widowhood among women are associated with delusional disorder but all such observations need to be unambiguously replicated.

ETIOLOGY The cause of delusional disorder is unknown. The epidemiological and clinical literature suggests that certain risk factors may be relevant to etiology and deserve further research elaboration. These risk factors are found in Table 13.2-7. Whether they are risk predictors or simply characteristics or markers of the disorder is unknown. Familial psychiatric disorder, including delusional disorder, is the best documented risk factor at present.

Table 13.2-7 Risk Factors Associated With Delusional Disorder

Genetic or family studies that have begun to appear in the literature indicate the possible specific family transmission of delusional disorder. A recent study of genetic variation in deoxyribonucleic acid (DNA) sequence coding for dopamine type 4 (D 4) receptor proteins strongly suggests the involvement of the relevant gene in conferring susceptibility to delusional disorder. The comparison subjects either had schizophrenia or were normal controls. Paranoid features, including the types of delusions encountered in these disorders, occur in a large and growing number of conditions ( Table 13.2-2). Differences in classifying idiopathic delusional disorder add to the problems of understanding causation. Theories and explanations of delusions abound in the literature but empirical evidence to support those theories is limited. With so many uncertainties, any conclusions concerning the cause of delusional disorder must be made cautiously. Delusional disorder is an uncommon, probably heterogeneous, group of illnesses whose validity has been questioned since Kahlbaum published his views. The major phenomenological feature of these conditions is the formation and persistence of delusions. It is well known that delusions occur in a variety of psychiatric and medical conditions, and that the pathogenesis of delusions is not fully understood. Hence, discussion of etiology in the delusional disorders can proceed along two lines: (1) determining the distinctiveness of the category itself, (2) examining the theories proposed to account for the pathogenesis of delusion formation per se, and (3) integrating the available evidence into testable proposals. Distinctiveness of Delusional Disorder An issue that is central to attributing causation is whether delusional disorder represents a separate group of conditions or is an atypical form of schizophrenic and mood disorders. The relevant data come from a limited number of studies and is inconclusive. Epidemiological data suggest that delusional disorder is a separate condition; it is far less prevalent than schizophrenic or mood disorders; age of onset is later than in schizophrenia although men tend to experience the illness at earlier ages than women; and the sex ratio is different from that of mood disorder, which occurs disproportionately among women. Findings from family or genetic studies also support the theory that delusional disorder is a distinct entity. If delusional disorder is simply an unusual form of schizophrenic or mood disorders, the incidence of these latter conditions in family studies of delusional disorder patient probands should be higher than that of the general population. However, this has not been a consistent finding. A recent study concluded that patients with delusional disorder are more likely to have family members who show suspiciousness, jealousy, secretiveness, even paranoid illness, than families of controls. Other investigative efforts have found paranoid personality disorder and avoidant personality disorder to be more common in the relatives of patients with delusional disorder than in the relatives of controls or of schizophrenic patients. A recent study documented modest evidence for an increased risk of alcoholism among the relatives of patients with delusional disorder as compared to probands with schizophrenia, probands with psychotic disorder not otherwise specified, and probands with schizophreniform disorder. Investigations into patient's natural history also lend support to the suggestion that delusional disorder is a distinct category: age of onset appears to be later than in

schizophrenia and outcome generally is better for delusional disorder patients than for schizophrenia patients. Although fraught with methodological shortcomings, premorbid personality data indicate that schizophrenia patients and patients with delusional disorder differ early in life. The former are more likely to be introverted, schizoid, and submissive; the latter extroverted, dominant, and hypersensitive. Delusional disorder patients may have below-average intelligence. Precipitating factors, especially related to social isolation, conflicts of conscience, and immigration, are more closely associated to delusional disorder than schizophrenia. These characteristics support Kraepelin's view that environmental factors may play an important etiological role. Clinical characteristics such as greater intensity of delusions, uncommon occurrence of negative symptoms, and possible association with cerebrovascular disorder in late-onset cases also suggest differences from late-onset schizophrenia. Recent observations of successful treatment with pimozide (Orap) in several subtypes of delusional disorders suggest the possibility of a common pathogenetic mechanism in these disorders. Follow-up studies indicate that the diagnosis of delusional disorder remains fairly stable: only a small proportion of cases (3 to 22 percent) are diagnosed later as having schizophrenia, and even fewer (6 percent) are diagnosed later as having a mood disorder. Outcome in terms of hospitalization and occupational adjustment is markedly more favorable for delusional disorder than for schizophrenia. When social or occupational functioning is poor in delusional disorder, it generally occurs as the result of the delusional beliefs themselves, not because of cognitive impairment or negative symptoms. The evidence argues in favor of the distinctiveness of delusional disorder, but it is likely that at least some patients diagnosed as having delusional disorder will develop schizophrenia or mood disorders. Hence, current clinical criteria have limitations and need improvement, which may be possible with the use of laboratory techniques or more specified clinical definitions. Furthermore, the data suggest that delusional disorder is relatively chronic and is probably biologically distinct from other psychotic disorders.

PATHOGENESIS Although a clear understanding of the pathogenesis of delusions remains an unfulfilled hope, several major theories have been advanced. Any adequate hypothesis for delusion formation must deal with certain facts: (1) delusions occur in a variety of medical and psychiatric diseases; (2) not all persons with such conditions develop delusions; (3) the types of delusions are relatively few and strikingly repetitious despite the variety of diseases; (4) delusions can clear rapidly with treatment of the underlying condition or its termination; (5) delusions can persist, and even become systematized; (6) delusions often accompany perceptual changes such as hallucinations or impaired sensory input; (7) delusions may be highly encapsulated features in persons such that their functioning may not be compromised socially, intellectually, or emotionally. Also, any adequate hypothesis must respond to two questions. First, why does the patient have a delusion? This is a question concerning the form of the psychopathology. Second, why does the patient have this particular delusion? This is a question concerning the content of the psychopathology. There are three categories of theory in delusion formation. 1. Delusions arise in an otherwise intact cognitive system because a deviant pattern of motivational interest is present (psychodynamic mechanism, social attribution theory). 2. Delusions arise as the result of a fundamental cognitive defect that impairs the patient's capacity to draw valid conclusions from evidence (disorder of reasoning). 3. Delusions arise from normal cognitive processes directed at explaining abnormal perceptual experiences (psychobiological mechanism, anomalous experience hypothesis). These theories need not be mutually exclusive. Delusional beliefs probably are the result of different processes involving one or more of the proposed mechanisms. Psychodynamic Mechanism In 1911 Freud published “Psychoanalytic Notes Upon an Autobiographical Account of a Case of Paranoia (Dementia Paranoides).” His interpretation of this case, which became the foundation of the psychodynamic theory of paranoia, was based on his reading of the memoirs of the presiding judge of a Dresden appeals court, Daniel Paul Schreber, who had suffered episodes of psychiatric illness in 1884, 1885, and 1893. The second episode led to two prolonged hospitalizations from which the patient obtained discharge in 1902 following legal action, although he was still delusional. Freud asserted that Schreber's 1903 account, Memoirs of My Nervous Illness, offered a legitimate basis for theory, as “paranoiacs cannot be compelled to overcome their internal resistances, and ... in any case they only say what they choose to say ....” Freud argued that the written case report can take the place of personal acquaintance, and in the case of Schreber, Freud never saw the patient. Freud asserted that Schreber's case illustrated a general mechanism of delusion formation involving denial or contradiction and projection of repressed homosexual impulses that break out from the unconscious. The forms of delusion in paranoia can be represented as contradictions of the proposition “I (a man) love him (a man).” The following examples illustrate the forms of illogic. 1. Delusion of persecution. In the contradiction ‘I do not love him, I hate him,” a hatred that persons deem unacceptable at the conscious level is transformed and becomes instead: “He hates (elaborated to “persecutes”) me.” Patients can then rationalize their anger by consciously hating those persons whom they perceive to hate them. 2. Delusion of erotomania. The proposition “I do not love him—I love her” is transformed through projection to “She loves me—and so I love her.” 3. Delusional jealousy. To protect against unwarranted, threatening impulses the patient transforms the proposition in this manner: “I do not love him—she (a wife, lover) loves him.” Hence, jealous delusions represent the transformed attractions of the deluded for the lover. 4. Delusion of grandiosity (megalomania). Here the contradiction made is, “I do not love him, I love myself.” The essence of the theory is that delusions represent attempts to manage the stirrings of unconscious homosexuality. According to the classic theory, the dynamics of unconscious homosexuality are similar for female as well as male patients. Comment Many theorists have added to the psychodynamic lore on delusion formation from the standpoint of understanding personality factors. For example, some of the vulnerability to delusion formation may be related to deficiently developed trust, narcissistic dynamics, or exaggerated traits such as hypersensitivity. Critique Freud's mechanism of delusions sidesteps the distinction between form and content in psychopathology. He proposes an inferential process to account for the particular delusion but does not clearly address the issue of why a delusion is formed rather than another symptom, such as hallucination. Verification of the hypothesized mechanism clearly rests on finding evidence that delusions are associated with indications of homosexual tendencies. The theory has been perpetuated in part because an absence of homosexuality can never be proved, and such tendencies can be used as a pillar, even if not a scientifically or empirically demonstrable pillar, in the psychodynamic argument. The few experimental attempts made to test the hypothesis have been inconclusive or equivocal. Although homosexual concerns have been found among some delusional patients, the variety of conditions with similar delusions argues against a common mechanism of unconscious homosexuality in all. Persons who delusional patients say are persecuting them are not always known by them, nor is the persistence of such delusions adequately accounted for in that formulation. Nevertheless, the classic approach has had immense influence and has provided important psychoanalytical concepts, such as projection, and an awareness that developmental experiences may operate to influence the content of delusional thinking. Systematic empirical study would be valuable. Disordered Reasoning Because the definition of delusion ( Table 13.2-1) emphasizes the operation of reasoning processes that have gone haywire, it is not surprising that a number of attempts have been made to establish that disorder of reasoning is related to delusion formation and that such disorders can be observed among deluded patients. Related to the psychodynamic formulation is the proposal that delusions arise on the basis of defects in formal logical reasoning. Popular in the 1950s and 1960s, this view, promulgated by Eilhard von Domarus among others, suggested that errors in logic such as the principle of identity (two subjects are identical on the grounds of identical predicates) have an etiological role. For example, “Charles Manson used drugs; I use drugs, therefore I am Charles Manson.” The empirical assessment of that proposal has failed to establish that deluded patients exhibit more defects in reasoning; rather it appears that normal and deluded persons both make similar errors of reasoning with comparable frequencies. Two other proposals involving disturbance in reasoning have been studied recently. The first portrays the difficulty underlying delusion formation as a failure in the application of Bayesian reasoning. According to this model of developing beliefs, making choices, and drawing conclusions, delusional patients accept conclusions at levels of probability too low for acceptance by nondelusional persons. However, attempts to demonstrate that failure have had equivocal results. The second proposal suggests that the reasoning processes of delusional patients are influenced by the subject's tendency to assign meaning in a biased manner. The bias arises in making judgments about one's own behavior and that of another person by assigning motives and characteristics to the person involved. Application of this model reflecting motivational and reasoning difficulties (based on social attribution theory) has been tested, but the results do not provide sound support for the formulation. Other Psychological Mechanisms In Manic Depressive Insanity and Paranoia, Kraepelin considered the delusions of paranoia to be the “morbidly transformed expression of the natural emotions of the human heart” and, more specifically, “a kind of psychological compensation for the disappointments of life.” He dismissed

the Freudian psychodynamic mechanism on the grounds that it did not refer to a clear concept of paranoia and that it was not supported by evidence. He also emphasized consitutional factors, especially disturbances of judgment, in his formulation. Other authors have made similar suggestions about the role of need fulfillment in the development of paranoia. For example, delusions of persecution might serve to maintain the self-esteem of the deluded person, according to a social attribution view about delusion formation in which a normal bias—that of assigning blame for negative outcomes to other persons or circumstances—is exaggerated. Critique These contributions do not address the issue of pathogenesis rigorously. They explain the content of the delusion but not its form. The commonness of the risk factors or antecedent features cited repeatedly as central to delusion formation contrasts dramatically with the uncommonness of delusional disorder. Psychobiological Mechanisms The French neurologist Gaëtan G. de Clerambault proposed in 1942 that chronic delusions resulted from abnormal neurological events. Infections, lesions, intoxication, and other forms of damage produce automatisms that puzzle or distress the patient initially and eventually demand explanation. The explanations take the form of delusions. Automatisms include hallucinations, a constant parade of memories, feelings of familiarity, false recognition, arresting of thought, disturbances in attention, bizarre tactile sensations, and even kinesthetic sensation. The view that delusions are an explanation for hallucinations is an old concept in psychiatry that has not been well formulated. The fact that hallucinations have been introduced into and retracted from the definition of paranoia over the years also reflects a lack of clarity regarding a possible connection between the two forms of psychopathology. In 1974 Brendan Maher proposed a similar hypothesis that conceptualized delusions as explanations of anomalous experiences that arise in the environment, the peripheral sensory system, or the central nervous system. A central tenet of his view is that the processes whereby delusional beliefs are formed are similar in their essential nature to those that operate in the formation of normal beliefs and even of scientific hypotheses. Integral to the hypothesis is the assumption that components of this normal operational sequence have a neural substrate that may be activated either by sensory input (as in the hallucinatory effects of drugs) or by the effects of brain damage (as in alcoholism). The activation of any part of the sequence demands explanation and may thus give rise to delusions. The sequence, activated by disturbances in sensory experience, emotional incongruity, or central nervous system abnormalities, has the following stages: (1) anomalous experience, (2) feelings of significance, (3) testing for reality of experience, (4) developing tentative hypotheses, (5) additional observation, (6) exploring insights, and (7) confirmation of the insight by selective observation. In Maher's explanation, the patient is delusional because he or she actually experiences anomalies that demand explanation. The particular content of the delusion is drawn from the past or current circumstances, experience, and the personal and cultural background of the patient. The explanation answers questions such as the following: What is happening? Why? Why do other people deny it is happening? Why is it only happening to me? Who is responsible for it? The delusional explanation offers relief from puzzlement, and that relief works against abandonment of the explanation. Critique The psychobiological formulation has gone largely unstudied, but there is supporting evidence in the form of studies of altered perception among patients and healthy controls experiencing sensory impairment or sensory deprivation, and among persons taking various drugs of abuse. These studies have demonstrated a high incidence of delusion formation. The failure to detect a fundamental defect in the cognitive process of delusional patients or to identify basic differences in belief formation between persons with delusions and normal controls provides indirect support as well. Indeed, delusions are formed in persons with a range of levels of intelligence and education, further supporting the view that a disturbance in the cognitive processes is not the source of the problem. Also a number of medical conditions show evidence of delusions but no history of cognitive impairment. Clearly, this hypothesis warrants further examination, and it remains to be seen how applicable it is to conditions, such as delusional disorder, in which the occurrence of hallucinations is debated. Sensory impairment and central nervous dysfunction, although apparently likely, have not been firmly established for the disorder. The anomalous experience hypothesis focuses on the psychological mechanisms underlying delusion formation, but a complementary proposal concerns the anatomic loci associated with delusional thinking. Jeffrey Cummings and others have used the growing data on the psychopathological consequences of neurological disease to suggest that delusions occur in diseases involving the limbic system—in particular, temporal lobe structures and caudate nuclei. Diseases characterized by excessive dopaminergic activity or reduced cholinergic activity also carry a heightened risk of delusion formation. Cummings further hypothesizes that the common locus of delusion formation is limbic dysfunction that predisposes the individual to misinterpretation of the environment accompanied by inappropriate perception of threat. Both disease- and patient-related factors influence the content, complexity, and timing of the delusion.

PATHOGENESIS Although limited by the spareness of research in the area, observations of pharmacological treatment provide complementary insights into the pathogenetic puzzle. Data from treatment reports on delusional disorder suggest that pimozide (Orap) a highly specific dopamine-blocking agent, has greater effectiveness than typical antipsychotic drugs in this condition; some data even suggest that it has a unique role. There are several pharmacological effects of pimozide, in addition to dopamine receptor blockade, that may help explain its effectiveness: (1) relative lack of nonadrenergic blocking action (2) calcium channel antagonism, and (3) opioid receptor blockade. The effect of opiated receptor blockade has been proposed as relevant to reported specific effectiveness in delusional infestation partly based on observations of opiate receptor blocking interventions in delusional disorder somatic type, with delusions of infestation. Intravenous administration of the opioid agonist fentanyl (sublimaze) led to intensified cutaneous sensations whereas administration of naloxone (Narcan) an opioid antagonist, resulted in complete remission of the patient's cutaneous sensation. That pimozide is especially effective in delusional disorder, somatic type, supports the notion that its opiate receptor antagonism blocks central recognition of abnormal peripheral sensation; such a view is consistent with the anomalous experience hypothesis. Other Relevant Factors Delusions have been linked to a variety of additional factors such as social and sensory isolation, socioeconomic deprivation, and personality disturbance. The deaf, the visually impaired, and possibly immigrants with limited ability in a new language may be more vulnerable to delusion formation than the normal population. Vulnerability is heightened with advanced age. Delusional disturbance and other paranoid features are common in the elderly. In short, multiple factors are associated with the formation of delusions, and the source and pathogenesis of delusional disorders per se have yet to be specified. Integration The pathogenesis of delusions in general and delusional disorder in particular remains a field of hypotheses with little firm grounding. A variety of theories exist, but empirical support for any theory is markedly limited. Of those available, however, the anomalous experience hypothesis appears to be the best supported and certainly is the most consistent with research findings from other domains. Given the research explosion in neuroscience and psychopathology, this hypothesis should be explored as fully as possible. In delusional disorder, for example, the anomalous experience hypothesis needs to be further specified, for example, on what kinds of anomalous experience could lead to the jealousy delusion, the erotomanic delusion, and so forth. Studies now under way in the misidentification delusions, such as the Capgras's syndrome, provide a model for how such research might be directed. Progress may result from further studies of the neurobiology underlying successful treatment strategies in delusional disorder as well.

DIAGNOSIS AND CLINICAL FEATURES Delusional Disorder Diagnosing delusional disorders requires that the clinician match the features of the case to the appropriate criteria ( Table 13.2-8). When the clinician has successfully ruled out other disorders, certain features of the case can help to substantiate the diagnosis of delusional disorder. The ICD-10 criteria for delusional disorder are listed in Table 13.2-9.

Table 13.2-8 DSM-IV Diagnostic Criteria for Delusional Disorder

Table 13.2-9 ICD-10 Diagnostic Criteria for Delusional Disorders

DSM-IV defines the core psychopathological feature of delusional disorder as persistent, nonbizarre delusions not explained by other psychotic disorders. Onset can be sudden, following a precipitating event that the patient often reports, or the disorder may emerge gradually and may become chronic. Behavioral and emotional responses are generally appropriate: neither a mood disorder nor the volitional, thinking, and emotional disturbances of schizophrenia are present (including hallucinations, which are quite restricted in delusional disorder). In general, patients with delusional disorder show little disorganization or impairment in their behavior or in the clarity of their thinking. The delusions are unusual yet they refer to aspects of life that might occur, such as being conspired against, cheated on, physically ill, in love, jealous, and so forth. They are, as George Winokur has suggested, “possible,” rather than totally incredible and bizarre as are many of the delusions of schizophrenia. Delusions are categorized according to their content; the most common are characterized by persecution, disease, and jealousy. The delusions are fixed (persistent) and unarguable. Patients interpret facts to fit the delusion rather than modifying the delusion to fit the facts. There is systematization in the elusional thinking, meaning that a single theme or series of connected themes is present with links to the predominant delusion. Normal life and functioning gradually give way to the dominance of delusional concerns. Many have proposed that there is a descriptive continuum between paranoid personality disorder, delusional disorder, and the paranoid subtype of schizophrenia in terms of degrees of disorganization and impairment. However, there is little evidence to support the concept that these disorders share more than overlapping psychopathology. The presence of hallucinations in delusional disorder has been debated, with some theorists arguing that schizophrenia is a more likely diagnosis in such cases and others not, so long as the hallucinations are not marked and persistent. The resolution of this issue remains distant, but it is reasonable to consider infrequent, poorly organized, and simple hallucinations that are not a prominent part of the psychopathology to be a feature of delusional disorder. The hallucinations are usually auditory but may be visual and tend to be more common in acute cases. Other types of hallucinations may occur; however, tactile or olfactory hallucinations may be present and may even be prominent if they are related to the delusional theme. The person's emotional contact and behavior are generally intact. The emotional response is usually consistent with the delusional concern, and the mood is often appropriately depressed, frustrated, or even intensely angry or elated. Restlessness and agitation may be present. Loquaciousness and circumstantiality, usually accompanying descriptions of the delusions, are found in some patients, but formal thought disorder as sometimes found in schizophrenia is absent. Persons with delusional disorder may behave in a remarkably normal way much of the time; they become strikingly different when the delusion is focused on, at which time thinking, attitude, and mood may change direction abruptly. A. Munro has called this shift in response a characteristic, possibly unique feature of delusional disorder. In the delusional mode the patient is hyperalert, preoccupied, and driven by the delusional concern. In the normal mode, the patients mood becomes calm, the conversation neutral, and the patient finds it easier to focus on other issues. The shift between modes can be difficult for lay persons to comprehend. Social and marital functioning are more likely to be compromised than intellectual and occupational functioning. Associated features in delusional disorder include those of the paranoid syndrome ( Table 13.2-3). The degree of hostility and suspiciousness may be such that violent or aggressive behavior results. Litigious behavior is common among such patients. However, some patients, notably those with somatic delusions, may not display hostility, anger, or even suspiciousness to any considerable degree. MENTAL STATUS EXAMINATION The patient's complaints are brought to the attention of the clinician by the patient or a third party, such as police, family, neighbors, or a consulted physician or attorney. The patient may have attracted attention by asking for protection, quarreling with neighbors, visiting too many clinics, or similar behavior. The complaint focuses on the distressing behavior and possibly on incidental symptoms. The patient will not complain of a psychiatric condition; in fact, he or she will deny that or the presence of any psychiatric symptoms. Often to the surprise of those expecting to observe a range of mental deviances, examination leads to the discovery that thinking, orientation, affect, attention, memory, perception, and personality are intact. The patient's thinking is so clear and the delusional features are so central to his or her concerns that the clinician begins to anticipate the interview responses of the patient to the point that accurate predictions of specific actions and reactions are possible. Such predictability may distinguish the behavior of the patient with delusional disorder from behavior associated with other psychotic conditions. The patient's behavior and responses to the interview are consistent with the range of features in other paranoid conditions. There may be hostility, anger, lack of cooperation, and a sarcastic or challenging quality in most of what the patient says. The capacity to act in response to delusions is an important dimension of the evaluation. Level of impulsiveness should be assessed and related to any potential for violent or suicidal behavior. The patient's self-righteousness, the intensity of the delusional experience, and its emotional impact on the patient may be clues to possible violent behavior; any plans for harming others, including homicide, should be inquired about. Suicidal behavior is an equally important concern. Impulses for self-harm arise in settings of frustration, demoralization, and even depression. If such thoughts exist, the patient should be asked how they were handled in the past. Jealousy and erotomania are perhaps especially important concerns in the assessment of possible aggression and violence. Stalking, history of abuse, and arrest records should be inquired about. Careful judgment and diplomatic interviewing are especially important in such presentations. ASSESSMENT OF DELUSIONS The detection of delusions solidifies the judgment that a paranoid condition is present. Delusions are usually easy to detect. Features of behavior (Table 13.2-3) may suggest their presence. Associated psychopathological symptoms such as hallucinations, disturbed form of thought, and mood disorder may also indicate that delusions are part of the clinical picture. The clinical challenge is clear in subtle cases. Fundamentally, the clinician must make a judgment based on available observations and the reported private mental experience of the patient. Attempts to dissuade the patient with counterevidence and counterarguments may be useful in determining whether the patient's beliefs can be influenced in ways that are usually sufficient to change a nondelusional person's mind. Spending time in discussion with the patient to grasp the nature of delusional thinking in terms of its themes, impact on the patient's life, complexity, systematization, and related features may be crucial in making the judgment. The most sensible guideline for all cases of suspected delusional thinking is to establish as comprehensive a picture as possible concerning the condition of the patient, including the patient's subjective private experience and evidence of psychopathological symptoms. Such information should reduce much of the uncertainty of the evaluative process. PERSECUTORY TYPE The delusion of persecution is a classic symptom of delusional disorder; persecutory type and jealousy type delusions are probably the forms seen most frequently by psychiatrists. In contrast to persecutory delusions in schizophrenia, the clarity, logic, and systematic elaboration of the persecutory theme in delusional disorder leave a remarkable stamp on this condition. The absence of other psychopathology, of deterioration in personality, or of deterioration in most areas of functioning also contrasts with the typical manifestations of schizophrenia.

A 56-year old woman, X-ray technician who had emigrated as an adult from Europe, and married late in life, presented to the emergency room. Her complaints were that her husband's business partner of many years intended to get her husband to resign from the business and to destroy their home. Over a number of months she had become gradually aware that a variety of apparently inconsequential incidents (such as unusual cars parked on her isolated residential street, seeing individuals she knew at restaurants, and feeling as if she were being followed each time she drove her car) pointed to a conspiracy to disrupt and ultimately destroy their lives. Her delusion of persecution was remarkably systematized and detailed; her mood in describing this was tense and irritable. There was no evidence of hallucinations, confusion, thought disorder, or mood disorder. Cognition was intact. The patient was quite intelligent and saw the clinical consultation as a means of assisting her husband to deal with the distress of being targeted in such a manner. (The husband had accompanied his wife on these consultations. He also had experienced some delusional thinking in accord with hers.) The patient showed no evidence that suggested suicidality or potential for violence toward others. She initially refused all medication but gradually over several months of therapy and parallel frequent legal consultations agreed reluctantly to take risperidone (Risperda) and later, for postpsychotic depression, paroxetine (Paxil). She responded within weeks to 0.5 to 1 mg of risperidone administered daily or on alternate days; she refused to take the medication continuously. Within a year, she began to focus on other issues and the emotional intensity of the delusional concerns diminished although they could be aroused with modest stimulation in conversation or from happenings in her home or neighborhood. JEALOUS TYPE Delusional disorder with delusions of infidelity has been called conjugal paranoia when it is limited to the delusion that a spouse has been unfaithful. The eponym Othello syndrome has been used to describe morbid jealousy that can arise from multiple concerns. The delusion usually afflicts men, often those with no prior psychiatric illness. It may appear suddenly and serve to explain a host of present and past events involving the spouse's behavior. The condition is difficult to treat and may diminish only on separation, divorce, or death of the spouse. Richard Krafft-Ebing described the symptom of delusional jealousy in alcoholics in 1891 and believed that extreme jealousy was pathognomonic for alcoholism. Other disorders with this symptom were later described. A recent retrospective analysis of 8134 psychiatric inpatients disclosed a prevalence of delusional jealousy of 1.1 percent among the major diagnostic groups. Among ICD-9 paranoid disorders, a 6.7 percent lifetime point prevalence was determined. Delusional disorder with alcohol dependence frequently shows the single delusion of jealousy, a persistent feature that sometimes remits if alcohol abuse is brought under control. In personality disorders the symptom may be confused with extreme jealousy, but other psychotic features should be absent. The prevalence of delusional jealousy among hospitalized patients with mood disorder was a surprisingly low 0.1 percent. A study of 26,000 psychiatric inpatients using DSM-III-R criteria yielded a 0.17 percent rate of delusional disorder, jealous type. Jealous delusions occur much more frequently in other disorders than in delusional disorder. Marked jealousy (usually termed pathological or morbid jealousy) is thus a symptom of many disorders including schizophrenia (where female patients more commonly display this feature), epilepsy, mood disorders, drug abuse, and alcoholism—for which treatment is directed at the primary disorder. Jealousy is a powerful emotion; when it occurs in delusional disorder or as part of another condition it can be potentially dangerous and has been associated with violence, notably both suicide and homicide. The forensic aspects of the symptom have been noted repeatedly, especially its role as a motive for murder. However, physical and verbal abuse occur more frequently than extreme actions among individuals with this symptom. Caution and care in deciding how to deal with such presentations are essential not only for diagnosis, but also from the point of view of safety. A 47-year-old carpenter was brought for psychiatric examination following complaints by neighbors about his loud yelling and verbal abuse of his girlfriend. The patient resented the psychiatric referral, but was willing to give an account of his concerns. His girlfriend, he complained, was having an affair with someone, but he was not sure who the interloper was. On his own, however, he had begun gathering evidence: strands of hair found in the apartment, photographs of soiled sheets, and suspicious items from the trash—all of which he claimed proved that an affair was ongoing. He revealed plans to tape-record, possibly videotape, his girlfriend's activities while he was on the job. Upon admitting that he had told his girlfriend that he would kill her if the affair persisted, he was admitted to the hospital. He was treated with a serotonin–dopamine antagonist in low dosages and responded with a reduction in the intensity of his rage and preoccupation. Eventually, he left the hospital, but only after his girlfriend had moved away. He still harbored suspicions but accepted the termination of the relationship without voluble opposition. EROTOMANIC TYPE Patients with erotomania have delusions of secret lovers. Most frequently the patient is a woman, but men are also susceptible to the delusion. The patient believes that a suitor, usually more socially rominent than herself, is in love with her. The delusion becomes the central focus of the patient's existence and the onset can be sudden. Erotomania, the psychose passionelle, is also referred to as de Clérambault's syndrome to emphasize its occurrence in different disorders. Besides being the key symptom in some cases of delusional disorder, it is known to occur in schizophrenia, mood disorder, and other organic disorders. There is no mention of erotomania in DSM-III: the condition was termed atypical psychosis. DSM-III-R reinstated the condition, and it remains in DSM-IV. Patients with erotomania frequently show certain characteristics: they are generally but not exclusively women, unattractive in appearance, in low-level jobs, and they lead withdrawn, lonely lives being single and having few sexual contacts. They select secret lovers who are substantially different from themselves. They exhibit what has been called paradoxical conduct, the delusional phenomenon of interpreting all denials of love, no matter how clear, as secret affirmations of love. The course may be chronic, recurrent, or brief. Separation from the love object may be the only satisfactory means of intervention. Although men are less commonly afflicted by this condition than women, they may be more aggressive and possibly violent in their pursuit of love. Hence, in forensic populations men with this condition predominate. The object of aggression may not be the loved individual but companions or protectors of the love object who are viewed as trying to come between the lovers. The tendency toward violence among men with erotomania may lead initially to police rather than psychiatric contact. In certain cases resentment and rage in response to an absence of reaction from all forms of love communication may escalate to a point that the love object is in danger. A 29-year-old male financial analyst, while having lunch in a downtown restaurant observed the arrival of a well-known local media personality, an attractive woman about his age. He experienced several moments of eye contact with the woman and became convinced that she had fallen in love with him. There ensued a barrage of flowers, letters, phone calls, and even several attempts to meet with her at her workplace. The woman rebuffed all such efforts and eventually called the police. The man was arrested on a stalking charge after he was observed following the woman to her residence. He was angry and threatening to the police, finally admitting that he had purchased a handgun but refusing to give a reason for the purchase. He was remanded to a forensic psychiatric unit, treated with pimozide, and eventually discharged on a court-supervised probation. SOMATIC TYPE Delusional disorder with somatic delusions has been called monosymptomatic hypochondriacal psychosis. The condition differs from other conditions with hypochondriacal symptoms in degree of reality impairment. In delusional disorder the delusion is fixed, unarguable, and presented intensely, because the patient is totally convinced of the physical nature of the disorder. In contrast, persons with hypochondriasis often admit that their fear of illness is largely groundless. The content of the somatic delusion may vary widely from case to case. Munro has described the largest series of cases and has used the content of delusions to define three main types: (1) delusions of infestation (including parasitosis); (2) delusions of dysmorphophobia, such as of misshapenness, personal ugliness, or exaggerated size of body parts (this category seems closest to that of body dysmorphic disorder); and (3) delusions of foul body odors or halitosis. This latter category, sometimes referred to as olfactory reference syndrome, appears somewhat different from the category of delusions of infestation in that patients with the former have an earlier age of onset (mean 25 years), male predominance, single status, and absence of past psychiatric treatment. Otherwise the three groups, although individually low in prevalence, appear to overlap. The frequency of these conditions is low, but they may be underdiagnosed because patients present to dermatologists, plastic surgeons, and infectious disease specialists more often than to psychiatrists in the unremitting search for curative treatment. This may partially account for Kraepelin's skepticism about the occurrence of this form of paranoia. Several recent reports indicate that pimozide (a diphenylbutyliperidine and highly specific dopamine blocker) and certain serotonin-specific reuptake inhibitors may be effective in treatment of such disorders, even in cases with a variety of delusional themes. There may be a heightened association of shared psychotic disorder involving primary cases of hypochondriacal delusion; one series reported a quarter of cases with such an association. Patients with this condition have a poor prognosis without treatment. It affects both sexes roughly equally. A previous history or family history of psychotic disorder is uncommon. In younger patients, a history of substance abuse or head injury is frequent. Although anger and hostility are commonplace, shame, depression, and avoidant behavior are even more characteristic. Suicide, apparently motivated by anguish, is not uncommon.

A 40-year-old single unemployed man is referred by his primary care physician because of repeated consultations related to his complaint of hair loss. A dermatologist evaluated the patient, found no pathology, and told the patient that the minimal hair loss was normal. The patient refused to accept this judgment and demanded a further consultation. Because of managed-care restrictions, the patient consulted two additional specialists with his own (meager) funds with similar results. He had quit his job because of embarrassment about the hair loss and had become increasingly indebted financially. The psychiatric consultation infuriated him but he cooperated because he thought that the hair loss had begun with some “pills” he had been prescribed several years previously for anxiety and insomnia and that a psychiatrist might have something to add to understanding his case, including perhaps an antidote that might relieve the loss of hair. Treatment with an antidepressant agent proved unsatisfactory and the patient was started on an atypical antipsychotic drug with modest success. He complained less frequently about the hair loss and eventually began to express concern about his loneliness and his fear of being a burden to his aging parents, whom he lived with for financial reasons. His insight, however, remained limited and he intermittently voiced his concerns about his appearance and hair loss to his psychiatrist. GRANDIOSE TYPE Delusions of grandeur (megalomania) have been noted for years. They were described in Kraepelin's paranoia and have been associated with conditions fitting the description of delusional disorder. Whether this subtype occurs in clinical practice sufficiently enough to warrant a classification is debatable. A 51-year-old man was arrested for disturbing the peace. Police had been called to a local park to stop him from carving his initials and those of a recently formed religious cult into various trees surrounding a pond in the park. When confronted, he had scornfully argued that, having been chosen to begin a new townwide religious revival, it was necessary for him to publicize his intent in a permanent fashion. The police were unsuccessful at preventing the man from cutting another tree and made the arrest. Psychiatric examination was ordered at the state hospital, and the patient was observed there for several weeks. He denied any emotional difficulty and had never received psychiatric treatment. There was no history of euphoria or mood swings. The patient was angry about being hospitalized and only gradually permitted the doctor to interview him. In a few days, however, he was busy preaching to his fellow patients and letting them know that he had been given a special mandate from God to bring in new converts through his ability to heal. Eventually, his preoccupation with special powers diminished and no other evidence of psychopathology was observed. The patient was discharged, having received no medication at all. Two months later he was arrested at a local theater, this time for disrupting the showing of a film that depicted subjects he believed to be satanic. MIXED TYPE The category of mixed type applies to patients with two or more delusional themes. However, this diagnosis should be reserved for cases in which no single delusional type predominates. UNSPECIFIED TYPE The category of unspecified type is reserved for cases in which the predominant delusion cannot be subtyped within the previous categories. A possible example is certain delusions of misidentification, for example, Capgras's syndrome, named after the French psychiatrist who described the illusion des sosies or the illusion of doubles. The delusion in Capgras's syndrome is the belief that a familiar person has been replaced by an impostor or persons. Others have described variants of the Capgras's syndrome, namely the delusion that persecutors or familiar persons can assume the guise of strangers ( Frégoli's phenomenom) and the very rare delusion that familiar persons could change themselves into other persons at will ( intermetamorphosis). Each disorder is not only rare but is highly associated with schizophrenia, dementia, epilepsy, and other organic disorders. Reported cases have been predominantly in women, have had associated paranoid features, and have included feelings of depersonalization or derealization. The delusion may be shortlived, recurrent, or persistent. It is unclear whether delusional disorder can appear with such a delusion. Certainly, the Frégoli and intermetamorphosis delusions have bizarre content and are unlikely, but the delusion in Capgras's syndrome is a possible candidate for delusional disorder. The role of hallucination or perceptual disturbance in this condition needs to be explicated. Shared Psychotic Disorder Shared psychotic disorder (also referred to over the years as shared paranoid disorder, induced psychotic disorder, folie à deux, and double insanity) was first described by Lasegue and Falret in 1877. It is probably rare, but incidence and prevalence figures are lacking and the literature consists almost entirely of case reports. The disorder is characterized by the transfer of delusions from one person to another. Both persons are closely associated for a long time and typically live together in relative social isolation. In its most common form, folie imposée (which is covered by the DSM-IV criteria in Table 13.2-10), the individual who first has the delusion (the primary case) is often chronically ill and typically is the influential member of a close relationship with a more suggestible person (the secondary case) who also develops the delusion. The secondary case is frequently less intelligent, more gullible, more passive, or more lacking in self-esteem than the primary case. If the pair separates, the secondary case may abandon the delusion, but this outcome is not uniformly seen. The occurrence of the delusion is attributed to the strong influence of the more dominant member. Old age, low intelligence, sensory impairment, cerebrovascular disease, and alcohol abuse are among the factors associated with this peculiar form of psychotic disorder. A genetic predisposition to idiopathic psychoses has also been suggested as a possible risk factor. The ICD-10 criteria for induced delusional disorder are given in Table 13.2-11.

Table 13.2-10 DSM-IV Diagnostic Criteria for Shared Psychotic Disorder

Table 13.2-11 ICD-10 Diagnostic Criteria for Induced Delusional Disorder

Other special forms have been reported, such as folie simultanée, where two people become psychotic simultaneously and share the same delusion. Occasionally, more than two individuals are involved (e.g., folie à trois, quatre, cinq; also folie à famille), but such cases are especially rare. The most common relationships in folie à deux are sister-sister, husband-wife, and mother-child, but other combinations have also been described. Almost all cases involve members of a single family. There is some question whether patients with such conditions are truly delusional rather than highly impressionable, as frequently there is merely passive acceptance of the delusional beliefs of the more dominant person in the relationship until they are separated, at which point the unusual belief may remit spontaneously. In the DSM-IV criteria the requirement that the secondary case not have a psychotic disorder prior to onset of the induced delusion illustrates the relevance of this question. Also, the psychopathology of secondary cases varies. In DSM-III such patients were required to meet the criteria for paranoid disorder (i.e., show evidence of disturbed personality and perhaps evidence of other psychiatric disorder, mental subnormality, or dementia); some cases may fit the definition of delusional disorder.

A 40-year-old woman consulted physicians to help cure her problem of disagreeable body odor. The physicians failed to satisfy the woman's hopes of diagnosis and treatment, because they found nothing wrong with her. They did occasionally recommend psychiatric consultation, which she refused. Her husband, a quiet, retiring man of 35, accompanied his wife to all medical specialist consultations. When questioned, he shared his wife's concerns about body odor and provided many examples of how distressing this problem had become. When he was told that there really was nothing wrong with his wife, he objected repeatedly and proclaimed that the doctors were incompetent. A psychiatrist was called to the clinic to see the couple and found consistent stories from both. The woman accepted a recommendation for hospitalization on the psychiatry-medical unit, and the husband returned home. After weeks of evaluation and treatment, the woman was discharged. The husband had stopped visiting her, and when informed that his wife would be coming home he said that he thought she had been cured of her problem. However, 3 months later the couple was once again visiting different specialists. A 52-year-old man was referred by the court for inpatient psychiatric examination after being charged with disturbing the peace. He had been arrested for disrupting a trial, complaining of harassment by various judges. He had walked into a courtroom, marched to the bench, and begun to berate the probate judge. While in the hospital, he told in detail of conspiratorial goings-on in the local judiciary. A target of certain judges, he claimed he had been singled out for a variety of reasons for many years: he knew what was going on; he had kept records of wrongdoings; and he understood the significance of the whole matter. He refused to elaborate on the specific nature of the conspiracy. He had responded to it with frequent letters to newspapers, the local Bar association, and even to a Congressional subcommittee. His mental state, apart from his story and a mildly depressed mood, was entirely normal. A family interview revealed that his wife and several grown children had shared the belief in a judicial conspiracy directed against the patient for a number of years. There was no change in delusional thinking in the patient or the family after 10 days of observation and the patient refused follow-up treatment. The intensity of conviction is governed by the presence of the primary case in the life of the secondary case. Protection is provided by others who share the delusion and believe that the response is reasonable. Munro has found that shared psychotic disorder is frequently associated with delusional disorder, somatic type. In the second case described for persecutory delusional disorder, the husband, a somewhat passive and isolated man, shared his wife's convictions. With her treatment, he also became less concerned about a conspiracy and began to share his doubts about the whole matter with his therapist. A recent summary of the Japanese literature indicated that in 97 cases of fulie à deux, the phenomenology and epidemiology were similar to those in western reports.

PATHOLOGY AND LABORATORY EXAMINATION Pathology As in most psychiatric conditions, there is no evidence of localized brain pathology to correlate with clinical psychopathology in patients with delusional disorder. These patients seldom die early and show no consistent abnormalities on neurological examination. Delusions can complicate many disorders and virtually all brain disorders. Certain disorders produce delusions at rates greater than that expected in the general population: for example, epilepsy (especially of the temporal lobe), degenerative dementias (dementia of the Alzheimer's type and vascular dementia), cerebrovascular disease, extrapyramidal disorders, and traumatic brain injury. Although many types of delusions have been reported in patients with brain disorders, there appear to be particular connections between delusion phenomenology and certain kinds of brain dysfunction. For example, patients with more severe cortical impairment tend to experience more simple, transient, persecutory delusions. This type of delusional experience is characteristic of conditions such as Alzheimer's disease, dementia and metabolic encephalopathy that are also associated with significant cognitive disturbance. More complex (i.e., elaborate and systematic) delusional experiences tend to be more chronic, intensely held, resistant to treatment, and associated with neurological conditions producing less intellectual impairment and strong affective components. Those features occur in patients with neurological lesions involving the limbic system or subcortical nuclei rather than cortical areas. That, coupled with the observation of response of some patients to drug treatment, such as pimozide and other medications, provides a rational basis on which to hypothesize the presence of subcortical pathology, possibly involving systems subserving temporolimbic areas. Available evidence suggests that if there is a lesion, it will be subtle. Imaging studies have begun to yield subtle findings about delusional disorder. In one study using quantitative volumetry in magnetic resonance imaging, 16 patients with delusional disorder showed lateral ventricle enlargement greater than in subjects with schizophrenia ( N = 31) and almost twice that of age-matched healthy controls (N = 35). Although this study showed no evidence of cortical infarcts (cerebrovascular injury), other studies have suggested that unsuspected cerebral infarction may occur in a high proportion of late-onset cases with delusional disorder. A further examination of these 16 delusional disorder subjects revealed that the degree of physiological right-left asymmetry was significantly greater in the temporal lobes. Another study has tentatively concluded that eye-tracking dysfunction in the saccadic system is present in delusional disorder, possibly reflecting some attentional impairment related to voluntary saccadic eye movement areas. Despite the subtle nature of such findings, future empirical studies, guided by etiological hypotheses, could lead to breakthroughs. Given the low incidence of delusional disorder, intensive studies of specific cases and of conditions with delusions from known causes (and with identifiable neuropathologies) offer useful beginning points. Recent studies of misidentification syndromes (e.g., Capgras's syndrome) offer the prospect of developing more refined models of neuropathological mechanisms for delusional disorder. Laboratory Examination A range of assessments is often necessary, but several have a high likelihood of detecting key factors in the case. The use of drug-screening measures is particularly valuable given the marked delusional responses induced by a number of substances, especially alcohol, amphetamines, cocaine, and other central nervous system stimulants. Neuropsychological assessment may help to disclose evidence of impaired intellectual functioning suggestive of brain abnormalities. The assessment of intelligence may show discrepancies between verbal and performance scores as well as scatter in overall performance. Limited data on delusional disorder (especially the more chronic forms) suggest that average or marginally low intelligence is characteristic of patients with this condition. A preliminary comparison of patients with late-onset delusional disorder and schizophrenia has indicated neuropsychological impairment to be somewhat less for the former group. Projective testing such as the Rorschach test has limited value in making the diagnosis but may confirm features consistent with it. Deviation on the paranoia scale of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) has strong correlations to paranoid features and may help substantiate the diagnosis or raise it as a possibility.

DIFFERENTIAL DIAGNOSIS Delusional Disorder Because delusional disorders are uncommon, idiopathic, and possess features characteristic of the full range of paranoid illnesses, differential diagnosis has a clearcut logic: delusional disorder is a diagnosis of exclusion. There are many conditions to consider ( Table 13.2-4), especially the more common disorders associated with paranoid features ( Table 13.2-12). To avoid premature diagnosis, careful evaluation is required.

Table 13.2-12 More Common Disorders Associated With Paranoid (Delusional) Features

Clinical assessment of paranoid features requires three steps. Initially, the clinician must recognize, characterize, and judge as pathological the presence of paranoid features. Next, the clinician should determine whether they form a part of a syndrome or are isolated. Finally, a differential diagnosis should be developed. The first of

the three steps must be pursued thoroughly. The clinician must be aware that a range of objective traits or behaviors ( Table 13.2-3) is often found in paranoid illness and may constitute the only clue that a paranoid illness is present. Patients with paranoid symptoms are frequently unwilling to reveal their subjective experiences to examiners or to cooperate in the clinical investigation. Careful interviewing of the patient and other informants may disclose evidence that the behavior is clearly psychopathological; in other cases, however, that conclusion must await further observations. Sometimes investigation is required to determine whether the belief is indeed delusional or not. Premature acceptance that the patient has delusional disorder has at times been an embarrassment to some clinicians who learn that the patient was not deluded. If the judgment that the patient is delusional seems unassailable, then careful elaboration of the nature of the delusion is called for. The delusional thinking should be examined for its fixity, logic, encapsulation, degree of systematization and elaboration, and its effect on planning and action. Having determined that a paranoid condition is present, the clinician should attend to premorbid characteristics (personality, adjustment, symptom development, medical problems, and so forth), the course, and associated symptoms to detect patterns of syndromic psychopathology or isolated symptom presentations—this is step two. The discovery of clouded consciousness, perceptual disturbance, other psychopathology, physical signs, or confusing symptoms may suggest different causes for paranoid features. Isolated acute paranoid symptoms, on the other hand, often appear early in medical illness. Finally, the clinician should resist the temptation to make the diagnosis of schizophrenia or delusional disorder prematurely in cases where paranoid features are present because these features occur regularly in a variety of psychiatric and medical illnesses. Consequently, awareness of the multiple causes of paranoid features (step one) is essential to completing the differential diagnosis (step three). Certain principles should guide effective assessment. First, it is important to have knowledge of the paranoid features and patterns of the clinical disorders in which they occur. For example, a small percentage (perhaps 10 percent) of schizophrenia cases have their onset after age 40, and most idiopathic psychiatric conditions do not begin after age 50. Second, the premorbid status of the patient should be determined. Generally, a normal premorbid state suggests that acute paranoid features are the consequence of medical disease. Third, an abrupt change in personality, mood, ability to function, and mental state should be noted because this may indicate complications resulting from medical disease. Fourth, in those cases in which there is evidence that the patient has been refractory to psychotropic medication or psychotherapy, the continuing presence of paranoid features should alert the clinician to consider alternative diagnoses. The final diagnosis in cases where paranoid features are prominent should be made only following: (1) a complete medical and psychiatric history with special attention (because of their high prevalence) to alcohol and other drug substance use (including drugs of abuse, prescribed drugs, and over-the-counter medication use history); (2) a thorough physical examination, including neurological and mental status examinations; (3) appropriate laboratory studies, particularly serological, toxicological, endocrine, microbiological, radiological, and electroencephalographic studies. There are certain delusional conditions that, because of their frequency and seriousness, should be routinely considered in the differential diagnosis, as among the most likely sources of delusions (Table 13.2-13). For example, delirium, dementia, psychotic disorder due to a general medical condition, and substance-induced psychotic disorder should receive special attention. Awareness of the potential for patients with each of these disorders to present with delusions in a state of clear consciousness prior to the elaboration of the defining syndromal symptoms should be kept in mind.

Table 13.2-13 Differential Diagnosis of Delusional Disorder

Psychotic Disorder Due to a General Medical Condition, With Delusions Delusions arise in a number of organic diseases and syndromes, many of which are listed in Table 13.2-2. What they frequently have in common is a disturbance of perception, particularly of visual and auditory functioning. Physical, neurological, and mental status studies as well as laboratory examinations will usually detect the organic causes of delusions. Each evaluation should focus on perceptual disturbance. Medical conditions associated with delusions should be searched for according to the guidelines outlined concerning differential diagnosis. Substance-Induced Psychotic Disorder, With Delusions Drug intoxications are particularly relevant to this disorder. Substances of abuse, such as amphetamines, hallucinogens, phencyclidine, and cocaine; over-the-counter drugs, such as sympathomimetics; and prescribed drugs, such as steroids, methyldopa (Aldomet) and levodopa (Dopar, Larodopa) can cause psychotic disorder, with delusions, sometimes without prominent cognitive impairment. In acute states, confusion, disorientation, and clouding of consciousness may be evident; in chronic cases the picture may be more difficult to distinguish from delusional disorder because cognitive changes are less pronounced. A careful drug history and screen may establish the diagnosis. A history of alcohol abuse or dependence is so common that it should always be considered; alcoholism is often associated with jealousy, persecutory ideas, and poor impulse control. Cognitive Disorders Dementia should be considered when paranoid features occur, particularly in older persons. Mental status examination should uncover characteristic cognitive changes absent in delusional disorder. Delirium, with its fluctuating course, confusion, memory impairment, and transient delusions, contrasts with the clarity of mental functioning and the persistence of delusions in delusional disorder and should be considered in acute cases with paranoid features. Schizophrenia Delusions may be the presenting feature of schizophrenia and this diagnosis should be considered when the delusions are implausible or bizarre, affect is blunted or incongruous with thinking, auditory and possibly visual hallucinations are prominent, thought disorder is pervasive, or role functioning is impaired. Patients with paranoid schizophrenia may have somewhat less bizarre delusions, but role functioning is impaired; also prominent auditory hallucinations are often present, unlike in delusional disorder. Shared Psychotic Disorder The delusions and symptoms of shared psychotic disorder may resemble those of delusional disorder; however, the delusions arise in the context of a close relationship with a delusional person, are identical in content to the delusions of that person, and diminish or disappear when secondary and primary cases are separated. Mood Disorders With Psychotic Features The persistent and profound dysphoric mood of patients with depression often points to the proper diagnosis; in delusional disorder, affect may be intense, but is not itself an overwhelming or preoccupying experience to the patient. Delusions in depression, if present, are frequently related to mood (mood-congruent delusions) and usually indicate severe depression. For example, patients with feelings of worthlessness or guilt may consider that persecution against them is justified as a punishment for their evil ways. Somatic delusions may be puzzling to differentiate if the clinician fails to consider associated psychopathological features. If delusions occur exclusively during mood episodes, the diagnosis is mood disorder with psychotic features. Depression refers to a host of signs and symptoms, and usually has a constellation of neurovegetative features (affecting appetite, sleep, libido, energy, and so forth) that are not part of delusional disorder. Moreover, depression is frequently cyclical and is often associated with a positive family history of mood disorder. Patients with delusional disorder, in contrast, are remarkably free of symptoms other than the delusion. Chronic demoralization may result from repeated failure to obtain the kind of response desired in delusional disorder. Not infrequently, mood symptoms that meet the criteria for a mood episode are present in a delusional condition. Delusional disorder is diagnosed only if the total duration of all mood episodes remains brief relative to the total duration of the delusional disturbance. There is some evidence to suggest that depression is the most common comorbid condition in delusional disorder. Manic Episode Manic delusions, often grandiose and therefore mood congruent, occur in the severest stages of this illness. This could mislead the diagnostician, but the cyclical nature, the marked change in mood (often euphoric or irritable at a very intense level), the reduced need for sleep, increased energy, easy distractibility, lack of focused concentration ability, lack of social inhibition, and increased activity level of manic episodes should be decisive in distinguishing that condition from

delusional disorder. Obsessive-Compulsive Disorder Severe forms of this disorder should be considered in the differential diagnosis, especially obsessive-compulsive disorder with poor insight. Preoccupation with fear, unusual rituals, and obsessional beliefs may be puzzling, yet the pervasive effects of the condition on functioning differ from the experience of delusional disorder. Moreover, delusions and hallucinations should be absent. In practice, this differential diagnosis may be difficult to determine without a period of observation. In some cases it may be necessary to make the diagnosis and that of delusional disorder. Somatoform Disorders Severe forms of body dysmorphic disorder may be difficult to distinguish from delusional disorder. The degree of conviction about imagined physical disfigurement may be the only guide for differential diagnosis. Lack of other features of psychopathology, often present in such cases, may also help to make the distinction. Hypochondriasis may also be distinguished on the basis of absence of delusions, although many of the behaviors associated with delusional disorders, somatic type, may occur. Usually such patients reveal some doubt or uncertainty about the validity of their health preoccupations. Their overvalued beliefs about disease or affliction may clearly resemble delusional disorder, somatic type; severe cases may require considerable diagnostic effort, and as in obsessive compulsive disorder, also require a second diagnosis of delusional disorder. Paranoid Personality Disorder Individuals with paranoid personality disorder by definition have abundant paranoid features. They are persistently oversensitive, ready to take offense, suspicious, resentful, rigid, and frequently self-centered. Rather than delusions, such persons tend to report strongly held ideas (overvalued ideas); generally, however, they are believed to be free of delusions, which is the most useful differential feature. There is some evidence that this personality pattern occurs often enough in families of probands with delusional disorder to suggest a possible genetic connection between the two. Schizoid Personality Disorder and Schizotypal Personality Disorder Paranoid features may occur in patients with these personality disorders as well. The pervasive disturbance in personality functioning and the absence of delusions and other psychotic features are usually definitive distinguishing characteristics. Delusional disorder has generally not been associated with this type of premorbid pattern of personality. Disorders of Aging Any discussion of differential diagnosis of paranoid features is incomplete unless consideration is given to the occurrence of paranoid features in the elderly. Paranoid features develop frequently in the elderly, and assessment in such cases should be particularly thorough because information about paranoid features among the aged is limited. There are several facts worth knowing: (1) the association of depressive illness with paranoid features is high enough to warrant suspicion of mood disorder in all cases with paranoid features: (2) there appears to be a late-onset syndrome sometimes labeled late paraphrenia or late-onset schizophrenia in which paranoid characteristics and hallucinosis frequently occur (this diagnosis, however, is warranted only when no other disorder can be diagnosed): (3) the sudden onset of acute paranoid features in the elderly can be a sign of cerebrovascular injury or other medical illness; (4) many of the medical conditions associated with delusions have increased incidence in the elderly population; for example, delusions can arise in the early course of presenile dementia and senile dementia conditions when deficits in clinical examination probes or neuropsychological performance may be inconspicuous; (5) perhaps most important for the general clinician is to recognize sources of increased risk of paranoid disorder among older individuals. It is now known that many factors contribute to the incidence of paranoid features in the aged, including lack of stimulating company, isolation, physical illness, the aging process itself, loss of hearing, and loss of visual acuity, each of which should be carefully assessed. Delusional disorder may be present in the elderly, may even have its onset in the elderly, but the frequency of other causes of paranoid features calls for a prudent, systematic search. Shared Psychotic Disorder Malingering, factitious disorder with predominantly psychological signs and symptoms, psychotic disorder due to a general medical condition, and substance-induced psychotic disorder need to be considered in the differential diagnosis of shared psychotic disorder. The boundary between shared psychotic disorder and generic group madness, such as among the victims of the Jonestown massacre in Guyana, is unclear.

COURSE AND PROGNOSIS Delusional Disorder Onset can begin in adolescence but generally occurs from middle to late adulthood with variable patterns of course, including lifelong disorder in some cases. Studies generally indicate that delusional disorder does not lead to severe impairment or change in personality, but rather to a gradual, progressive involvement with the delusional concern. Suicide has been associated with such disorders, although most patients live a normal life span. The base rate of spontaneous recovery may not be as low as previously thought, especially because only the more severely afflicted patients are referred for psychiatric treatment. Retterstol's personal follow-up investigation of a large series of cases has provided much of the viewpoint on the natural history of the disorder. The more chronic forms of the illness (patients presenting with features for more than 6 months) tend to have their onset early in the fifth decade. Onset is acute in nearly two-thirds of the cases, and gradual in the remainder. In 53 percent the delusion has disappeared at follow-up, is improved in 10 percent, and is unchanged in 31 percent. In more acute forms of the illness the age of onset is in the fourth decade, a lasting remission occurs in over half of patients, and a pattern of chronicity develops in only 10 percent; a relapsing course has been observed in 37 percent. Thus the more acute and earlier the onset of the illness, the more favorable the prognosis. The presence of precipitating factors signifies a positive outcome, as does female sex and being married. In terms of prognosis, the persistence of delusional thinking is most favorable for cases with persecutory delusions, and somewhat less favorable for delusions of grandeur and jealousy. However, outcome in terms of overall functioning appears somewhat more favorable for the jealousy subtype. Such patients may experience fewer hospitalizations and are less likely to have severe psychotic or schizophrenic deteriorations. Work status at follow-up has indicated that the majority of patients are employed. These observations, although limited to few cases, provide some basis for optimism: perhaps half of cases with delusional disorders may remit, but relapse and chronicity are common. Comorbidity Depression can be diagnosed as a coexistent disorder in the course of delusional disorder. Evidence indicates that depression is an independent disorder in such cases, that is, the disorders appear to be coincidental in their combination rather than related etiologically. This judgment must be regarded as somewhat tentative, but the clinical value of recognizing comorbid (and often treatable) conditions is straightforward. Shared Psychotic Disorder The nature of the disorder suggests that separation of the submissive person who has shared psychotic disorder (the secondary case) from the dominant person (the primary case) should result in the resolution and disappearance of the psychotic symptoms in the submissive person. Often, the submissive person requires treatment with antipsychotic drugs, just as the dominant person needs antipsychotic drugs for the psychotic disorder. Because the persons are almost always from the same family, they usually live together after being released from hospital. If separated, the patient will experience a possible remission; if not separated, the patient may have a similar prognosis as the primary case.

TREATMENT Delusional Disorder Delusional disorder has generally been regarded as resistant to treatment and interventions have often focused on managing the morbidity of the disorder by reducing the impact of the delusion on the patient's (and family's) life. However, in recent years the outlook has become less pessimistic or restricted in planning effective treatment for these conditions. The goals of treatment are to establish the diagnosis, to decide on appropriate interventions, and to manage complications (Table 13.2-14). Fundamental to the success of these goals is an effective and therapeutic doctor-patient relationship, which is far from easy to establish. The patients do not complain about psychiatric symptoms and often enter treatment against their will; even the psychiatrist may be drawn into their delusional nets.

TABLE cellSpacing=0 cellPadding=0 align=left border=0 hspace="10" vspace="5"> Table 13.2-14 Diagnosis and Management of Delusional Disorder

Psychosocial Treatments There is not enough evidence to substantiate the claims for any particular school or approach in talking with the patient. Insight-oriented therapy is usually contraindicated, but a combination of supportive psychotherapeutic approaches and possibly cognitive-behavioral interventions is sensible. It is unlikely that there is any psychiatric condition that requires greater diplomacy, openness, and reliability from the therapist. Considerable skill is required to deal with the profound and intense feelings that accompany these disorders. Awareness of the fragile self-esteem and unusual sensitivity of these patients is essential for general management and somatic treatment. Clinical experience indicates that direct questioning about the veracity of the delusion, apart from carefully establishing its nature and the evidence to support it during clinical evaluation, is seldom helpful. Although forging an alliance may be especially difficult, responding to the patient's distress rather than to the delusion itself may be effective. Understanding that fear and anxiety serve to stimulate hostility may be the key to adopting a flexible approach that promotes empathy but maintains physical and emotional distance. Patients with the disorder suffer; they often feel demoralized, miserable, isolated, and abandoned. They may face rejection at home, from police or medical specialists, or on the job. However, they can be approached, and their treatment can focus on these experiences. The goals of supportive therapy are to allay anxiety and initiate discussion of troubling experiences and consequences of the delusion, thereby gradually to develop a collaboration with the patient. In some patients this strategy allows the psychiatrist to suggest means of coping more successfully with the delusional thinking. For example, psychiatrists might encourage patients to keep their delusions to themselves because others might feel surprised, dismayed, or amazed, all at considerable cost to the patient. It may be possible to provide educational intervention to help amenable patients to understand how factors such as sensory impairment, social and physical isolation, and stress contribute to making matters worse. In all such approaches, the overriding aim is to assist in a more satisfying general adjustment. Cognitive approaches have attempted to reduce delusional thinking through modification of the belief itself, focusing on the associated reasoning or the reality testing of the deluded patient. Unlike noncognitive behavioral approaches that center attention on reduction of verbal behavior (talking about the delusion), this strategy seeks a more lasting and clinically meaningful intervention through multiple techniques that keep the relationship with the patient collaborative. These techniques include distancing, homework, and exploration of emotions associated with various delusions. The effectiveness of cognitive and behavioral therapies has not been studied enough to justify recommendation. Additionally, it is important to determine the long-term as well as the short-term impact of these treatments; nevertheless, they are promising enough to justify continued assessment. Somatic Treatment Delusional disorder is a psychotic disorder by definition, and the natural presumption has been that the condition would respond to antipsychotic medication. Because controlled studies are limited and the disorder is uncommon, the results required to support this practice empirically have been only partially obtained. The disparate findings in the recent literature on delusional disorder treatment have been summarized recently, with several qualifications. Of approximately 1000 articles published since 1961, the majority since 1980, 257 cases of delusional disorder (consistent with DSM-IV criteria) of which 209 provided sufficient treatment detail to make comparison, were assessed. Overall treatment results indicated that 80.8 percent of cases either recovered fully or partially. Pimozide (the most frequently reported treatment) produced full recovery in 68.5 percent and partial recovery in 22.4 percent of cases ( N = 143) treated whereas there was full recovery in 22.6 percent and partial recovery in 45.3 percent of cases ( N = 53) treated with typical neuroleptic agents [e.g., thioridazine (Mellaril), haloperidol (Haldol), chlorpromazine loxapine (Thorazine), perphenazine (Trilafon), and others]. The remaining cases ( N = 13) were noncompliant with any treatment, a finding the authors regard as an underestimation (6.2 percent). There were no specific conclusions drawn regarding treatment with selective serotonin reuptake inhibitors, (SSRIs), although a number of such reports have been published. While treatment of the somatic subtype generated the largest number of reports, these authors' meta-analysis indicated that the patterns of response were similar across all subtypes of delusional disorder. Follow-up data and personal experience indicated that long-term, possibly permanent, administration of medication is necessary to maintain remission. The results of treatment with the serotonin-dopamine antagonists (i.e., clozapine [Clozaril], risperidone olanzapine [Zyprexa], and others) is preliminary. Two known cases of the persecutory subtype have been treated successfully with risperidone and there are published reports of clozapine effectiveness in the persecutory subtype (N = 2) and the somatic subtype (N = 2), and of risperidone effectiveness in the somatic subtype ( N = 1). Unfortunately, systematic case series will develop slowly, but these preliminary results suggest that the atypical neuroleptic agents may add to the available treatment options. Given the limited samples available, case reports are especially valuable; although many authors recommend multisite trials (to augment the small numbers of cases available at any one site), it would be beneficial for further single case reports to be published in the meanwhile. The existing literature could be improved with more attention paid to diagnosis, prior treatments, outcome, and level of compliance, as well as dosage schedules, adverse effects, length of treatment, as well as the reasons for selecting or changing particular agents. Use of ( N = 1) single case research design strategies might also enhance the generalizability of findings. The impression is growing that antipsychotic drugs are effective, and a trial, especially with pimozide or a serotonin-dopamine antagonist is warranted. Certainly, trials of antipsychotic medication make sense when the agitation, apprehension, and anxiety that accompany delusions are prominent. Delusional disorders respond less well generally to electroconvulsive treatment than do major mood disorders with psychotic features. Some cases may respond to SSRIs, especially cases of body dysmorphic disorder with delusional concerns ( Table 13.2-15). Where differential diagnosis is unclear between delusional disorder and psychotic depression, a trial of combined therapy with antipsychotic and antidepressant medications therapy may be worthwhile. When standard strategies are unsuccessful, trials of lithium (Eskalith) or of anticonvulsant medication such as carbamazepine (Tegretol) probably should be considered. However, no systematic information to support such approaches is yet available.

Table 13.2-15 Pharmacological Agents With Reports of Successful Use in Delusional Disorder

Somatic treatment is difficult to implement on two levels, The patients' insistence on lack of psychiatric problems may be an insurmountable barrier to initiating treatment, and their sensitivity to all adverse effects may constitute an additional frustrating factor in their care. Noncompliance continues to be a frequent observation in published clinical studies. An open and clear approach to warn patients about and to assist them through possible unpleasant experiences is essential, but the intrinsic nature of active resistance to psychiatric intervention also requires attention. In general, some patients, especially younger patients with delusional disorder, respond to supportive management and somatic treatment. Unfortunately, others, especially the elderly, may be refractory to attempts to reduce their delusional thinking. In all cases goals that are realistic and modest are the most sensible. As most of the difficulty of this disorder results from the effects of the patient's actions concerning the delusions, any preventive approach in that domain has considerable value. Hospitalization Most delusional disorder patients can be treated effectively in outpatient settings; hospitalization may be necessary when there is potentially dangerous behavior or unmanageable aggressiveness. The patient may show signs of poor impulse control, excessive motor and psychic tension, unremitting anger, brooding, suicidal tendencies, and even threats of self-harm or aggression toward others. Suicidal ideation and planning are also potential grounds for hospitalization. Follow-up studies report suicide above the population base rate; patients with erotomania, jealousy, and persecutory delusions are particularly at risk. Once the psychiatrist decides to hospitalize the patient, it is preferable to inform the patient tactfully that voluntary hospitalization is necessary. If this strategy fails, legal means must be undertaken to commit the patient to a hospital. Shared Psychotic Disorder The initial step in treatment is minimally the temporary separation of the affected person from the source of the delusions, the dominant partner. This step may not only be therapeutic but diagnostic when evidence of reduced delusional thinking and preoccupation accrue. The patient may need significant support to compensate for the loss of that person. The patient with shared psychotic disorder should therefore be carefully observed for the remission of the delusional symptoms. Antipsychotic drugs can be used if the delusional symptoms have not abated in 1 or 2 weeks. Psychotherapy with nondelusional members of the patient's family should be undertaken, and psychotherapy with both the patient with shared psychotic disorder and the dominant partner may be indicated later in the course of treatment. In addition, the mental disorder of the dominant partner should be treated. The clinician might use family therapy and social support to modify the family dynamics and to prevent the recurrence of the syndrome. It is often useful to make sure that the family unit is exposed to input from outside sources to decrease the family's isolation. In short, a comprehensive approach emphasizing support and, when necessary, medication is useful.

SUGGESTED CROSS-REFERENCES Conditions to be differentiated from delusional disorders are discussed in Chapter 12 on schizophrenia, in Chapter 14 on mood disorders, in Chapter 16 on somatoform disorders, in Chapter 24 on paranoid personality disorder, in Chapter 5 on obsessive-compulsive disorder, and in Chapter 10 on mental disorders due to a general medical condition. Aging and psychiatric disorders in the elderly is covered in Chapter 51. SECTION REFERENCES Baker PB, Cook BL, Winokur G: Delusional infestation: The interface of delusions and hallucinations. Psychiatr Clin North Am 18:345, 1995. Bentall RP, Kaney S, Dewey ME: Paranoia and social reasoning: An attribution theory analysis. Br J Clin Psychiatry 30:13, 1991. Catalano M, Nobile M, Norelli E, Nothen M, Smeraldi E: Distribution of a novel notation in the first error of the human dopamine D4 receptor gene in psychotic patients. Biol Psychiatry

34:459, 1993.

*Copeland JR, Dewey ME, Scott A, Gilmore C, Larkin BA, Cleave N, McCracken CF, McKibbin PE: Schizophrenia and delusional disorder in older age: Community prevalence, incidence, comorbidity, and outcome. Schizophr Bull 24:153, 1998. Cummings JL: Psychosis in neurologic disease: Neurobiology and pathogenesis. Neuropsychiatry Neuropsychol Behav Neurol 3:144, 1992. de Clerambault GG: Les Psychoses Passionelles, Oeuvre Psychiatrique, Presses Universitaires de France, Paris, 1942. Eastham JH, Jeste DV: Treatment of schizophrenia and delusional disorder in the elderly. Eur Arch Psychiatry Clin Neurosci 247:209, 1997. Freud S: Psychoanalytic notes upon an autobiographical account of a case of paranoia (dementia paranoides). In Standard Edition of the Complete Work of Sigmund Freud, vol 12. Hogarth Press, London, 1966. Gambini O, Colombo C, Cavallaro R, Scarone S: Smooth pursuit eye movements and saccadic eye movements in patients with delusional disorder. Am J Psychiatry 150:1411, 1993. Herlitz A, Forsell Y. Episodic memory deficit in elderly adults with suspected delusional disorder. Acta Psychiatr Scand 93:355, 1996. Howard R. Induced psychosis. Br J Hosp Med 51:304, 1994. Howard RJ, Almeida O, Levy R, Graves P, Graves M: Quantitative magnetic resonance imaging volumetry distinguishes delusional disorder from late-onset schizophrenia. Br J Psychiatry 1995.

165:474,

Howard RJ, Graham C, Sham P, Dennehey J, Castle DJ, Levy R, Murray R. A controlled family study of late-onset non-affective psychosis (late paraphrenia). Br J Psychiatry 170:511, 1997. Jaspers K: General Psychopathology. University of Manchester Press, Manchester, 1963. Kashiwase H, Kato M: Folie a deux in Japan-analysis of 97 cases in the Japanese literature. Acta Psychiatr Scand 96:231, 1997. Kendler KS: Demography of paranoid psychosis (delusional disorder). Arch Gen Psychiatry 39:890, 1982. Kendler KS, Walsh D: Schizophreniform disorder, delusional disorder and psychotic disorder not otherwise specified: Clinical features, outcome, and familial psychopathology. Acta Psychiatr Scand 91:370, 1995. Kitamura H. A case of somatic delusional disorder that responded to treatment with risperidone. Psychiatry Clin Neurosci 51:337, 1997. Kolle K: Der Wahnkranke in Lichte alter and neuer Psychopathologie, Thieme, Stuttgart, 1957. Kraepelin E: Dementia Praecox and Paraphrenia, RN Barclay, translator Livingstone, Edinburgh, 1989. Lo Y, Tsai SJ, Chang CH, Hwang JP, Sim CB: Organic delusional disorder in psychiatric in-patients: comparison with delusional disorder. Acta Psychiatr Scand 95:161, 1997. *Maher BA: Delusions: Contemporary etiological hypotheses. Psychiatr Ann 22:260, 1992. Maher BA, Spitzer M: Delusions. In Comprehensive Handbook of Psychopathology, ed 2, HE Adams, PB Sutker, editors. Plenum, New York, 1993. *Manschreck TC: Pathogenesis of delusions. Psychiatr Clin North Am 18:213, 1995. Manschreck TC: The assessment of paranoid features. Compr Psychiatry 20:370, 1979. Manschreck TC, Petri M: The paranoid syndrome. Lancet 2:251, 1978. *Manschreck TC: Delusional disorder: The recognition and management of paranoia. J Clin Psychiatry 57(Suppl):32, 1996. *McAllister TW: Neuropsychiatric aspects of delusions. Psychiatr Ann 22:269, 1992. *Meloy JR, editor: The Psychology of Stalking. Academic Press, San Diego, CA, 1998. Menzies RPD, Federoff JP, Green CM, Isaacson K: Prediction of dangerous behavior in male erotomania. Br J Psychiatry 166:529, 1995.

Mowat RR: Morbid Jealousy and Murder. Tavistock, London, 1966. *Munro A, Mok H: An overview of treatment in paranoia/delusional disorder. Can J Psychiatry 40:616, 1995. *Munro A: Delusional Disorder. Cambridge University Press, New York, 1999. Opler LA, Klahr DM, Ramirez PM: Pharmacologic treatment of delusions. Psychiatr Clin North Am 18:379, 1995. Retterstol N: Paranoid and Paranoiac Psychoses. Charles C Thomas, Springfield, IL, 1966. Segal JH: Erotomania revisited: From Kraepelin to DSM-III-R. Am J Psychiatry 146:1261, 1989. Schreber D: Memoirs of My Nervous Illness. Bentley R, Cambridge, MA, 1995. *Serretti A, Lattuada E, Cusin C, Smeraldi E: Factor analysis of delusional disorder symptomatology. Compr Psychiatry 40:143, 1999. Soares JC, Gershon S. Therapeutic targets in late-life psychoses: Review of concepts and critical issues. Schizophr Res 27:227, 1997. Spitzer M: On defining delusions. Compr Psychiatry 31:377, 1990. Spitzer RL, First MB, Kendler KS, Stein DJ: The reliability of three definitions of bizarre delusions. Am J Psychiatry 150:880, 1993. Winokur G: Familial psychopathology in delusional disorder. Compr Psychiatry 26:241, 1985.

Textbook of Psychiatry

13.3 ACUTE AND TRANSIENT PSYCHOTIC DISORDERS AND CULTURE-BOUND SYNDROMES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 13. OTHER PSYCHOTIC DISORDERS

13.3 ACUTE AND TRANSIENT PSYCHOTIC DISORDERS AND CULTURE-BOUND SYNDROMES JUAN E. MEZZICH, M.D., PH.D., KEH-MING, LIN, M.D., M.P.H., AND CHARLES CAMPBELL HUGHES, P H.D. Definition And Comparative Nosology Etiology Diagnosis and Clinical Features DSM-IV Pathology and Laboratory Examinations Course and Prognosis Treatment Suggested Cross-References

While schizophrenia and mood disorders have commanded attention for many years and are likely to continue doing so for the foreseeable future, several other types of psychotic conditions are emerging as significant. Among these are psychotic disorders associated with general medical diseases and with the use of psychoactive substances as well as a complex group of acute and brief psychotic disorders. Interest in the latter group stems from several factors. One concerns the phenomenological intricacy of disorders in this group. While all basically share loss of touch with reality or bizarre behavior as core psychopathology, they may diverge extensively in other aspects of their symptomatological profile. Another factor involves geographical epidemiology, with a disproportionately high frequency of acute and brief psychoses reported in the developing countries of the Americas, Asia, and Africa. A third factor involves cultural framework. Most of the syndromic or nosological predecessors of the acute and brief psychoses have been described in defined cultural contexts, whether as bouffée délirante in France, psychogenic psychosis in Scandinavia, cycloid psychosis in Germany, or the variety of transient psychoses reported in the traditional societies of the developing world. The crucial role of the last factor connects the nosological category of acute transient psychoses to the culture-bound syndromes. The importance of cultural framework is certainly relevant to the full range of psychiatric disorders, both from clinical psychopathological and epidemiological perspectives, but it is most distinctive and illustrative in reference to culture-bound syndromes of both psychotic and nonpsychotic types.

DEFINITION AND COMPARATIVE NOSOLOGY ICD-10 The acute psychoses described in northern European countries and in developing countries have been, for the first time, accommodated and organized in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), under the category of acute and transient psychotic disorders. The conditions are formulated and arranged according to the following principles, in order of priority: 1. An acute onset (less than 2 weeks) as the key criterion for the whole group. Acute onset denotes a change within 2 weeks or less from a state without psychotic features to a clearly abnormal psychotic state (not necessarily at its peak severity). 2. The presence of typical syndromes. Those include, first, a rapidly changing and variable state called polymorphic, prominent in acute psychoses described in several countries, and, second, the presence of typical schizophrenic symptoms. 3. The presence or absence of associated acute stress (within 2 weeks of the first psychotic symptoms). P>Complete recovery usually occurs within 1 to 3 months (depending on the specific disorder), often within a few weeks or days. Only a small proportion of patients with these conditions develop persistently disabling states. DSM-IV The evaluation of a psychotic patient requires consideration of the possibility that the psychotic symptoms result from a general medical condition (e.g., a brain tumor) or the ingestion of a substance (e.g., phencyclidine). Those two situations are classified in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as psychotic disorder due to a general medical condition and substance-induced psychotic disorder, respectively. DSM-IV also includes a diagnosis of catatonic disorder due to a general medical condition to emphasize the special considerations regarding the differential diagnosis of catatonic symptoms. DSM-IV also includes psychotic disorder not otherwise specified for psychotic disorders that do not meet the criteria for any other specific psychotic disorder. In previous editions of DSM these were called atypical psychoses.

ETIOLOGY Both psychosocial and biological factors appear to play significant roles in the causation of acute brief psychoses and culture-bound syndromes. More than one factor may be present in any particular case, including a combination of psychosocial and biological factors. Psychosocial Factors The diagnosis of psychotic disorders depends primarily on an accurate and thoughtful assessment of delusions, hallucinations, and bizarre psychomotor behaviors. Culture profoundly influences the meaning and nature of symptoms in the psychotic disorders reviewed in this chapter as well as the characteristics and meaning of the context and the consequences of the behaviors at hand. Attention to cultural framework can help one interpret behaviors properly and minimize misdiagnosis and diagnostic ambiguity in cross-cultural clinical situations. Lacking adequate information on what constitutes normal behavior patterns or culturally sanctioned idioms of distress, clinicians evaluating patients with different cultural, ethnic, or religious backgrounds are likely to misidentify less severe complaints or behaviors as delusional, hallucinatory, or bizarre. Similarly, they are likely to suspect the existence of major psychopathology in patients with fleeting psychotic manifestations. Spiritual and religious beliefs can present major diagnostic dilemmas for clinicians. Beliefs in witchcraft and sorcery are common in many societies and may or may not be delusional. Spiritism, Santeria, and various other religious movements and different forms of shamanism practiced in many parts of the world encourage and sanction personal communication and active involvement with the dead, with spirits, and with the various deities. Such supernatural and mystical practices and experiences do not necessarily indicate psychopathology. However, such culturally congruent beliefs often also exert substantial pathoplastic influences on symptom formation in psychotic patients. Similarly, possession and trance phenomena are frequently seen in most non-Western societies, and it is often difficult to determine whether those experiences, in a particular case, are part of an ongoing psychotic process or are culturally and contextually appropriate. Among the social factors that have been the subject of empirical research in recent years is (particularly among women) departure from the parental village for a number of reasons (e.g., marriage) and return to the parental village, including participation in events such as births and weddings. Investigators have also found a history of job stress (particularly among men) associated with the emergence of clinical manifestations. Other social factors can also significantly influence symptom formation in psychiatric patients, thereby complicating the diagnosis of psychotic conditions. Sustained exposure to racist and discriminatory behaviors tends to increase vigilance and suspiciousness among members of ethnic minorities, and it may contribute to a higher propensity for paranoid symptoms in such persons. Paranoid symptoms are also more prevalent among those, such as refugees, who are forced to live in an unfamiliar cultural milieu. Fear of political persecution is a reality of life for persons living under oppressive regimes, and it may contribute to a higher prevalence of paranoid ideation in such societies. Because of those complications, it is often difficult to determine whether paranoid experiences among recent immigrants and sojourners are reactive or indicate a more serious and enduring psychotic process. Biological Factors A variety of biological factors can have etiological involvement in the development of acute grief psychoses and culture-bound syndromes. One is infectious diseases, especially prevalent in developing countries. Empirical research documents the presence of fever in a disproportionately high number of patients with acute transient psychotic disorders. Physical conditions (e.g., cerebral neoplasms, particularly of the occipital or temporal areas) can induce hallucinations. Sensory deprivation, as occurs in blind and

deaf persons, can also result in hallucinatory or delusional experiences. Lesions involving the temporal lobe and other cerebral regions, especially the right hemisphere and the parietal lobe, are often associated with delusions. Psychoactive substances are common causes of psychotic syndromes. The most commonly involved substances are alcohol, indole hallucinogens (e.g., lysergic acid diethylamide [LSD], amphetamines, cocaine, mescaline, phencyclidine [PCP], and ketamine. Many other substances, including steroids and levothyroxine (Levoxyr, synthroid) can be associated with substance-induced hallucinations.

DIAGNOSIS AND CLINICAL FEATURES ICD-10 ICD-10 provides general criteria for acute and transient psychotic disorders as well as criteria for four specific disorders ( Table 13.3-1). ICD-10 also includes two residual categories for acute and transient psychotic disorders.

Table 13.3-1 ICD-10 Diagnostic Criteria for Acute and Transient Psychotic Disorders

Acute Polymorphic Psychotic Disorder Without Symptoms of Schizophrenia Acute polymorphic psychotic disorder without symptoms of schizophrenia is characterized by obvious but variable, rapidly changing hallucinations, delusions, and perceptual disturbances, often accompanied by emotional turmoil (happiness and ecstasy or anxiety and irritability). The criteria for manic episode, depressive episode, or schizophrenia are not met. The disorder tends to have an abrupt onset (less than 48 hours) and then a rapid resolution of symptoms. If symptoms persist for more than 3 months, the diagnosis should be changed (e.g., to persistent delusional disorder or some other nonorganic psychotic disorder). The diagnosis accommodates bouffée délirante and cycloid psychosis, both either unspecified or without symptoms of schizophrenia, as the following excerpt from the ICD-10 Casebook illustrates. Mrs. Charrière is a 25-year-old Frenchwoman. Problem Mrs. Charrière was brought by ambulance to a hospital emergency department in the city where she lived. Her husband reported that she had been perfectly normal until the previous evening, when she had come home from work complaining that “strange things were going on” at her office. She had noticed that her colleagues were talking about her, that they had been quite different all of a sudden, and that they had started behaving as if they were acting a part. Mrs. Charrière was convinced that she had been put under surveillance and that someone was listening in on her telephone conversations. All day she had been feeling as if she were in a dream. When she looked in the mirror, she had seemed unreal to herself. She had become increasingly anxious, incoherent, and agitated during the course of the day and had not been able to sleep at all during the night. She had spent most of the night looking out of the window. Several times she pointed at the crows in a nearby tree and told her husband, “The birds are coming.” In the morning, Mr. Charrière found his wife on her knees as if she were praying. She knocked her head repeatedly against the floor and talked in a rambling way, declaring that she had been entrusted with a special mission, that her boss was a criminal, there were spies everywhere, and something terrible would happen soon. All of a sudden she calmed down, smiled at her husband, and told him that she had decided to convert from Catholicism to Islam. At that stage she became quite elated, started laughing and shouting, and declared that she and her husband could pray to the same god from then on. Shortly afterward she was terrified again and accused her husband of trying to poison her. History Mrs. Charrière was brought up in a town in the west of France, where her parents owned a small restaurant. She did well in school, went on to college, and trained as an interpreter. During her training she met her future husband, who had come to France from Algeria to train as an interpreter himself. Because both she and her husband were agnostics, the fact that they came from different religious backgrounds had never been a problem. She took a job with an administration related to the European Communities, and her husband found a position with an international interpreting company. The couple were doing well, they had bought a nice house on the outskirts of Mrs. Charrière's home town, and were planning to have a child in the near future. Mrs. Charrière's parents were in good health. She had a brother and two sisters. At age 18 her younger sister had had a nervous breakdown and in the ensuing years had been hospitalized repeatedly in a psychiatric hospital with a diagnosis of schizophrenia. Both Mrs. Charrière and her husband refrained from drinking alcohol and were strongly opposed to any kind of drugs, including prescription medicines. Mr. Charrière described his wife as an outgoing, sociable, and perfectly normal woman. However, he was quite worried about what was happening, all the more since she appeared to have symptoms resembling those he had observed in his sister-in-law. Findings On admission Mrs. Charrière was frightened and bewildered but was oriented in time, place, and person. She was restless and constantly changed position, standing and sitting, moving about the room, shouting and screaming, weeping and laughing. She talked in a rambling way, shifting from one subject to another without any transition. Something criminal was going on at her office, she said, and she had discovered a secret plot. There were microphones hidden everywhere, she added, and “the birds are coming.” She wondered whether the physician was a real physician or “a spy in disguise.” She went on to speak about “my mission,” declared that Jesus had been a false prophet, that Muhammad was the real prophet, and that she would convince the world of what was right and wrong. She then began to explain that the truth was to be found in numbers. The digit “3” signifies good, she said, and the digit “8” represents evil. Suddenly she started to weep, explaining that her parents had died and that she wished to join them in heaven. During the first days of hospitalization, Mrs. Charrière continued presenting a rapidly changing symptomatology. Her mood frequently shifted from sadness to elation, and the content of her delusions changed from persecution to mysticism. On several occasions she came out of her room and complained that she had heard people speaking about her, even when there was no one in the vicinity. When asked to describe what she was hearing, she spoke of voices coming from the corridor. She firmly denied that the voices might emanate from within her own body. The physical examination did not reveal any abnormality. Results of blood tests, including thyroid function, were within normal limits, as were all other special investigations such as an electroencephalogram and brain scan. Course Mrs. Charrière was treated with 30 mg of haloperidol (Haldol) during the first week, and with half this dose for the following week. After 2 weeks all of her symptoms had disappeared, and she was discharged on medication. She was seen once a week in the outpatient department for another month, during which the medication was progressively reduced and then stopped completely. Two months after the onset of the delusional episode, the patient continued to be free of symptoms. Discussion The significant features of Mrs. Charrière's disorder were acute polymorphous delusions, rapidly changing mood disturbances, perplexity, depersonalization, and derealization without clouding of consciousness, and occasional auditory hallucinations. The disorder developed to its peak in 24 hours and was resolved in a few weeks, with complete recovery within 6 weeks. The patient had no psychiatric history.

continued to be free of symptoms. Discussion The significant features of Mrs. Charrière's disorder were acute polymorphous delusions, rapidly changing mood disturbances, perplexity, depersonalization, and derealization without clouding of consciousness, and occasional auditory hallucinations. The disorder developed to its peak in 24 hours and was resolved in a few weeks, with complete recovery within 6 weeks. The patient had no psychiatric history. The psychiatrist who dealt with this case made a diagnosis of bouffée délirante. This concept goes back to the French psychiatrist Valentin Magnan, whose pupil Paul Legrain, proposed the following diagnostic criteria: an acute onset of the disorder “like a bolt from the blue” in the absence of a psychosocial stressor; the presence of unsystematized and rapidly changing “polymorphic” delusions; the presence of emotional turmoil with intense and changing feelings of anxiety, happiness, or sadness; the presence of perplexity, depersonalization, or derealization without clouding of consciousness; and resolution of the disorder with complete recovery within 2 months. In the ICD-10, the subtyping of acute and transient psychotic disorders rests on the acuteness of onset, the presence of typical syndromes, and the presence of associated stress. In the case of Mrs. Charrière, the onset was abrupt (i.e., the symptoms appeared within less than 48 hours), the syndrome was polymorphic, there were no typically schizophrenic symptoms, and the onset of the disorder was not associated with acute stress. Therefore, Mrs. Charrière's disorder must be coded as acute polymorphic psychotic disorder, without symptoms of schizophrenia, and without associated acute stress. (Reprinted with permission from ICD-10 Casebook.) Acute Polymorphic Psychotic Disorder With Symptoms of Schizophrenia Acute polymorphic psychotic disorder with symptoms of schizophrenia is as polymorphic as the preceding disorders, but is additionally characterized by the consistent presence of typical schizophrenic symptoms. If the schizophrenic symptoms last more than 1 month, the diagnosis should be changed to schizophrenia. The disorder accomodates the concepts of bouffée délirante and cycloid psychosis, both with symptoms of schizophrenia. Acute Schizophrenia-Like Psychotic Disorder Acute schizophrenia-like psychotic disorder is characterized by the consistent and stable presence of typical schizophrenic symptoms, without the polymorphic character of the foregoing disorders. If the schizophrenic symptoms last more than 1 month, the diagnosis should be changed to schizophrenia. Other Acute, Predominantly Delusional Psychotic Disorders The other disorders are characterized by relatively stable delusions or hallucinations, without fulfilling the criteria for either schizophrenia or the acute polymorphic psychotic disorders. If the delusions persist for more than 3 months, the diagnosis should be changed to persistent delusional disorder and, if only the hallucinations persist, to other nonorganic psychotic disorder. The disorder accommodates the concepts of psychogenic paranoid psychosis and paranoid reaction. Halime is a 22-year-old student. She is in her first year of medical school in Egypt. Problem Accompanied by her mother, Halime came to see the physician at the psychiatric outpatient clinic. She was complaining about her nose. For the preceding week, from time to time she could smell a foul odor and was very afraid that it came from herself. She reported hearing voices talking about her behavior and telling her what to do. She had become extremely irritable and was unable to sleep. All these problems began 10 days after returning to her home in Alexandria on summer vacation from the medical school. She could find no obvious reason for the foul smell and the voices, but she thought the condition might be the result of witchcraft. She had developed a friendship with a young man, a fellow student at the medical school, and suddenly, just before the vacation, he had asked her to marry him. She was very surprised, became frightened, and had refused, which had upset him. She now suspected that her boyfriend had caused a spell to be cast on her because of her refusal. Halime's family said her condition was gradually getting worse. The foul smell and the voices seemed to affect her more each day. History Halime was the first of two children born to a family of average income in Alexandria. Her father was a mechanic and seemed to be a rather shy and gentle person. The mother was ambitious and expressed great concern for her daughter's education. Her family reported that they had great hope that their first child would be a boy. The parents treated Halime as if she were a boy for the first 3 years of her life until the birth of a second child, which was a son. There was no information about mental disorders in the family. Halime was introverted, thoughtful, and rather stubborn, with only a few friends. She had a high moral standard and had never dated or had sexual relations. She was doing very well at medical school and was determined to become a great physician in a culture where there is still some resistance to women physicians. She had always been physically strong and had excellent health. Findings On admission to the clinic, Halime was found to be very self-conscious and tried to avoid being seen by other people. She appeared tense and sad and seemed close to tears. She was reluctant and mentioned with hesitation some “extraordinary experiences.” These included the foul smell, which was like burned meat, and the voices that kept commenting on her behavior. She said the voices described what she was doing “here and now” and added comments. One example she gave of what the voices were saying was, “You are now speaking to the physician. You hope that he can help you, don't you? No hope. We shall overcome.” She explained that she believed this was the result of the witchcraft to which she had been subjected. She seemed able to differentiate in her mind between normal and abnormal perceptual experiences. She stated that she was able to make this distinction but was unable to do anything about the voices. She showed emotional response of normal modulation, and no abnormalities of speech were observed. She was fully oriented as to time, place, and person and showed no impairment of memory. Her attention seemed sharpened, but her concentration was slightly diminished. Careful physical and neurological examinations revealed no abnormality. An electroencephalogram with nasopharyngeal electrodes and a computed tomography scan also showed only normal results, and laboratory investigations, including thyroid parameters, were all normal. Course Halime was prescribed haloperidol (3 mg per day) and a hypnotic. In the course of 4 days, the voices and the foul smell gradually disappeared. At the next visit to the clinic a week later, she complained of drowsiness and fatigue, aching and stiffness in the muscles, and difficulties with concentration. Her haloperidol was reduced to 1 mg per day, and the hypnotic was discontinued. After this she gradually improved, and after an additional 2 weeks she appeared well and was able to manage without medication. Discussion After a sudden proposal of marriage less than 2 weeks before, Halime developed within just a few days a psychotic disorder with olfactory and auditory hallucinations and with commenting voices mentioning her in the third person. Her explanation about witchcraft cannot for certain be considered delusional in a culture where there is widespread belief in this phenomenon, although someone of her educational level would be expected to consider such belief as a superstition. Otherwise, Halime showed remarkable insight into the nature of her condition, with little or no impairment of her sense of reality. She showed no major disturbance of consciousness. No sign of organic etiology was observed, and psychoactive substance use was not suspected. She did not meet the symptomatic criteria for an affective episode. On antipsychotic treatment she had a complete remission within 3 weeks. Thus, she had an acute and transient psychotic disorder. The symptomatology was not polymorphic but included a schizophrenic first-rank symptom of commenting voices. The subtype, therefore, will be schizophrenia-like disorder. The psychotic disorder followed, within 2 weeks, an event that may be considered stressful to a young female in Halime's cultural setting. The full diagnosis therefore will be other acute predominantly delusional psychotic disorder, without associated acute stress. (Reprinted with permission from ICD-10 Casebook.)

Mr. Dubois is a 43-year-old Frenchman. Problem Mr. Dubois was convinced that he was being watched and that someone was listening in on his telephone conversations. He was referred for psychiatric consultation by his family physician because he became increasingly anxious and felt that “strange things” were going on around him. The problems had begun a week earlier, when Mr. Dubois started having doubts about whether his father, who had died more than 5 years before, was really dead or was still alive and being held hostage by the local municipal council, of which he had been a member until shortly before his death. After all, Mr. Dubois thought, his father had been the most honest man in the world, and it was likely that he had vehemently opposed a shady deal that the council had decided to pursue despite his misgivings. Mr. Dubois had the impression that people looked at him “in a knowing way” or talked or behaved as if they wanted to convey secret messages. On several occasions, when he was alone, he heard voices whispering something he was not able to understand and noticed that normally static objects seemed to move before his eyes. History Mr. Dubois came from a small industrial town. His father worked in the local steel factory and was very active in the labor union. The son was a bright student. He went to college and trained as a primary school teacher. He took up a teaching position in his home town, got married, had two children, and led a quiet and rather uneventful life. The patient's father died of a heart attack at the age of 65. Although he had already retired from his job at that time, he had remained active in local politics. He had been a member of the municipal council until a few months before his death and had left the council only because he was compelled to resign as a result of some disagreements with his colleagues. He had felt very bitter about what he considered an unfair ousting, became morose, and hardly went into town afterward. In the view of his family, the forced resignation from the council contributed greatly to his death. Mr. Dubois's mother was alive and well, and he had a brother who lived abroad. There was no history of mental illness in the family. The patient felt quite depressed after his father's death but did not have any other psychiatric symptoms before his current episode. His physical health had always been excellent. He had never smoked, did not take drugs, and drank no alcoholic beverages except for an occasional beer or glass of wine. Mrs. Dubois described her husband as hard-working, conscientious, and somewhat rigid in his opinions and with a tendency to bear grudges. Findings On arrival at the psychiatrist's consulting room, Mr. Dubois was anxious, distressed, and bewildered but oriented in time, place, and person. He talked in a coherent way and, although initially suspicious, eventually gave a detailed account of what he had experienced during the previous week. He was convinced that there was a conspiracy against his family and that it had to do with his father's political activities. He remembered his father's funeral, but he was convinced that the coffin must have been empty. In his opinion the conspirators had kidnapped his father and had been holding him as a hostage all these years. Now they had decided to destroy the rest of the family. The patient admitted that he had been under stress for some time, that he had too much work, and that he had let himself get involved in too many activities both at school and outside of school. During the previous week he had not been able to sleep for more than a few hours each night, and he felt exhausted. He did not feel depressed, and in particular he had no feelings of self-reproach or guilt and no thoughts of suicide. He was aware, however, that something was wrong and agreed to stay in the hospital. The physical examination did not reveal any abnormality. The results of blood tests, including thyroid function, were within normal limits, as were all other special investigations such as an electroencephalogram and brain scan. Course Mr. Dubois was treated with a haloperidol (30 mg) during the first week, with the dose halved for the second week. After 2 weeks all of the symptoms had disappeared, and Mr. Dubois was discharged on medication. He was seen once a week in the outpatient department for another month, during which the medication was progressively reduced and then stopped completely. Six months after the onset of his delusional episode, the patient continued to be free of symptoms. Discussion The significant features of Mr. Dubois's disorder were acute delusions, together with occasional auditory hallucinations and disturbance of visual perception. The disorder developed to its peak in a few days and was resolved in a few weeks, with complete recovery occurring within 6 weeks. The patient had no psychiatric history. The patient was convinced that his father, who had died 5 years before, was in fact alive and held hostage by a group of conspirators. Although extremely improbable, his delusions cannot be considered theoretically and physically completely impossible and thus bizarre (as in a schizophrenia-like disorder). Mr. Dubois's disorder otherwise meets the general criteria of an acute and transient psychotic disorder. It developed in a few days and could not be attributed to an organic mental disorder or a metabolic disturbance affecting the central nervous system, or to a mood disorder or the use of a psychoactive substance. The symptoms did not change rapidly in both type and intensity, so they cannot be coded as acute polymorphic disorder. Because Mr. Dubois does not fulfill the symptomatic criteria for schizophrenia, the most probable diagnosis is other acute predominantly delusional psychotic disorder. The onset of the disorder was preceded by a period of overwork, but this did not amount to significant stress. Other Acute and Transient Psychotic Disorders Other acute psychotic disorders not classifiable under the preceding categories are included in this category provided there is no evidence of an organic cause. Examples include acute psychoses with definite but fleeting delusions or hallucinations, and states of undifferentiated excitement.

Miss Maruyami is Indonesian. She is 30 years old and single and lives with her widowed mother. Problem Miss Maruyami was brought to the psychiatric hospital by an uncle and two brothers-in-law, who had to hold her tightly to prevent her from running away. They almost had to carry her. She was hissing, spitting, and kicking about with her legs so that she was hardly able to walk. Four days earlier she had returned from the market in a state of agitation and mild confusion. She claimed that one of the merchants had accused her of shoplifting, and, when she protested, he had further accused her of being an idler and a prostitute who ought to be sent to jail. Since then she had appeared restless, irritable, suspicious, and hardly able to sleep. At night she went about the house checking the locks and peeping through the windows at the neighbor's house in which she could see some shadows and lights move about. She felt that something hostile was going on and that the neighbor was spying on her because he wanted to rape her and kill her. She did not dare leave the house, and she refused to take any food or water; she claimed it had an odd taste because it had been poisoned by the neighbor. She also tried to prevent her mother from eating and drinking, and she threw away the food and vegetables. She became increasingly disturbed, sat staring wildly ahead of her, and hardly responded when her mother talked to her. When a sister and a brother-in-law came to persuade her to see a physician, she recognized them only with difficulty and ran to her room and locked herself up. On the night of her admission to the hospital, she suddenly left the house and attacked a passing neighbor with a large stone, knocking him to the ground. As the man lay there, Miss Maruyami hit him again and would have continued to do so if other neighbors had not restrained her. History Miss Maruyami grew up in a middle-class neighborhood in Jakarta. She was the youngest of six daughters. At school she was a good student but had only a few friends and usually kept to herself. She did not continue her education after her junior high school year because her parents had financial problems. Since then she had stayed at home and helped her mother look after the house. Her father, a merchant, died 10 years earlier when he was 60. Her mother is age 65 and is alive and well. Miss Maruyami's sisters are all married, but she is single and lives with her mother in a small house. Her relationship with her parents and sisters was good, although she was not particularly close to them. She was always a quiet person, spending much of her time lost in her thoughts, apparently daydreaming. She seemed shy and self-conscious, especially in public. She was noticeably overweight and often expressed fears that people were staring at her because of her obesity. These fears and suspicions became more marked as she grew older. Physically she was in good health, had never been to the hospital, and received no medication. Findings On her admission Miss Maruyami was in a state of psychomotor excitement with aggressive and violent outbursts. When left alone she became more quiet and sat staring ahead of her, with sudden startling reactions to minor noises. She did not know the time or the place, but was fairly oriented as to her personal data. Her speech was restricted and somewhat incoherent. She refused to have physical or laboratory examinations, but accepted an injection of 10 mg of haloperidol and 5 mg of biperiden (Akineton). After this she became quiet and relaxed and finally fell asleep. The following day she seemed considerably improved. She was fully oriented but slightly perplexed, with partial amnesia about the previous few days. She only partly remembered her persecutory delusions. Confronted with the incident at the marketplace, she had a prolonged crying spell; became mildly excited, with fluctuations in attention and awareness of her surroundings; and finally again became herself. She did not remember having hallucinations or other unusual experiences. She no longer believed that the neighbors wanted to kill her, and she wanted to get back home to her mother. She was discharged after 3 days, during which she continued to be quite natural without further medication. Physical and neurological examinations, an electroencephalogram, and laboratory tests were all normal. The neighbor, who had suffered a minor concussion of the head as a result of the attack, was not severely wounded. Being married to a distant relative of Miss Maruyami's mother, he did not want to bring the incident to the attention of the legal authorities. Discussion Miss Maruyami developed a peracute psychotic disorder with persecutory delusions and possibly also with hallucinations, severe psychomotor excitation with violent behavior, and transient states of confusion. The disorder developed immediately after an event that she experienced as severely traumatic. She recovered with complete remission occurring within 1 week. It is a matter for discussion whether her transient states of confusion actually fulfill the criteria for organically caused clouding of consciousness. Otherwise, no signs of organic disorder were observed. Psychoactive substance abuse was not suspected. Miss Maruyami therefore most probably had an acute and transient psychotic disorder but did not fulfill the symptomatic criteria for an affective episode. The symptomatology was mixed and atypical, not pointing to any specific subtypes of acute psychotic disorders. The most likely diagnosis, therefore, is probably other acute and transient psychotic disorder. It may further be discussed whether the traumatic event described would be considered as severely stressful to most people in similar circumstances within the same culture. In Miss Maruyami's case, she seems to have been made particularly susceptible by the presence of pronounced personality traits of introversive seclusion and hypersensitive self-consciousness, which with the present information is not sufficient for a subsidiary diagnosis of a personality disorder. The diagnosis therefore would be other acute and transient psychotic disorder, with associated acute stress. Acute and Transient Psychotic Disorder, Unspecified The residual category accommodates such concepts as brief reactive psychosis not otherwise specified. ICD-10 also includes another residual category for psychoses that do not meet the criteria for any other ICD-10 psychotic disorder ( Table 13.3-2).

Table 13.3-2 ICD-10 Diagnostic Criteria for Other Nonorganic Psychotic Disorders

DSM-IV Psychotic Disorder Due to a General Medical Condition The DSM-IV diagnosis of psychotic disorder due to a general medical condition ( Table 13.3-3) combines into one diagnosis the two similar diagnostic categories in the revised third edition of DSM (DSM-III-R), organic delusional disorder and organic hallucinosis. The phenomena of the psychotic disorder are defined in DSM-IV by further specifying the predominant symptoms. When the diagnosis is used, both the medical condition and the predominant symptom pattern should be included in the diagnosis (e.g., psychotic disorder due to a brain tumor, with delusions). The DSM-IV criteria further specify that the disorder does not occur exclusively while the patient is delirious or demented and that the symptoms are not better accounted for by another mental disorder.

Table 13.3-3 DSM-IV Diagnostic Criteria for Psychotic Disorder Due to a General Medical Condition

Substance-Induced Psychotic Disorder DSM-IV has combined the various DSM-III-R diagnostic categories that relate to psychoactive substance–induced psychotic disorders into a single diagnostic category, substance-induced psychotic disorder ( Table 13.3-4). The diagnosis is reserved for persons who have substance-induced psychotic symptoms in the absence of reality testing. Persons who have substance-induced psychotic symptoms (e.g., hallucinations) but who have retained reality testing should be classified as having a substance-related disorder (e.g., phencyclidine intoxication with perceptual disturbances). The intent of including the diagnosis of substance-induced psychotic disorder with the other psychotic disorder diagnoses is to prompt the clinician to consider the possibility that a substance is causally involved in the production of the psychotic symptoms. The full diagnosis of substance-induced psychotic disorder should include the type of substance involved, the stage of substance use when the disorder began (e.g., during intoxication or withdrawal), and the clinical phenomena (e.g., hallucinations or delusions).

Table 13.3-4 DSM-IV Diagnostic Criteria for Substance-Induced Psychotic Disorder

Psychotic Disorder Not Otherwise Specified The psychotic disorder not otherwise specified category is used for patients who have psychotic symptoms (e.g., delusions, hallucinations, and disorganized speech and behavior) but who do not meet the diagnostic criteria for other specifically defined psychotic disorders. In some cases the diagnosis of psychotic disorder not otherwise specified may be used when not enough information is available to make a specific diagnosis. DSM-IV has listed some examples of the diagnosis to help guide clinicians ( Table 13.3-5).

Table 13.3-5 DSM-IV Psychotic Disorder Not Otherwise Specified

Culture-Bound Syndromes Perhaps the most dramatic example of the difficulties in applying Western-based nosological concepts and criteria cross-culturally can be found in the ongoing controversy surrounding the culture-bound syndromes. As pointed out by the United States National Institute of Mental Health Culture and Diagnosis Group, the term “culture-bound syndrome” denotes recurrent, locality specific patterns of aberrant behavior and troubling experiences that appear to fall outside conventional Western psychiatric categories. These include categories in folk nosological systems (often organized in relation to perceived cause and symptom clusters) as well as idioms of distress or culturally salient expressions for securing social support and communicating symptoms. A variety of disorders discussed in the cross-cultural psychiatric and anthropological literature do not conform with conventional DSM-IV or ICD-10 diagnostic categories. In previous diagnostic classifications such disorders were often called atypical psychoses or were placed in the category psychotic disorder not otherwise specified. Taken as a whole, however, labeling these seemingly bizarre and culturally different patterns of disorder psychotic is somewhat problematic. The symptoms displayed include many clinical expressions of lesser severity than those of typical psychotic disorders. Frequently the diagnosis of a psychotic disorder is made simply on the basis of category label rather than a close examination of the symptomatic data. Further discussion of these disorders are discussed with a selection of such syndromes in Table 13.3-6.

Table 13.3-6 Culture-Bound Syndromes

While all psychiatric diagnoses are influenced by their cultural context, perhaps the most dramatic example of the difficulty in applying Western-based nosological concepts and criteria cross-culturally can be found with respect to the so-called culture-bound syndromes. The controversy arises over the issue of whether the assumptions embedded in Western diagnostic schemes (e.g., DSM or ICD) relating to concepts of normality and the assemblages of symptoms characteristic of a discrete disorder are universally applicable in all cultural settings. The term “culture-bound syndrome” evolved, in fact, to denote recurrent, locality-specific patterns of aberrant behavior and troubling experiences that appear to fall outside conventional Western psychiatric categories. The descriptive phrases formerly used to refer to such phenomena include “cultural and ethnic psychoses and neuroses” and “atypical and exotic psychotic syndromes.” The culture-bound syndrome is now generally accepted to refer to culturally based and named patterns of symptoms of mental distress or maladaptive behavior that are prominent in folk belief and practice. Such patterns have etiologies framed by lay cultural assumptions, which in numerous cases are based upon the effects of sorcery, breach of taboo, intrusion of a disease object, intrusion of a disease-causing spirit, or loss of soul. The psychodynamics often represent an exaggerated or pathological reaction to conflicts engendered by central values and behavioral norms in the society. Since they are embedded in the group's ethnomedical practice, institutionalized patterns of diagnoses and societal response typically include treatment by indigenous healers. Assessment of such syndromes must start with recognition that each human society has an indigenous body of beliefs and practices directed at explaining and treating disease and disorder, and patients internalize that worldview during the process of enculturation. They share their experiences and deal with distress through the currency of commonly understood symbols and meanings. In that light, the diagnostic encounter itself can be used as a point of entry into the patient's world, a “classroom for investigation and discovery.” One cannot become an anthropological expert about each and every possible cultural group but one can try to learn by asking patients to share the cultural norms as they understand them.

PATHOLOGY AND LABORATORY EXAMINATIONS A large number of general medical problems may cause or exacerbate patients' psychotic conditions, often involving confusing and puzzling presentations. They include such conditions as infections (including human immunodeficiency virus [HIV] infection), head trauma, endocrine disorders (Cushing's and Addison's diseases and disorders of the thyroid and parathyroid glands), autoimmune diseases (systemic lupus erythematosus), vitamin deficiencies, seizure disorder, genetic diseases (Wilson's disease, acute intermittent porphyria), drug and toxin exposures, and the effects of psychoactive drugs. Those conditions are usually included in the differential diagnosis of any psychotic disorder, but they should be given more careful consideration when the patient's symptom profile is polymorphic or inchoate. For such patients laboratory tests should include not only the routine chemistry panels (electrolytes, glucose determination, complete blood counts, renal and liver functions) and urinalysis, but also thyroid function test, syphilis tests, and determination of serum cortisol concentration, vitamin B 12 and foliate concentrations, and calcium and phosphate concentrations. In addition to a chest X-ray and an electrocardiogram (ECG), an electroencephalogram (EEG) should also be considered. An EEG with sleep deprivation and nasopharyngeal leads also has been recommended. Computerized EEG (brain mapping), magnetic resonance imaging (MRI), single photon emission computered tomography (SPECT), and neuropsychological testing may yield useful information. Psychosocial assessment should include a careful review of the patient's life history, with special attention to the patient's personality traits and recent stresses. A detailed assessment of family history and dynamics should also be included. Contextual factors, such as psychosocial stressors and supports, should be carefully appraised, along with the ability of the person to perform basic roles (e.g., occupationally, with family and socially).

COURSE AND PROGNOSIS Patients with an acute and transient psychotic disorder usually experience complete recovery within 1 to 3 months (depending on the specific disorder), often within a few weeks or days, and only a small proportion of patients develop persistently disabling states. Limited data on the longitudinal course of patients with culture-bound syndromes suggest that some of them eventually develop clinical features compatible with a diagnosis of schizophrenia, bipolar disorder, cognitive disorder, or other psychotic disorders. Thus gathering information from all possible sources is crucial. Since clinical pictures evolve over time, thorough reevaluations should be conducted periodically to refine the diagnosis and improve clinical care.

TREATMENT The treatment plan for any patient must be individualized, but that principle is particularly important when dealing with cases of acute and transient psychotic disorders and culture-bound psychotic disorders. Because these conditions are intricate and heterogeneous, no standard treatment strategy exists that can be applied to most cases. However, a number of general principles are crucial for the cases of those patients. Careful evaluation, clinical observation, and comprehensive information gathering are the cornerstones of treatment planning for any psychiatric or general medical disorder. Longitudinal assessments are particularly important in the management of patients who are experiencing acute and transient psychotic disorders and culture-bound disorders. A multiaxial assessment using such schemas as those in ICD-10 and DSM-IV can substantially enhance the validity of diagnosis and the effectiveness of clinical care. A systematic evaluation of the cultural framework of the individual's identity, illness explanations, social context and functioning, and the doctor-patient relationship can be conducted along the lines of DSM-IV. Because all the disorders discussed in this section share the presence of psychosis, pharmacotherapy frequently involves the use of antipsychotic drugs. Some evidence indicates that the dosage of antipsychotic drugs necessary for acute transient psychotic disorders is significantly lower than that required for other psychotic conditions, especially schizophrenia. It is thus prudent to use the lowest dose that can control the patient's symptoms. Since acute and transient psychotic disorders are often episodic, intermittent use of antipsychotic drugs, guided by the emergence of psychotic symptoms, is worth considering. Depending on the clinical features of particular patients, many other psychiatric medicines have also been recommended. They include benzodiazepines for controlling agitation, lithium (Eskalith, Lithobid) for modulating mood swings, and antidepressants for ameliorating depressive symptoms. These medicines are often used in conjunction with antipsychotic agents. Anticonvulsants such as carbamazepine (Tegretol) have been reported effective in treating a number of psychotic patients with atypical features. Limited research has been conducted to date on the efficacy of various psychosocial interventions for managing acute and transient psychotic disorders and culture-bound disorder, but it seems reasonable to consider findings from studies involving other psychotic conditions. These include approaches based on expressed emotion concepts, psychoeducational and skill-competence training, and Thomas McGlashan's phase-specific theory on the need for stimulation in schizophrenic patients (the avoidance of excessive stimuli in the acute phase and the uses of structured activities and stimuli in later phases). It is important to consider involving the family in therapy and to establish a supportive and trusting therapeutic relationship. The importance of cultural issues in the evaluation and treatment of atypical psychoses can hardly be exaggerated, especially when dealing with patients from non-Western and ethnic minority populations. Cultural information is not only crucial for accurate diagnosis, but also indispensable in the formulation of treatment plans. Treatment approaches that do not take the patient's sociocultural background into account are likely to fail, no matter how well intentioned the therapists may be. For example, in cultures in which family and group harmony and unity are valued over individual independence, the rigid application of Western-based psychotherapeutic techniques may exacerbate, rather than ameliorate, the patient's psychopathological condition. Consideration of the intercultural elements in the clinician-patient relationship is also fundamental for establishment of rapport and effective engagement of the patient and the family in the treatment process. One promising avenue is collaboration with indigenous healers. Several researchers have reported on their success in the use of indigenous and traditional healers in the treatment of psychiatric patients, especially those whose psychotic conditions are substantially connected to culture-specific beliefs (e.g., fear of voodoo death). Others have mentioned the potential pitfalls and problems in such collaboration. Decisions about involving indigenous healers should be individualized and thoughtfully planned, taking into consideration the setting, the thoughtfulness and flexibility of the available healers, the type of psychopathology, and the patient's characteristics. The World Health Organization (WHO) has long advocated implementation at the local level of a policy of close collaboration between the

conventional health system and traditional medicine, particularly between individual health professionals and traditional practitioners. Wohl has stressed the implications for therapeutic practice of the need to understand the cultural dynamics of a patient's background. While this is important for therapy with any patient, it is particularly necessary in the treatment of a suspected culture-bound syndrome: Much of the time in the practice of psychotherapy, culture remains silent, part of a non instrusive background, an invisible yet pervasive feature of the context of psychotherapy ... Psychotherapies differ as the cultures in which they were born and nurtured differ, and each bears the indelible imprint of its culture source. Psychotherapy and the human relationships that comprise both its subject matter and the medium in which it is performed have embedded within them values, rules, assumptions, myths, and rituals of a particular culture. Psychotherapy is thus inescapably bound to a particular cultural framework. Treatment of a culture-bound syndrome poses several diagnostic challenges, the first of which is determining whether the symptomatology represents a culturally appropriate adaptive response to a situation (although it may be different from the therapist's). What are clinicians to do if confronted with a series of symptoms in a patient that do not fit their conventional diagnostic model? Clinicians are well advised to (1) know or search out the demographics of the local population or catchment area being served; (2) recognize that there is always a local pattern of conceptualization, naming, vocabulary, explanation, and treatment of patterns of distress that afflict a community, including mental disorders; and (3) talk with the family, get instructed in local customs; or search out other modes of documentation. But while the observed symptom may be familiar in a general sense to the clinician (although pathoplastically different), what separates such an event from conventional understanding is the meaning of the symptom for patients and those who share their cultural background. Determining that meaning and particularly their belief about what has caused the distress, is an important entry point in facilitating therapeutic management and enhancing adherence to the treatment plan. As part of taking the history, ask these patients what they think could have caused the problem, requesting the “patient's explanatory model”: (1) What do you think has caused your problem? (2) Why do you think it started when it did? (3) What do you think your sickness does to you? How does it work? (4) How severe is your sickness? Will it have a short or long course? (5) What kind of treatment do you think you should receive? Such insight into the dynamics of the patient's world facilitates the clinician's efforts to adapt his or her techniques (e.g., general activity level, mode of verbal intervention, content of remarks, tone of voice) to the cultural background of clients; communicate acceptance of and respect for the patients in terms that make sense within their cultural frame of reference; and be open to the possibility of more-direct intervention in the life of the patient than conventional approaches might suggest. In conclusion, the treatment of patients experiencing acute transient psychotic disorders and culture-bound syndromes, even more than that of patients with other psychiatric disorders, should be personalized and comprehensive, using judiciously all biological, psychological, and social therapies pertinent to the problem at hand and keeping in mind the cultural framework of the patients and their families.

SUGGESTED CROSS-REFERENCES Culture-bound syndromes are discussed further in Section 4.1 on anthropology and psychiatry. Cultural psychiatry is also discussed in Section 4.4. The influences of culture on the nature of and responses to psychiatric disorders are discussed in Section 4.2 on sociology and psychiatry. Section 4.3, on evolutionary biology and psychiatry, is also relevant. Section 9.2 covers international perspectives on psychiatric diagnosis. Section 13.1 is devoted to other psychotic disorders, including brief psychotic disorder. SECTION REFERENCES Akerele O: The best of both worlds: Bringing traditional medicine up to date. Soc Sci Med 24:177, 1987. Bustamante JA: Psiquiatria Ciencia y Técnica. Instituto Cubano del Libro, La Habana, 1972. *Collins PY, Wig NN, Day R, Varma VK, Malhotra S, Misra AK, Schanzer B, Susser E: Psychosocial and biological aspects of acute brief psychoses in three developing country sites. Psychiatr Q 67:177, 1996. Cooper JE, Jablensky A, Sartorius N: WHO Collaborative studies on acute psychoses using the SCAAPS schedule. In Psychiatry: A World Perspective. CN Stefanis, AD Rabavilas, CR Soldatos, editors. Elsevier, Amsterdam, 1990. Draguns JG: Dilemmas and choices in cross-cultural counseling: The universal versus the culturally distinctive. In Counseling Across Cultures, ed 3, PB Pedersen, JG Draguns, WJ Lonner, JE Trimble, editors. University of Hawaii Press, Honolulu, 1989. Fabrega H: An ethnomedical perspective on Anglo-American psychiatry. Am J Psychiatry 146:588, 1989. Farmer AE, Falkowski WF: Maggot in the set, the snake factor, and the treatment of atypical psychosis in West African women. Br J Psychiatry 146:446, 1985. Fisher W, Piazza CC, Page TJ: Assessing independent and interactive effects of behavioral and pharmacological interventions for a client with dual diagnoses. J Behav Ther Exp Psychiatry 1989.

20:241,

Hughes CC: Culture in clinical psychiatry. In Culture, Ethnicity, and Mental Illness, A Gaw, editor. American Psychiatric Press, Washington, DC, 1993. Hughes CC: The culture-bound syndromes and psychiatric diagnosis. In Culture and Psychiatry Diagnosis, JE Mezzich, A Kiemman, H Fabrega, DL Parron, editors. American Psychiatric Press, Washington, DC, 1996. Indian Council of Medical Research: Collaborative Study on the Phenomenology and Natural History of Acute Psychosis. Indian Council of Medical Research, New Delhi, 1989. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A: Schizophrenia: Manifestations, Incidence and Course in Different Cultures; A World Health Organization Ten-Country Study. Psychol Med 20(Suppl):1, 1992. Johnson FA: African perspectives on mental disorder. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, Berlin, 1994. Jorge MR, Mezzich JE: Latin American contribution to psychiatric nosology and classification. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, Berlin, 1994. Karno M, Jenkins JH: Cultural considerations in the diagnosis of schizophrenia and related disorders and psychotic disorder not otherwise classified. In DSM-IV Source Book, TA Widiger, A Frances, HA Pincus, MB First, R Ross, W Davis, editors. American Psychiatric Press, Washington, 1994. Kirmayer LJ: The place of culture in psychiatric nosology: Taijin Kyofusho and DSM-III-R. J Nerv Ment Dis 179:19, 1991. Kleinman A: Rethinking Psychiatry. Free Press, New York, 1988. Lee S: Culture in psychiatric nosology: The OCMD-Z-R and the International Classification of Mental Disorders. Cult Med Psychiatry 20:421, 1996. Leonhard K: Aufteilung der Endogenen Psychosen. Akademic Verlag, Berlin, 1957. Lin K-M: Cultural influences on the diagnosis of psychotic and organic disorders. In Culture and Psychiatric Diagnosis, JE Mezzich, A Kleinman, H Fabrega, DL Parron, editors. American Psychiatric Press, Washington, DC, 1996. Lin K-M, Kleinman AM: Psychopathology and clinical course of schizophrenia: A cross-cultural perspective. Schizophr Bull 14:555, 1988. Manschreck TC, Petri M: The atypical psychoses. Cult Med Psychiatry 2:233, 1978. Mezzich JE, Jorge MR: Psychiatric nosology: Achievements and challenges. In International Review of Psychiatry, JA Costa e Silva, CC Nadelson, editors. American Psychiatric Press, Washington, DC, 1993. *Mezzich JE, Kleinman A, Fabrega H, Parron DL: Culture and Psychiatric Diagnosis. American Psychiatric Press, Washington, DC, 1996. Mezzich JE, Kleinman A, Fabrega H, Parron DL, Good BJ, Lin K-M, Manson S, editors: Cultural issues section. In DSM-IV Source Book, TA Widiger, A Frances, HA Pincus, MG First, R Ross, W

Davis, editors. American Psychiatric Press, Washington, DC, 1997. Otero AA: Tercer Glorario Cubano de Psiquiatría (GC-3). Havana Psychiatric Hospital, Ministry of Public Health, Havana, Cuba, 1998. Perris C: A Study of Cycloid Psychoses. Munksgaard, Copenhagen, 1974. Pull CB, Chaillet G: The nosological views of French-speaking psychiatry. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, Berlin, 1994. Sartorius N, DeGirolano G, Andrews G, German GA, Eisenberg L: Treatment of Mental Disorder: A Review of Effectiveness. World Health Organization and American Psychiatric Press, Washington, DC, 1993. Seguín CA: Psiquiatría Folklórica. Ediciones Errmar, Lima, Peru, 1979. Shen YC: On the second edition of the Chinese Classification of Mental Disorder. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, Berlin, 1994. Simons RC: Boo! Culture, Experience and the Startle Reflex. New York: Oxford University Press, 1996. *Simons RC, Hughes CC: The Culture-Bound Syndromes: Folk Illnesses of Psychiatric and Anthropological Interest. D Reidel, Dordrecht, Holland, 1985. Strömgren E: Scandinavian contributions to psychiatric nosology. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, Berlin, 1994. *Susser E, Wanderling E: Epidemiology of non-affective acute remitting psychosis vs schizophrenia. Arch Gen Psychiatry 51:294, 1994. Takahashi S: Diagnostic classification of psychotic disorders in Japan. In Psychiatric Diagnosis: A World Perspective, JE Mezzich, Y Honda, MC Kastrup, editors. Springer-Verlag, Berlin, 1994. Tanaka-Matsumi J: Taijinkyofusho: Diagnostic and cultural issues in Japanese psychiatry. Cult Med Psychiatry 23:1, 1979. Wig NN, Parhee R: Acute and transient psychoses: A view from the developing countries. In International Classification in Psychiatry: Unity and Diversity, JE Mezzich, M von Cranach, editors. Cambridge University Press, Cambridge, 1988. World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders. Clinical Descriptions and Diagnostic Guidelines. World Health Organization, Geneva, 1992. Yamashita I: Periodic Psychosis of Adolescence. Hokkaido University Press, Hokkaido, Japan, 1993.

Textbook of Psychiatry

13.4 POSTPARTUM PSYCHIATRIC SYNDROMES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 13. OTHER PSYCHOTIC DISORDERS

13.4 POSTPARTUM PSYCHIATRIC SYNDROMES RUTA NONACS, M.D., PH.D. AND LEE S. COHEN, M.D. History Definition Etiology Diagnosis and Clinical Features Differential Diagnosis Course and Prognosis Treatment Suggested Cross-References

During the postpartum period up to 85 percent of women experience some type of mood disturbance ( Table 13.4-1). For most women the symptoms are transient and relatively mild; however, some women experience a more disabling and persistent form of mood disturbance. Although postpartum mood disorders are relatively common, depressive symptoms that emerge during the postpartum period are frequently overlooked by patients and their caregivers. Puerperal affective illness places both the mother and infant at risk and has been associated with significant long-term effects on child development and behavior. Therefore, prompt recognition and treatment of puerperal mood disorders are essential.

Table 13.4-1 Classification of Postpartum Mood Disorders

HISTORY Although Hippocrates is often acknowledged as the first to have recognized postpartum mental illness, historians have noted that what Hippocrates described as a mania related to lactation was more likely delirium associated with puerperal sepsis, which was relatively common in ancient Greece. There was virtually no mention of puerperal mental illness until the 1700s and 1800s, when case reports of “puerperal insanity” began to appear in the French and German medical literature. In 1818 Jean Esquirol was the first to provide detailed, quantitative data on 92 cases of puerperal psychosis drawn from his studies at the Salpetriere during the Napoleonic Wars. However, it is Victor Louis Marce, a French physician, who is best known for his descriptions of postpartum psychiatric illness. In his famous text published in 1856, Traite de la Folie des Femmes Enceintes, he laid the foundation for modern conceptualizations of mental illness related to pregnancy and the postpartum period. He was also the first to suggest that physiological changes associated with the puerperium influence maternal mood. Although puerperal psychosis was familiar to most clinicians by the late nineteenth century, less attention was given to milder forms of puerperal illness. It was not until the 1960s that B. Pitt first described an “atypical” depression (later called “maternity blues”) that affected mothers soon after childbirth and, in contrast to puerperal psychosis, was relatively mild and short-lived. The concept of a more severe form of nonpsychotic depressive illness (i.e., postpartum depression) emerged during the 1970s. Large, population-based studies, which relied upon structured interviews and standardized diagnostic criteria to identify psychiatric illness in new mothers, demonstrated high rates of mild to moderate depression in women during the first 6 months after delivery. Recent studies have consistently identified the postpartum period as a time of increased risk for the development of psychiatric illness in women. One of the most frequently cited studies on affective illness during the puerperium described a sharp peak in the number of psychiatric admissions during the first 3 months after delivery. Subsequent studies indicate that women who present with significant psychiatric symptoms during the postpartum period suffer most commonly from a mood disorder, either major depressive disorder or a bipolar disorder. During the postpartum period women appear to be at much higher risk for the development of psychiatric illness than at other times in their lives. Various investigators have argued that postpartum mental illness consists of a group of psychiatric disorders that are specifically related to pregnancy and childbirth and therefore exists as a distinct diagnostic entity. However, recent evidence suggests that affective illness that emerges during the puerperium does not differ significantly from affective illness occurring in women at other times. This opinion is reflected in the fourth edition of Diagnostic and Statistic Manual of Mental Disorders (DSM-IV), which includes postpartum psychiatric illness as a subtype of either bipolar disorder or major depressive disorder.

DEFINITION Postpartum psychiatric illness is typically divided into three categories: (1) postpartum blues, (2) nonpsychotic postpartum depression, and (3) puerperal psychosis (Table 13.4-1). It is helpful to conceptualize these disorders as existing along a continuum, as there may be significant overlap between these three diagnostic subtypes. Although these subtypes vary in severity, it is not clear if they actually represent three distinct disorders.

ETIOLOGY The puerperium is a period during which significant physiological and psychosocial changes occur. The extent to which a rapidly changing hormonal environment influences the emergence of mood illness has been considered by many. In fact, it was Victor Louis Marce who first suggested, long before the emergence of the modern field of endocrinology, that a physiological transition occurring after delivery may play an important role in the pathogenesis of puerperal illness. Other investigators have emphasized the importance of biological vulnerability to psychiatric illness during the puerperium and have suggested that some individuals may be more susceptible to the physiological changes characteristics of the postpartum period. However, the impact of psychosocial factors in the development of mood disorder during the postpartum period cannot be underestimated. Given the multiplicity of these factors and the complexity of their interactions, it has been extremely difficult to identify risk factors for puerperal psychiatric illness and to reliably predict who will experience postpartum mood disturbance. Demographic Variables Many groups have investigated the relationship between risk for postpartum blues and depression and various demographic variables including age, marital status, parity, education level, and socioeconomic status; however, there is little consistent evidence to suggest that any particular demographic factor places a woman at increased risk for puerperal affective illness. Although most studies do not find a strong relationship between age and risk for puerperal illness, there is at least one report of high rates (26 percent) of postpartum depression in adolescent mothers. It has been significantly more difficult to identify risk factors for puerperal psychosis, given the low prevalence of this subtype of postpartum illness. Some reports suggest that primiparous women are more vulnerable to postpartum psychosis than multiparous women. Other studies suggest that various obstetrical complications

(e.g., prolonged labor, caesarean section, stillbirth) may increase the likelihood of postpartum psychosis. Psychosocial Factors Psychosocial variables appear to play an important role in determining vulnerability to affective illness during the postpartum period. Many studies have sought to link certain personality traits and coping styles with risk for postpartum illness but have yielded inconsistent findings. In contrast, several groups have demonstrated that stressful life events during pregnancy or near the time of delivery appear to increase the likelihood of postpartum depressive illness. One of the most consistent findings is that among women who report marital dissatisfaction or inadequate social supports, postpartum depressive illness is more common. History of Psychiatric Illness Although it has been difficult to identify specific demographic and psychosocial variables that consistently predict risk for postpartum illness, there is a well-defined association between all types of postpartum psychiatric illness and a personal history of mood disorder ( Table 13.4-2). At highest risk are women with a history of postpartum psychosis; up to 70 percent of women who have had one episode of puerperal psychosis will experience another episode following a subsequent pregnancy. Similarly, women with histories of postpartum depression are at significant risk, with rates of postpartum recurrence as high as 50 percent. Women with bipolar disorders also appear to be particularly vulnerable during the postpartum period, with rates of postpartum relapse ranging from 20 to 50 percent.

Table 13.4-2 History of Psychiatric Illness and Risk for Puerperal Relapse

The extent to which a history of major depressive disorder influences risk for postpartum illness is less clear. As compared to women who have experienced only nonpuerperal depressive episodes, women with histories of postpartum depression are clearly at greater risk. Women with histories of mild to moderate affective illness who remain euthymic during pregnancy are probably at lower risk for postpartum depression than women with severe, recurrent depression. For all women (with or without histories of major depression), the emergence of depressive symptoms during pregnancy increases the likelihood of postpartum depression. Hormonal Factors The postpartum period is characterized by a rapid shift in the hormonal environment. Within the first 48 hours after delivery, estrogen and progesterone concentrations fall dramatically; similarly, cortisol concentrations drop after delivery. As these steroid hormones have been implicated in the pathogenesis of nonpuerperal mood disorders, many investigators have proposed a role for these hormones in the emergence of a mood disorder during the postpartum period. Progesterone Several anecdotal reports have suggested that mood disturbance during the puerperium may be related to declining concentrations of progesterone and have suggested a beneficial effect of progesterone hormone replacement in the treatment of postpartum psychiatric illness. However, several studies have found no consistent differences in postpartum progesterone concentrations between depressed and nondepressed women. Estrogen Several studies have explored the relationship between postpartum estrogen levels and risk for postpartum blues and depression and have suggested that postpartum estrogen deficiency may result in postpartum mood disturbance. Although some studies have observed lower estrogen levels in women who developed postpartum blues and depression, most of the studies have yielded negative findings. Cortisol Concentrations of cortisol, which are high late in pregnancy, peak during labor and delivery. Cortisol concentrations drop rapidly after delivery and then return to baseline levels gradually over the next month. While disturbances in the hypothalamic-pituitary-adrenal axis may play an important role in at least some cases of nonpuerperal major depression, recent studies do not consistently support a relationship between cortisol levels and postpartum blues or depression. The dexamethasone (Dexacidin) suppression test does not appear to distinguish between depressed and nondepressed women during the acute puerperium. Thyroid Hormones Thyroxine concentrations are high during pregnancy and fall during the postpartum period. Abnormalities in thyroid function tests are relatively common findings during the postpartum period, and clinical hypothyroidism is present in up to 10 percent of women after childbirth. Although thyroid dysfunction, particularly hypothyroidism, may produce psychiatric symptoms, no studies have consistently reported an association between postpartum depression or blues and thyroid dysfunction (either hypothyroidism or hyperthyroidism).

DIAGNOSIS AND CLINICAL FEATURES Postpartum psychiatric disorders have not been listed separately in recent revisions of the DSM, and no specific criteria for the diagnosis of postpartum psychiatric illness have been provided. According to DSM-IV, postpartum psychiatric illnesses may be indicated with a postpartum onset specifier. The specifier with postpartum onset may be used to describe a major depressive, manic, or mixed episode (in major depressive disorder or bipolar I or II disorder) or brief psychotic disorder, when the episode occurs within the first 4 weeks after delivery ( Table 13.4-3). In contrast, the Marce Society, an international scientific organization dedicated to the study of postpartum psychiatric disorders, defines postpartum psychiatric illness as any episode occurring within the first year after childbirth.

Table 13.4-3 DSM-IV Criteria for Postpartum Onset Specifier

Given the prevalence of mood disturbance during the puerperium, it is most striking that diagnoses of postpartum mood disorders are so commonly missed. The emergence of mood disorder during the puerperium is often overlooked or ignored by both patients and their caregivers. Some studies report that less than one-third of women with postpartum illness seek professional help. It is common for women to report the persistence of depressive symptoms for many months before the initiation of treatment. Although the symptoms of depression may remit spontaneously, many women are still depressed at 1 year after childbirth. The reasons for this delay in treatment are not well understood. What is clear, however, is the significant impact of untreated depression on both mother and infant. Untreated depression may contribute to the development of a more chronic and refractory mood disorder in the mother. There are also significant data that demonstrate the adverse effects

of maternal depression on the cognitive, emotional, and social development of the child. Given these significant risks, prompt recognition and treatment of postpartum mood disorders are essential. Postpartum Blues Many women experience mild depressive symptoms during the first week after delivery, which are commonly known as postpartum blues or “baby blues.” Depending on the criteria used to diagnose the blues, prevalence estimates range from 30 to 85 percent. Women with postpartum blues report a variety of symptoms, including dysphoria, mood lability, irritability, tearfulness, anxiety, and insomnia. These symptoms typically peak on the fourth or fifth day after delivery and remit spontaneously by the tenth postpartum day. Postpartum blues are relatively benign and are, by definition, time-limited. While the occurrence of postpartum blues does not necessarily reflect psychopathology in the mother, some women with blues will go on to develop postpartum depression. Women with histories of mood disorder require close monitoring, as some data suggest that blues may herald the development of major depressive disorder in women who have had previous episodes of affective illness. Symptoms of the blues that persist beyond the second postpartum week require further evaluation to rule out the evolution of a more serious affective illness. Postpartum Depression Major depressive disorder is relatively common during the postpartum period. Both retrospective and prospective community-based studies have revealed rates of postpartum minor and major depression in the range of 10 to 15 percent. These rates of depression reported in puerperal cohorts are similar to those observed in nonpuerperal populations of women. While some women report the acute onset of symptoms shortly after delivery, depression more commonly develops insidiously over the first 6 postpartum months. A significant proportion of women actually experience the onset of depressive symptoms during pregnancy. The signs and symptoms of postpartum depression are generally indistinguishable from those characteristic of nonpsychotic major depressive disorder that occurs in women at other times. Dysphoric mood, irritability, anhedonia, insomnia, and fatigue are frequently reported; somatic complaints are also common. Ambivalent or negative feelings toward the infant are often reported, and it is common for a woman with postpartum depression to express doubts or concerns about her ability to care for her child. In its most severe form, postpartum depression may result in profound dysfunction. Suicidal ideation is frequently reported; however, suicide rates appear to be relatively low in women who become depressed during the postpartum period. Although few studies have evaluated the prevalence of comorbid psychiatric illness in this population, severe anxiety and obsessionality are prominent in women with puerperal illness. Symptoms of generalized anxiety, panic disorder, and obsessive-compulsive disorder are often observed in women with postpartum depression. Puerperal Psychosis Puerperal psychosis is the most severe form of postpartum psychiatric illness. In contrast to postpartum blues and depression, puerperal psychosis is a rare event that occurs in approximately 1 to 2 per 1000 women after childbirth. Its presentation is often dramatic, with onset of psychosis as early as the first 48 to 72 hours postpartum. Most women with puerperal psychosis develop symptoms within the first 2 to 4 weeks after delivery. In women with this disorder, psychotic symptoms and disorganized behavior are prominent and cause significant dysfunction. Puerperal psychosis resembles a rapidly evolving affective psychosis with manic, depressive, or mixed features. The earliest signs are typically restlessness, irritability, and insomnia. Women with this disorder typically exhibit a rapidly shifting depressed or elated mood, disorientation or depersonalization, and disorganized behavior. Delusional beliefs often center on the infant and include delusions that the child may be defective or dying, that the infant has special powers, or that the child is either Satan or God. Auditory hallucinations that instruct the mother to harm or kill herself or her infant are sometimes reported. Although most believe that this illness is indistinguishable from an affective (or manic) psychosis, some have argued that puerperal psychosis may be clinically distinct in that it is more commonly associated with confusion and delirium than nonpuerperal psychotic mood disorder. Screening Severe postpartum depression and psychosis are easily recognized; however, milder or more insidious forms of depressive illness are frequently missed. Even severe depressive symptoms that arise during the puerperium may be dismissed by both patients and caregivers as normal or natural consequences of childbirth. Since it is difficult to reliably predict which women in the general population are likely to develop puerperal illness, it is advisable to screen all women for depression during the postpartum period. The greatest obstacle to the diagnosis of postpartum depression is the extent to which clinicians fail to inquire about affective symptoms in women during the postpartum period. The standard postpartum obstetrical visit at 6 weeks and subsequent pediatric appointments are ideal times to screen for postpartum depressive illness. Screening for mood disorders during the postpartum period may, however, be more difficult than at other times. Many of the neurovegetative signs and symptoms characteristic of major depression (e.g., sleep and appetite disturbance, diminished libido, low energy) are also observed in nondepressed women during the acute puerperium. Various rating scales that have been used to facilitate the diagnosis of depression in nonpuerperal cohorts (e.g., Beck Depression Inventory) have not been validated in puerperal populations. In contrast, the Edinburgh Postnatal Depression Scale (EPDS) is a 10-item, self-rated questionnaire ( Table 13.4-4) that has been used extensively for the detection of postpartum depression and has demonstrated satisfactory sensitivity and specificity in women during the postpartum period. Although not commonly employed, the EPDS could easily be integrated into the routine evaluation of women in both obstetrical and pediatric settings and would alert the physician to those women who are in need of a more thorough psychiatric evaluation.

Table 13.4-4 Edinburgh Postnatal Depression Scale (EPDS)

DIFFERENTIAL DIAGNOSIS Various medical illnesses may mimic psychiatric illness during the postpartum period. Hypothyroidism is relatively common in women after delivery and may cause a constellation of symptoms resembling major depressive disorder. Women with a preexisting psychiatric illness may experience exacerbation of symptoms during the puerperium. Furthermore, any psychiatric illnesses may emerge for the first time during the postpartum period. Schizophrenia or schizoaffective disorder, particularly when characterized by prominent positive symptomatology, may be difficult to distinguish from puerperal psychosis. Whereas mood disorders are the most common type of postpartum psychiatric illness, anxiety symptoms are common during the postpartum period and many present either with or without a coexisting mood disorder. The postpartum period may represent a time of increased risk for the development of panic disorder and obsessive-compulsive disorder.

COURSE AND PROGNOSIS The duration of postpartum illness appears to be variable. Puerperal episodes are often relatively short-lived and last no more than 3 months. Many women, however, have a more prolonged illness, and several studies suggest that depressive episodes tend to be longer and more severe in those with histories of major depressive disorder; some reports suggest that duration may be related to the severity of illness. In general, women with postpartum mood disorders have a good prognosis. In about half of the cases, puerperal depression or psychosis represents the first onset of psychiatric illness. Although there appears to be a subpopulation of women who have only puerperal episodes of psychiatric illness, the majority of women with a postpartum mood disorder will go on to have nonpuerperal episodes of psychiatric illness. Rates of recurrence appear to be particularly high in women with bipolar disorders.

Postpartum mood disorders are associated with recurrent psychiatric illness in the mother. The failure to treat may contribute to the emergence of a long-term and more treatment refractory mood disorder. There is data to suggest that the outcome is better in those that receive treatment early during the course of illness. There is a growing body of literature that demonstrates the detrimental effect of maternal depression on child development. Attachment difficulties are common in new mothers and may be quite severe in women with postpartum depression or psychosis. Long-term follow-up studies have shown that behavioral difficulties were more common in the children of mothers who suffered from postpartum depression. These children also performed worse on structured tests of cognitive ability than children who had mothers who were not depressed. One of the most disastrous outcomes involves harm to the infant. Child abuse and neglect are more common among women who suffer from postpartum psychiatric illness. Infanticide is relatively uncommon; however, it is more likely to occur in women who present with psychotic symptoms.

TREATMENT Like nonpuerperal depressive illness, postpartum mood disorders present along a continuum. Patients may experience mild or moderate symptoms, or they may present with a more severe depression, characterized by prominent neurovegetative symptoms and marked impairment of functioning. A clinician's approach to the patient should be guided by the type and severity of the symptoms and the degree of functional impairment. However, before initiating psychiatric treatment, medical causes for mood disturbance (e.g., thyroid dysfunction, Sheehan's syndrome) must be excluded. Initial evaluation should include a thorough history, physical examination, and routine laboratory tests. Postpartum Blues As postpartum blues are usually mild in severity and resolve spontaneously, no specific treatment other than support and reassurance is indicated. Although the symptoms may be distressing, they typically do not affect the mother's ability to function and to care for her infant. Psychiatric consultation is generally not required; however, the patient should be instructed to contact her obstetrician or primary care provider if the symptoms persist longer than two weeks to ensure the early identification of a more severe affective illness. Women with histories of psychiatric illness, particularly postpartum depression, should be monitored more closely, as they are at higher risk for significant puerperal illness. Postpartum Depression Although postpartum depression is relatively common, few studies have systematically assessed the efficacy of nonpharmacological and pharmacological therapies in the treatment of this disorder. However, there are no data that suggest that postpartum depression should be managed differently than nonpuerperal major depressive disorder. There is, nonetheless, an apparent tendency to treat women with postpartum depression with less urgency than nonpuerperal patients, which places both the mother and infant at risk. In the absence of systematically derived data, depression that emerges during the postpartum period demands the same intensity of treatment as depression that occurs at other times; the earlier the treatment is initiated, the better the prognosis. Nonpharmacological Therapy Nonpharmacological therapies are frequently employed in the treatment of postpartum depression; however, there are limited data to support the efficacy of these interventions. Although studies that have assessed the use of insight-oriented psychotherapy in the treatment of postpartum depression have yielded inconsistent findings, more structured types of individual psychotherapy have shown promise. Interpersonal therapy is a time-limited and interpersonally oriented psychotherapy that has been used successfully (in nonpuerperal cohorts) to treat acute episodes of depression. This modality of therapy focuses primarily on interpersonal relationships and has been adapted for the treatment of postpartum depression. In this setting, interpersonal therapy may be used to address the following issues: role transition, disruption of relationships with the spouse and other social supports, and interaction with the infant. In a recent pilot study, interpersonal therapy was shown to be effective for the treatment of women with mild to moderate postpartum major depressive disorder. Cognitive-behavioral therapy may also be useful in this setting. A recent randomized, placebo-controlled treatment trial demonstrated that short-term cognitive behavioral therapy was as effective as treatment with fluoxetine (Prozac) in women with postpartum depression. Sessions were structured to focus on issues specific to new mothers with postpartum depression: inability to cope with the demands of caring for a child, perceived lack of support, absence of enjoyable activities. A significant reduction in depressive symptoms was observed in women after six sessions of cognitive-behavioral therapy delivered over a 12-week period. These nonpharmacological interventions may be particularly useful for those patients who are reluctant to use psychiatric medications or for patients with milder forms of depressive illness. These interventions would ideally be performed in the home by a visiting nurse or another trained individual. Further investigation is required to determine the efficacy of this modality in women who suffer from more severe forms of postpartum mood disturbance. Pharmacological Therapy To date, few studies have assessed the efficacy of antidepressant medications in the treatment of postpartum mood disturbance. The majority of these studies have been open trials, although more recent investigations have employed a double-blind design. Several studies have demonstrated the efficacy of antidepressant medications (e.g., fluoxetine, sertraline [Zoloft] venlafaxine [Effexor]) in the treatment of postpartum major depressive disorder. In all of these studies, standard antidepressant doses were effective and well tolerated. The choice of an antidepressant drug should be guided by the patient's prior response to antidepressant medication and a given medication's adverse effect profile. Fluoxetine and the other selective serotonin reuptake inhibitors (SSRIs) are ideal first-line agents because they are anxiolytic, generally nonsedating, and well tolerated. Tricyclic drugs are frequently used and, because they tend to be more sedating, may be more appropriate for women who present with sleep disturbance. Given the severity of anxiety symptoms in women with postpartum depression, the adjunctive use of a benzodiazepine (e.g., clonazepam [Klonopin], lorazepam [Ativan]) may be very helpful. Women who plan to breastfeed must be informed that all psychiatric medications, including antidepressant drugs, are secreted into the breast milk. Concentrations in the breast milk appear to vary widely; however, there is no data to suggest that one antidepressant agent is safer than another for women who are nursing. Available data on the use of tricyclic drugs, fluoxetine, and sertraline during breastfeeding suggest that severe complications related to neonatal exposure to psychotropic medications in breast milk appear to be rare; however, the long-term effects of even trace amounts of medication on the developing brain are not known. Inpatient Hospitalization In cases of severe postpartum depression, inpatient hospitalization may be required, particularly for patients who are at risk for suicide. In the United Kingdom innovative treatment programs involving joint hospitalization of the mother and baby have been successful; however, mother-infant units are much less common in the United States. In women with severe postpartum illness, electroconvulsive therapy (ECT) should be considered early because it is safe and highly effective. In choosing a treatment strategy, it is important to consider the impact of prolonged hospitalization of the mother on infant development and attachment. Hormonal Therapy The postpartum period is associated with rapid shifts in the reproductive hormonal environment, most notably a dramatic fall in estrogen and progesterone levels. With increasing evidence to suggest that gonadal steroids modulate neurotransmitter systems involved in the pathogenesis of mood illness, many have proposed a role for hormonal manipulation in the treatment of postpartum mood disturbance. Some authors have suggested that progesterone is helpful in the management of postpartum depression; however, systematically derived data do not demonstrate its usefulness in this setting. A.J. Gregoire and colleagues described a beneficial effect of exogenous estrogen therapy in women with postpartum depression. Although this study was small and was confounded by the inclusion of patients treated with antidepressant medication prior to receiving hormonal therapy, it is the first study to demonstrate that estrogen alone (or possibly when used as an adjunct to an antidepressant agent) may be useful in the treatment of postpartum depression. At this point it is unclear which patients are likely to respond to this type of hormonal therapy. In cases of moderate to severe depression, first-line pharmacological treatment should be an antidepressant medication. Puerperal Psychosis Puerperal psychosis is a psychiatric emergency that typically requires inpatient treatment; however, systematically derived guidelines for the treatment of this disorder are lacking. Given the well-established relationship between puerperal psychosis and bipolar disorders, some have argued that postpartum psychosis is indistinguishable from a manic psychosis and should be treated similarly. Short-term treatment with an antipsychotic medication as well as a mood stabilizer is appropriate. Most groups have used lithium in the treatment of postpartum psychosis; the efficacy of other mood stabilizers (i.e., valproic acid [Depakene], carbamazepine [Tegretol]) in this setting is not known. Breastfeeding is typically avoided in women treated with lithium, as it is secreted at high levels into the breast milk and may cause neonatal toxicity. ECT (often bilateral) is well tolerated and rapidly effective. Failure to treat puerperal psychosis aggressively places both the mother and infant at increased risk for harm. Rates of infanticide associated with untreated puerperal psychosis have been estimated to be as high as 4 percent; the risk for suicide in this population is also extremely high. Although some authors recommend the discontinuation of psychotropic medications soon after the psychosis clears, others suggest a longer duration of treatment, arguing that women are at risk for psychiatric illness for up to 1 year after childbirth. Prolonged exposure to conventional antipsychotic agents should be minimized,

given the risk of tardive dyskinesia. When neuroleptic medications are discontinued, they should be tapered slowly and with close observation for early signs of recurrence. Treatment with a mood stabilizer should be maintained beyond the resolution of active symptoms to reduce risk for relapse. The appropriate duration of treatment with a mood stabilizer has not been well established. Whether all patients with puerperal psychosis should subsequently receive maintenance treatment with a mood stabilizer for an indefinite period of time is controversial, although several studies suggest that recurrent mood illness (most commonly bipolar disorder) is the rule following an episode of puerperal psychosis. Prevention It is not possible to reliably predict which women in the general population will experience postpartum mood disturbance. The identification of women at greatest risk for puerperal illness improves the likelihood of early diagnosis and treatment and provides an opportunity to limit morbidity in the mother and her infant. It is possible to identify certain subgroups of women who are more vulnerable to postpartum mood disorder. Women with histories of affective illness are at particular risk for puerperal worsening of mood. Risk for puerperal relapse as a function of subtype is summarized in Table 13.4-2. As it is possible to identify certain subgroups of women who are at risk for postpartum illness, many investigators have explored the appropriateness of prophylactic intervention. Several studies have demonstrated that women with histories of bipolar disorders or puerperal psychosis benefit from prophylactic lithium therapy instituted just prior to delivery (at 36 weeks gestation) or no later than the first 48 hours postpartum. Prophylactic lithium appears to significantly reduce relapse rates, as well as to diminish the severity and duration of puerperal illness. Yet to be adequately investigated is the extent to which other populations of women may also benefit from pharmacological prophylaxis. A pilot study described a beneficial effect of prophylactic antidepressants administered to women with histories of postpartum depression. The efficacy of prophylactic antidepressants in women with recurrent, nonpuerperal depression is currently under investigation. Psychosocial interventions, such as psychoeducational and supportive groups, are frequently included in the care of women during the postpartum period. The extent to which these interventions are effective in preventing postpartum mood disturbance has not been systematically studied. Several investigators have explored the use of psychoeducational groups during pregnancy and the postpartum period and have demonstrated a significant reduction in the incidence of postpartum depression in women who received this intervention, as compared to untreated controls. Interpersonal therapy has been used successfully in nonpuerperal cohorts with major depressive disorder to prevent recurrence. Although not yet studied in puerperal populations, IPT and similar techniques may be performed prophylactically during the postpartum period and may be of some value. Those providers who routinely participate in acute and short-term postpartum care (e.g., visiting nurses) may be ideally suited to screen for and intervene in cases of postpartum distress or mood disturbance. In summary, prophylaxis against postpartum depressive illness may be conceptualized along a continuum where some women are at low risk for puerperal illness whereas others appear to be at high risk for puerperal decompensation. This spectrum of patients at risk for puerperal mood disturbance and the potential role of pharmacological and nonpharmacological prophylaxis is outlined in Table 13.4-5. While a less aggressive “wait-and-see” approach is appropriate for women with postpartum blues or women without histories of psychiatric illness, women at high risk, particularly those with histories of postpartum illness, deserve close monitoring as well as specific prophylactic measures. Further characterization of these subgroups of women and the prophylactic treatments suited to each is clearly warranted.

Table 13.4-5 Risk Factors and Treatment Options for Postpartum Mood Disturbance

SUGGESTED CROSS-REFERENCES Further information on the reproductive endocrinology of pregnancy and the postpartum period and guidelines for the use of psychotropics during pregnancy and lactation can be found in Section 28.2 on psychiatry and reproductive medicine. Mood disorders are discussed at length in Chapter 14, and brief psychotic disorder is discussed in Section 13.1. Psychopharmacology is covered in Chapter 31. SECTION REFERENCES Appleby L, Warner R, Whitton A, Faragher B: A controlled study of fluoxetine and cognitive-behavioral counselling in the treatment of postnatal depression. Br Med J 314:932, 1997. Brockington IF: Motherhood and Mental Illness. Grune & Stratton, New York, 1982. Brockington IF, Cernik KF, Schofield EM, Downing AR, Francis AF, Kelan C: Puerperal psychosis: Phenomena and diagnosis. Arch Gen Psychiatry 38:829, 1981. Cohen LS, Sichel DA, Robertson LM, Heckscher E, Rosenbaum JF: Postpartum prophylaxis for women with bipolar disorder. Am J Psychiatry 152:1641, 1995. Cooper PJ, Murray L: The course and recurrence of postnatal depression. Br J Psychiatry 166:191, 1995. *Cox JL, Holden JM, Sagovsky R: Detection of postnatal depression: Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 150:782, 1987. Cox JL, Murray D, Chapman G: A controlled study of the onset, duration and prevalence of postnatal depression. Br J Psychiatry 163:27, 1993. Cummings EM, Davies PT: Maternal depression and child development. J Child Psychol Psychiatry 35:73, 1994. Davidson J, Robertson E: A follow-up study of postpartum illness, 1946–1978. Acta Psychiatr Scand 71:451, 1985. Gregoire AJP, Kumar R, Everitt B, Henderson AF, Studd JW: Transdermal estrogen for treatment of severe postnatal depression. Lancet 347:930, 1996. *Hendrick V, Altshuler LL, Suri R: Hormonal changes in the postpartum and implications for postpartum depression. Psychosomatics 39:93, 1998. Kendell RE, Chalmers JC, Platz C: Epidemiology of puerperal psychoses. Br J Psychiatry 150:662, 1987. Kennerely H, Gath D: Maternity blues, I. Detection and measurement by questionnaire. Br J Psychiatry 155:356, 1989. Klompenhouwer JL, van Hulst AM: Classification of postpartum psychosis: A study of 250 mother- and baby-admissions in the Netherlands. Acta Psychiatr Scand 84:255, 1991. *Llewellyn A, Stowe ZN: Psychotropic medications in lactation. J Clin Psychiatry 59 (Suppl):41, 1998. *Murray L: The impact of postnatal depression on infant development. J Child Psychol Psychiatry 33:543, 1992. O'Hara MW, Schlechte JA, Lewis DA, Wright EJ: Prospective study of postpartum blues: Biologic and psychosocial factors. Arch Gen Psychiatry 48:801, 1991.

O'Hara MW: Postpartum depression: Causes and consequences. Springer-Verlag, New York, 1994. Pitt B: ‘Atypical' depression following childbirth. Br J Psychiatry 114:1325, 1968. Stewart DE, Klompenhouwer JL, Kendall RE, Van Hulst AM: Prophylatic lithium in puerperal psychosis: The experience of three centers. Br J Psychiatry 158:393, 1991. Stowe ZN, Casarella J, Landrey J, Nemeroff CB: Sertraline in the treatment of women with postpartum major depression. Depression 3:49, 1995. Stuart S, Couser G, Schilder K, O'Hara MW, Gorman L: Postpartum anxiety and depression: Onset and comorbidity in a community sample. J Nerv Ment Dis 186:420, 1998. *Stuart S, O'Hara MW: Interpersonal psychotherapy for postpartum depression: A treatment program. J Psychother Pract Res 4:18, 1995. Wisner KL, Wheeler RN: Prevention of recurrent postpartum major depression. Hosp Community Psychiatry 45:1191, 1994.

Textbook of Psychiatry

14.1 MOOD DISORDERS: INTRODUCTION AND OVERVIEW Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.1 MOOD DISORDERS: INTRODUCTION AND OVERVIEW HAGOP S. AKISKAL, M.D. The Scope of Mood Disorders Definitions Greco-Roman Descriptions of Melancholia and Mania Modern Era Contemporary Models of Depression Theoretical Synthesis Suggested Cross-References

For nearly 2500 years mood disorders have been described as the most common diseases of mankind, but only recently have they commanded major public health interest. The World Health Organization has ranked depression fourth in a list of the most urgent health problems worldwide. The U.S. Agency for Health Care Policy and Research, a federal agency concerned with medical practice from a public health perspective, devoted 2 volumes to depression among the first 10 it has published on such topics as pain, hypertension, diabetes mellitus, and coronary artery disease. A University of California psychiatrist, Kenneth Wells, demonstrated that the disability induced by depression compares with and often exceeds those of such diseases. Depressive disorders afflict at least 20 percent of women and 12 percent of men at some time during their lives. Despite the availability of effective treatments, many persons with mood disorders are disabled, and rates of suicide (which occurs in about 15 percent of depressive disorders) are high in both young and (especially) elderly men. Although depressive disorders are more common in women, more men than women die of suicide. The suboptimal outcome of mood disorders documented in recent research reports cannot be ascribed to underdiagnosis and undertreatment alone for several reasons. First, Gerald Klerman and colleagues have suggested that the incidence of mood disorders may be increasing in younger age groups, especially in cohorts born in the 1960s, and may be associated with rising rates of alcohol and substance abuse. Second, mood disorders, once believed to be essentially adult disorders, are increasingly diagnosed in children and adolescents. Third, clinical studies suggest higher rates of chronicity, recurrence, and refractoriness than previously believed. For instance, chronicity, reported by Emil Kraepelin to occur in no more than 5 percent in the early twentieth century in Germany, is now seen in 15 to 20 percent of affectively ill patients in Western countries. Nonetheless, outcome studies coming from university centers tend to overestimate the proportion of cases with less favorable prognosis, and undeniably, many patients seen in private practice experience a favorable outcome. Also, a recent report indicates that depressed patients treated by psychiatrists in private settings receive much better care than those in other settings.

THE SCOPE OF MOOD DISORDERS In Europe where the concept of mood disorders has historically embraced a broad spectrum of disorders, two British schools of thought have been influential. The Maudsley school—Aubrey Lewis and his followers—has promoted a continuum model, from anxiety disorders to mild neurotic depressions to severe endogenous and psychotic depressions. The Newcastle school, led by Martin Roth, has sharply demarcated those conditions from one another. Although vestiges of both approaches are still influential in clinical and basic research, their significance is presently overshadowed by continental European studies that subdivide mood disorders on the basis of polarity: unipolar (depressive episodes only) and bipolar (depressive episodes plus manic, hypomanic, or mixed episodes). That subdivision, supported by studies in the United States, has served as the basis for much recent research into the classification of mood disorders, as reflected in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Despite such official sanction, many authorities today continue to see considerable continuity between recurrent depressive and bipolar disorders. Emerging data also tend to favor a continuum between juvenile and adult mood disorders. This is based on the pioneering contributions by Elva Poznanski at the University of Michigan, as well as the work of Leon Cytrin and colleagues at the National Institute of Mental Health (NIMH), and Joachim Puig-Antich conducted at Columbia University in New York. Childhood bipolarity, too, is receiving increasing clinical attention, thanks to the seminal work of Elizabeth Weller and colleagues, originally conducted at Ohio State University. Finally, the work of Gabrielle Carlson and Michael Strober (when they collaborated at the University of California at Los Angeles) and clinical observations by this author on the juvenile offspring of adult bipolar disorders patients have led to a greater appreciation of the bipolar nature of complex clinical presentations of affective illness in children. Current concepts of mood disorders in the United States embrace a wide spectrum, including many conditions previously diagnosed as schizophrenia, personality disorder, or neurosis. The diagnostic shift occurred in part as a result of the U.S.-U.K. Diagnostic Project, which demonstrated that schizophrenia was being diagnosed at the expense of mood disorders (Fig. 14.1-1). Conceptual boundaries were further broadened by the availability of new and effective treatments and by the unacceptable risk for tardive dyskinesia and suicide in persons with misdiagnosed mood disorders. More generally, present research interest in mood disorders in the United States emanated from a landmark 1969 NIMH conference on the psychobiology of affective illnesses: the NIMH Collaborative Depression Study—a long-term prospective project deriving directly from recommendations made at the conference—has legitimatized the broader perspective.

FIGURE 14.1-1 Comparison of British (London) and United States (New York) concepts of schizophrenia. (Reprinted with permission from Cooper JE, Kendell RE, Garland BJ, Sharpe L, Copeland JRM, Simon R: Psychiatric Diagnosis in New York and London. Oxford University Press, London, 1972.)

Unfortunately, findings published by Martin Keller and collaborators in the 1980s documenting gross undertreatment of mood disorders continue to describe the current treatment landscape worldwide. Whatever changes have occurred in diagnostic practice do not appear to have significantly affected the morbidity and mortality of mood disorders. This is all the more scandalous because the 1990s have seen new classes of user-friendly antidepressant and mood-stabilizing agents as well as depression-specific psychotherapies. In the author's opinion, this state of affairs results in part from the fact that both specialized and primary care training in mood disorders have failed to keep pace with recent advances. The situation is analogous to adult-onset diabetes with approximately 50 percent of cases undetected or inadequately controlled, both of which seem to lag behind the field of hypertension, in which early detection and treatment have significantly reduced complications such as stroke. Efforts by patient advocacy organizations—often in concert with national psychiatric organizations and governmental mental health agencies—appear to be increasing public and government awareness of mood disorders. But ultimately, the challenge is to provide all primary care physicians with the requisite hands-on experience in this prevalent group of disorders. Since mood disorders underlie 50 to 70 percent of all suicides, effective treatment of these disorders on a national level should, in principle, drastically reduce this major complication of mood disorders. A small-scale Swedish study has yielded promising results in this regard. In addition, clinical findings in recurrent mood

disorders have clearly shown the value of lithium prophylaxis in the prevention of suicide as well as overall mortality.

DEFINITIONS Mood disorders encompass a large group of psychiatric disorders in which pathological moods and related vegetative and psychomotor disturbances dominate the clinical picture. Known in previous editions of DSM as affective disorders, the term mood disorders is preferred today because it refers to sustained emotional states, not merely to the external (affective) expression of the present emotional state. Mood disorders are best considered as syndromes (rather than discrete diseases) consisting of a cluster of signs and symptoms sustained over a period of weeks to months, that represent a marked departure from a person's habitual functioning and tend to recur, often in periodic or cyclical fashion. Major Depressive Disorder and Bipolar Disorder Major depressive disorder (unipolar depression) is reported to be the most common mood disorder. It may manifest as a single episode or as recurrent episodes. The course may be somewhat protracted—up to 2 years or longer—in those with the single-episode form. Whereas the prognosis for recovery from an acute episode is good for most patients with major depressive disorder, three out of four patients experience recurrences throughout life, with varying degrees of residual symptoms between episodes. Bipolar disorders (previously called manic-depressive psychosis) consists of at least one hypomanic, manic, or mixed episode. Mixed episodes represent a simultaneous mixture of depressive and manic or hypomanic manifestations. Although a minority of patients experience only manic episodes, most bipolar disorder patients experience episodes of both polarity. Manias predominate in men, depression and mixed states in women. The bipolar disorders were classically described as psychotic mood disorders with both manic and major depressive episodes (now termed bipolar I disorder), but recent clinical studies have shown the existence of a spectrum of ambulatory depressive states that alternate with milder, short-lived periods of hypomania rather than full-blown mania (bipolar II disorder). Bipolar II disorder, which is not always easily discriminable from recurrent major depressive disorder, illustrates the need for more research to elucidate the relation between bipolar disorder and major depressive disorder. Dysthymia and Cyclothymia Clinically, major depressive episodes often arise from a low-grade, intermittent, and protracted depressive substrate known as dysthymic disorder. Likewise, many instances of bipolar disorders, especially ambulatory forms, represent episodes of mood disorder superimposed on a cyclothymic background, which is a biphasic alternating pattern of numerous brief periods of hypomania and numerous brief periods of depression. Dysthymic and cyclothymic disorders represent the two prevalent subthreshold mood conditions roughly corresponding to the basic temperamental dysregulations described by Kraepelin and Ernst Kretschmer as predisposing to affective illness. It is not always easy to demarcate full-blown syndromal episodes of depression and mania from their subthreshold counterparts commonly observed during the interepisodic periods. The subthreshold conditions appear to be fertile terrain for interpersonal conflicts and postaffective pathological character developments that may ravage the lives of patients and their families. In North America many such patients end up being labeled with borderline personality disorder, which unfortunately often tends to obscure the affective origin of the presenting psychopathology. Cyclothymic and dysthymic conditions also exist in the community without progression to full-blown mood episodes. As such, they are best considered, respectively, as trait bipolar and trait depressive conditions. Understanding the factors that mediate transition from trait to clinical state is important for preventing manic and major depressive episodes. Other Subthreshold Mood States Epidemiological studies both in Europe and North America have also revealed other subsyndromal conditions with depressive and hypomanic manifestations with few symptoms (oligosymptomatic mood states) and of short duration (brief episodes). Variously referred to as “minor,” “subsyndromal,” “brief,” or “intermittent,” these descriptions do not merely represent arbitrary lowering of diagnostic thresholds, but herald increasing realization of their importance in early detection of at-risk individuals, as has happened in other medical fields (e.g., diabetes mellitus and essential hypertension). If disabling mood disorders afflict 5 to 8 percent of the general population (Epidemiologic Catchment Area [ECA] study), milder but still clinically significant mood disorders would raise lifetime rates to 17 percent (National Comorbidity Study [NCS]); if subclinical mood states are added, that figure doubles to involve a third of the general population (as reported, for instance, by Kenneth Kendler and colleagues). Comorbidity Mood disorders overlap considerably with anxiety disorders. As summarized in an NIMH monograph, anxiety disorders can occur during an episode of depression, may be a precursor to the depressive episode, and, less commonly, may occur during the future course of a mood disorder. Those findings suggest that at least some depressive disorders share a common diathesis with certain anxiety disorders. More-recent clinical experience suggests intriguing comorbidity patterns between bipolar II disorder on one hand and panic, obsessive-compulsive, and social phobic states on the other. Furthermore, bipolar I and II disorders are particularly likely to be complicated by use of alcohol, stimulants, or both. In many cases the alcohol or substance abuse represents an attempt at self-treatment of the mood disorder. Finally, physical illness—both systemic and cerebral—occurs in association with depressive disorders with a greater frequency than expected by chance alone. Unless properly treated, such depression negatively impacts on the prognosis of the physical disorder. More provocatively, there is current reawakening in the contribution of cerebral and cardiovascular factors to the origin of late-onset psychotic depressions (previously classified as “involutional melancholia”). An integrated framework of pathogenesis is necessary for understanding psychopharmacological, somatic, and psychotherapeutic approaches in the clinical management of patients with mood disorders. A historical perspective on current developments is also a valuable lesson in the study of mood disorders.

GRECO-ROMAN DESCRIPTIONS OF MELANCHOLIA AND MANIA Much of what is known today about mood disorders was described by the ancient Greeks and Romans, who coined the terms melancholia and mania and noted their relation. The ancients also hypothesized a temperamental origin for those disorders. Much of modern thinking about mood disorders (e.g., the work of the French and German schools in the middle and latter part of the nineteenth century, which influenced current British and American concepts) can be traced back to these ancient concepts. Melancholia Hippocrates (460–357 BC) described melancholia (“black bile”) as a state of “aversion to food, despondency, sleeplessness, irritability, and restlessness.” Thus, in choosing the name of the condition, Greek physicians (who may have borrowed the concept from ancient Egyptians) postulated the earliest biochemical formulation of any mental disorder. They believed that the illness often arose from the substrate of the somber melancholic temperament which, under the influence of the planet Saturn, made the spleen secrete black bile, ultimately leading to mood darkening through its influence on the brain. Greek descriptions of the clinical manifestations of depression and of the temperament prone to melancholia are reflected in the DSM-IV and in the subdepressive lethargy, self-denigration, and habitual gloom of the person with dysthymic disorder. One Hippocratic aphorism recognized the close link between anxiety and depressive states: “Patients with fear of long-standing are subject to melancholia.” According to Galen (131–201 AD), melancholia manifested in “fear and depression, discontent with life, and hatred of all people.” A few hundred years later another Roman, Aurelianus, citing the now lost works of Soranus of Ephesus, amplified the role of aggression in melancholia (and its link to suicide) and described how the illness assumed delusional coloring: “Animosity toward members of the household, sometimes a desire to live and at other times a longing for death, suspicion on the part of the patient that a plot is being hatched against him.” In addition to natural melancholia, which presumably arose from an innate predisposition to overproduce the dark humor and led to a more severe form of the malady, Greco-Roman medicine recognized such environmental contributions to melancholia as immoderate consumption of wine, perturbations of the soul due to the passions (e.g., love), and disturbed sleep cycles. Autumn was considered the season most disposing to melancholy. Mania A state of raving madness with exalted mood was noted by the ancient Greeks, although it referred to a somewhat broader group of excited psychoses than in modern nosology. Its relation to melancholia was probably noted as early as the first century BC, but according to Aurelianus, Soranus discounted it. Nonetheless, Soranus had observed the coexistence of manic and melancholic features during the same episode, consisting of continual wakefulness and fluctuating states of anger and merriment, sometimes of sadness and futility. Soranus thus seemed to have described what today are called mixed episodes in DSM-IV and ICD-10. Natural melancholy was generally considered a chronic disorder, but Soranus noted the tendency for attacks to alternate with periods of remission. Although others prior to him hinted at it, Aretaeus of Cappadocia (ca. 150 AD) is generally credited with making the connection between the two major mood states: “It appears to me that melancholy is the commencement and a part of mania.” He described the cardinal manifestations of mania as it is known today: There are infinite forms of mania but the disease is one. If mania is associated with joy, the patient may laugh, play, dance night and day, and go to the

market crowned as if victor in some contest of skill. The ideas the patients have are infinite. They believe they are experts in astronomy, philosophy, or poetry. Aretaeus described the extreme psychotic excitement that could complicate the foregoing clinical picture of mania: The patient may become excitable, suspicious, and irritable; hearing may become sharp... get noises and buzzing in the ears; or may have visual hallucinations; bad dreams and his sexual desires may get uncontrollable; aroused to anger, he may become wholly mad and run unrestrainedly, roar aloud; kill his keepers, and lay violent hands upon himself. Noting the fluctuating nature of symptoms in the affectively ill, Aretaeus commented They are prone to change their mind readily; to become base, mean-spirited, illiberal, and in a little time extravagant, munificent, not from any virtue of the soul, but from the changeableness of the disease. Aretaeus was thus keenly aware of the characterological distortions so commonly manifested during the different phases of cyclical mood disorders. Finally, consolidating the knowledge of several centuries, Aretaeus described mania as a disease of adolescent and young men given intermittently to “active habits, drunkenness, lechery” and an immoderate lifestyle (what today might be called cyclothymic disorder). Exacerbations were most likely to occur in the spring. Affective Temperaments The concept of health and disease in Greco-Roman medicine was based on harmony and balance of the four humors, of which sanguine humor was deemed the healthiest. But even a desirable humor like blood, which made people habitually active, amiable, and prone to jest, could in excess lead to the pathological state of mania. The melancholic temperament, dominated by black bile and predisposed to pathological melancholia, was described as lethargic, sullen, and given to brooding or contemplation; its modern counterparts are depressive personality disorder (now in a DSM-IV appendix) and its clinical expression as dysthymic disorder (included in both ICD-10 and DSM-IV). A long tradition dating back to Aristotle (384–322 BC) attributed creative qualities to the otherwise tortured melancholic temperament in such fields as philosophy, the arts, poetry, and politics. The remaining two temperaments, choleric and phlegmatic, were less desirable, as yellow bile made people choleric (irritable, hostile, and given to rage) and phlegm made them phlegmatic (indolent, irresolute, and timid). The choleric and phlegmatic temperaments would probably be recognized today as borderline personality disorder and avoidant or schizoid personality disorder, respectively. Many of the original Greek texts on melancholia were transmitted to posterity through medieval Arabic texts such as those of Ishaq Ibn Imran and Avicenna (and their Latin rendition by Constantinus Africanus). In describing different affective states, Avicenna developed the theory of the temperaments to its fullest. He speculated that a special form of melancholia supervened “if black bile be mixed with phlegm” when the illness was “coupled with inertia, lack of movement, and quiet.” Further, mania was not necessarily linked to the sanguine (what today is termed “hyperthymic”) temperament, as many forms of excited madness were believed to represent a mixture of black and yellow bile. Avicenna further observed that the appearance of anger, restlessness, and violence heralded the transition of melancholia to mania. Those elaborations on Galen's tempermental types might be considered the forerunners of current personality dimensions, deriving mood states from various mixtures of neuroticism and introversion-extroversion. (What both ICD-10 and DSM-IV describe as cyclothymic disorder represents the intense mood lability of high neuroticism coupled with cyclic alternation between extroversion and introversion). Speculation on how diverse depressive phenomena could be understood as a mix of humors anticipated modern multiple-transmitter hypotheses of depression. Ishaq Ibn Imran summarized the existing knowledge of melancholia by considering the interaction of genetic factors (“injured prenatally as the result of the father's sperm having been damaged”) with a special temperament given to “mental overexertion”—though not necessarily physical overactivity—that in turn was associated with “disruption of the correct rhythms of sleeping and waking.” Those views, too, have a very modern ring to them.

MODERN ERA The first English text (Fig. 14.1-2) entirely devoted to affective illness was Robert Burton's Anatomy of Melancholy, published in 1621. A scholarly review of medical and philosophical wisdom accumulated in past centuries, it also anticipated many modern developments. The concept of affective disorder endorsed by Burton was rather broad (as it always has been in the United Kingdom), embracing mood disorders and many disorders today considered somatoform disorders, including hypochondriasis. Although he described “causeless” melancholias, Burton also categorized the various forms of love melancholy and grief. Particularly impressive was his catalogue of causes, culminating in a grand conceptualization:

FIGURE 14.1-2 Frontispiece of Robert Burton's Anatomy of Melancholy (1621).

Such as have Saturn misaffected in their genitures such as are born of melancholy parents as offend in those six non-natural things, are of a high sanguine complexion are solitary by nature, great students, given to much contemplation, lead a life out of action, are most subject to melancholy. Of sexes both, but men more often. Of seasons of the year, autumn is most melancholy. Jobertus excepts neither young nor old. Burton's six nonnatural things referred to such environmental factors as diet, alcohol, biological rhythms, and perturbations induced by passions such as intense love. Burton himself did not definitively indicate age prevalences. Like nearly all of his predecessors, he favored male (rather than the currently reported female) preponderance. Finally, Burton considered both the melancholic (contemplative) and the sanguine (hot-blooded) temperaments to be substrates of melancholia. Burton's work thus linked certain forms of depression with the softer expressions of the manic disposition, or bipolar II disorder, from which he himself appears to have suffered. The eighteenth and nineteenth centuries introduced humane hospital care of the mentally ill, thereby permitting systematic clinical observation of the psychopathology and outcome of mood disorders. Concept of Affective Disorder Although Celsus (ca. AD 30) had described “forms of madness that go no further than sadness,” the French alienist Jean-Philippe Esquirol (1840) may have been the first psychiatrist in modern times to suggest that a primary disturbance of mood might underlie many forms of depression and related paranoid psychoses. Until Esquinol's work, melancholia had been categorized as a form of insanity (i.e., ascribed to deranged reasoning or thought disturbance). Esquirol's observations on melancholic patients led him to postulate that their insanity was partial (dominated by one delusion, a monomania) and that “the symptoms were the expression of the disorder of the affections. The source of the evil is in the passions.” He coined the term “lypemania” (from the Greek, “sorrowful insanity”) to give nosological status to a subgroup of melancholic disorders that were affectively based. Esquirol cited Benjamin Rush (1745–1813), the father of American psychiatry, who had earlier described tristimania, a form of melancholia in which sadness predominated. Esquirol's influence led other European psychiatrists to propose milder states of melancholia without delusions, which were eventually categorized as simple melancholias and ultimately as primary depressions. Such descriptions culminated in the Anglo-Saxon psychiatric term “affective disorder,” coined by Henry Maudsley

(1835–1918), the renowned British psychiatrist after whom the London hospital is named. Manic-Depressive Illness and the Question of Psychogenic Depressions Although the connection between mania and depression had been sporadically rediscovered since it was first described 2000 years ago, the clinical work that finally established “circular insanity” (Jean-Pierre Falret's term) as “folie à double forme” (Jules Baillarger's term) was undertaken by these two Esquirol disciples in the 1850s. That accomplishment built on Philippe Pinel's reforms, which championed humane treatment of the mentally ill in Paris around the turn of the eighteenth century and emphasized systematic clinical observations of patients, detailed in case records. French alienists made longitudinal observations on the same patient from one psychotic attack into another. Further, Esquirol had introduced chronicling events in statistical tables. Thus, the Hippocratic approach to defining a particular case by its onset, circumstances, course, and outcome was applied by French alienists in studying the affectively ill. The humanitarian reforms introduced in the nineteenth century ensured that standards of general health and nutrition would improve the outlook for the mentally ill—especially those with potentially reversible disorders such as affective disorders—who could now be discharged from the asylums. The French school then, by segregating the nondeteriorating mood disorders from the dementing types of insanity, paved the way for the Kraepelinian system. Kraepelin's (1856–1926) unique contribution was not so much grouping together all the forms of melancholia and mania, but his methodology and painstaking longitudinal observations, which established manic-depressive illness as a nosological entity and (he hoped) a disease entity. His rationale was (1) the various forms had a common heredity measured as a function of familial aggregation of homotypic and heterotypic cases; (2) frequent transitions from one form to the other occurred during longitudinal follow-up; (3) a recurrent course with illness-free intervals characterized most cases; (4) the superimposed episodes were commonly opposite to the patient's habitual temperament; that is, mania was superimposed on a depressive temperament and depression was superimposed on a hypomanic temperament; and (5) both depressive and manic features could occur during the same episode (mixed states). Kraepelin's synthesis was developed as early as the sixth (1899) edition of his Lehrbuch der Psychiatrie and most explicitly stated in the opening passages of the section on manic-depressive psychosis in the eighth edition (published in four volumes, 1909–1915): Manic-depressive insanity includes on the one hand the whole domain of so-called periodic and circular insanity, on the other hand simple mania, the greater part of the morbid states termed melancholia and also a not inconsiderable number of cases of confusional insanity. Lastly, we include here certain slight and slightest colorings of mood, some of them periodic, some of them continuously morbid, which on the one hand are to be regarded as the rudiment of more severe disorders, on the other hand, pass over without boundary into the domain of personal predisposition. For Kraepelin, the core pathology of clinical depression consisted of lowered mood and slowed (retarded) physical and mental processes. In mania, by contrast, the mood was elated and both physical and mental activity accelerated. His earlier observations on what he termed “involutional melancholia” (referring to 40- to 65-year-old patients with extreme anxiety, irritability, agitation, and delusions) had led him to separate that entity from the broader manic-depressive rubric. But, in the eighth edition of Lehrbuch der Psychiatrie, he united melancholia with the manic-depressive group, with the justification that it was a special form of mixed state and that follow-up conducted by his pupil Dreyfus had demonstrated unmistakable excited phases. The classification of depressive disorders is still evolving. Karl Leonhard in 1957, Jules Angst in 1966, Carlo Perris in 1966, and George Winokur, Paula Clayton, and Theodore Reich in 1969, working independently in four different countries, proposed that depressive disorders without manic or hypomanic episodes (major depressive disorder) that appear in middle age and later are distinct from depressive episodes that begin at earlier ages and alternate with manic or hypomanic episodes (bipolar disorder). The main difference between the two affective subtypes is the greater familial loading for mood disorder—especially for bipolar disorder—among bipolar disorder probands. Kraepelin had conceded the occurrence of psychogenic states of depression occasioned by situational misfortune. Manic-depressive illness, on the other hand, he believed to be hereditary. Yet he could not document postmortem anatomopathological findings in the brains of manic-depressive patients. Therefore, manic-depression had to be considered a functional mental disorder in which brain disturbances were presumed to lie in altered physiological functions. Such biological factors were deemed absent in the psychogenic depressions. Thus, Kraepelin's classification of mood disorders is both dualistic and unitary. It is dualistic to the extent that he designated them as either psychologically occasioned or somatically caused. It is unitary with respect to disorders in the latter group, which have been termed endogenous affective disorders (i.e., due to internal biological causes). In other words, Kraepelin restricted the concept of clinical depression to what DSM-IV terms “major depressive disorder with melancholic features.” Moreover, he postulated a continuum between that condition and what DSM-IV and ICD-10 now term “bipolar disorders.” As summarized in Table 14.1-1, endogenous depressions have been contrasted with those of exogenous cause (i.e., external and, presumably, psychogenic causes). Transitions between the two groups are so frequent, however, that the two-type thesis of depression has been largely abandoned in official classifications in North American psychiatry. In one study conducted by the author's mood clinic team in Memphis during the 1970s, 100 patients with neurotic depression (the prototype of exogenous depression), prospectively followed over 3 to 4 years, developed episodes with endogenous, psychotic, and even bipolar features ( Table 14.1-2). Nonetheless, the endogenous-exogenous dichotomous grouping still has some adherents worldwide who continue to research its potential for clinical predictions. Such research generally attempts to validate the various subtypes on the basis of their clinical characteristics rather than presumed cause. Today most mood disorders experts would probably agree that depressive illness has endogenous and exogenous components in most patients presenting clinically. Consensus would be less likely on how to delimit clinical depressive disorder from comorbid disorders such as the various anxiety disorders, substance use disorders, and personality disorders. Clarifying the boundaries between those disorders has emerged as a principal challenge in the classification of mood disorders.

Table 14.1-1 Overlapping Dichotomies of Affective Disorders That Are Not Necessarily Synonymous

Table 14.1-2 Three- to Four-Year Prospective Follow-up in Neurotic Depressions (N = 100)

Cartesian thinking in seventeeth-century France conceptually separated mind from body, thereby providing physicians autonomy over the somatic sphere, free from interference by the Church. The dichotomous paradigm ensured that study of the two aspects of the human organism would not be confounded by the complexities of mind-body interactions. That is one reason why Kraepelin's descriptive observations have proved valuable to subsequent generations of clinicians. Further, his approach exemplifies the best tradition of scientific humanism in medicine: description and diagnostic categorization of an individual patient are necessary for the physician to apply the knowledge gained from past observation of similarly described and diagnosed patients. One limitation to the Kraepelinian approach is that because of its biological reductionism, it is not sufficiently articulate to account for mind-body interactions in the genesis of mental disorders. Depressions as Psychobiological Affective Reaction Types Bridging the divide between psyche and soma was the ambition of Swiss-born Adolf Meyer (1866–1950), who dominated psychiatry from his chair at Johns Hopkins University during the first half of the twentieth century. Meyer coined the term “psychobiology” to emphasize that both psychological and biological factors could enter into the causation of depressive and other mental disorders. Because of the nascent state of brain science during Meyer's time, he was more adept at biography than biology and therefore paid greater attention to psychosocial causation. He preferred the term depression (pressed down) to melancholia because of its lack of biological connotation. He conceived of depressive states in terms of unspecified constitutional or biological factors interacting with a series of life situations beginning at birth or even at conception. From that viewpoint arose the unique importance accorded personal history in depressive reactions to life events. Meyer's terminological revision left a somewhat confusing legacy in that the term depression is now applied to a broad range of affective phenomena ranging from sadness and adjustment disorders to clinical depression and bipolar disorders. Repercussions can be seen in the low threshold for diagnosing major depressive disorder in DSM-IV, which makes it difficult to differentiate major depressive disorder from transient life stresses that produce adjustment disorder with depressed mood. Nosological nuances to which Meyerians paid little attention, such as the difference between melancholic depression and more mundane depressions, are not just a matter of semantics. To the extent that those two forms of depression are seen in different clinical settings, hypotheses based on one population may not apply to the other. For instance, uncontrollable traumatic events may have taught study subjects to feel helpless or to view the world in a negative light, but that does not equate with clinical depression; nor does the process appear to be specific to depression. Failure to make such nosological distinctions further clouds interpretations of the results of trials comparing psychotherapy and pharmacotherapy for depressive disorders. On the other hand, the Meyerian emphasis on biographical factors for the patient represented a more practical approach to depth psychology. Recent sociological interpretations of depression can also be traced to Meyer's work. But in the final analysis, the Meyerian concern for the uniqueness of the individual has proved heuristically sterile. It deemphasizes what is diagnostically common to different individuals, thereby obscuring the relevance of accrued clinical wisdom for the index patient. For that reason the Meyerian approach, after enjoying clinical popularity for several decades in North America, has given way to neo-Kraepelinian rigor. However, the psychobiological vision of bridging biology and psychology, one of the major preoccupations of psychiatric thought and research today, owes much to Meyer's legacy.

CONTEMPORARY MODELS OF DEPRESSION From classical times through the early part of the twentieth century, advances in understanding mood disorders involved conceptual shifts from supernatural to naturalistic explanations, from reductionistic, unitarian theories of causation to pluralistic theories, and from dualism to psychobiology. Knowledge of those conceptual developments provides a useful base from which to scrutinize more-recent models and concepts of mood disorder, developed later in the twentieth century. The new approaches, derived from competing theoretical positions, have generated models for understanding various aspects of mood disorders, particularly depressive disorders (Table 14.1-3).

Table 14.1-3 Contemporary Major Models of Depression

The formative influence of early experience as it is dynamically shaped by emerging mental structures during development is the common denominator for the psychoanalytic concepts of psychopathological phenomena. By contrast, behavioral approaches in their more traditional formulations focus on the pathogenetic impact of proximate contexts. The cognitive approaches, which are akin to the behavioral-pathogenetic tradition, nonetheless concede that negative styles of thinking might mediate between proximate stressors and more remote experiences. All three schools—psychoanalytic, behavioral, and cognitive—emphasize psychological constructs in explaining the origin of mood disorders. The biological models, on the other hand, are concerned with defining the somatic mechanisms that underlie or predispose to morbid affective experiences. The schism between psychological and biological conceptualizations is an instance of the mind-body dichotomy that has characterized the Western intellectual tradition since Descartes. After all, psychological and somatic approaches represent merely convenient investigational strategies that attempt to bypass the methodological gulf between mental and neural structures. The ultimate aim is to understand how mood disorders develop within the psychoneural framework of a given person. Aggression-Turned-Inward Model Sigmund Freud was initially interested in a psychoneural project for all mental phenomena. Limitations of the brain sciences of the day led him to adopt instead a model that relied on a concept of mental function borrowed from physics. The notion that depressed affect is derived from retroflexion of aggressive impulses directed against an ambivalently loved internalized object was actually formulated by his Berlin disciple Karl Abraham and later elaborated by Freud. Abraham and Freud hypothesized that turned-in anger was intended as punishment for the love object that had thwarted the depressed patient's need for dependency and love. Because, in an attempt to prevent the traumatic loss, the object had already been internalized, the patient now became the target of his or her own thanatotic impulses. A central element in those psychic operations was the depressed patient's ambivalence toward the object, which was perceived as a frustrating parent. Aggression directed at a loved object (parent) was therefore attended by considerable guilt. In the extreme such ambivalence, guilt, and retroflexed anger could lead to suicidal behavior. According to that model, depression was an epiphenomenon of the transduction of thanatotic energy, a reaction that took place in the closed hydraulic space of the mind. Freud's earlier writings had similarly portrayed anxiety as derived from the transformation of dammed-up sexual libido. Although Freud envisioned that psychoanalytic constructs would one day be localized neuroanatomically, the hydraulic mind is a metaphor that does not refer to actual physiochemical space in the brain. The conceptualization of emotional behavior as an arena of incompatible forces confined to a psyche that is relatively impervious to current influences outside the organism is the major liability of the aggression-turned-inward model and perhaps of orthodox psychoanalysis itself. Although the sexual energy transduction hypothesis of anxiety has been discarded in modern psychoanalytic thought, in modified version the aggression-turned-inward model continues to be used in clinical conceptualization today. The lingering popularity of the model may be due in part to its compatibility with the clinical observation that many depressed patients suffer from lack of assertion and outwardly directed aggressiveness. Yet a substantial number of hostile depressed patients are also encountered in clinical practice (indeed “depression with anger attacks” has been recently described), and clinical improvement in most patients typically leads to decreased, not increased, hostility. Those observations shed doubt on the aggression-turned-inward mechanism as a universal explanation for depressive behavior. Finally, little evidence exists to support the contention that outward expression of anger has therapeutic value in clinical depression. Outwardly directed hostility in depression is not a new clinical observation: Greco-Roman physicians had noted it. Hostility is best considered a manifestation rather

than a cause of depressive disorder, especially when the disorder is attended by mixed bipolar features. The hostility of the depressed patient can also be understood as an exaggerated reaction to frustrating love objects, as secondary to self-referential attribution, or simply as nonspecific irritability of an ego in affective turmoil; this could in part be a function of a concurrent personality disorder from the erratic cluster. Such common-sense explanations that do not invoke unobservable hydraulic transmutations have greater appeal from heuristic and clinical perspectives. Object Loss and Depression Object loss refers to traumatic separation from significant objects of attachment. Ego-psychological reformulations of the Abraham-Freud conceptualization of depression have paid greater attention to the impact of such losses on the ego, deemphasizing the id-libidinal and related hydraulic aspects. The depressant impact of separation events often resides in their symbolic meaning for a person rather than in any arbitrary objective weight that the event may have for clinical raters. However, love loss, bereavement, and other exits from the social scene, as defined by the London psychiatrist Eugene Paykel, are presently the concepts most commonly used in practice and research. Although love melancholy had been described since antiquity, the two affective states were systematically compared for the first time in Freud's 1917 paper on mourning and melancholia. According to current data, the transition from grief to pathological depression occurs in no more than 10 percent of adults and 20 percent of children. These figures suggest that such transition occurs largely in persons predisposed to mood disorders. John Bowlby of the Tavistock Clinic, London, did a comprehensive clinical investigation of the attachment that the child establishes with the mother or mother substitutes during development, a bond considered the prototype for all subsequent bonds with other objects. Like many psychoanalytic explanations of adult symptom-formation, the object loss model is formulated as a two-step hypothesis, consisting of early breaks in affectional bonds, which provide the behavioral predisposition to depression, and adult losses, which are said to revive the traumatic childhood loss and so precipitate depressive episodes. However, the role of proximate separations in provoking depressive reactions rests on more solid clinical evidence than the hypothesized sensitization resulting from developmental object loss. That realization has led Bowlby to regard childhood sensitization resulting from early deprivation as a generic characterological vulnerability to a host of adult psychopathological conditions. Compared with aggression turned inward, object loss is more directly relevant to clinical depression; yet it is still pertinent to question whether it is an etiological factor. Studies at the Wisconsin Primate Center have indicated that optimal homeostasis with the environment is most readily achieved when the individual is securely attached to significant others, and the dissolution of such ties appears relevant to the emergence of a broad range of psychopathological disturbances rather than depression per se. A related methodological question is whether object loss operates independently of other etiological factors. For instance, a history of early breaks in attachment may reflect the fact that one or both of the patient's parents had mood disorder, with resultant separation, divorce, suicide, and so forth. On balance, the ego-psychological object loss model is conceptually superior to its id-psychological counterpart. In postulating an open system of exchange between a person and the environment, the model permits consideration of etiological factors other than separation, such as heredity, character structure, and adequacy of social support—all of which might modulate the depressant impact of adult separation events. Conceptualizing the origin of depression along those lines is in the mainstream of current ideas of adaptation, homeostasis, and disease. An important treatment implication is the value of social support in preventing relapse and mitigating chronicity of depression. That is indeed an ingredient in the interpersonal psychotherapy of depression, which can be conceptualized as a form of brief, focused, and practical psychodynamic therapy. Loss of Self-Esteem and Depression Reformulation of the dynamics of depression in terms of the ego suffering a collapse of self-esteem represents a further conceptual break with the original id-psychological formulation; depression is said to originate from the ego's inability to give up unattainable goals and ideals. The model further posits that the narcissistic injury that crushes the depressed patient's self-esteem is imposed by the internalized values of the ego rather than the hydraulic pressure of retroflected thanatotic energy deriving from the id. Because the construct of the ego is rooted in social and cultural reality, loss of self-esteem may result from symbolic losses involving power, status, roles, identity, values, and purpose for existence. Thus, the existential and sociocultural implications of depression conceived as a derivative ego state provide the clinician with a far more flexible and pragmatic tool for understanding depressed persons than the archaic hydraulic metaphors related to libidinal vicissitudes. That model represents one of the first attempts to formulate depression in terms that subsequent psychological theory and research could operationalize in more testable form. Self-esteem is part of the habitual core of the individual and hence is integral to the personality structure. Indeed, low self-esteem conceived as a trait is a major defining attribute of the depressive (melancholic) personality. While it is understandable how such individuals can easily sink into melancholia in the face of environmental adversity, it is not obvious why persons with apparently high self-esteem (e.g., those with hypomanic and narcissistic personalities) also succumb to melancholy with relative ease. To explain such cases, one must invoke an underlying instability in the system of self-esteem that renders it vulnerable to depression. The opposite is also known to occur; that is, manic episodes may develop from a baseline of low self-esteem, as in the case of bipolar disorder patients with antecedent traits of shyness, insecurity, and dysthymia. The foregoing considerations suggest that the vicissitudes of self-esteem deemed central to the model of depression as loss of self-esteem are manifestations of a more fundamental mood dysregulation. In classical psychoanalysis, such dysregulation is considered of constitutional origin. In general, attempts by psychoanalytic writers to account for bipolar oscillations have not progressed beyond metapsychological jargon, with the possible exception of denial of painful affects as a mechanism in the phenomenology of mania. Cognitive Model The cognitive model, developed by Aaron Beck at the University of Pennsylvania, hypothesizes that thinking along negative lines (e.g., thinking that one is helpless, unworthy, or useless) is the hallmark of clinical depression. In effect, depression is redefined in terms of a cognitive triad, according to which patients think of themselves as helpless, interpret most events unfavorably vis-à-vis the self, and believe the future to be hopeless. In more recent formulations in academic psychology, these cognitions are said to be characterized by a negative attributional style that is global, internal, and stable and to exist in the form of latent mental schemata that generate biased interpretations of life events. Because the cognitive model is based on retrospective observations of already depressed persons, it is virtually impossible to prove that causal attributions such as negative mental schemata precede and hence predispose to clinical depression; they can just as readily be regarded as subclinical manifestations of depression. The theoretical importance of the cognitive model lies in the conceptual bridge it provides between ego-psychological and behavioral models of depression. It has also led to a new and widely accepted system of psychotherapy that attempts to alter the negative attributional style, to alleviate the depressive state, and, ultimately, to fortify the patient against future lapses into negative thinking, despair, and depression. The cognitive model, therefore, has the cardinal virtue of focusing on key reversible clinical dimensions of depressive illness, such as helplessness, hopelessness, and suicidal ideation, while providing a testable and practical psychotherapeutic approach. That approach, however, is less likely to succeed in patients with the full-blown melancholic manifestations of a depressive disorder. It is doubtful that negative cognitions alone could account for the profound disturbances in sleep, appetite, and autonomic and psychomotor functions encountered in melancholic depressions. Further, conceptualizing a multifaceted malady such as depression largely or solely as a function of distorted cognitive processes is reminiscent of pre-Esquirolian notions that emphasized impaired reasoning in the development of depression. Learned Helplessness Model The learned helplessness model is in some ways an experimental analogue of the cognitive model. The model proposes that the depressive posture is learned from past situations in which the person was unable to terminate undesirable contingencies. The model is based on experiments in dogs that were prevented from taking adaptive action to avoid unpleasant electrical shock and subsequently showed no motivation to escape such aversive stimuli, even when escape avenues were readily available. Armed with evidence from many such experiments, a University of Pennsylvania psychologist, Martin Seligman, postulated a trait of learned helplessness (a belief that it is futile to initiate personal action to reverse aversive circumstances) formed from the cumulation of past episodes of uncontrollable helplessness. The learned helplessness paradigm is a general one and refers to a broader mental disposition than depression. Thus, it is potentially useful in understanding such diverse conditions as social powerlessness, defeat in sporting events, and posttraumatic stress disorder. In addition, past events might shape a characterological cluster, consisting of passivity, lack of hostility, and self-blame, relevant to certain depressive phenomena. The low hostility observed in some patients during clinical depression could, for instance, be ascribed to the operation of such factors. Learned helplessness could thereby provide plausible links between aspects of personal biography and clinical phenomenology in depressive disorders. Therapeutic predictions for alleviating depression and related psychopathological states capitalize on new cognitive strategies geared to modifying expectations of uncontrollability and the negative attributional style. This illustrates how insights gained from experimental paradigms can be fruitfully combined to address clinical disorders.

Nonetheless, the clinician should be wary of unwarranted clinical extrapolations. For instance, some therapists have argued that the depressed patient's passivity is manipulative, serving to obtain interpersonal rewards. It has also been claimed that such factors have a formative influence on the development of the depressive character. That interpretation appears more relevant to selected aspects of depression than to the totality of the disorder. Depressive behavior and verbalizations clearly have a powerful interpersonal impact, but casting depression as merely a masochistic lifestyle developed to secure interpersonal advantages represents a mechanistic circular argument that could be viewed as disrespectful of the clinical agony of patients with mood disorders. Finally, although most formulations focusing on helplessness have emphasized acquisition through learning, recent experimental research in animals tends to implicate genetic factors in the vulnerability to learning to behave helplessly. The value of the helplessness paradigm may reside in its utility to predict a variety of subthreshold affective disturbances generic to civilian reactions to adversity and trauma. Depression and Reinforcement Other behavioral investigators, notably Oregon psychologist Peter Lewinsohn, have developed clinical formulations of depression that hinge on certain deficits in reinforcement mechanisms. According to the reinforcement model, depressive behavior is associated with lack of appropriate rewards and, more specifically, with receipt of noncontingent rewards. The model identifies several contributory mechanisms. Some environments may consistently deprive persons of rewarding opportunities, thereby placing them in a chronic state of boredom, pleasurelessness, and, ultimately, despair. That reasoning, however, may offer more insight into social misery than clinical depression. A more plausible postulated mechanism is the provision of rewards that are not in response to the recipient's actions; in other words, the gratis provision of what a person considers undeserved rewards may lead to lowering of self-esteem. Predisposition to depression is formulated in terms of deficient social skills, which are hypothesized to decrease a person's chances of responding to potentially rewarding contingencies in any environment. Indeed, recent research on the relation between personality and depression suggests that such deficits might underlie certain depressive states. Therefore, psychotherapeutic approaches designed to enlarge a patient's repertoire of social skills may prove valuable in preventing some types of depression. The concepts of depression that have been derived from behavioral methodology and developed in the past several decades are scientifically articulate and therefore testable approaches to clinical depression. Yet, the important distinction between depression on self-report inventories and clinical depression is sometimes overlooked. Further, the behavioral model does not address the distinct possibility that reinforcement deficits may in part represent the psychomotor deficits of depressive illness. Nevertheless, by focusing on reward mechanisms, the behavioral model provides a conceptual bridge between purely psychological and emerging biological conceptualizations of depression. Biogenic Amine Imbalance Formulation of sophisticated biological explanations of mood disorders had to await development of neurobiological techniques that could probe parts of the brain involved in emotions. Although the complex physiology of the limbic-diencephalic centers of emotional behavior generally cannot be directly observed in humans, much has been learned from animal work. The limbic cortex is linked with both the neocortex, which subserves higher symbolic functions, and the midbrain and lower brain centers, which are involved in autonomic control, hormonal production, and sleep and wakefulness. Norepinephrine-containing neurons are involved in many functions that are profoundly disturbed in melancholia, including mood, arousal, appetite, reward, and drives. Other biogenic amine neurotransmitters that mediate such functions are the catecholamine dopamine, especially important for pleasure, sex, and psychomotor activity, and the indoleamine serotonin, involved in the regulatory control of affects, aggression, sleep, and appetite, among others. Cholinergic neurons, secreting acetylcholine at their dendritic terminals, are generally antagonistic in function to catecholaminergic neurons. Although the opioid system might, on experimental and theoretical grounds, also serve as one of the neurochemical substrates for mood regulation, in the author's opinion no cogent model of mood disorders involving that system has appeared to date. Likewise, biochemical formulations of mood disorders have paid relatively little attention to the major excitatory brain neurotransmitter glutamate and the inhibitory neurotransmitter g-aminobutyric acid (GABA). Biogenic Amine Hypotheses Joseph Schildkraut at Harvard University and William Bunney and John Davis at NIMH published the first formal hypothesis connecting depletion or imbalance of biogenic amines (specifically norepinephrine) and clinical depression. The serotonin counterpart of the model was emphasized in the models proposed by Alec Coppen in England and I. P. Lapin and G. F. Oxenkrug in Russia. Both catecholamine and indoleamine hypotheses were essentially based on two sets of pharmacological observations. First, reserpine (which decreases blood pressure by depleting biogenic amine stores) precipitates clinical depression in some patients. Second, antidepressant medications (which alleviate clinical depression) raise the functional capacity of the biogenic amines in the brain. This style of thinking is known as the pharmacological bridge, extrapolating from evidence on mechanism of drug action to the neurotransmitter pathologies presumed to underlie a given psychiatric disorder. Such pharmacological strategies have been of heuristic value in developing research methods for investigation of mood disorders and schizophrenia. Indeed, the research methodology developed by the relatively few investigators working in the area in the past three decades is among the most elegant in the history of psychiatry. Variations of the biogenic amine model assign somewhat different relative weights to the biogenic amines norepinephrine and serotonin in the development of pathological mood states. Arthur Prange and colleagues at the University of North Carolina formulated a permissive biogenic amine hypothesis in which serotonin deficits permit expression of catecholamine-mediated depressive or manic states. That hypothesis was supported by subsequent animal research showing that an intact serotonin system is necessary for optimal functioning of noradrenergic neurons. Omission of tryptophan from the diet of antidepressant-responsive depressed patients may annul the efficacy of the antidepressant; among healthy volunteers, that special diet also induces sleep electroencephalographic characteristics of clinical depression. Although such findings are provocative, the precursor-loading strategy to increase the brain stores of serotonin (e.g., with L-tryptophan) has not been unequivocally successful in reversing clinical depression. Dietary loading with catecholamine precursors has fared even worse than serotonin-precursor loading in the treatment of depression. The cholinergic-noradrenergic imbalance hypothesis proposed by David Janowsky and colleagues represents yet another attempt to elucidate the roles of biogenic amines. This hypothesis, along with the related cholinergic supersensitivity hypothesis developed by J. Christian Gillin, has been tested extensively at the University of California at San Diego. Subsequent formulations by Larry Siever and Kenneth Davis at the Mount Sinai Hospital in New York have refocused on noradrenergic dysregulation. The model envisions oscillation from one output mode to the other at different phases of depressive illness. In a provocative extrapolation from that model, bipolar depression would have low noradrenergic output, but many instances of major depressive disorder, just like some anxiety disorders, could be biochemically conceptualized as high-output conditions. Despite more than three decades of extensive research and indirect evidence, however, no deficiency or excess of biogenic amines in specific brain structures has been shown to be necessary or sufficient for the occurrence of mood disorders. It has been possible neither to confirm the putative role of central norepinephrine in depression nor to discard it altogether. The role of dopamine as formulated by the Italian pharmacologist Gian Luigi Cessa, though studied less extensively than that of norepinephrine, deserves greater recognition: it might have relevance to atypical and bipolar depression as well as mania. Except for preliminary data from a small brain imaging study showing blunted serotonin responsivity in prefrontal and temporoparietal areas in unmedicated major depressive disorder patients, the evidence for serotonergic disturbance in depression is based on indirect evidence. Moreover, the putative permissive role of serotonin is better documented for aggressive suicide attempts. Serotonergic dysfunction might subserve other conditions characterized by lack of inhibitory control, among them obsessive-compulsive disorder, panic disorders, bulimia nervosa, certain forms of insomnia, alcoholism (alcohol abuse or dependence), and a host of impulse-ridden personality disorders. Such considerations have led Dutch psychiatrist Herman van Praag and his colleagues to postulate a dimensional neurochemical disturbance generic to a large group of disorders within the traditional nosology. This hypothesis might be variously regarded as a challenge to psychiatric nosology or as a statement of the need to supplement clinical classification with biochemical parameters. It is implied that the foregoing biochemical faults are genetically determined. Although biogenic amine models of mood disorders were developed retrospectively from the pharmacologic action of antidepressant and thymoleptic agents, they have stimulated development of new classes of antidepressants with more selective action on specific neurotransmitter receptors. Their introduction has virtually revolutionized the treatment of depression. Yet the fundamental biochemistry of mood disorders is still far from being understood. Curiously, though selective in action, the new compounds working on the serotonin system have broad effectiveness in a variety of mood-related conditions such as dysthymic disorder, obsessive-compulsive disorder, panic disorder, social phobia, borderline personality disorder, and bulimia nervosa. Such data indirectly favor the hypothesis of an underlying biological commonality to several of these disorders. New antidepressants with dual action on both serotonergic and noradrenergic receptors and emerging data on their possible greater efficacy in melancholic depressions do suggest that the biochemistry of mood disorders involves more-complex dysregulation than is implied in single-neurotransmitter hypotheses. The work of George Henninger and colleagues at Yale University further suggests that monoamines better explain how antidepressants facilitate recovery from depression than the fundamental causes of depression. Emerging biochemical paradigms are moving away from distal biochemical lesions to focus on molecular perturbations closest to the putative genetic underpinnings of mood disorders. Originally tied to the mechanism of action of mood stabilizers in bipolar disorder, such work is exploring second messenger systems, phosphorylation G proteins, signal transduction, deoxyribonucleic acid (DNA) transcription, and messenger ribonucleic acid (RNA) translation. Again, the search for biochemical

mechanisms is inseparable from the putative mechanism of action of thymoleptic agents. Neuroendocrine Links Functionally inadequate mobilization of neurotransmitters in the face of continued or repeated stress, as indirectly reflected in pathological modification of noradrenergic and serotonergic receptor function, could represent neurochemical final common pathways of homeostatic failure. Such mechanisms could also provide links with psychoendocrine dysfunction; the hypothesized neurotransmitter deficits may underlie the disinhibition of the hypothalamic-pituitary-adrenal axis, characterized by steroidal overproduction, the most widely studied endocrine disturbance in depressive illness. When challenged with dexamethasone (Decadron), the altered axis resists suppression, thereby offering Bernard Carroll's team (then at the University of Michigan) the possibility of developing the dexamethasone suppression test (DST) for melancholia (subsequently shown to have uncertain specificity for melancholia). That line of research has culminated in the demonstration by the Emory University's Charles Nemeroff of increased concentrations of corticotropin-releasing factor (CRF) in the cerebrospinal fluid of patients with major depressive disorder. CRF also appears relevant to the pathophysiology of anxiety disorders, such as panic disorder. Another neuroendocrine index of noradrenergic dysregulation, blunted growth hormone response to the a 2-adrenergic receptor agonist clonidine, likewise points to limbic-diencephalic disturbance. However, studies performed in the United States suggest that it is positive in both endogenous depression and severe anxiety disorder (panic disorder). Thyroid-stimulating hormone (TSH) blunting upon thyrotropin stimulation, another common neuroendocrine disturbance in depression, also shows limited specificity. What is remarkable, however, is that the DST, clonidine (Catapres), and thyrotropin challenge data in aggregate identify most persons with clinical depression. Such evidence of midbrain disturbance argues for considering clinical depression to be a legitimate disease. The disease concept of depression is further buttressed by computed tomography scans showing enlarged pituitary and adrenal glands. Stress and Depression The concept of a pharmacological bridge implies two-way traffic. The hypothesized chemical aberrations may be primary or biologically induced. Provision should also be made, however, for the likelihood that psychological events that precipitate clinical depression might induce or initiate neurochemical imbalance in vulnerable subjects. That suggestion is supported by studies in animals, in which separation and inescapable frustration effect profound alterations in the turnover of biogenic amines and in postsynaptic receptor sensitivity. Thus, in genetically predisposed persons, environmental stressors might more easily lead to perturbations of limbic-diencephalic neurotransmitter balance. Finally, in vulnerable individuals, especially during the formative years of childhood, psychological mechanisms might more easily perturb midbrain neurochemistry. Traumatic experiences appear particularly potent in this regard. Neurophysiological Approaches Neuronal Hyperexcitability Lithium is known to replace intracellular sodium and hyperpolarize the neuronal membrane, thereby decreasing neuronal excitability. Abnormalities in neuronal electrolyte balance (an excess of residual sodium, defined by radioisotope techniques) and hypothesized secondary neurophysiological disturbances were the focus of British investigations by Alec Coppen and colleagues in the early 1960s. The existing data appear compatible with the hypothesized movement of excess sodium into the neuron during an episode of mood disorder and redistribution toward the pre-illness electrolyte balance across the neuronal membrane during recovery. Intraneuronal sodium leakage is postulated in both depressive and manic disorders but deemed more extreme in the latter. Because the harmonious activity of the neuronal cell and, by implication, that of a group of neurons depends on the electrical gradient maintained across its membrane by differential distribution of sodium, abnormalities in sodium concentrations and transport are hypothetically relevant to the production of an unstable state of neurophysiological hyperexcitability. In formulating their thesis of neurophysiologic arousal in melancholic states, Joseph Mendels and Peter Whybrow (both of whom at various times worked at the University of Pennsylvania) have capitalized on the foregoing electrolyte disturbances. The view that mania represents a more extreme electrophysiological dysfunction in the same direction as depression violates the common-sense notion of symptomatological opposition between the two kinds of disorder, yet it may in part account for the existence of mixed states in which symptoms of depression and mania coexist. The NIMH team led by Frederick Goodwin first showed that a substantial minority of depressed patients with a bipolar substrate respond to lithium salts, which further supports the concept of a neurophysiological common denominator to mania and depression. Perturbations of calcium metabolism also appear limited to bipolar patients. Therapeutic implications of this observation (e.g., the use of calcium channel inhibitors in bipolar I disorder) have not yielded consistent results. Finally, rubidium, another alkali metal, has been explored in the depressive phase of bipolar disorders, again with inconclusive results. Rhythmopathy European studies have shown that depressed patients are phase advanced in many biological rhythms, including the latency to the first rapid eye movement (REM) in sleep. Shortened REM latency, which has been extensively studied by David Kupfer and colleagues at the University of Pittsburgh, has been proposed as another laboratory test for depressive disorder. Formulations of circadian rhythms by Thomas Wehr and Norman Rosenthal, working at NIMH, have focused on abnormalities on brain regulation temperature, activity, and sleep cycles. Others have investigated the role of the pineal hormone melatonin. These neurophysiologic considerations have paved the way for new therapeutic opportunities. Sleep deprivation and exposure to bright white light can correct phase disturbances and thereby terminate depressive episodes, especially in patients with periodic and seasonal depressions. Daniel Kripke, working at the University of California at San Diego, has shown that the average citizen is light deprived and that phototherapy can benefit many forms of depression. Although the specificity and efficacy of these neurophysiological indexes and manipulations for clinical depression require more extensive research, cumulatively they point to midbrain dysregulation as the likely common neurophysiological substrate of depressive disorders. The foregoing considerations further suggest that the ancient Greeks, who ascribed melancholia to malignant geophysical influences, did not indulge in mere poetic metaphor. The ancients had observed the disturbed circadian patterns and advocated their readjustment to restore euthymia. Affective Dysregulation A major challenge for research in mood disorders is to characterize the basic molecular mechanisms that underlie the neurophysiological rhythmopathies, which in turn might account for the recurrent nature of the affective pathology as envisioned by Kraepelin. This means that in the most typical recurrent forms of the disorders, the constitutional foundations (manifested as cyclothymic and dysthymic traits) are so unstable that the illness may run its entire course more or less autonomously, with the environment largely serving to turn on and off the more florid phases (episodes). The Parisian psychiatrist Jean Delay, a pioneer in psychopharmacology in the 1950s, has also emphasized affective dysregulation as the fundamental pathology in the spectrum of mood disorders. Robert Post (at NIMH) has hypothesized that the electrophysiological substrates could be so kindled that an oligoepisodic disorder initially triggered by environmental stressors could assume an autonomous and polyepisodic course. He hypothesizes that this phenomenon might occur because neuronal perturbations brought about by stressors in the early course of mood disorders get incorporated into the DNA. This fascinating kindling hypothesis, however, does not seem to pertain to common mood disorders, but those with extreme cyclicity. The monograph on manic-depressive illness by Goodwin and Kay Jamison presents in-depth arguments for this cyclical paradigm of thymopathy.

THEORETICAL SYNTHESIS Pathophysiological Understanding Modern psychobiology attempts to link experience and behavior to the central nervous system. Building conceptual bridges between the psychological and biological approaches to mood disorders requires sophisticated strategies that go beyond the Cartesian notion of limited mind-body interactions through the pineal gland and the generalizations of the Meyerian school. In collaboration with William McKinney in 1973, the author developed the conceptual framework that considers the affective syndromes as the final common pathway of various psychological and biological processes. The overarching hypothesis is that psychological and biological etiological factors converge in reversible deficits in the diencephalic substrates of pleasure and reward. Those areas of the brain subserve the functions that are disturbed in melancholia and mania. The integrative model links the central chemistry and physiology of reward mechanisms with the object loss and behavioral models of depression, both of which give singular importance to the depressant role of loss of rewarding interpersonal bonds. A key element of the model is the circadian disturbances observed since ancient times in both depressive and manic syndromes. Both syndromes are conceptualized as clinical manifestations of a disordered limbic system with its subcortical and prefrontal extensions. Brain-imaging studies in melancholic patients by Wayne Drevets at Washington University have tentatively visualized limbic disturbances extending into subcortical structures and occurring primarily in those with a familial diathesis for depression. The amygdala plays a key role in this model. Clinical experience and research data suggest that multiple factors described below converge to produce dysregulation leading to the final common pathway of clinical depression and mania. Heredity Current evidence indicates a significant genetic role in the causation of bipolar and recurrent major depressive disorders. Although it is not known exactly what is inherited, recent research suggests that heritability involves a broad spectrum of disorders, including milder depressive states. Genetic heterogeneity is likely, and may involve inheritance of a single dominant gene with variable penetrance or in greater likelihood, polygenic inheritance. Different genetic mechanisms will probably involve more than one disorder (e.g., depression and generalized anxiety; bipolar I disorder, stimulant abuse, and alcohol dependence; bipolar II disorder, mood disorder with seasonal patern, bulimia nervosa, and borderline personality).

Developmental Predisposition Parents with mood disorders are often in conflict, which may lead to separation, divorce, and suicide. It can be said that heredity often determines the type of environment into which the child predisposed to mood disorder is born. Developmental object loss, although not specifically involved in causing mood disorder, might modify the expression of the illness, possibly by leading to earlier onset, more-severe episodes, and an increased likelihood of personality disorder and suicide attempts. Temperament Since ancient times, persons prone to mania and melancholia have been described as possessing certain temperamental attributes, representing variations on the theme of what today is subsumed under cyclothymic, dysthymic, and anxious-inhibited temperaments. Many monozygotic twins discordant for full-blown mood disorders studied by Aksel Bertelsen's Danish research team exhibited affective instability with temperamental moodiness, which strongly suggests that such attributes are genetically determined. Research conducted by Kendler's team at the Medical College of Virginia further suggests that several of the temperamental attributes might be transmitted as part of the genetic liability to mood disorders. The author's research has identified such temperaments in the prepubertal offspring of parents with bipolar I disorders, suggesting that they precede by years to decades the overt onset of major mood disorder episodes. The high expressed emotion atmosphere and the negative critical remarks by relatives and affectively unstable patients documented in the recent psychological literature on mood disorders often reflect the interpersonal clashes between patients and their temperamentally intense relatives. Thus, temperaments appear intimately involved in generating much interpersonal friction, emotional arousal, and sleep loss (just to cite common perturbations) thereby eliciting many of the life stressors that precipitate affective episodes. The use of stimulant drugs either to self-treat lethargy or enhance hypomanic traits could further contribute to episode precipitation. Life Events Most individuals do not develop clinical depression when exposed to environmental adversity. Such adversity seems to play a pathogenic role primarily in those with an affective diathesis. Actually, the work of Kenneth Kendler at the Medical College of Virginia indicates that genetic factors might underlie the depressive disorder patients' susceptibility to life events. Furthermore, current data suggest that social stressors in the onset of depression are more relevant to the first few episodes of the illness. The evidence linking such events to mania is less robust. At any rate, stressful events often appear to be triggered by the temperamental instability that precedes clinical episodes. Interpersonal losses are common events in the lives of individuals with intense temperaments. Indeed, a recent study by Peter McGuffin's team at the Institute of Psychiatry, London, raised the possibility that one mechanism by which heredity produces depression is by creating environmental adversities in the lives of individuals predisposed to this illness. This work is now replicated by independent groups of investigators. Whatever the origin of environmental adversity, it is common clinical experience that loss represents an important, perhaps even central, theme in clinical depression. Variables that seem to modulate the impact of adult losses include concurrent life events, resultant changes in lifestyle, lack of interpersonal support, deficient social skills, and the symbolic meaning of the putative loss. The research program of George Brown and his followers in London capitalizes on the foregoing considerations, particularly the importance of early and proximate losses in socioeconomically disadvantaged women who lack supportive relationships. However, that conceptualization downplays the degree to which the social context of the depression reflects the dysthymic temperamental liabilities of those depressed women. Recent research indicates that even social support is determined to a considerable degree by the genetic mechanisms that underlie mood disorders. Biological Stressors Many physical diseases and pharmacological agents are known to precede the onset of both depressive and manic episodes. Like psychosocial stressors, however, they do not generally seem to cause de novo episodes but mobilize them in persons with a personal and family history of mood disorders. Thyroid disturbances have an important role in practice, because they seem to underlie some cases with rapid cycling in bipolar females. Sex Clinical and epidemiological studies concur in suggesting that women are at higher risk for mood disorders, with the risk highest for depression. This now appears in part a function of anxious-depressive traits represented by neuroticism. These traits have strong genetic determinants. Women have higher concentrations of monamine oxidase (the enzyme that breaks down monamine transmitters) in the brain and more precarious thyroid status. In addition, low estrogen and high progesterone concentrations have been postulated as possible mediating factors in postpartum depressions, premenstrual accentuation of affective instability, and women's vulnerability to the depressant effect of steroidal contraceptives. Personality factors might also be relevant to the sex differences in depression. In recent collaborative work with University of Pisa psychiatrist Giulio Perugi, the author has proposed the hypothesis that female sex might favor greater expression of dysthymic attributes, whereas hyperthymic traits appear favored by male sex. Those considerations tend to parallel, respectively, the “ruminative” and “active” cognitive response styles reported by Stanford's Susan Nolen-Hoeksema to distinguish the sexes. What specific sex-related biographical factors might interact with sex-related biological factors to produce such trait differences is presently largely unknown. An intriguing possibility is that women, because of their temperamental inclination to depressive cognitions, might more adversely respond to childhood adversities, as well as being more specifically vulnerable to adult stressors related to bonding with men and child rearing. Research by Mark George and colleagues has raised the provocative possibility that women overrespond to sad circumstances over a lifetime, thereby permanently altering anterior limbic and prefrontal brain function in a depressive direction. The integrative model presented here (Fig. 14.1-3) goes beyond the general provisions of the unified approach developed a quarter century earlier. It is submitted that at least in the highly recurrent forms of the malady, affective temperaments represent the intermediary stage between remote (hereditary) and proximate (stressful) factors and that limbic-diencephalic dysfunction is best characterized as the biological concomitant of the clinical manifestations of the affective syndromes. Like the temperamental dysregulations, these biological disturbances represent a putative stage in the pathogenetic chain. They emerge as temperamental instabilities that react to, provoke, or invite life events, substance use, and alterations in circadian rhythms, which in turn appear to usher in the behavioral, emotional, and cognitive manifestations of the illness.

FIGURE 14.1-3 An integrative pathogenetic model of mood disorders.

THERAPEUTIC PERSPECTIVES The foregoing integrative model envisions the joint use of somatic-pharmacological and psychosocial interventions. Although the milder forms of mood disorders can be managed with psychotherapy, somatic treatments are usually required to reverse the biological disturbances in melancholia before the patient can respond to interpersonal feedback. Depressive disorders with psychotic features often necessitate more definitive somatic interventions such as electroconvulsive therapy. Continued psychopharmacological treatment is also effective in decreasing rates of relapse and future recurrence in most. Psychosocial therapy by skilled clinicians can provide support, combat demoralization, change maladaptive self-attributions, and improve conjugal and vocational functioning. Whether such therapy can also modify personality traits to fortify the patient against new episodes is a future research challenge. In the author's view, it may prove more profitable to attempt to help patients explore professional and object choices that match their temperamental proclivities and assets, which in turn might provide them greater harmony and adaptation in life. Although much needs to be learned about the indications for medication and psychotherapy in different subtypes of mood disorders, research to date not only does not support a negative interaction between the two forms of treatment but on selected parameters suggests additive and even synergistic interaction. There is a great need for patients, their families, and clinicians to understand how a biologically driven illness like depression should be approached from a pragmatic psychotherapeutic perspective. The challenge for psychiatric research in the decade ahead is to elucidate the basic mechanisms whereby the predisposing, precipitating, and mediating variables reviewed here and others yet to be identified interact to produce the final common path of decompensation in melancholia. Because of the heterogeneity of depressive conditions presenting as a psychobiological final common clinical syndrome and because antidepressant agents, irrespective of specificity to one or another biogenic amine, are about equally effective in two-thirds of those with depressive disorders, the antidepressant agents may be acting not on the primary lesions of these disorders but on a neurochemical substrate distal to the underlying biological faults. The choice of antidepressants is still highly determined by the

side effect profile least objectionable to a given patient's physical status, temperament and lifestyle. That so many different classes of antidepressants—with different mechanisms of action—have been marketed in the 1990s represents indirect evidence for heterogeneity of biochemical lesions. The investigation of central neurotransmitter receptor function continues to occupy much current effort to delineate the putative mechanism of antidepressant action and side effects of classic agents as well as the new compounds which have made the treatment of depression “clinician and patient friendly.” Whether study of specific recepters will unravel the molecular mystery of depression remains to be seen. During the past decade, studies have begun on antidepressant and mood-stabilizing effects on molecular mechanisms believed to be closer to the “genetic underpinnings” of mood disorders. Herein is the promise of the future, a new generation of psychiatrists conversant with both clinical phenomenology and molecular biology. Data suggest that the biological specificity of genetic factors in mood disorders might be translated into distinct temperamental dysregulations, which in turn might predispose to different affective subtypes. Returning to the therapeutic arena, mounting evidence indicates that in depressed patients with bipolar disorder, antidepressants might provoke mixed episodes, hypomanic episodes, or both, and possibly increase later cycling. The kindling-sensitization model suggests the utility of anticonvulsant medication on episode escalation and might represent yet another example of pathophysiological intervention. Whatever the merit of this model, the last decade has witnessed intense clinical and research interest and Food and Drug Administration approval of clinical introduction of divalproex (Depakene) for bipolar I disorder, and many other promising anticonvulsants are being developed for that disorder. Anticonvulsant mood stabilizers appear to possess a broad spectrum of activity on bipolar disorders, including mixed dysphoric and rapid-cycling forms. Lithium, by contrast, seems more specific to euphoric mania. Psychoeducational interventions geared to disturbed rhythms of the disorder represent another example of rational therapeutics. Mood clinics should help patients and their significant others to dampen stimulation so that it is kept at an optimal level for depressed patients with cyclothymic traits. All offending drugs (e.g., cocaine, caffeine, and sedative-hypnotic agents) should gradually be eliminated, and circadian disruptions and sleep loss minimized. The greater challenge is learning how to curb the ill-advised actions of patients with cyclical depressions. Psychoeducation and psychotherapy have the task of ameliorating the resulting social problems. Compliance with mood-stabilizer regimens that for many would attenuate episodes and prevent such sequelae is difficult to achieve. Research on compliance-enhancing techniques is needed for the more efficient use of mood stabilizers. It is tempting to suggest that biogenic amines, the “humors” of modern psychobiology, play the same heuristic role as the ancient humors did for many centuries. The black humor, appropriately evoked in the construct of melancholia in DSM-IV, may not have the same claim for etiological relevance to depressive disorders as norepinephrine and serotonin, but at least has a classical heritage. Dopamine, by contrast, may represent the sanguine humor that drives hypomanic temperaments and manic behavior. When genetic factors contributing to clinical depression and mania are discovered, in all likelihood they will be more linked to temperamental dispositions than to fullblown affective disease phenotypes. The clinician will still need to interpret the myriad of influences that impinge on such inclinations to produce disease in an individual patient. That is, fundamental scientific advances in mood disorders, rather than diminishing the role of practitioners, will actually increase it. In any discipline, scientific truth is a function of its technology, but understanding the phenomena under consideration is a matter of philosophical temperament that seeks integration and the hope for a unified vision. Research into the causes and treatment of mood disorders has generated abundant recent data suitable for integration into theory and practice, and conceptualizing the origin and treatment of mood disorders can no longer be justified on the grounds of ideological preference alone.

SUGGESTED CROSS-REFERENCES Anxiety disorders are covered in Chapter 15. The other sections of Chapter 14 cover the various aspects of mood disorders in detail. Epidemiology is the subject of Section 14.2; neurobiologic aspects are the focus of Section 14.4; Section 14.3 is a discussion of genetic aspects; psychodynamic aspects are the subject of Section 14.5. Clinical features are covered in Section 14.6, somatic treatment in Section 14.7 and Section 14.8, and a discussion of psychosocial treatments concludes the chapter in Section 14.9. SECTION REFERENCES Abraham K: Notes on the psychoanalytical investigation and treatment of manic-depressive insanity and allied conditions. In Selected Papers of Karl Abraham. Hogarth Press, London, 1948. Ahrens B, Müller-Oerlinghausen M, Schou M, Wolf T, Alda E, Grof P, Grof G, Lenz C, Simhandl K, Thau P, Vestergaard R, Möller HJ: Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis. J Affect Disord 33:67, 1995. Akiskal HS: Toward a temperament-based approach to depression: Implications for neurobiologic research. Adv Biochem Psychopharmacol 49:99, 1995. Akiskal HS, Downs J, Jordan P, Watson S, Daugherty D, Pruitt DB: Affective disorders in referred children and younger siblings of manic-depressives: Mode of onset and prospective course. Arch Gen Psychiatry 42:996, 1985. *Akiskal HS, McKinney WT: Depressive disorders: Toward a unified hypothesis. Science 182:20, 1973. *Andrews G, Slade T, Peters L: Classification in psychiatry: ICD-10 versus DSM-IV. Br J Psychiatry 174:3, 1999. Aretaeus of Cappadocia: The Extant Works of Aretaeus, the Cappadocian, F Adams, editor-translator. Sydenham Society, London, 1856. Beck AT: Depression: Causes and Treatment. University of Pennsylvania Press, Philadelphia, 1967. Bertelsen A, Harvald B, Hauge M: A Danish twin study of manic-depressive disorders. Br J Psychiatry 130:330, 1977. Bowlby J: Process of mourning. Int J Psychoanal 45:317, 1961. Brown GW, Harris T: Social origins of depression: A study of psychiatric disorder in women. Tavistock, London, 1978. Bunney WE Jr, Davis JM: Norepinephrine in depressive reactions: A review. Arch Gen Psychiatry 13:483, 1965. Carlson GA, Strober M: Manic-depressive illness in early adolescence. A study of clinical and diagnostic characteristics in six cases. J Am Acad Child Psychiatry 17:138, 1978. Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF, James NM, Kronfol Z, Lohr N, Steiner M, de Vigne JP, Young E: A specific laboratory test for the diagnosis of melancholia: Standardization, validation, and clinical utility. Arch Gen Psychiatry 38:15, 1981. Coppen A: The biochemistry of affective disorders. Br J Psychiatry 113:1237, 1967. Cytryn L, McKnew D: Growing Up Sad: Childhood Depression and Its Treatment. Norton, New York, 1996. Delay J: Les Déréglements de L'humeur. Presses Universitaires de France, Paris, 1946. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME: A functional anatomical study of unipolar depression. J Neurosci 12:3628, 1992. Freud S: Mourning and melancholia. In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 4. Hogarth Press, London, 1975. George MS, Ketter TA, Parekh PI, Horwitz B, Herscovitch P, Post RM: Brain activity during transient sadness and happiness in healthy women. Am J Psychiatry 152:341, 1995. Gershon ES, Hamovit J, Guroff JJ, Dribble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI, Goldin LR, Bunney WE: A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry 39:1157, 1982. Gessa GL: Dysthymia and depressive disorders: Dopamine hypothesis. Eur Psychiatry 11:123s, 1996. Gilbert P: Human Nature and Suffering. Erlbaum, New York, 1989. Gillin JC, Sitaram N, Duncan WC: Muscarinic supersensitivity: A possible model for the sleep disturbance of primary depression? Psychiatry Res 1:17, 1979.

*Goodwin FK, Jamison KR: Manic-Depressive Illness. Oxford University Press, New York, 1990. Heninger GR, Delgado PL, Charney DS: The revised monoamine theory of depression: A modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 29:2, 1996. Jackson SW: Melancholia and Depression: From Hippocratic Times to Modern Times. Yale University Press, New Haven, 1986. Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1:632, 1972. Keller MB, Klerman GL, Lavori PW, Fawcett JA, Coryell W, Endicott J: Treatment received by depressed patients. JAMA 248:1848, 1982. Kendler KS, Gardner CO: Boundaries of DSM-IV: An evaluation of DSM-IV criteria. Am J Psychiatry 155:172, 1998. Kendler KS, Karkowski-Shuman L: Stressful life events and generic liability to major depression: Genetic control of exposure to the environment? Psychol Med 27:359, 1997. Kendler KS: Social support: A genetic-epidemiological analysis. Am J Psychiatry 154:1398, 1997. Kendler KS, Eaves LJ, Walters EE, Neale MC, Heath AC, Kessler RC: The identification and validation of distinct depressive syndromes in a population-based sample of female twins. Arch Gen Psychiatry 53:391, 1996. *Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry 50:853, 1993. Kessler RC, Zhao S, Blazer DG, Swartz M: Prevalence, correlates, and course of minor depression and major depression in the national comorbidity survey. J Affect Disord 45:19, 1997. Klerman GL, Lavori PW, Rice J, Reich T, Endicott J, Andreasen NC, Keller MB, Hirschfield RM: Birth-cohort trends in rates of major depressive disorder among relatives of patients with affective disorder. Arch Gen Psychiatry 42:689, 1985. *Kraepelin E: Manic-Depressive Insanity and Paranoia, RM Barclay, translator, GM Robertson, editor. Livingstone, Edinburgh, 1921. Krishman KR: Pituitary size in depression. J Clin Endocrinol Metab 72:256, 1991. Kupfer DJ: REM latency: A psychobiologic marker for primary depressive disease. Biol Psychiatry 11:159, 1976. Lapin IP, Oxenkrug GF: Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1:132, 1969. Leonhard K: The Classification of Endogenous Psychoses, R Berman, translator. Irvington, New York, 1979. Lewinsohn PM, Youngren MA, Grosscup SJ: Reinforcement and depression. In The Psychobiology of Depressive Disorders; Implications for the Effects of Stress , RA Depre, editor. Academic Press, New York, 1979. Lewis A: States of depression: Their clinical and aetiological differentiation. Br Med J 2:875, 1938. Mann JJ, Malone KM, Diehl DJ, Perel J, Cooper TB, Mintun MA: Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients. Am J Psychiatry 153:174, 1996. Maser JD, Cloninger CR, editors: Comorbidity of Mood and Anxiety Disorders. American Psychiatric Press, Washington, DC, 1990. McGuffin P, Katz R, Bebbington P: The Camberwell Collaborative Depressive Study: III. Depression and adversity in the relatives of depressed probands. Br J Psychiatry 152:775, 1988. Murray CJL, Lopez AD, editors: The Global Burden of Disease. World Health Organization, Geneva, 1996. Nazroo JY, Edwards AC, Brown GW: Gender differences in the onset of depression following a shared life event: A study of couples. Psychol Med 27:9, 1997. Nemeroff CB, Widerlov E, Bissette G: Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science

226:1342, 1984.

Nolen-Hoeksema S, Morrow J, Frederickson BL: Response styles and the duration of episodes of depressed mood. J Abnorm Psychol 102:20, 1993. Parry B: Reproductive factors affecting the course of affective illness in women. Psychiatr Clin North Am 12:221, 1989. Post RM: Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999, 1992. Poznanski E, Zrull JP: Childhood depression: Clinical characteristics of overtly depressed children. Arch Gen Psychiatry 23:8, 1970. Prange AJ Jr, Wilson IC, Lynn CW, Alltop LB, Stikeleather RA: L-Tryptophan in mania: Contribution to a permissive hypothesis of affective disorders. Arch Gen Psychiatry

30:56, 1974.

*Puig-Antich J: Affective disorders in children and adolescents. In Psychopharmacology: The Third Generation of Progress , HY Meltzer, editor. Raven, New York, 1987. Rihmer Z, Rutz W, Pihlgren H: Depression and suicide on Gotland: An intensive study of all suicides before and after a depression-training programme for general practitioners. J Affect Disord 35:147, 1995. Schulberg HC: Treating major depression in primary care practice. Eight-month clinical outcomes. Arch Gen Psychiatry 53:913, 1996. Seligman MD: Helplessness: On Depression, Development and Death. Freeman, San Francisco, 1975. Siever LJ, Davis KL: Overview: Toward a dysregulation hypothesis of depression. Am J Psychiatry 142:1017, 1985. Steffens DC, Krishnan KR: Structural neuroimaging and mood disorders: Recent findings, implications for classification and future directions. Biol Psychiatry 43:705, 1998. van Praag HM, Kahn RS, Asnis GM, Wetzler S, Brown SL, Bleich A, Korn ML: Denosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders. J Affect Disord 13:1, 1987. Wehr TA, Rosenthal NE: Seasonality and affective illness. Am J Psychiatry 146:829, 1989. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam E, Lee CK, Lellouch J, Lépine JP, Newman SC, Rubio-Stipec M, Wells JE, Wickramaratne PJ, Wittchen HU, Yeh EK: Cross-national epidemiology of major depression and bipolar disorder. JAMA 276:293, 1996. Wilhelm K, Parker G, Hadzi-Pavlovic D: Fifteen years on: Evolving ideas in researching sex differences in depression. Psychol Med 27:875, 1997. Weller EB, Weller RA: Bipolar disorder in children: Misdiagnosis, underdiagnosis, and future diagnosis. J Am Acad Child Adolesc Psychiatry 34:709, 1995. Wells K, Steward A, Hays R, Burnam M, Rogers W, Daniels M, Berry S, Greenfield S, Ware J: The functioning and well-being of depressed patients: Results from the medical outcomes study. JAMA 262:914, 1989. Whybrow P, Mendels J: Toward a biology of depression: Some suggestions from neurophysiology. Am J Psychiatry 125:45, 1969. Winokur G, Clayton PJ, Reich T: Manic-Depressive Illness. Mosby, St Louis, 1969. Zis KD, Zis A: Increased adrenal weight in victims of violent suicide. Am J Psychiatry 144:1214, 1987.

Textbook of Psychiatry

14.2 MOOD DISORDERS: EPIDEMIOLOGY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.2 MOOD DISORDERS: EPIDEMIOLOGY DAN G. BLAZER II, M.D., PH.D. Introduction Case Identification Distribution of Cases Historical Trends Identification of Causes Demographic Factors Prognosis Use of Health Services Suggested Cross-References

INTRODUCTION Since the 1980s community-based epidemiologic studies of mood disorders throughout the world have been significantly influenced by two large community-based surveys in the United States, the 1981 Epidemiologic Catchment Area Study and the 1991 National Comorbidity Survey. Not only did these surveys provide estimates of the prevalence and distribution of discrete psychiatric disorders (in synchrony with the shifting orientation from symptom burden to operational psychiatric diagnoses reflected in the third edition of Diagnostic and Statistical Manual of Mental Disorders (DMS-III) and its successors, they also demonstrated the feasibility of identifying psychiatric patients by use of assessment procedures that could be administered by nonprofessional interviewers. ECA investigators used the Diagnostic Interview Schedule (DIS) and NCS investigators used a modified version of the Composite International Diagnostic Interview (CIDI). These case assessment procedures have now been used in countries throughout the world, including Canada, Finland, Korea, Taiwan, and New Zealand. Most of the data presented in this chapter derive from community-based estimates of the frequency, distribution, and correlates of depressive symptoms and major depressive disorder as estimated from these studies. Bipolar disorders receive less attention than they do in clinical studies because community-based epidemiological data are sparse. The lifetime prevalence of mood disorders is high in Western society. Estimates of the lifetime prevalence of mood disorders are presented in Table 14.2-1.

Table 14.2-1 Lifetime Prevalence of Some DSM-IV Mood Disorders

CASE IDENTIFICATION Case identification (i.e., determining who should be diagnosed as experiencing a mood disorder versus who is only expressing a normal fluctuation in mood) has been at the center of debate regarding the true frequency of mood disorders in the community. This debate derived largely from the significant variance in the estimates of the current and lifetime prevalence of major depressive disorder in the ECA and NCS studies, as demonstrated in Figure 14.2-1, Figure 14.2-2, Figure 14.2-3 and Figure 14.2-4. This debate has relevance to clinicians who treat patients experiencing mood disorders, for they must distinguish normal variations in mood from the mood disorders. The diagnostic criteria for the specific mood disorders in the DSM, which has gone through four editions since its inception, are not easily applied in epidemiological studies. Some diagnostic categories, such as adjustment disorder with depressed mood, cannot be operationalized in standardized interviews because the criteria require a subjective clinical judgment (e.g., the mood disturbance must be related to a specific stressor). Other diagnoses are too inclusive when applied to community samples (e.g., major depressive disorder). Patients identified by current diagnostic criteria are therefore a heterogeneous mix with little clinical relevance beyond symptom severity. In other words, the borderline between clinical depression and normal fluctuation in mood is fuzzy. Even the presence or absence of a symptom may be disputed.

FIGURE 14.2-1 Current prevalence of major depressive disorders by age and gender. (Data derived from the Epidemiologic Catchment Area Study.)

FIGURE 14.2-2 Current prevalence of major depressive disorders by age and gender. (Data derived from the National Comorbidity Survey.)

FIGURE 14.2-3 Lifetime prevalence of major depressive disorders by age and gender. (Data derived from the Epidemiologic Catchment Area Study.)

FIGURE 14.2-4 Lifetime prevalence of major depressive disorders by age and gender. (Data derived from the National Comorbidity Survey.)

Some persons in community samples may exhibit depressive syndromes that do not fit the DSM diagnostic system (e.g., for major depressive disorder or dysthymic disorder), but they nevertheless suffer disabling depressive symptoms. Much attention has been focused in recent years on so-called minor or subsyndromal depressive disorder, a syndrome defined by symptoms that are less severe than those of major depressive disorder and of shorter duration than those of dysthymic disorder. The frequency of minor depression was estimated to be nearly 4 percent in the ECA study. Minor depression has generally been divided into two categories: less severe episodes that occur in conjunction with major depressive disorder and symptoms that occur spontaneously. Persons identified in community surveys as experiencing minor depressive disorder have been shown in prospective studies to be at greater risk for time lost at work and increased use of general health services than persons without depressive symptoms. In addition, their risk factor profile is similar to that for major depressive disorder. Another problem that complicates estimation of the frequency of mood disorders in the community is deterioration of memory over time. Recall of past symptoms is only modestly accurate compared with clinical records of previous depressive episodes. The threshold for reporting a symptom of depression may be higher in a community than in a clinical setting because clinicians often probe for evidence of a symptom that the patient initially denies. Most interview instruments used in epidemiological surveys to identify DSM diagnoses, such as the DIS used in the ECA, were developed in clinical settings and were standardized with classic patients who present to psychiatric treatment settings. In contrast, the modified version of the CIDI used in the NCS (see below) was designed to probe for past history of symptoms more thoroughly than he DIS, because the emphasis of the CIDI was on identifying affected persons in the community who were not experiencing clinically significant depressive symptoms and who had never sought psychiatric treatment. As the threshold for case identification is lower with the CIDI, the estimate of both current and lifetime prevalence of mood disorders is higher. Most persons identified as having mood disorder in the community with the CIDI experience little disruption in function and do not seek psychiatric treatment. Should persons who meet strict fourth edition of DSM (DSM-IV) criteria when interviewed by nonclinicians and asked in detail about past and present symptoms be considered to have true cases of mood disorder, especially major depressive disorder? Therein lies much of the debate. Comorbidity presents another problem to psychiatric epidemiologists who study mood disorders in community settings. More often than not, symptoms of anxiety and depression overlap. Many subjects receive concurrent diagnoses of major depressive disorder, dysthymic disorder, and generalized anxiety disorder. Most community survey subjects cannot accurately remember whether depression or anxiety was the first syndrome experienced. Do major depressive disorder and generalized anxiety disorder coexist, or is anxiety an epiphenomenon of major depressive disorder? That question remains unanswered. Nevertheless, development of standardized instruments for case identification in the community, such as the DIS and CIDI, has made it possible to investigate empirically the utility of psychiatric diagnosis. For example, when investigators do not agree upon the frequency of mood disorder with seasonal pattern (i.e., seasonal affective disorder) they can explore their disagreements by using the same criteria and diagnostic instruments for case identification. A recent study demonstrated that though a seasonal pattern of mood swings is common among persons in the community (approximately 8 percent), the frequency of mood disorder with a seasonal pattern, as defined by DSM-IV, is less than 1 percent, even when the most liberal interpretation of the criteria is applied.

DISTRIBUTION OF CASES Estimates of the prevalence of major depressive disorder by age and gender from the ECA and NCS studies are presented in Figure 14.2-1 and Figure 14.2-2. The DIS was administered for case finding in the ECA study to over 18,000 community and institutionalized subjects (18 + years of age) at five sites throughout the United States—New Haven, East Baltimore, St. Louis, the Piedmont of North Carolina, and Los Angeles. The large numbers of subjects and oversampling of subjects not accurately represented in previous studies, such as African-Americans, Hispanics, and elderly persons, enabled much better estimates of the actual distribution of cases. Over 8000 subjects (15 to 54 years of age) from a nationwide sample were administered a modified version of the CIDI in the NCS study. Age, Sex, and Residence The most striking finding from the ECA study was a much higher prevalence of all the mood disorders among persons under the age of 45 than in persons 45 years of age and older. Rates were comparable across ECA sites, except for a lower prevalence in North Carolina. The North Carolina sample was composed of both urban and rural residents. Persons in urban areas were as likely to be diagnosed with a mood disorder in North Carolina as in urban areas at other ECA sites. In contrast, rural subjects in North Carolina had much lower rates of major depressive disorder than rural subjects at other ECA sites. In the NCS study, variance by age and geographic location was much less prominent. The most consistent finding across epidemiological studies of the mood disorders, confirmed by the ECA and NCS studies, is the relatively higher prevalence of major depressive disorder in women than in men. The sex differences are consistent across the life cycle but are much more prominent in young adult and middle-aged persons than in elderly persons and childhood depressive disorders. Because alcohol abuse and mood disorders are often inherited in the same family and alcohol abuse and dependence is more prevalent in men than in women, some have theorized that depressive disorders and alcohol abuse/dependence are phenotypic variants of the same genotype. Little empirical evidence supports this theory. Sex differences begin in early adolescence and persist at least until midlife. However, women with a previous history of a depressive episode are no more likely to experience a new episode than men with a previous history of a depressive episode. This suggests that the higher risk in women results from women having a higher

risk of experiencing major depressive disorder for the first time. Psychosocial explanations for the higher prevalence of major depressive disorder among women are thus considered the most likely explanation of the sex differences. Epidemiologists have identified stressors that may contribute to increased stress experienced by women, such as maintaining multiple roles as homemaker, professional, wife, and mother. Race and Ethnicity As illustrated in Figure 14.2-5, the prevalence of the mood disorders does not vary significantly by race or ethnicity. In most epidemiological studies of psychiatric disorders, racial differences in the rates can be explained by socioeconomic and educational differences. The ECA was the first study in Western society that permitted direct comparison of whites, African-Americans, and Hispanics. Previous comparisons, which could not control for geographical differences, were subject to significant bias because prevalence estimates clearly vary by place of residence. The NCS results are similar to the ECA results, though as noted, the overall rates are higher.

FIGURE 14.2-5 Current (1-year) prevalence of major depressive disorder by race or ethnicity. (Data derived from the Epidemiologic Catchment Area Study.)

International Studies Perhaps the most frequently cited epidemiologic study prior to the ECA and NCS studies was the Stirling County Study from Nova Scotia, Canada. The current prevalence of major depression was estimated to be 4.7 percent in men and 6.0 percent in women. Most studies in developed countries estimate the distribution of major depressive disorder to be greater in women than in men, in young adulthood than in midlife and old age, in urban residents than in rural residents, and among single or divorced persons than among married persons. Few studies document a racial difference when social class and education are controlled. In a recent comparison of population-based epidemiologic studies in 10 countries—the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Taiwan, Korea, and New Zealand—the lifetime prevalence for major depressive disorder ranged from 1.5 percent in Taiwan to 19 percent in Beirut. Current prevalence ranged from 0.8 percent in Taiwan to 5.8 percent in New Zealand. The difference in prevalence estimates across countries suggests that cultural differences or differences in risk factors may influence the expression of major depression. Depressive Symptoms The differential frequency of clinically significant depressive symptoms parallels that of major depressive disorder, although the age differences are not nearly so great. In most studies, 8 to 20 percent of community-study participants report depressive symptoms at a level above the cutoff used to screen for major depressive disorder, such as 16 + on the Center for Epidemiologic Studies Depression Scale (CES-D). As with all good screening tests, many potential patients are screened out with more-specific case-identification techniques, such as a standardized diagnostic instrument. Therefore, many persons who appear positive on screening do not meet criteria for specific DSM-IV mood disorders. Those who do appear positive on screening for depressive symptoms, however, experience higher mortality rates, higher disability rates, and poor social functioning. Incidence Because major depressive disorder is common and tends to remit and recur, the incidence is relatively high. The annual incidence of major depressive disorder in the ECA study was 1.59 percent overall. The distribution by age and gender is presented in Figure 14.2-6. A survey in Lundby, Sweden, revealed an annual first incidence of depression (depression in persons who never experienced depression before) of 0.43 percent in men and 0.76 percent in women. Up to the age of 70, the cumulative probability of a first episode of depression was 27 percent in men and 45 percent in women, making depression one of the most important public health problems (Fig. 16.2-7).

FIGURE 14.2-6 Annual incidence of major depressive disorders by age and gender. (Data derived from the Epidemiologic Catchment Area Study.)

Setting The prevalence of major depressive disorder is much higher in treatment settings than in the community at large. Most investigators find that 10 to 15 percent of persons in acute hospital settings and long-term care facilities meet the criteria for the diagnosis of major depressive disorder. An additional 20 to 30 percent of persons in treatment settings report clinically significant subsyndromal depression (minor depression). The similarities between those patients with major depressive disorder to patients found in psychiatric treatment settings has yet to be documented. Although some depressed medically ill patients respond to antidepressant therapy and brief psychotherapy, many have comorbid conditions that render traditional therapies ineffective. Depression is also more prevalent in primary care settings than in the general population. Using case-identification methods similar to those in the ECA study, the current prevalence of depression is about twice that found in the general population. In most surveys of primary care clinics, over 20 percent of patients report clinically significant depressive symptoms. Major depressive disorder is diagnosed in one-third to one-half of these outpatients. Young women are at greatest risk for depression in primary care, and most persons who report depressive symptoms to a health care professional report them to a primary care physician.

HISTORICAL TRENDS The higher prevalence of depression in younger age groups than in older ones has led to the hypothesis that birth cohorts born after World War II are at appreciably greater risk for major depressive disorder than older birth cohorts in advanced Western society. The trend has been observed not only in the United States but also in Sweden, Germany, Canada, and New Zealand. A number of observations made prior to the ECA study suggest that prevalence rates of depressive disorders are changing. Relevant factors include a progressively lower age of onset of depressive disorders reported in community studies, an increase in childhood mood disorders seen by pediatricians and mental health workers, a decrease in deaths from suicide among the elderly (until about 1980), and a lower average age of onset for depressive disorders in clinical samples since World War II. For example, the risk of first-onset depression was higher for younger birth cohorts than for older birth cohorts in Sweden ( Fig. 14.2-7). The trends in suicide data parallel the trends in mood disorders (i.e., suicide rates are much higher in younger persons today than they were in younger persons 30 years ago). Suicide rates in older adults have increased by 25 percent since 1980.

FIGURE 14.2-7 Risk of contracting a first-onset depressive disorder for younger birth cohorts and older birth cohorts in Sweden. (Data derived from Hagnell O, Lanke J, Rorsman B, Ojesjo L: Are we entering an age of melancholy? Depressive illnesses in a prospective study epidemiological study over 25 years: The Lundby Study, Sweden. Psychol Med 12:279, 1982.)

Factors That Influence Historical Trends Three factors influenced historical trends in the relative prevalence of mood disorders by age: period effect, age effects, and cohort effects. Period effects are changes in the prevalence of an illness secondary to environmental stressors on the population or particular age groups within the population at a specific period in history. (For example, the uncertainty of employment among college graduates and the trend among younger persons to delay marriage during the 1990s may place young adults at greater risk for depression and suicide because of economic impairment and lack of affiliative relations.) Age effects are the biological and psychosocial factors that predispose an individual to develop a particular disorder during a specific part of the life cycle. (For example, the genetic predisposition to develop major depressive disorder is probably greatest during the 30s, whereas the predisposition to develop a bipolar disorder is greatest during the 20s.) Age-related changes in the brain, such as increased subcortical hyperintensities on brain magnetic resonance imaging, may also be associated with mood disorders. Perhaps the most consistently observed age effect relevant to mood disorders that has been observed during the 20th century is the positive association between age and suicide among white males in the United States. Cohort effects are the relative differences in rates of illness across different generations. A cohort is usually defined by the year or decade of birth. Persons born in a given year may be at greater risk for an illness, such as major depressive disorder, throughout their lives. Suicide data reveal marked cohort trends throughout the 20th century. (For example, persons currently 75 to 85 years of age [approximately the birth cohorts of 1915 to 1925] have exhibited lower suicide rates at all ages than either the 1900 or the 1940 birth cohorts.) Considerable statistical and methodological problems confound sorting out the relative contribution of period, age, and cohort effects upon the prevalence and incidence of mood disorders by age. First, these effects undoubtedly interact. Stressors during a particular period interact with age-related vulnerability. (For example, the current high rate of substance abuse among adolescents may reflect both the vulnerability of adolescents to substance abuse, an age effect, and the greater availability of drugs to adolescents, a period effect.) Second, older persons may not recognize major depressive episodes as such and so do not report them, thus setting the threshold for identifying depression among community-dwelling elders higher. Yet age does not appear to affect the rate of hospitalization for mood disorders. The more severe cases of major depressive disorder are hospitalized, regardless of age, and the relative cohort differences persist in hospitalization rates. Most investigators have explained the current data as reflecting a period effect. They argue that the risk for depressive disorders increased dramatically for all ages from about 1965 to 1975 but has since stabilized at a higher incidence. Young persons are more vulnerable to that period effect, however, and therefore carry the greatest burden of depressive disorders. A young person who experiences a major depressive episode is likely to exhibit ongoing and severe depressive episodes for many years. Therefore, clinicians can expect to see the current cohort of younger persons bear the burden of major depressive disorder for a long time. Despite being the healthiest and most affluent generation of the 20th century, younger persons may be placed at greater risk for major depressive disorder by a number of environmental risk factors, including increased urbanization, increasing social isolation and anomie, changes in occupational roles and career trajectories for both men and women, increased secularization, and increasing geographic mobility.

IDENTIFICATION OF CAUSES The risk factors for bipolar I disorder and major depressive disorder identified from community- and clinically based epidemiological studies are summarized in Table 14.2-2. Most have been replicated, yet some most interesting hypotheses about risk for mood disorders have failed to hold up with repeated study. For example, an increased risk for major depressive disorder was discovered in an isolated community of Hutterites who live near the border between the United States and Canada, suggesting that the rigid moral control they exert predisposes community members to depression. Most community studies, however, fail to find that identification with or participation in particular religious groups is associated with an increased risk for major depressive disorder. In contrast, virtually every community survey has demonstrated increased risk for major depressive disorder and depressive symptoms in persons who report negative life events.

Table 14.2-2 Risk Factors for Bipolar I Disorder and Major Depressive Disorder

DEMOGRAPHIC FACTORS Sex Almost all community-based epidemiological surveys of mood disorders that compare prevalence by sex find that women are twice as likely as men to experience an episode of major depressive disorder. Few investigators discount this finding as an artifact of prejudice in the diagnostic criteria for major depressive disorder or of increased help-seeking behavior among women. Yet female sex has not been demonstrated to be a risk factor per se. The social environment of women and a higher threshold for reporting depressive symptoms in men may account for the increased association. Yet, as discussed above, no mechanism for this apparent increased risk has been established. Age The average age of onset for both major depressive disorder and bipolar disorders falls between 20 and 40 years. Recent studies also confirm that major depressive disorder can occur in childhood. Bipolar I disorder typically has an earlier age of onset than major depressive disorder, with an average of 30 years. Yet both major depressive disorder and bipolar disorder can first occur at any time during adulthood. Nothing suggests that young age per se places a person at greater risk for the mood disorders (though genetic factors may have their greatest influence at a younger age). Social factors appear to place younger persons at greater risk than elderly persons. Biological predisposition to major depressive disorder may actually increase with age.

Race and Ethnicity Race or ethnicity has not proved to be a significant risk factor for either bipolar I disorder or major depressive disorder. In some community surveys, African-Americans experience a higher prevalence of depressive symptoms. The racial difference usually disappears, however, when other factors, such as socioeconomic status, age, and residence, are controlled. Because treatment for mood disorders is less common for African-Americans than for whites, prevalence studies based on treatment samples usually contain proportionately more whites. Rates for major depression were estimated as higher among Hispanics than among whites and African-Americans in the NCS study in controlled analyses. To date, too few Asians have been included in community-based studies in North America and Europe to permit comparative estimates of risk for Asians. The similarity in overall rates across racial or ethnic groups does not necessarily mean a similarity across all symptoms. For example, older African-Americans have been found more likely to complain of interpersonal problems when depressed and less likely to complain of depressed mood than older whites. Socioeconomic Status The findings from community-based studies relating to socioeconomic status as a risk factor for-depression are mixed. The overall ECA studies found only a weak correlation between major depressive disorder or bipolar disorders and lower socioeconomic status. The North Carolina ECA study, however, found a consistent relation between socioeconomic status and major depressive disorder, even when multiple potential confounders, such as race and residence, were controlled. In the NCS study, both lower income and education were associated with higher prevalence of major depression. Studies prior to the ECA and NCS found a consistent positive relation between lower socioeconomic status and depression. In one classic study reported by A.B. Hollingshead and Frederick C. Redlich, depressive symptoms were strongly associated with the lower social classes. In a more recent study, working-class women from an eastern suburb of London were much more likely to suffer depressive symptoms than women from higher social classes. Marital Status Marital status appears to be one of the most consistent risk factors for both depressive symptoms and major depressive disorder. Rates for major depressive disorder are highest among separated and divorced persons and lowest among single and married persons. Recent widowhood is associated with higher rates of major depressive disorder across the life cycle. The risk appears to vary with sex. Single women have lower rates of depression than married women, whereas married men have lower rates than single men. However, the investigator must not confound marital status with the loss of a spouse through death or divorce (a stressful life event). If a woman was widowed during the 6 months prior to the study, then the event not the status is perhaps the causative factor. In addition, cause and effect may be reversed (e.g., depressive illness may place a person at greater risk for divorce). In most studies, however, separated or divorced status places a person at greater risk for depression, even if the marital breakup occurred long before the assessment. The ECA studies, unlike previous studies, also documented a much higher prevalence of bipolar disorders among separated and divorced persons than among those who were single. The highest rates, however, were found among those who were cohabiting, even when adjusting for age, sex, and race or ethnicity. The association of the mood disorders and marital status is also reflected in the association of mood disorders with household size. Major depressive disorder is twice as common among persons living alone than among those who live with others. In persons not living alone household size is not associated with depression. Marital status may not be the proximal causative factor. The perception of social support and lack of conflict within the social network are critical factors in protecting against mood disorders. Longitudinal studies of the social network and neuroses have shown that the most important predictors of depression are not the objective characteristics of the network but rather the perception of how adequately the network assisted the person. Large-scale community-based investigations of the risk factors for major depressive disorder cannot disentangle the subtleties of the complex interactions between persons and their social network. (For example, dissolution of a difficult marriage may relieve long-standing depressive symptoms.) Family History Most epidemiological studies of treatment samples have shown a consistent increase in family history of mood disorders among subjects, especially in first-degree relatives. A family history of suicide and alcoholism has also been repeatedly found to be more common among depressed subjects than among controls. Most experts attribute the increased risk for depression when family history is positive to a genetic predisposition; yet shared family environment may also contribute to the increased risk. Genetic transmission is much more firmly established for bipolar I disorder than for major depressive disorder. In family members of bipolar subjects, both bipolar disorder and major depressive disorder are more prevalent. Early Childhood Experience Much attention has been directed to the association of early childhood experience with onset of mood disorders later in life. Although the complexities of a psychodynamic investigation of childhood traumas cannot be applied in community-based epidemiological studies, even cursory investigation of childhood experiences has revealed correlates. Parental loss before adolescence is a well-documented risk factor for adult-onset depression. A deprived and disrupted home environment also constitutes a risk. Methodological problems make objective study of childhood trauma and deprivation difficult. Some events (e.g., divorce or separation of parents) can be documented reliably, but others (e.g., parental neglect) are quite subjective. The report of parental neglect by a depressed adult may vary depending on the respondent's emotional state at the time of the interview. Personality Attributes Personality attributes are closely associated with early childhood experience as a risk for mood disorders in later life. Persons predisposed to develop a depressive disorder lack energy, are more introverted, worry, are more dependent, and are hypersensitive. Major depressive disorder is also frequently comorbid with the Axis II disorders; yet the study of the relation of depression and personality is confounded by the time at which personality is studied. Epidemiologists rarely have the opportunity to assess personality before the onset of the first episode of depression. If personality is assessed during an episode of depression, then the depressive symptoms mask certain personality traits and exaggerate others. When a person has experienced and recovered from a depressive episode, its impact on personality makes accurate assessment of premorbid personality difficult. (For example, the personality characteristics associated with depression are exactly those that might emerge in response to the experience of a serious psychiatric disorder.) Social Stressors Social stressors have received more attention than other risk factors for major depressive disorder across the life cycle, except sex. Three kinds of social stressors can be distinguished: life events, chronic stress, and daily hassles. Life events are the kind most often explored in epidemiological studies. They are identifiable, discrete changes in life patterns that disrupt the usual behavior and threaten the person's well-being. Bereavement, the reaction to loss of a loved one, is the prototypic stressful life event. Chronic stress includes long-term conditions that challenge the person, including financial deprivation, ongoing interpersonal difficulties (e.g., conflict in the workplace), and persistent threat to security (e.g., living in a dangerous neighborhood). Daily hassles are ordinary but stressful occurrences that are ubiquitous in modern life (e.g., managing household finances and unpleasant interactions with neighbors). Most epidemiological studies reveal a relation between stressful life events, especially negative events, and the onset and outcome of major depressive disorder. Nevertheless, the use of stressful life event scales such as the Schedule of Recent Events introduces many potential biases into the study of stressors and depression. Such scales usually tally the number of events and weight them according to a predetermined algorithm. Most schedules weight events on the basis of normative data from the population. Because the data usually derive from weightings provided by young adults, they do not necessarily apply across the life cycle. (For example, retirement in late life may be a positive event, whereas premature retirement in midlife may present problems that can precipitate a depressive disorder.) The perception of the event is probably more important than the event itself. More-sensitive measures of stressful events document not only the event itself but the subject's response to it. Was the event perceived to be positive or negative? Even the death of a spouse may be viewed as a positive event if it occurred after a protracted and disabling illness during which the subject was the caretaker. Was the event perceived to be important or unimportant? For some older persons a move may be extremely traumatic, especially if it is the first move in half a century. For others, a move may be a usual and relatively unimportant event, especially in a society in which mobility is becoming more the norm. Was the event expected or unexpected? If income decreases at retirement at a rate expected by the retiree, then the loss of income is much less stressful than if a person is forced to take an unexpected cut in salary while still in the workforce. The accumulation of stressful negative life events does appear to predispose a person to episodes of major depressive disorder. In a study from New Haven, depressed patients had an average increased frequency of eight life events during the 6 months preceding the onset of depressive symptoms. Those events included marital arguments, marital separation, starting a new type of work, change in work conditions, serious personal illness, death of an immediate family member, serious illness of family members, and a family member leaving home. Stressful events are also associated with the persistence of depressive disorders. In a study from England, adverse events during the year following the initial episode of depression were associated with a poorer outcome of the episode. The adverse effects of life events may be offset by neutralizing events. (For example, if a woman loses her job but soon after finds another job with equal pay and benefits, then the adverse event is neutralized.) In addition, the impact of a stressful life event may vary depending upon when that event occurs in the natural history of a mood disorder. Persons experiencing a recurrent major depressive disorder are less likely to report a stressful event associated with the onset of episodes after the first two episodes of depression. The phenomena of kindling may become the predominant impetus for recurrent depressive episode. Chronic stress can place a subject at greater risk for major depressive disorder than specific stressful life events. The stress of service in the Persian Gulf War led to increased frequency of major depressive disorder among military personnel. As long as soldiers are deployed, they have difficulty recovering from the major

depressive episode. In addition, the long-term effects of being deployed also may increase the risk of depression following military service. Persons usually have more difficulty coping with a chronic stressful situation than with specific events. Few studies document the association of daily hassles with the onset of major depressive disorder. Yet, impulsive acts such as a suicide attempt may be closely associated with daily hassles to which the subject cannot adapt within the context of a stressful life event or chronic stress. That is, daily hassles may be the straw that breaks the camel's back. Social Support Factors in the social environment that may modify the effects of social stressors have received increased attention in the epidemiological investigation of both physical and psychiatric disorders. One factor is social support, the provision of meaningful, appropriate, and protective feedback from the social environment that enables a person to negotiate environmental stressors. In theory, social support is an attractive concept, for it is potentially more amenable to intervention than environmental stressors. The roots of the construct social support go back at least to the early twentieth century, when Emile Durkheim proposed that persons who are not integrated into society (the condition called “anomie”) are at greater risk for suicide. Social support has four components: the social network, social interaction, perceived social support, and instrumental support. The social network is assessed by identifying those individuals or groups of individuals (e.g., a spouse and children) who are available to the subject. The absence of a spouse is a risk factor for major depressive disorder. Social interaction is assessed by determining the frequency of interactions between the subject and other network members. A number of studies confirm that social isolation (i.e., a deficit in social interaction) places a subject at greater risk for depression. Yet the quality of the interaction appears to be more important than the frequency of interaction. Perceived social support is assessed by determining the subjective evaluation by the individual of the dependability of the social network, the ease of interaction with the network, the sense of belonging to the network, and the sense of intimacy with network members. The association of major depressive disorder and expressed absence of a confidant exemplifies the relation between perceived inadequate support and depression. Instrumental support is assessed by determining the concrete and observable services that are provided to the subject by the social network (for example, cooking meals, financial assistance, and nursing services for the physically ill). Although such support is essential to the well-being of the young and the elderly in society, few studies document the association of depression with a deprivation of instrumental support. The physical health of the person is a confounding factor. The need for instrumental support is usually not recognized until the person exhibits an actual need for such services. In addition, the perception of the availability of those services in a time of crisis may not reflect the actual availability. The construct of social support is strongly influenced by the construct of social integration. An integrated society is a social system that ensures the patterns of interpersonal behavior that are essential to the survival and welfare of its members. Those patterns enable persons to obtain what is needed for subsistence and protection against weather and disease, control hostility and other forms of social disruption, create new members and their education and communication, store information, and permit decision making and united action. Alexander Leighton and his colleagues undertook the most ambitious epidemiological studies of social integration and mental health in a survey of communities in Nova Scotia. Social scientists and anthropologists studied each community to determine its relative integration versus disintegration. At all ages, the rates of depressive disorders (and other psychiatric disorders) were higher in disintegrated communities. Studies of social integration are not as proximal to the individual as studies of social stressors and social support because measures of social integration are not specific to the individual. Studies of integration are ecological, for they document that the overall functioning of the community is associated with the overall level of psychopathology. Most ecological studies in psychiatric epidemiology have been limited to comparisons of communities by traditional parameters, most commonly, urban versus rural residence. The hypothesis is that rural communities are less stressful than urban communities. In the ECA study of North Carolina, major depressive disorder was twice as common in the urban community, with the largest differences among the young (under 45 years of age) and among women. Those urban-rural differences in prevalence persisted even when the comparison was controlled for race, socioeconomic status, marital status, and age. Nevertheless, most ecological studies fail to demonstrate that after adjusting for other factors, communities determined to be socially integrated protect against mood disorders. The reason, probably, is that investigators are usually studying diverse communities and thus the concept of social integration is probably not relevant in complex societies in which communities are layered upon one another or are patterned together in a mosaic that cannot be easily disaggregated. Another risk factor for depression is unemployment. At present, most men and women under the age of 65 are in the labor force. Men and women who were unemployed for at least 6 months during the 5 years prior to the ECA survey were more than three times as likely as others to report symptoms of an episode of major depressive disorder during the year prior to the survey. In the NCS study, the rate of major depression was three times higher in persons not working than in those working. Homemakers were nearly three times more likely to experience major depression than the employed as well. The multiple risk factors for mood disorders form a web of causation. Each factor cannot only affect the subject directly but can interact with other factors. Mathematical models of causative factors are therefore useful for determining the relative importance and complex interaction of those factors. Models include linear and logistic regression analyses. An example is presented in Table 14.2-3. In this logistic regression analysis, sex, education, income, marital status, employment, and household composition are the control (or adjusted) variables. The net effect of risk factors in the NCS is presented as an odds ratio, an approximation of the relative risk of persons with the characteristic developing a major depressive episode compared with that of persons without the characteristic. For example, the risk for females is 1.36 times greater than that for males.

Table 14.2-3 Adjusted Odds Ratios for Prevalence of Current (30-day) Major Depressive Episode, by Selected Demographic Characteristics

PROGNOSIS Two recent studies have concentrated on the public health impact of depressive disorders, because of their chronic and disabling nature. In the first, over 1000 patients in a variety of primary care settings were screened for depression. Patients with either depressive disorder or depressive symptoms (without a diagnosis of a specific mood disorder) tended to have worse physical, social, and role functioning. When their objective health status was controlled, they perceived their current health to be worse than did patients who were not depressed, and they reported more physical pain. The poor functioning associated with depressive symptoms, with or without a diagnosis of a mood disorder, was comparable to or worse than that in eight major chronic medical conditions. The number of days in bed with depressive symptoms was significantly greater than with hypertension, diabetes, or arthritis. In the second study, the ECA sample in North Carolina, persons with a diagnosis of major depressive disorder or dysthymic disorder and with symptoms of minor depressive disorder were followed for 1 year. Compared with asymptomatic individuals, persons with major depressive disorder had a fivefold greater risk of disability, and persons with minor depressive disorder had one-and-one-half times the risk. Persons with minor depressive disorder were at greater risk of developing major depressive disorder at 1-year follow-up. A number of natural history studies of mood disorders have been performed on clinical samples. The most extensively studied cohort derives from the Psychobiology

of Depression Study and consists of over 500 young adult and middle-aged subjects diagnosed with either bipolar I disorder or major depressive disorder. Following diagnosis about 50 percent of subjects recovered during the first year, but fewer than 30 percent of the others recovered during subsequent years. Comorbid dysthymic disorder with a slow onset accompanying psychotic symptoms was associated with less likelihood for recovery. Relapse rates are high for major depressive disorder immediately following recovery. Superimposed dysthymic disorder and a history of three or more major depressive episodes were associated with relapse. Bipolar I disorder patients with only manic episodes had better outcomes than those with major depressive disorder. However, bipolar I patients with a mixed episode (depression and mania) or with rapid cycling had worse outcomes than those with major depressive disorder.

USE OF HEALTH SERVICES Health services for mood disorders are provided in general health care settings and in specialty settings. Most mental health visits reported by subjects in the ECA study, regardless of disorder, occurred in primary care settings for older persons and in specialty settings for younger persons. Women use mental health services in both settings about twice as often as men. Visits are about equally distributed between general medical providers and mental health specialists. Persons who were depressed used health services more frequently than those with no psychiatric disorder.

SUGGESTED CROSS-REFERENCES An overview of epidemiology is given in Section 5.1. Social origins of mood disorders are discussed in Section 4.2. Classification of mental disorders is presented in Chapter 9. Specific review of the genetics of mood disorders can be found in Section 14.3. The role of stress in the etiology of psychiatric disorders is discussed in Section 25.9. Suicide is discussed in detail in Section 29.1. The epidemiology of psychiatric disorders in late life is reviewed in Section 51.1b. SECTION REFERENCES Blacker CVR, Clare AW: Depressive disorder in primary care. Br J Psychiatry 150:737, 1987. Blazer DG, Bachar IR, Manton KG: Suicide in late life: Review and commentary. J Am Geriatr Soc 34:519, 1986. Blazer DG, George LK, Landerman R, Pennybacker M, Melville ML, Woodbury M, Manton KG, Jordan K, Locke B: Psychiatric disorders: A rural/urban comparison. Arch Gen Psychiatry 42:651, 1985. *Blazer DG, Kessler RC, McGonagle KA, Swartz MS: The prevalence and distribution of major depression in a national community sample: The National Comorbidity Survey. Am J Psychiatry 151:979, 1994. *Blazer DG, Kessler RC, Schwartz M: Epidemiology of recurrent major and minor depression with a seasonal pattern. Br J Psychiatry 172:164, 1998. *Broadhead WE, Blazer DG, George LK, Tse CK: Depression, disability days, and days lost from work in a prospective epidemiologic survey. JAMA 264:2524, 1992. Coryell W, Aksikal HS, Lyon AC, Winokur G, Maqer JD, Mueller TL, Keller MB: The time course of nonchronic major depressive disorder. Arch Gen Psychiatry

51:405, 1994.

Durkheim E: Suicide: A Study in Sociology. Free Press, New York, 1951. Eaton JW, Weil RI: Culture and Mental Disorders. Free Press, New York, 1955. Eaton WW, Kramer M, Anthony JC, Dryman A, Shapiro S, Locke BZ: The incidence of specific DIS/DSM-III mental disorders: Data from the NIMH Epidemiologic Catchment Area Program. Acta Psychiatr Scand 79:163, 1989. Endicott J, Spitzer RL: A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837, 1978. *Hagnell O, Lanke J, Rorsman B, Ojesjo L: Are we entering an age of melancholy? Depressive illnesses in a prospective epidemiological study over 25 years: The Lundby Study, Sweden. Psychol Med 12:279, 1982. Hirschfeld RMA, Klerman GL: Personality attributes and affective disorders. Am J Psychiatry 136:67, 1979. Hollingshead AB, Redlich FC: Social Class and Mental Illness. Wiley, New York, 1958. Keller MB, Shapiro RW, Lavori PW, Wolfe H: Recovery in major depressive disorder. Arch Gen Psychiatry 39:905, 1982. *Kendler KS, Gardner CO, Prescott CA: Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry 56:322, 1999. *Kendler KS, Prescott CA: A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry 56:39, 1999. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Esllerman S, Wittchen H, Kendler KS: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8, 1994. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB: Sex and depression in the National Comorbidity Survey 1: Lifetime prevalence, chronicity and recurrence. J Affect Dis

29:85, 1993.

Klewna GL, Weissman MM: Increasing rates of depression. JAMA 261:2229, 1989. Koeniq HG, Meador K, Cotlen HJ, Blazer D: Depression in elderly hospitalized patients with medical illness. Arch Intern Med 148:1929, 1988. *Leighton AH: My Name Is Legion. Basic Books, New York, 1959. Leighton DC, Harding JS, Macklin DB, Macmillan AM, Leighton AH: The Character of Danger: Psychiatric Symptoms in Selected Communities. Basic Books, New York, 1963. Morris JN: Uses of Epidemiology, ed 3. Churchill Livingstone, London, 1975. Paykel ES: Life stress and psychiatric disorder. In Stressful Life Events: Their Nature and Effects, BS Dohrenwend, BP Dohrenwend, editors. Wiley, New York, 1974. Robins LN, Helzer JE, Croughan J, Ratcliff K: National Institute of Mental Health Diagnostic Interview Schedule: Its history, characteristics, and validity. Arch Gen Psychiatry

38:381, 1981.

Rorsman B, Grasbeck A, Hagnell O, Lanke J, Ohman R, Ojesjo L, Otterbeck L: A prospective study of first-incidence depression: The Lundby Study, 1951–1972. Br J Psychiatry 156:336, 1990. *Rosenthal NE, Mazzanta CM, Barnett RL, Hardin TA, Turner EH, Lam GK, Ozaki N, Goldman D: Role of serotonin transporter promoter repeat length of polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder. Molecular Psychiatry 3:175, 1999. Shapiro A, Skinner EA, Kessler LO, Von Korff M, German PS, Tischler GL, Leaf PJ, Benham L, Cottler L, Regier DA: Utilization of health and mental health services: Three Epidemiologic Catchment Area sites. Arch Gen Psychiatry 41:971, 1984. Somervell PD, Leaf PJ, Weissman MM, Blazer DG, Bruce ML: The prevalence of major depression in black and white adults in five United States communities. Am J Epidemiol

130:725, 1989.

Tennant C: Female vulnerability to depression. Psychol Med 15:733, 1985. *Weissman M, Merikanges KR, Boyd JH: Epidemiology of affective disorders. In Psychiatry, vol 1, section 60, R Michels, AM Cooper, S Guze, LL Judd, GL Klerman AJ Solni, AJ Stunkard, PJ Wilner, editors. Lippincott, New York, 1991. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu H, Joyce PR, Karam EG, Lee C, Lellouch J, Lepine J, Newman SC, Rubio-Stipec M, Wells JE, Wickrafnaratne PJ, Winchen H, Yeh E: Cross-national epidemiology of major depression and bipolar disorder. JAMA 276:293, 1996. Weissman MM, Livingston B, Leaf PJ, Florio L-P, Ilolzer C: Affective disorders. In Psychiatric Disorders in America: The Epidemiologic Catchment Area Study, LN Robins, DA Regier, editors. Free Press, New York, 1991. Wells KB, Siewart K, Hays RD, Burnam A, Rogers W, Daniels M, Berry S, Greenfield S, Ware J: The functioning and well-being of depressed patients: Results from the Medical Outcomes Study. JAMA 262:954, 1989.

Textbook of Psychiatry

14.3 MOOD DISORDERS: GENETICS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.3 MOOD DISORDERS: GENETICS JOHN R. KELSOE, M.D. Genetic Epidemiology Mode of Transmission Genetic Relationships Within the Spectrum of Mood Disorders Interpretations of the Genetic Features of Mood Disorders Complex Genetic Disorders Positional Cloning of Complex Disorders Results of Genetic Linkage and Association Studies The Highs and Lows of Past Bipolar Linkage Studies Genetic Counseling Future Directions Suggested Cross-References

The familial nature of mood disorders has been a widely observed phenomenon since antiquity. However, only in the last century have systematic studies been conducted that document the degree and nature of this familiality as well as its genetic determinants. In the past two decades molecular genetic technology has brought a new era in the understanding of a wide range of genetic traits and disorders. The application of this technology promises a new, more fundamental understanding of biological etiology of mood disorders and may also produce revolutions in both diagnosis and treatment. Yet mood disorders and other psychiatric disorders are difficult problems for genetic analysis, and early attempts at such analysis using both epidemiological and molecular tools have yielded sometimes contradictory and confusing results. However, as the volume of data increases and more sophisticated analytical methods are used these large problems should become more tractable so the benefits of this approach can be realized.

GENETIC EPIDEMIOLOGY By determining the rates of illness in different types of relatives, genetic epidemiological studies can provide much information about the familial and genetic nature of a disorder. The questions that can be addressed include: Are mood disorders familial? Are they genetic? What portion of the etiology is genetic? How are the genes for mood disorder transmitted? How do different forms of mood disorder differ in their genetic transmission? How are different forms of mood disorder related to each other? Numerous such studies conducted over the last century provide much information about the genetic transmission of mood disorders. However, these studies have various methodological limitations. Foremost among these is the range of diagnostic methods used. Many of these studies were conducted before the distinction between depressive (unipolar) and bipolar disorders, and hence results of these studies pool both illnesses. Similarly, many of these studies preceded the introduction of operationalized diagnostic criteria. Therefore, it may not be clear exactly how the diagnoses were made, making it difficult to compare or pool results across studies. Of the studies that distinguish unipolar and bipolar disorder, bipolar disorder has received more attention because of its greater degree of familiality. Another methodological issue important to such studies is ascertainment bias. If the results of a study are to be meaningfully generalized to the population, the subjects must be selected in a systematic and nonbiased fashion. For example, if probands (the first ill subject identified in a family) are selected on the basis of their strong family history, then the results of a family study may inaccurately indicate a strong familial rate of illness in the population. A similar error will be made if ill family members are preferentially selected for study. Systematic ascertainment methods attempt to avoid such bias by studying all patients who present within a certain environment, such as a mood disorders clinic. Many of these studies are also limited by use of the family history method. In this approach, the rates of illness in family members of probands are determined by systematically questioning probands about their families. Though several excellent standardized instruments for the family history method exist, this method is inherently less accurate than using direct interviews of each family member to make a diagnosis. Family Studies Family studies address the question of whether a disorder is familial. More specifically, is the rate of illness in the family members of someone with the disorder greater than that of the general population? Typically, all subjects with the disorder in a given environment or population are identified and questioned about illness in their first-degree relatives. The rates of illness are then compared with either the rates in the general population or the rates in first-degree relatives of control subjects. Rates of illness are typically adjusted for age to indicate the morbid risk (i.e., the risk that an individual will develop an illness at some point of his or her life). Table 14.3-1 illustrates several such studies of bipolar disorders. They indicate a morbid risk of bipolar disorder in first-degree relatives of bipolar disorder probands that ranges between 3 and 8 percent. Compared with a 1 percent rate in the general population, this reflects a substantial familial increase. Similarly, studies of families of probands with depressive disorder (unipolar) reveal morbid risks for depressive disorders among first-degree relatives which are two to three times those of the general population. These data argue strongly for the familial nature of mood disorders. Furthermore, depressive disorders generally occur at a higher rate in the families of probands with bipolar disorders, and the rate of bipolar disorder is elevated in the families of probands with depressive disorders. In fact, depressive disorders are typically the most common mood disorder in families of probands with bipolar disorders. This familial overlap suggests some common genetic underpinnings between these two forms of mood disorder.

Table 14.3-1 Selected Family Studies of Bipolar Disorders

Twin Studies The family study data clearly indicate that mood disorders are familial. However, such studies cannot distinguish whether genetic or environmental factors mediate the familial transmission. Families might share a variety of different environmental factors that could transmit the illness. Such factors might be behavioral but could also be shared exposure to infectious agents, toxins, or other brain insults. Twin studies provide the most powerful approach to separating genetic from environmental factors, or “nature” from “nurture.” Many strategies for twin studies have been used, but most commonly both monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs are identified in which one twin has a mood disorder. The other twins are then examined to determine the proportion of twin pairs in which both twins are affected, termed the concordance rate. Typically, twin pairs are selected who have been raised together, so that environmental factors are shared equally. A difference in concordance rate between the MZ and DZ pairs, therefore, reflects the role of heritable genetic factors. An alternative powerful strategy is to study twin pairs raised apart; however, such samples are much more difficult to obtain. Table 14.3-2 summarizes several twin studies of mood disorders. Considering depressive and bipolar disorders together, these studies find that the concordance rate for mood disorder in the MZ twins is two to four times that in the DZ twins. These are the most compelling data for the role of genetic factors in mood disorders.

Further, the concordance rate for MZ twins is not 100 percent. Thus nonheritable environmental factors also play a significant role in mood disorders. In studies that distinguish bipolar from unipolar disorders, the MZ to DZ concordance ratio for bipolar-bipolar pairs is higher than that for unipolar-unipolar pairs, which indicates greater genetic involvement in bipolar disorders than in unipolar depressive disorders. Furthermore, the rate of depressive disorders is elevated in monozygotic cotwins of probands with bipolar disorders, and to a lesser extent, the rate of bipolar disorders is elevated in the cotwins of probands with depressive disorders. This is consistent with the family data, and it argues for a genetic overlap between bipolar and depressive disorders.

Table 14.3-2 Selected Twin Studies of Mood Disorders

Adoption Studies Adoption studies provide an alternative approach to separating genetic and environmental factors in familial transmission. A variety of limitations of twin studies have been raised, including the argument that parents treat monozygotic twins and DZ twins differently, so environment is not equally shared. Adoption studies have been conducted using a variety of experimental designs, but the most common is the adoptee-as-proband strategy. In this approach, probands are identified who have a mood disorder and who were adopted away at birth, thus separating nature and nurture. The rates of psychiatric illness are then determined in both the biological and adoptive parents. Only a limited number of such studies have been reported, and their results have been mixed. Julien Mendlewicz and John Ranier found a threefold increase in the rate of bipolar disorders in the biological relatives of probands with bipolar disorders. They also observed a twofold increase in the rate of depressive disorders in biological relatives. Similarly, in a Danish sample, Paul Wender and coworkers reported a threefold increase in the rate of unipolar disorder and a sixfold increase in the rate of completed suicide in the biological relatives of mood disorder probands. Other studies, however, have been less convincing. Using affectively ill mothers as probands, Remi Cadoret found a nonsignificant trend toward increased unipolar depressive disorders in the adopted children. In a Swedish sample, Anne-Liis Von Knorring and coworkers found no increase in mood disorders in the biological parents of adoptees with mood disorders. Overall, these results support the role of genetics and are consistent with the twin data. The difficulty of obtaining subjects and the resulting small sample sizes may help explain why these data are weaker than the twin data.

MODE OF TRANSMISSION If mood disorders are in large part caused by genetic factors, then what is the nature of its genetic transmission? Segregation analysis of the family study data has been used to attempt to answer this question. Are mood disorders the result of one or a few genes transmitted in a mendelian fashion? Or do many genes interact within each individual to predispose to illness? Different modes of transmission result in different patterns of inheritance of illness. By examining these patterns in families, one may attempt to distinguish the different possible modes of transmission. For example, in a simple dominant genetic disorder, one expects to observe that half of the children of an affected parent are also affected. In a recessive disorder, only one-quarter of the children of two nonaffected carriers should be affected. More-complex modes of inheritance involving multiple genes result in other patterns of illness that can be sought in the family data. Typically, in segregation analysis, the predicted patterns of several different models of transmission are tested to see which best fits the observed family data. The results of such analyses have been mixed. Several such analyses have been inconclusive and excluded all tested models of transmission. Other, more recent analyses using large samples and more-sophisticated genetic models have supported the presence of an autosomal dominant major locus. Most such studies have focused on bipolar disorders because of their greater heritability. However, a recent segregation analysis of early-onset, recurrent depressive disorder has supported the presence of major gene effects with autosomal recessive or codominant modes of transmission. Other studies have supported a multifactorial-threshold model for mood disorders. In these models, the additive effects of multiple genes produce a unitary predisposition common to all mood disorders. Different mood disorders result at different thresholds in this single underlying genetic liability. X-linkage has also been argued based on the observation that female relatives of probands with bipolar disorders have a twofold higher risk for disorders than males. This is also supported by evidence for decreased male to male transmission of bipolar disorders. Drawing any definitive conclusions from such complex and inconsistent data is difficult. The complexity likely results from the presence of multiple genes with multiple modes of transmission. In the face of such heterogeneity, the sample sizes and statistical methods used may have limited power to demonstrate a given mode of transmission consistently. The data do suggest that of the many genes probably operating in mood disorders, some have a major effect on predisposition, and in bipolar disorders these major genes are likely to have autosomal dominant or perhaps X-linked inheritance. Consistent with such heterogeneity, recent analyses have argued for more-complex modes of transmission in which multiple genes interact to predispose to illness. Several other intriguing results emerge from the family study data. Subjects with mood disorders are more likely to marry spouses who also have mood disorders than is expected by chance. This is termed assortative mating, and it leads to a higher rate of families in which the illness can be traced to both the mother's and the father's side of the family than would be expected by chance. Such bilineal families may play an important role in the interaction of multiple genes in the population. Family studies have also indicated that the rate of mood disorders is increasing over time in the population, termed the cohort effect (Fig. 14.3-1). Among family members of probands with bipolar disorders, those born more recently have a higher risk for bipolar disorders and an earlier age of onset. The cause of the cohort effect is unknown. It has been speculated to be a result of changing environmental stresses in our society, an artifact of recollection, or possibly an indication of a genetic effect termed anticipation.

FIGURE 14.3-1 Age-related penetrance curves for bipolar disorder. The risk for bipolar disorder among relatives of bipolar disorder probands is depicted as a function of age. The probability of having bipolar disorder, or penetrance, increases with age. The cohort effect is illustrated by the different age-dependent risk curves for relatives within three different age groups. Relatives born more recently have a higher rate of bipolar disorder and an earlier age of onset. (Reprinted with permission from Rice J, Reich T, Andreasen NC, Endicott J, van Eerdewegh M, Fishman R, Hirshfeld RM, Klerman GL: The familial transmission of bipolar illness. Arch Gen Psychiatry 44:441, 1987.)

GENETIC RELATIONSHIPS WITHIN THE SPECTRUM OF MOOD DISORDERS The genetic relation between the various forms of mood disorder has received much study and debate. Bipolar and depressive disorders are widely considered to have some sort of common genetic underpinning, though its exact nature is unclear. The twin and family data reviewed above argue for more depressive disorders occurring in the twins or other relatives of probands with bipolar disorders than is expected by chance. However, it is less clear that bipolar disorders occur in the relatives of probands with depressive disorders at an elevated rate. Twin studies indicate that polarity is usually consistent in MZ twins (i.e., bipolar-bipolar or unipolar-unipolar pairs are much more common than bipolar-unipolar pairs. Yet bipolar-unipolar pairs do occur. These data suggest that bipolar and unipolar disorders are genetically neither completely identical nor completely distinct. Rather, there is a partial genetic similarity. A possible model for the relationship between these genes and disorders is illustrated in Figure 14.3-2. In this model, some or all of the genes for bipolar disorders may also result in depressive disorders. In addition, a larger pool of genes predisposes only to depressive disorders. Therefore, the rate of unipolar disorder would be clearly elevated in families with bipolar disorder. However, because only a minority of cases of unipolar disorder result from bipolar genes, only a small increase in the rate of bipolar disorders would be seen in the relatives of probands with depressive disorders. Such overlapping relationships between genes and disorders may also occur for other forms of mood disorders. A more definitive understanding of these relationships will likely require identification of the specific genes involved.

FIGURE 14.3-2 This model of the relation between genes for bipolar and depressive disorders posits that most genes for bipolar disorders can predispose to either bipolar or depressive disorders. A larger set of genes predisposes only to unipolar disorder. Hence, a subset of those with depressive disorders carries genes that may also predispose to bipolar disorders.

This model predicts that a portion of those with unipolar disorder carry genes that may also predispose to bipolar disorder. Such patients have been said to have “bipolar III” disorder by some writers and have been the subject of much discussion and investigation. They are presumably identified by a family history of bipolar disorder or a history of developing hypomania or mania only in response to antidepressant treatment. Similarly, Hagop Akiskal and coworkers have described a hypomanic-like personality style termed hyperthymic temperament. Depressive disorder patients with hyperthymic temperament likely carry some bipolar disorder genes. Such hyperthymic-depressive patients are more likely to have a family history of bipolar disorder and to develop mania spontaneously. These depressive disorder patients with a bipolar disorder genetic diathesis may also be more likely to respond to lithium augmentation of antidepressant treatment. Other forms of mood disorders have also been postulated to be at least somewhat genetically distinct. Several studies have reported that though the risk for bipolar I disorder is similar in the relatives of probands with bipolar I or bipolar II disorder, the risk for bipolar II disorder is greater than that for bipolar I disorder in the relatives of probands with bipolar II disorder. This suggests that bipolar II disorder to some extent breeds true and that a subset of the genes for bipolar disorders predispose preferentially to bipolar II disorder. However, studies of patients with rapid-cycling bipolar disorder find that rapid cycling in the proband does not affect the risk for mood disorders or rapid cycling in relatives. This argues that rapid cycling is not a distinct genetic subform of bipolar disorder. The genetic relation of schizoaffective disorder to mood disorders is a complex question that involves the role of psychosis in the genetics of mood disorders. The genetic nature of schizoaffective disorder also bears on the genetic relation between schizophrenia and mood disorders. Studies examining familial risks in relatives of schizoaffective disorder patients have led to inconsistent results, some finding an increased risk of schizophrenia and some an increased risk of bipolar disorder. A possible explanation is that patients with schizoaffective disorder represent a mixture, some with bipolar and some with schizophrenia diatheses. This notion is supported by data that show an increased rate of bipolar disorders among relatives of probands with the bipolar type of schizoaffective disorder. The rate of schizophrenia has also been reported to be increased among the relatives of probands with the depressive type of schizoaffective disorder. Alternatively, it has been proposed that the Kraepelinian distinction between the disorders is not valid and that schizophrenia and mood disorders lie at the extremes of a spectrum of a common genetic liability. Recent linkage studies (reviewed below) may be beginning to support the existence of some genetic loci common to both schizophrenia and bipolar disorders.

INTERPRETATIONS OF THE GENETIC FEATURES OF MOOD DISORDERS The above data argue that mood disorders are not simple genetic traits. No one gene consistently causes illness in all cases in a simple and predictable fashion. In genetic terms, there is not a 1 to 1 relation between the expressed trait (phenotype) and genes (genotype) transmitted in a simple mendelian fashion. Therefore, mood disorders are said to be complex genetic disorders rather than simple mendelian traits. What factors contribute to this complexity? The twin data argue compellingly that genes account for only 50 to 70 percent of the etiology of mood disorders. Environment or other nonheritable factors must explain the remainder. Thus, a predisposition or susceptibility to disease is inherited. The probability that someone will manifest a trait, given that they have a certain genotype, is termed the penetrance of the gene. Mood disorders are said to have “reduced penetrance” (less than 100 percent). Furthermore, the penetrance of the mood disorder genes increases from a low risk for illness in childhood to a maximum in adulthood. The cohort effect ( Fig. 14.3-1) further complicates the relation of penetrance to age, causing penetrance to vary with the date of birth. Therefore, families of people with mood disorders likely include individuals who have the genes for mood disorder but do not develop the disease. These are termed nonpenetrant carriers. The converse of this situation is individuals who have mood disorder but do not have the genes. Individuals with purely environmentally caused disease are termed phenocopies. These factors conspire to produce an indirect relationship between genes and disease. Variable expressivity refers to the phenomenon of the same gene or group of genes resulting in a variety of different forms of illness. The twin data clearly demonstrate this for mood disorders. Monozygotic twins with identical genomes are observed with one twin exhibiting bipolar and the other unipolar disorder. Nonheritable factors must play a role in the specific manifestation of the predisposition to mood disorder. Such variability in expression is not unique to psychiatric disorders. In neurofibromatosis, for example, ill individuals range in manifestations and severity from those with only pigmented retinal lesions to others with multiple large tumors—a range in expression that results from the same disease gene. Of the various factors complicating the genetic transmission of mood disorders, the most significant and the most challenging for gene mapping efforts is genetic heterogeneity. Heterogeneity refers to the likely occurrence of multiple genes in the etiology of illness. Only the identification of multiple disease genes can convincingly demonstrate genetic heterogeneity. However, the segregation analyses described above strongly suggest its presence. There are several critical questions about the nature of heterogeneity in mood disorders. How many genes are involved? How large an effect does each gene have? How do the genes interact to produce illness? These questions suggest a variety of models of heterogeneity, which can be broadly grouped into those in which disease results from a few genes with major effects (major loci) and those in which disease derives from the combined action of many genes with small effects (polygenic or oligogenic). The answers to these questions are not currently known for mood disorders. However, segregation analyses suggest a mixture of genes of both large and small effect, which are transmitted in a variety of ways. Evidence for several other complex forms of genetic transmission has also been reported for mood disorders. Some studies of bipolar disorder have indicated that the illness is more likely to be transmitted through mothers than through fathers. Such parent-of-origin effects imply a genetic phenomenon called imprinting. In imprinting, a genetic locus is processed differently in male and female meioses so that different traits result from maternal and paternal transmission. For example Angelman and Prader-Willi syndromes are two different mental retardation syndromes that result from different maternal or paternal imprinting of the same locus on chromosome 15.

Rather than yielding different phenotypes, the bipolar data suggest that the penetrance of bipolar genes may be affected by imprinting. Another nonmendelian genetic phenomenon reported in mood disorders is anticipation. In disorders displaying anticipation, the severity of the illness increases and the age of onset decreases with successive generations. Anticipation is generally associated with genetic mutations involving trinucleotide repeat expansions. In such disorders (e.g., Huntington's disease or fragile X mental retardation), the defective gene contains a region of deoxyribonucleic acid (DNA) in which a three-nucleotide sequence is repeated a variable number of times. For reasons currently not well understood, the number of repeats increases in successive generations until the gene's function is disrupted and illness results. Anticipation involving both increasing severity of illness and decreasing age of onset has been reported for bipolar disorder. Indirect evidence for the presence of trinucleotide repeat expansions has also been reported; however, no specific gene manifesting such a mutation has been described.

COMPLEX GENETIC DISORDERS Simple Mendelian Traits Complex genetic disorders are simply those that are not transmitted in classical mendelian patterns. A review of mendelian transmission thus provides a useful background for understanding complex genetic traits. Simple mendelian traits display genetic homogeneity; one gene transmits the trait with complete penetrance. Figure 14.3-3 illustrates the three primary modes of mendelian transmission. In genetic terminology, different forms of a given gene are termed alleles. A disease gene may have either a normal, nonmutated allele or a mutated, disease-causing allele. In dominant genetic disorders, only one copy of the disease allele is necessary to cause illness. Dominant illnesses are typically transmitted vertically from grandparent to parent to child. In the simplest case, half of the children of an affected parent will have the disease. In recessive disorders, both copies of the disease gene must be defective for disease to result. Heterozygotes with only one disease allele are nonaffected carriers. Disease typically results from the mating of two nonaffected carriers. One-quarter of the resulting children will be homozygous for the disease allele and hence ill. Recessive illnesses typically appear in a horizontal pattern in families (i.e., in cousins). The nature of the mutation in the gene determines whether it is transmitted in a dominant or recessive fashion. Recessive mutations typically deactivate genes that are expressed in excess. Therefore, an adequate amount of gene product can be produced by only one functioning copy. In dominant disorders, the amount of gene product expressed may be critical. A reduction in gene dosage, resulting from only one functioning copy, leads to illness. Alternatively, a dominant mutation may result in overfunctioning of the gene, which results in illness. In X-linked disorders the disease gene is located on the X chromosome. These may be either dominant or recessive. X-linked dominant disorders are more common in women, while X-linked recessive disorders are more common in men. Father to son transmission is impossible in X-linked disorders, since the father transmits the Y sex chromosome to sons.

FIGURE 14.3-3 Mendelian transmission. Simple mendelian disorders are transmitted by three different modes. Dominant disorders require only one copy of the disease allele for a family member to be affected. In recessive disorders, both copies of the disease gene must be defective. In X-linked disorders, the disease gene is carried on the X chromosome.

Heterogeneity Models Of the various factors that distinguish complex disorders from mendelian ones, the most important is the presence of multiple genes, or genetic heterogeneity. Multiple genes may combine to produce illness in a variety of different ways, as illustrated in Figure 14.3-4. These heterogeneity models fall into two categories based on genetic effect size. In single major locus models, only one disease gene is necessary to produce illness in a given individual. In an interfamilial heterogeneity model, one gene transmits the predisposition to illness in each family. However, there are different predisposing genes in different families. In an intrafamilial heterogeneity model, any one of multiple genes within the same family can transmit the illness.

FIGURE 14.3-4 Several different models for the role of multiple genes in genetic disorders. In single major locus heterogeneity models, a single gene is primarily responsible for the predisposition to illness in an individual. However, different single major loci may act in different families or within the same family. In oligogenic models, multiple genes each of smaller effect typically interact to produce the susceptibility to illness. In an additive model, the effects of these genes simply add together. In epistatic models, the overall effect exceeds the sum of each gene acting separately.

In oligogenic or polygenic transmission models, multiple genes of smaller effect interact to predispose to illness. In these models, one gene by itself is unlikely to cause illness. Rather, the probability of illness increases with the number of different genes involved. The terms “oligogenic” and “polygenic” are distinguished simply by whether a smaller or larger number of genes, respectively, are involved. In an additive polygenic model, each gene contributes a certain probability (penetrance) of manifesting the disorder. The total genetic liability to illness is then the sum of the probabilities contributed by all the polygenes. In Figure 14.3-4, under the additive model, the disease alleles for genes A and B alone each convey a 40 percent probability of illness. Individuals who carry the disease alleles for both A and B have an 80 percent risk for illness. The total risk is simply the sum of the risks for each individual polygene. In the epistatic model, the disease alleles at genes A and B each convey a relatively small effect alone. However, individuals with the disease alleles for both A and B have a risk for illness that exceeds the sum of risks for A and B. In the example in Figure 14.3-4, A and B each convey a 20 percent risk alone. The affected daughter with the AB genotype, however, has an 80 percent risk for illness. Epistatic interactions have been observed in many organisms and frequently reflect a “two-hit” effect on a biological system. For example, a neurotransmitter system may be able to tolerate a defect in gene A by increasing the activity of gene B. Similarly gene B may be able to compensate for a defect in A, so that individuals with defects in A or B alone may have only a limited risk for illness. However, if both A and B are defective, the system cannot compensate, and the risk for illness escalates. Quantitative Traits One of the many difficulties in psychiatric genetics studies is the definition of “affected.” Variable expressivity results in a variety of disorders from similar genotypes, and is frequently not clear which of these disorders should be considered “affected” for the purposes of genetic analyses. An alternative to such dichotomous definitions of phenotype is the use of quantitative phenotypes. Many biological variables are obvious quantitative phenotypes (e.g., blood pressure or height). However, it is not immediately obvious which mood disorder is “worse” or “more” than another. Nevertheless, quantitative phenotypes have been applied with some success to mood disorders. An example is the multiple-threshold model. Though quantitative phenotypes can result from single major loci, the concept has evolved historically in connection with polygenic traits. In such models, each polygene contributes in either an additive or epistatic fashion to the value of the

quantitative phenotype. Quantitative models offer a useful alternative to the dichotomous approach to phenotype. However, the basic problem is that mood disorder phenotypes are more complex than either the dichotomous or quantitative genetic models.

POSITIONAL CLONING OF COMPLEX DISORDERS Positional cloning refers to the use of molecular genetic methods to identify disease genes based on their chromosomal location. Such studies, directed at the identification of specific disease genes, are the focus of most recent research on the genetics of mood disorders. The methods and strategies of positional cloning are reviewed in more detail elsewhere in this text, but a brief description here prefaces a review of the problems faced in such studies of mood disorders and some of their potential solutions. DNA markers are segments of DNA of known chromosomal location that are highly variable among individuals. They are used to track the segregation of specific chromosomal regions within families affected with a disorder. When a marker is identified whose alleles consistently cosegregate with disease in families, it is said to be genetically linked, which implies that a gene for the disorder is physically near the marker on a chromosome. The Human Genome Project has provided thousands of such markers and precisely mapped them to chromosomal locations. By using several hundred markers, one can systematically survey the genome in search of markers linked to a disease. In this fashion, novel disease genes can be identified on the basis of their chromosomal location rather than their physiological function. This ability to identify novel genes without relying on knowledge of their function or the pathophysiology of the disorder makes positional cloning a powerful approach. This approach has led to the successful identification of genes for numerous diseases such as Huntington's disease and cystic fibrosis. The statistics of linkage analysis are either parametric or nonparametric. Parametric analyses assume a certain model of inheritance (e.g., dominant or recessive) and then test the marker data for the probability of fitting that assumed model. The statistic typically generated is the LOD score. The LOD score is the logarithm of the odds for linkage divided by the odds against linkage. A LOD score of 3 represents odds of 10 3 or 1000 to 1 in favor of linkage. The appropriate threshold for statistical significance of LOD scores varies with the nature of the analysis and is currently under some debate, but is in the range of 3.0 to 3.6. Nonparametric analyses do not require an assumption of model of inheritance. Instead, affected family members are tested for significantly increased sharing of marker alleles. The affected sib pair method and the affected pedigree member method exemplify this approach. Parametric methods generally have greater power to detect linkage if the correct model is used. Nonparametric methods have less power but are not vulnerable to error resulting from the use of an incorrect model of inheritance. When a chromosomal region is identified by genetic linkage studies in families, the disease gene has typically been localized to a region of between 5 and 30 million base pairs of DNA, which might contain several hundred genes. Genetic association studies are then sometimes used to locate the disease gene more precisely within this region. In these studies, markers are tested for significant differences in the frequencies of their alleles between unrelated groups of affected subjects and control subjects. Such differences may be observed if the DNA-sequence variation at the marker is the disease causing mutation itself. Alternatively, the marker allele may have no functional impact, but be so physically close to the disease causing mutation that they have been propagated together through the population. The marker allele and disease mutation are then said to be in linkage disequilibrium. In addition to fine mapping, association is also commonly used to test the role of a candidate gene whose known function suggests its possible involvement in the disorder. Physical mapping methods are also used to identify the exact disease gene. These methods involve cloning large regions of DNA and screening them for the presence of genes and possible disease-causing mutations in those genes. Difficulties of Mapping Complex Disorders Simple mendelian traits show a 1 to 1 correspondence between genotype and phenotype. Everyone in a family who has the disorder has the gene, and everyone who has the gene has the disorder. This allows extraction of maximal information regarding the possible cosegregation of marker and disorder in linkage studies. However, both reduced penetrance and phenocopies loosen the connection between genotype and phenotype and thus reduce the statistical power of linkage methods to identify genes. In complex disorders, it is neither clear that nonaffected individuals did not receive the disease allele nor that affected ones did. Thus one needs to study larger samples of families. Variable expressivity and difficulty in diagnosis introduce further uncertainty in modeling genetic transmission. It is not clear which of the spectrum of mood disorders should be considered “affected.” If the definition of affected is too narrow, then valuable information from family members with more subtle forms of illness may be lost. However, if the definition of affected is too broad, then error may be introduced by inclusion of too many phenocopies. Most linkage studies currently use a hierarchy of different definitions of illness, ranging from narrow to broad. For example, a narrow model might include as affected only those with bipolar disorder. A broad model would include bipolar disorder and recurrent major depression. The difficulty in making behavioral diagnoses adds further complexities. Psychiatric diagnoses rely on the accuracy of the subject's memories and judgments about behavior that depend on the individual's life and environment. Other difficulties arise out of the limitations of statistical methods. The most powerful statistical methods currently available are based on mendelian models of transmission. However, it seems clear that mood disorders are not transmitted according to these simple models. Currently most linkage studies are conducted using a variety of genetic models (e.g., dominant and recessive). However, only limited information is available about the robustness of applying these methods to nonmendelian and heterogeneous forms of transmission. Furthermore, recent simulation studies have indicated that even when linkage is established, a much larger chromosomal region is implicated in complex disorders than in mendelian ones. This makes the job of fine mapping and gene identification substantially larger. The greatest problem facing positional cloning studies is clearly heterogeneity. If mood disorders result from a relatively small number of genes with large effect, then they will be identified soon. However, if a large number of genes with small effect are involved, identifying them will require large sample sizes or a different approach altogether. Current data suggest that the number of genes probably lies somewhere between these extremes. The cost of heterogeneity in terms of sample size is illustrated in Figure 14.3-5. This simulation study, using affected sib pairs, indicates that if a gene is present in less than 25 percent of families under study, the total number of families required to detect linkage increases significantly.

FIGURE 14.3-5 Sample sizes required to detect linkage for different degrees of heterogeneity. The number of families with affected sib pairs required to detect linkage is depicted as a function of the degree of genetic heterogeneity. This power analysis for genetic linkage studies was performed by computer simulation of both an autosomal dominant and a recessive disorder with 50 percent penetrance. If a gene for a disorder occurs in less than 25 percent of families, the number of families required to detect it in a linkage study goes up substantially. (Reprinted with permission from Martinez MM, Goldin LR: The detection of linkage and heterogeneity in nuclear families for complex disorders: One versus two marker loci. Am J Hum Genet 44:552, 1986.)

Solutions for Mapping Complex Disorders Despite these problems, recently developed tools and strategies for linkage studies of complex traits promise to make the challenges of mood disorders more tractable. Many of these new developments involve using more-sophisticated statistical methods. Parametric methods have recently been developed that can model the interaction of two genes simultaneously. In this way, the power of parametric analytical methods can be applied to more-complex modes of inheritance. However, as more genes are included, the number of possible models for their interaction increases. This may make the choice of the correct model both more difficult and more important. For these reasons, nonparametric methods have recently received increasing attention. Since they do not depend on assumptions about the mode of transmission, they are less vulnerable to error resulting from use of the wrong model. However, they have lower statistical power to detect genes than do parametric methods using the correct model. Much effort has been focused on developing new nonparametric methods with greater statistical power. There is no current agreement on which

approach is superior. As a result, many investigators use both approaches. Various approaches to refining the phenotype may improve the odds of success in linkage studies. Studying subforms of illness, whose genetic distinctness is supported by epidemiological data, may allow investigators to reduce the number of genes under study. For example, bipolar II disorder or lithium-responsive illness may represent distinct subsets of bipolar genes. Such subforms of illness may be easier to map. Intermediate phenotypes may also be useful in this regard. Intermediate phenotypes are biologic markers associated with illness that segregate in families. Sleep electroencephalographic (EEG) measures and sensitivity to various pharmacological challenges exemplify such possible markers. Intermediate phenotypes can be used to identify psychiatrically well family members who carry susceptibility genes. In this way, these biological markers display higher penetrance than the psychiatric disorder itself and, therefore, retrieve more genetic information from family members. Furthermore, they may also reflect biologically distinct subforms of illness. The rapid progress of the Human Genome Project will provide new tools for genetic studies. The quality of markers and maps continues to improve. It is likely that within the next several years, all human genes will be identified and mapped, which will be invaluable for the identification of disease genes. The next wave of the Human Genome Project will develop a dense set of markers that will ultimately enable genome-wide association studies. By studying tens of thousands of markers in thousands of ill and control subjects, genes of small effect may be identified. Until recently, such an approach was not considered feasible; however, now both the dense map of markers and the technology for high-throughput screening seem in sight. Methods are now being developed to array genes or DNA markers on microchips allowing the simultaneous detection of thousands of markers. Ultimately, one can expect that most sequence variation in all human genes will be known. This knowledge combined with large samples for association studies should enable detection of virtually all genes involved in mood disorders, even if current linkage strategies are not successful.

RESULTS OF GENETIC LINKAGE AND ASSOCIATION STUDIES To date the search for genes for mood disorders has focused primarily on bipolar disorder because of the stronger evidence for its genetic basis. In its early years, this search exhibited a series of ups and downs of reported findings and subsequent nonreplications that was likened to the highs and lows of the illness itself. Such high-profile nonreplications led to frustration among investigators and concern that false-positive linkage results might be common. Many investigators argued for highly conservative thresholds for the statistical significance of linkage results to guard adequately against such events. However, subsequent experience has indicated that strongly positive results are relatively uncommon. Furthermore, simulation studies indicate that nonreplications should be expected, even for real loci, until enough data are accumulated to demonstrate linkage convincingly. Recently a number of positive results have emerged that are quite encouraging in terms of the ability of linkage analysis to identify genes for bipolar disorder. As more of the genome has been surveyed in larger sets of families, several loci have yielded modest evidence for linkage, which is being independently replicated in multiple datasets. It seems likely that at least some of these loci reflect the locations of real susceptibility genes; therefore, it seems appropriate to expect some nonreplications. The road to linkage success may involve neither too-readily dismissing modestly positive results nor too readily accepting strongly positive results but rather seeking independent confirmation. Some of the more prominent of these possible bipolar loci are summarized in Table 14.3-3 and reviewed below. The most notable aspect of the summary in Table 14.3-3 is the number of loci that have support from multiple independent datasets. Only time, further data, and the identification of actual disease genes will determine which of these are real disease loci.

Table 14.3-3 Summary of Loci Potentially Linked to Bipolar Disorders

THE HIGHS AND LOWS OF PAST BIPOLAR LINKAGE STUDIES Chromosomes 11 and X The first molecular genetic linkage study of mood disorder was conducted in the Old Order Amish population of southeastern Pennsylvania. Bipolar disorders are no more common or different in presentation in the Amish than in the general population. The Amish were chosen for study because they were genetically isolated. The current population of approximately 30,000 Amish are descended from about 50 couples who immigrated nearly 300 years ago from Germany and Switzerland. Since that time, for religious reasons, this group has remained isolated from the surrounding population. The primary advantage of studying such a group is the reduced genetic heterogeneity that results from a founder effect with subsequent genetic isolation. Other advantages of studying this group are its large families and the virtual absence of substance abuse. In 1987, Janice Egeland and coworkers reported evidence for linkage of bipolar disorders to markers at the insulin and Harvey ras loci on 11p15. Their data yielded an LOD score of nearly 5, or odds of 100,000 to 1 in favor of linkage. However, numerous other studies in different populations failed to replicate this result. Subsequently, reexamination of an updated and expanded version of the same Amish pedigree substantially reduced the evidence for linkage. Recently, however, association and linkage studies of the nearby tyrosine hydroxylase locus have supported the existence of a bipolar disorder locus in this region. A similar scenario played out in studies of the X chromosome. Much epidemiological data has suggested a possible X-linked locus for bipolar disorder. In 1987, Meron Baron and coworkers examined two nonmolecular X chromosomes markers, color blindness and glucose-6-phosphate dehydrogenase (G6PD), for linkage to bipolar disorder in a set of Israeli families. They found very strong evidence for linkage to these markers on Xq28. However, as with the Amish study, numerous other studies failed to replicate this result in different samples. Subsequently, the evidence for linkage was substantially reduced when several more-informative molecular genetic markers were examined. More recently, however, several studies have implicated a nearby region, Xq26, in studies of American and Finnish families. Therefore, despite their checkered history, evidence remains for both the 11p15 and Xq26–28 regions, but more data will be required to confirm these possible linkages. Chromosome 18 One of the most intriguing regions for possible bipolar susceptibility loci is on chromosome 18. Currently this region has the strongest data for linkage, because of the number of independent replications. Evidence for linkage to the pericentrometric region of chromosome 18 was first found by Wade Berrettini and coworkers in a series of 21 North American pedigrees. Subsequently, other studies replicated this finding and identified two more-distal regions on 18q. Some of these reports have found that the evidence for linkage was stronger in families with paternal or mixed transmission than in those with only maternal transmission. These data suggest a parent-of-origin effect at this locus. Other studies have argued that the evidence for linkage to chromosome 18 markers is strongest in families with comorbid panic disorder. Such data begin to suggest that different susceptibility loci may predispose to different forms of bipolar disorder with distinct clinical presentations. It is currently unclear whether these three different reported regions reflect three different susceptibility loci or if one or more reflect false-positive results. However, given the amount of independent data implicating this chromosome, it seems very likely that at least one locus for bipolar disorder resides on chromosome 18. Other Promising Genetic Loci Several other chromosomal regions have been implicated by multiple studies and may harbor bipolar susceptibility loci. Linkage to the marker PFKL on chromosome 21q was first reported by Richard Straub and coworkers, with most of the evidence coming from one extended pedigree. Subsequently, linkage to this region was replicated in several other studies. A locus for bipolar disorder on chromosome 12 was implicated initially by the serendipitous observation of cosegregation of bipolar disorder and a dermatological disorder, Darier's disease, in a Welsh family. Subsequently, Darier's disease was mapped to chromosome 12. Based on this observation, a set of Welsh families with bipolar disorder and without Darier's disease were studied, and modest evidence for linkage to the same region of chromosome 12 was obtained. Recently, Nicholas Barden and coworkers implicated this same region in a study of a large family from a population isolate in Quebec.

A region on 22q is interesting because it has been implicated in both bipolar disorder and schizophrenia. This region was originally investigated in schizophrenia because of the observation of psychosis in adolescents with the 22q11 deletion syndrome, velocardiofacial syndrome. Several studies have reported evidence of linkage of markers in this region to schizophrenia; other investigators have examined adolescents with velocardiofaciol syndrome and observed rapid-cycling mood disorders. Based on these data, Herbert Lachman and coworkers studied this region in a set of bipolar disorder families and found evidence suggesting linkage. A subsequent study of an expanded version of this family set has further strengthened this result. The National Institute of Mental Health (NIMH) consortium also reported evidence for linkage of bipolar disorders to 22q. Similar to these results on chromosome 22, the same regions on chromosome 13 and 18 have also been implicated in studies of both bipolar disorders and schizophrenia. This raises the intriguing possibility that some genes may play a role in the susceptibility to both disorders. Confirmation of this idea awaits further replication and the definitive identification of disease genes. However, if confirmed, these results may indicate a greater degree of genetic commonality between these two disorders than had been thought. The dopamine transporter has been implicated in bipolar disorders in a recent linkage study by John Kelsoe and coworkers. Its role as an important regulator of dopamine neurotransmission and the site of action of such stimulants as cocaine and amphetamine, make the dopamine transporter a compelling candidate gene. This gene has also been associated with attention-deficit/hyperactivity disorder in children, which occurs with greater frequency in families with bipolar disorder. Several complete genome surveys were reported recently that have added substantially to the bipolar linkage data now available. Several additional loci were implicated by these studies including markers on 5q and 4p. A genome survey of the Old Order Amish recently provided data for possible loci on chromosomes 6, 13, and 15. The NIMH Consortium for Linkage Studies of Bipolar Disorder recently reported its initial findings in one of the largest such datasets examined to date, suggesting new loci on chromosomes 1, 6, 7, and 10. Perhaps more importantly, their data support previously reported loci on 16, 21, 22, and X. Such possible replications imply that some genes for mood disorders have relatively large effect and will be detectable by current linkage strategies.

GENETIC COUNSELING Based on the observation of psychiatric illness in their own families or the increasing public awareness of psychiatric genetics, patients frequently ask clinicians three questions: Are mood disorders genetic? What is the risk to my children or grandchildren? Is there a blood test for the gene? The answer to the last question is the easiest, currently no blood test is available. However, such a test is likely to be available in the future, and it will raise a variety of serious practical and ethical issues. The answer to the first question is also easy: Yes, mood disorders are genetic, a position defended by the large body of epidemiological data summarized in this chapter. However, patients must understand that mood disorders are only partly genetic. The twin studies argue strongly that only 50 to 70 percent of the etiology of mood disorders is genetic. Therefore, a predisposition to illness is inherited that interacts with other, nonheritable factors. The risk to children and grandchildren is a difficult question that deserves the greatest consideration. The family data indicate that if one parent has a mood disorder, a child's risk for mood disorder is between 10 and 25 percent. If both parents are affected, this risk roughly doubles. A careful family history is needed for more accurate prediction of risk for a specific family. Several factors from the family history should be considered. The more members of the family that are affected, the greater the risk to a child, particularly if the disorder is in both parents' families. The risk is greater if the affected family members are first-degree relatives rather than more distant relatives. A family history of bipolar disorder conveys a greater risk for mood disorders in general and a much greater risk for bipolar disorder specifically. The presence of more-severe illness in the family also probably conveys a greater risk. All these factors should be considered in forming an estimate of risk for the concerned parent. Equally important to providing the estimate of risk is providing guidance in interpreting and responding to that information. Patients' reactions to risk information vary greatly depending on their own experience with the illness. Some will be relieved to find it so low, others fearful because it is so high. One must emphasize that their child carries a risk or predisposition to illness, not a certainty of illness. One can also describe the range of illness from mild to severe that could result and the availability and efficacy of treatment. Ultimately, the use of such information in family planning is a highly personal decision. Some patients may choose not to have children. For existing children, parents should be told about the typical age of onset, presenting symptoms, and the importance of early recognition and treatment. However, this must be balanced with the goal of not labeling the child or being overly protective.

FUTURE DIRECTIONS The gradual accumulation of a large body of data led to the successful identification of possible disease loci described above. Therefore, in the near future, gene mapping studies will likely continue to use current strategies. As still more data are accumulated, more reported loci will likely be confirmed, while others will prove false. It currently seems promising that many genes for mood disorders can be identified through such large, though tractable, projects. The development and study of the large samples required will necessitate large collaborative efforts between multiple groups of investigators using common diagnostic and genetic methods. The recent NIMH consortium is a model for such future collaborations. The variety of methodological advances and alternative approaches detailed above may further advance the project. Larger sets of family and genotypic data will enable application of new, more-sophisticated statistical methods. Larger datasets will also permit the possible subdividing of the disease into subforms based on clinical or biological measures. The rapid advance of the Human Genome Project will greatly facilitate this work by providing a much denser set of markers, a detailed physical map of the genome, and more efficient genotyping and sequencing methods. Ultimately, the identification and mapping of all human genes, the complete sequence of the human genome, and a catalog of human genetic variation will enable development of powerful novel approaches to complex disorders. Such tools and large samples will likely permit identification of most genes for mood disorders in the next several decades. What will be the implications of this knowledge? The most immediate impact may well be on public opinion. Psychiatrically ill persons have long suffered from the stigma and discrimination that portions of the public impose out of fear and ignorance. Acceptance of major mental illnesses as brain disorders has been slow. The definitive identification of genetic causes may be highly beneficial to public understanding and acceptance. This knowledge should also have a dramatic impact on our understanding of pathophysiology and approaches to treatment for mood disorders. Most current theories of pathophysiology are based on the mode of action of therapeutic agents, which were for the most part discovered serendipitously. The site of action of therapeutic drugs is not necessarily either the site of the genetic defect or the primary site of the pathophysiology. Identification of disease genes may point to entirely new systems involved in the pathophysiology or components of currently implicated systems that were previously unknown. It is hoped that such an understanding may lead to the rational drug design long sought by patients, clinicians, and pharmaceutical companies. The result may be new drugs that act by completely novel mechanisms, possibly with greater efficacy and specificity. Further down the genetic road lies the prospect of gene therapy for mood disorders. In this approach, DNA is used as a therapeutic agent, delivered to the relevant tissues by engineered viruses or other vectors. Such artificially delivered DNA can provide the correct version of a defective disease gene. Alternatively, a disease process might be ameliorated by changing the expression of other regulatory genes. Such an approach goes straight to the root of biology and pathology and offers the prospect of an extremely powerful and completely new treatment modality. Application to psychiatric disorders faces formidable problems and is likely to occur in the relatively distant future. However, trials of gene therapy for other, simpler disorders are going on today. The identification of disease genes will probably have a major impact on diagnosis and nosology. Just as the diagnosis of jaundice has given way to a classification scheme based on pathophysiology, in the future, the diagnosis of major mood disorders may be specific to disease mechanism. Mechanism-specific diagnoses may dictate the use of different, more specific and effective treatments. The field of pharmacogenetics promises genetic tests able to predict the best pharmacological treatment for specific patients based on an understanding of genetic differences in drug response. But such knowledge will also carry danger and responsibility. Premorbid DNA testing could become available that would indicate the degree of genetic vulnerability to major mood disorders. Those with psychiatric disorders will then face the same issues of genetic testing currently faced by families with Huntington's disease or breast cancer. Will at-risk family members want such information? How will they use it? How will they cope with it? How can psychiatrists assist them in these decisions? How can patients be protected from discrimination based on such information? In summary, genetic studies promise a new era of understanding and treatment of mood disorders. Identification of genes will not elucidate pathophysiology. It will merely point the way for the application of modern neuroscience methods in the equally large task of understanding mechanisms. Recent results suggest that such guidance may not be far away.

SUGGESTED CROSS-REFERENCES

A general review of basic molecular genetics is provided in Section 1.10. Principles of population genetics are discussed in Section 1.17. The concepts and methods of linkage analysis and their application to psychiatry are reviewed in Section 1.18. The epidemiology of mood disorders is discussed in Section 14.2. SECTION REFERENCES Akiskal HS: The prevalent clinical spectrum of bipolar disorders: Beyond DSM-IV. J Clin Psychopharmacol 16:4S, 1996. *Aita VM, Liu J, Knowles JA, Terwilliger JD, Baltazar R, Grunn A, Loth JE, Kanyas K, Lerer B, Endicott J, Wang Z, Penchaszadeh G, Gilliam TC, Baron M: A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Am J Hum Genet 64:210, 1999. Barden N, Morissette J, Shink E, Rochette D, Gagne B, Bordeleau L, Villeneuve A, Sher A, Shaw S, Hopkins P, Sherrington R: Confirmation of bipolar affective disorder susceptibility locus on chromosome 12 in the region of the Darier disease gene. Am J Med Genet 81:475, 1998. Baron M, Freimer NB, Risch N, Lerer B, Alexander JR, Straub RE, Asokan S, Das K, Peterson A, Amos J, Endicott J, Ott J, Gilliam TC: Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees. Nat Genet 3:49, 1993. Baron M, Risch N, Hamburger R, Mandel B, Kushner S, Newman M, Drumer D, Belmaker RH: Genetic linkage between X-chromosome markers and bipolar affective illness. Nature 326:289, 1987. *Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JIJ, Gershon ES: Chromosome 18 DNA markers and manic-depressive illness: Evidence for a susceptibility gene. Proc Natl Acad Sci USA 91:5918, 1994. Bertelsen A: A Danish twin study of manic-depressive disorders. In Origin, Prevention and Treatment of Affective Disorder, M Schou, E Stromgren, editors. Academic Press, London, 1979. Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M, Walker MT, Woodburn K, Sharp CM, Wright AF, Shibasaki Y, St Clair DM, Porteous DJ, Muir WJ: A locus for bipolar affective disorder on chromosome 4p. Nat Genet 12:427, 1996. Coon H, Jensen S, Hoff M, Holik J, Plaetke R, Reimherr F, Wender P, Leppert M, Byerley W: A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance. Am J Hum Genet 52:1234, 1993. Dawson E, Parfitt E, Roberts Q, Daniels J, Lim L, Sham P, Nothen M, Propping P, Lanczik M, Maier W, Reuner U, Weissenbach J, Gill M, Powell J, McGuffin P, Owen M, Craddock N: Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23-24.1. Am J Med Genet 60:94, 1995. Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR, Hostetter AM, Housman DE: Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 325:783, 1987. Ewald H, Mors O, Flint T, Koed K, Eiberg H, Kruse TA: A possible locus for manic depressive illness on chromosome 16p13. Psychiatr Genet 5:71, 1995. Freimer NB, Reus VI, Escamilla MA, McInnes LA, Spesny M, Leon P, Service SK, Smith LB, Silva S, Rojas E, Gallegos A, Meza L, Fournier E, Baharloo S, Blankenship K, Tyler DJ, Batki S, Vinogradov S, Weissenbach J, Barondes SH, Sandkuijl LA: Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23. Nat Genet 12:436, 1996. Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI, Goldin LR, Bunney WE: A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry 39:1157, 1982. Ginns EI, Ott J, Egeland JA, Allen CR, Fann CS, Pauls DL, Weissenbachoff J, Carulli JP, Falls KM, Keith TP, Paul SM: A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish. Nat Genet 12:431, 1996. Gurling H, Smyth C, Kalsi G, Moloney E, Rifkin L, O'Neill J, Murphy P, Curtis D, Petursson H, Brynjolfsson J: Linkage findings in bipolar disorder [Letter]. Nat Genet 10:8, 1995. Kallman F: Genetic principles in manic-depressive psychosis. In Depression, PH Hoch, J Zubin, editors. Grune & Stratton, New York, 1954. Kelsoe JR, Ginns EI, Egeland JA, Gerhard DS, Goldstein AM, Bale SJ, Pauls DL, Long RT, Kidd KK, Conte G, Housman DE, Paul SM: Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish. Nature 342:238, 1989. Kelsoe JR, Sadovnick AD, Kristbjarnarson H, Bergesch P, Mroczkowski-Parker Z, Drennan MD, Rapaport MH, Flodman P, Spence MA, Remick RA: Possible locus for bipolar disorder near the dopamine transporter on chromosome 5. Am J Med Genet 67:533, 1996. *Kendler KS, Pedersen N, Johnson L, Neale MC, Mathe AA: A pilot Swedish twin study of affective illness, including hospital- and population-ascertained subsamples. Arch Gen Psychiatry 50:699, 1993. *Kendler KS, Prescott CA: A twin study of major depression. Arch Gen Psychiatry 56:39, 1999. Lachman HM, Kelsoe JR, Remick RA, Sadovnick AD, Rapaport MH, Lin M, Pazur BA, Roe AA, Saito T, Papolos DF: Linkage studies support a possible locus for bipolar disorder in the velocardiofacial syndrome region on chromosome 22. Am J Med Genet 74:121, 1996. Leboyer M, Malafosse A, Boularand S, Campion D, Gheysen F, Samolyk D, Henriksson B, Denise E, des Lauriers A, Lepine JP: Tyrosine hydroxylase polymorphisms associated with manic-depressive illness. Lancet 335:1219, 1990. MacKinnon DF, Xu J, McMahon FJ, Simpson SG, Stine OC, McInnis MG, DePaulo JR: Bipolar disorder and panic disorder in families: An analysis of chromosome 18 data. Am J Psychiatry 155:829, 1998. Marazita ML, Neiswanger K, Cooper M, Zubenko GS, Giles DE, Frank E, Kupfer DJ, Kaplan BB: Genetic segregation analysis of early-onset recurrent unipolar depression. Am J Hum Genet 61:1370, 1997. Mendlewicz J, Rainer JD: Adoption study supporting genetic transmission in manic-depressive illness. Nature 268:327, 1977. *Nurnberger JIJ, DePaulo JR, Gershon ES, Reich T, Blehar MC, Edenberg HJ, Foroud T, Miller M, Bowman E, Mayeda A, Rau NL, Smiley C, Conneally PM, McMahon F, Meyers D, Simpson S, McInnis M, Stine OC, Detera-Wadleigh S, Goldin L, Guroff J, Maxwell E, Kazuba D, Gejman PV, Badner JA, Sanders AR, Rice J, Bierut L, Goate A: Genomic survey of bipolar illness in the NIMH genetics initiative pedigrees: A preliminary report. Am J Med Genet 74:227, 1997. Pekkarinen P, Terwilliger J, Bredbacka PE, Lonnqvist J, Peltonen L: Evidence of a predisposing locus to bipolar disorder on xq24–q27.1 in an extended Finnish pedigree. Genome Res 5:105, 1995. *Rice J, Reich T, Andreasen NC, Endicott J, van Eerdewegh M, Fishman R, Hirschfeld RM, Klerman GL: The familial transmission of bipolar illness. Arch Gen Psychiatry 44:441, 1987. Rosanoff AJ, Handy L, Plesset IR: The etiology of manic-depressive syndromes with special reference to their occurrence in twins. Am J Psychiatry 91:725, 1935. Sadovnick AD, Remick RA, Lam R, Zis AP, Yee IM, Huggins MJ, Baird PA: A mood disorder service genetic database: Morbidity risks for mood disorders in 3,942 first-degree relatives of 671 index cases with single depression, recurrent depression, bipolar I or bipolar II. Am J Med Genet 54:132, 1994. Schwab SG, Hallmayer J, Lerer B, Albus M, Borrmann M, Honig S, Strauss M, Segman R, Lichtermann D, Knapp M, Trixler M, Maier W, Wildenauer DB: Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am J Hum Genet 63:1139–1152, 1998. Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C, Clark CD, McInnis MG, Simpson SG, Breschel TS, Vishio E, Riskin K, Feilotter H, Chen E, Shen S, Folstein S, Meyers DA, Botstein D, Marr TG, DePaulo JR: Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet 57:1384, 1995. Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L, Alexander JR, Das K, Simon R, Fieve RR, Lerer B, Endicott J, Ott J, Gilliam TC, Baron M: A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nat Genet 8:291, 1994. *Tsuang MT, Faraone SV: The Genetics of Mood Disorders. Johns Hopkins University Press, Baltimore, 1990. *Vincent JB, Masellis M, Lawrence J, Choi V, Gurling HM, Parikh SV, Kennedy JL: Genetic association analysis of serotonin system genes in bipolar affective disorder. Am J Psychiatry 156:136, 1999.

Textbook of Psychiatry

14.4 MOOD DISORDERS: NEUROBIOLOGY Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.4 MOOD DISORDERS: NEUROBIOLOGY MICHAEL E. THASE, M.D. Clinical Phenomenology and the Brain Genetic Factors Etiology of Emotional Responses Stress and Animal Models of Depression Monoamine Disturbances Immunological Disturbance Sex Differences Future Directions Suggested Cross-References

The role of physical or biological factors in the pathogenesis of depression has been suspected since antiquity. However, it has only been in the latter half of the twentieth century that the technology and experimental methodology have been available to study these processes in mood disorder. During the past 40 years knowledge about the biology of the depressive disorders has grown by leaps and bounds as experimental methods have advanced from studies assaying peripheral specimens to investigations employing more direct measurements of cerebral metabolism, receptor function, and gene activity; regarding mania and bipolar disorders, however, there is comparatively less data.

CLINICAL PHENOMENOLOGY AND THE BRAIN The signs, symptoms, and subjective experiences of depressed people have long suggested dysfunction of core neurobiological processes. At one level depression involves multiple disturbances of information processing. People who are severely depressed automatically interpret experiences negatively and their access to memories is similarly biased. Cognition and problem-solving skills are further compromised by poor concentration, loss of abstraction, and decreased ability to perform effortful mental tasks. The virtual monologue of negative thoughts and images is often difficult to disrupt and, unlike normal sadness, ventilation to a confidante typically has little beneficial effect. In more extreme cases, delusions or hallucinations grossly distort reality testing. Mental life is thus disturbed by simultaneous excesses and deficits of activity in specific cortical regions, including the hippocampus, prefrontal cortex, and other limbic structures. Many severe depressions are characterized by a loss of mood reactivity. In essence, something that should elicit an uplift in mood does not do so. One correlate of this phenomenon is an apparent loss of reinforcer salience. Hedonic deficits also are apparent in a loss of gusto for food or sex and there can be significant weight loss, especially in the elderly. These disturbances point to abnormalities in neuroregulatory circuits involving the hypothalamus, nucleus accumbens, and thalamus. Another correlate of decreased mood reactivity is a fixity or slowing of expression, initiation of activity, and spontaneous movement. This loss of animation, called psychomotor retardation, is sometimes confounded by a superimposed state of “driven” psychomotor agitation. These stereotypic behaviors characteristically include biting at the nailbeds or lips, a furrowed brow, tugging at one's hair, and purposeless scratching, in addition to the pacing and frequent postural shifts that accompany most states of dysphoric arousal. Like hedonic deficits, psychomotor disturbances are more commonly observed in older people with depression, with agitation typically seen in the most severe or psychotic depressive syndromes. These observable signs point to the probable involvement of circuits joining prefrontal cortex, thalamus, striatum, and basal ganglia. Almost all depressed people report fatigue and an inability to feel refreshed by sleep. Some, particularly those under age 40, sleep excessively, whereas others, especially those over age 50, cannot maintain sleep or awaken spontaneously 1 to 2 hours earlier than desired. For those with such “terminal” insomnia, the morning hours are typically the worst of the day (i.e., diurnal mood variation). Such circadian disturbances strengthen the likelihood of thalamic dysregulation and also suggest abnormalities in the pons and medulla. These signs and symptoms often coaggregate, which has formed the basis for several of the classical clinical subtypes of depression. Thus, anhedonia and psychomotor disturbances are more commonly associated with weight loss, middle and terminal insomnia, preservative ruminations, and diurnal mood disturbance, a constellation of the syndrome classified as an endogenous, autonomous, biological, psychotic, or vital depressive subtype. The fact that such depressions are slow to remit spontaneously, yet relatively responsive to electroconvulsive therapy (ECT), clearly reinforce perceptions of underlying biological abnormalities. Such depressions often appear to arise without provocation by a significant stressor, hence the presumption of an autonomous or endogenous etiology. The apparent stability of this syndrome over the centuries is recognized explicitly by the contemporary use of the ancient Greek term melancholia, even though black bile is no longer considered to be an etiological factor. The depressions of early adult life tend to be “nonendogenous” and often seem to be imbedded with manifold psychosocial problems. Of course, an early age of onset may distort personality development and shape one's reportoire of coping skills, which increases the probability of handling stressors poorly. Moreover, such patients seem to elicit, provoke, or stumble into a disproportionately greater number of stressors. Historically, the association of an early age of onset with comorbid anxiety generally further solidified impressions of a conflicted or “neurotic depression.” The presumed lesser role of biological factors in neurotic depression was further suggested by less than gratifying responses to ECT and, when available, to tricyclic drugs. In addition to the nonendogenous and neurotic appellations, these early-onset depressions traditionally have been described as reactive, personal, or exogenous disorders. Many of these depressions run a chronic course that fluctuates between major and minor (dysthymic) levels. Emerging data on the utility of new antidepressant drugs, particularly serotonergic agents, suggests that biological abnormalities of a different kind might be associated with nonendogenous depression. A subset of nonendogenous depression was further described by “reverse” neurovegetative symptoms, namely, increased appetite, weight gain, and hypersomnolence. Such symptoms were considered uncommon in the late 1950s and 1960s and hence were referred to as atypical. However, as the average age of onset of depression declined into the early 20s and both research and practice has shifted to ambulatory settings, these atypical features are now commonplace. Reverse neurovegetative features are common in several forms of recurrent depression, including seasonal type (winter pattern), bipolar disorders, and major depressive disorder. These subtypes are characterized by an early age of onset and relatively poorer responses to tricyclic medications, as compared to monoamine oxidase inhibitors (MAOIs). Such observations suggest that differences in phenomenology could reflect more specific pathophysiological alterations that affect treatment response.

GENETIC FACTORS Mood disorders clearly run in families and, as a result, both genetic and environmental influences must be considered. At present, it is well established that bipolar I disorder is more heritable than the other mood disorders, that an early age of onset is associated with greater heritability, and that heritable risk decreases in proportion to the amount of genetic material shared by members of a pedigree. Thus, identical twins have greater heritable risk than fraternal twins, who have a risk comparable to siblings and parents. First-degree relatives, in turn, have greater risk than half-siblings, grandparents, or cousins. Research on fraternal and identical twins or use of the adopted-away paradigm further suggests that heritable risk transcends environmental influences. Thus, vulnerability to mood disorders is, in some fashion, encoded in human deoxynucleic acid (DNA). The next generation of molecular genetic studies should help to identify the specific genes and gene products that influence this risk. Although the significance of inherited vulnerability cannot be disputed, considerable variability exists both within and across groups with comparable risks. For example, in some at-risk pedigrees, alcohol use disorders and sociopathy are more common among male probands than depression. Among women, there is some evidence that environmental experiences may influence whether a generalized anxiety disorder or a depressive disorder is expressed. The late-onset mood disorders (i.e., those beginning past age 60) have relatively low rates of heritability. Even identical twins do not have 100 percent concordance of bipolar I disorder. Genetics therefore constitutes just one pathway of vulnerability or, perhaps more accurately, a foundation upon which other biopsychosocial risk factors may be expressed.

ETIOLOGY OF EMOTIONAL RESPONSES The mood disorders are conditions in which normal emotional responses are distorted into more extreme and persistent manifestations. Some consider normal sadness to be an analogue of depressed mood, and elation the normal counterpart of manic euphoria. Continuity between normal and pathological mood states is illustrated by grief or bereavement. Grief is a universal experience, yet it can segue almost inexorably into a state that is so extreme and disabling that professional attention is warranted. Although there are less obvious natural parallels to mania, it is not uncommon for hypomania to go unrecognized. For others, the intensity of new romantic love is associated with changes in perception, cognition, behavior, and judgment that border on manic excitement. The euphorogenic effects of cocaine and other psychostimulants amply document that the “hard wiring” for manic states exists and is expressed if the individual is exposed to the right neurochemical milieu. Predipositions to various emotional states, mood set points, appear to be partly heritable; this background emotional tone is referred to as temperament. Of particular importance to our current topic is a temperament characterized by excessive reactivity and behavioral inhibition, which can be recognized in infancy and is associated with enduring vulnerability to both depression, and anxiety, in adolescence and young adulthood. Similarly, onset of dysthymic traits in childhood presages extremely high rates of depressive and bipolar disorders in adolescence and adulthood. Modern theories of temperament and personality converage around several dimensions, including harm avoidance (neuroticism or behavioral inhibition). In bipolar disorders cyclothymic, extraverted, and novelty-seeking traits are more relevant. There is now considerable evidence that the basic emotions are manifest across human cultures. The capacity to recognize such emotions in others can be observed so early in infancy that innate processes are undoubtedly implicated. Sadness and crying, for example, may be viewed as universal distress signals. Behaviors consistent with basic emotional states can also be observed in other mammals. For example, certain behavioral predispositions towards aggressivity (or passivity) and social dominance (or subordination) appear to extend across vertebrate species. By virtue of the large neocortex, Homo sapiens are distinguished by the capacity to integrate, abstract, and synthesize complex symbolic representations of life experiences; to communicate experiences in direct, abstract, and elaborated forms; and to develop and maintain a self-concept that guides behavior in relation to others and an anticipated future. The domains of competence are similarly broader and diverse. Whereas a highly competent primate may earn a position of dominance if placed in a new group, only the human may seek such a position by drafting a curriculum vitae and lobbying vigorously, and only humans can intentionally misrepresent their competence or motivations, or be affected by the larger social network's knowledge of their past performances. The importance and intensity of human attachment bonds serves to facilitate the protracted task of childrearing and the necessary advantages of kinship. Indeed, for hundreds of thousands of years Homo sapiens adapted in a world in which the average life expectancy was less than 40 years and the infant mortality rate approached 50 percent. Although perhaps politically incorrect, it is not simply social Darwinism to suggest that necessary divisions of labor increased the chances of viable offspring and shaped evolution of gender differences in affectivity, affiliative behavior, and nuturance. Humans are also the slowest to mature of the mammals and functionally the most vulnerable and dependent upon caregivers for the longest period of time. Having evolved over at least 900,000 years, humans must now deal with the massive changes in environment and social structure that have taken place much too rapidly for natural selection to keep pace. In relative terms, the breathtaking sociocultural and technological changes of the twentieth century have occurred in less than one ten-thousandth of human experience! The resulting complexity of human social systems thus often overtaxes the integrative capacities of the large human neocortex. When such capacities are overwhelmed, humans have to cope and adapt with neural mechanisms that are phylogenetically similar to those of other mammals and vertebrates.

STRESS AND ANIMAL MODELS OF DEPRESSION Studies of rodents, dogs, cats, and nonhuman primates have confirmed that acute stress responses are characterized by activation of central and peripheral components of two interactive psychoneuroendocrine systems, the cortical-hypothalamic-pituitary-adrenocortical axis and the cortical-sympathomedullary axis. Although such acute stress responses are more akin to fear and anxiety than depression, it is the concepts of uncontrollability and inescapability that link the responses of other mammals to stress to human depression. Whereas stress acutely signals threat, it is loss, the anticipation of loss, or hopelessness that elicits sadness and despair. Acute stress activates noradrenergic cell bodies in the locus ceruleus, whose axons trigger increased noradrenergic output by the adrenal medulla. At a behavioral level there is heightened arousal, increased perceptual vigilance, and inhibition of consummatory activities such as hunger and sex. Stress also elicits synthesis and release of corticotropin-releasing hormone from neurons in the hypothalamus and cerebral cortex. This hormone activates the pituitary-adrenocortical components of stress response by causing increased release and synthesis of cortisol, adrenocorticotrophic hormone, and other glucocorticoids, and it synergistically enhances locus ceruleus activity as well. The acute response to stress is counterbalanced by homeostatic or adaptive mechanisms. These include feedback inhibition by glucocorticoid receptors in the hippocampus and pituitary, down-regulation of postsynaptic noradrenergic receptors, and inhibitory autoreceptors and heteroreceptors on presynaptic norepinephrine neurons. Parallel input from serotoninergic (5-HT) and g-aminobutyric acid (GABA) neurons also exert dampening or inhibitory effects. Exposure to prolonged, inescapable stress is associated with numerous adaptations and changes in neurobehavioral responses. Although corticosteroid levels may remain elevated, levels of norepinephrine, serotonin dopamine, and GABA in the brainstem and forebrain eventually decrease. Animals trapped in such a state cease trying to resist or escape, and show decreased grooming and appetitive behavior outside of the experimental situation. There are significant individual differences in development of such learned helplessness, as well as differences across pedigrees, or strains, and species. Nevertheless, antidepressant drugs have been shown to prevent, attenuate, or reverse learned helplessness across species. Studies of the experiences of primates in the wild are more relevant to the stresses faced by people than a rat's response to inescapable painful electric shock. These naturalistic studies demonstrate that a fall from a dominant role within a primate social hierarchy is associated with increased cortical-hypothalamic-pituitary-adrenocortical activity and decreased 5 serotonin neurotransmission. In the wild, subordinate animals with low concentrations of the serotoninergic metabolites 5-hydroxyinoleacetic acid (5-HIAA) are likely to be more aggressive and less sexually active. Moreover, when social status is manipulated by creating a new group from a cohort of subordinate primates, a dominance hierarchy will emerge and the winner will experience a corresponding increase in serotonergic function. Conversely, during times of adversity such as drought or famine, the socially dominant primate experiences an increase in cortical-hypothalamic-pituitary-adrenocortical activity. Early Adversity Physical, verbal, and sexual abuse have an indelible effect on the life trajectory. Although maltreatment has been well documented in the pathogenesis of posttraumatic stress disorder and borderline personality disorder, it now appears that such a history is also associated with an increased risk of depression. Studies of animal models confirm that lasting alterations in neuroendocrine behavioral response can result from severe early stress. More recently this vulnerability has been linked to possible enduring changes in gene expression. Animal studies indicate that even transient periods of maternal deprivation can have a similar effect on subsequent response to stress. Early loss and neglect, a correlate of having been raised by parents with a mood disorder, is not uncommon in the history of mood disorder patients. How to integrate these clinical observations with the data on early stress in animals remains a challenge.

MONOAMINE DISTURBANCES The area of scientific inquiry chosen is dependent on the knowledge base and experimental paradigms available to the investigator. In the early 1960s it was possible to measure catecholamine metabolites in body fluids and the principal indoleamine metabolite 5-HIAA in cerebrospinal fluid. However, the visualization of the functional brain was essentially impossible because waking electroencephalograms (EEGs) provided little useful information aside from documentation of epilepsy or diffusing slowing associated with delirium. In addition, there were multiple lines of evidence from pharmacological studies implicating perturbations of monoamine systems in both therapeutic and iatrogenic effects of drugs on mood and behavior. Relevant pharmacotherapies of the time included tricyclic antidepressants, MAOIs, dextroamphetamine (Dexedrine), and the

amine-depleting compound reserpine (Serpasil). Although the early biogenic amine hypotheses have undergone much revision, the critical importance of norepinephrine and 5-HT in the pathophysiology and physiology of mood disorders remains unquestioned. A second important monoamine, dopamine, has received less emphasis and there is also strong evidence of dysfunction in some forms of depressions. Since the mid-1960s there has been a shift in focus away from single neurotransmitters towards neurobehavioral systems, neural circuits, and more intricate regulatory mechanisms. Moreover, postsynaptic receptor families, presynaptic autoreceptors and heteroreceptors, second messengers, and gene transcription factors were not known when the original monoamine hypotheses were formulated. Noradrenergic Systems Noradrenergic neurons have their cell bodies in the locus ceruleus of the brainstem and project rostrally to the cerebral cortex, limbic system, basal ganglia, hypothalamus, and thalamus (Fig. 14.4-1). This diffuse distribution belies norepinephrine's role in initiating and maintaining limbic and cortical arousal, as well as in modulation of the function of other neurotransmitters. Noradrenergic projections to the hippocampus have recently been implicated in behavioral sensitization to stress, and prolonged activation of the locus cerulus contributes to the state of learned helplessness. The locus ceruleus also is the origin of neurons that project to the adrenal medulla, the principal source of norepinephrine into the peripheral blood circulation.

FIGURE 14.4-1 A lateral view of the brain demonstrates the course of the major nonadrenergic pathways emanating from the locus ceruleus and from the lateral brain stem tegmentum. (Reprinted with permission from Kandel ER, Schwartz JH, Jessell TM, editors: Principles of Neural Science, ed 3. Appleton & Lange, Stanford, CT, 1991.)

Novel stimuli increase the activity of the locus ceruleus, which in turn is decreased during vegetative functions, such as eating or sleeping. Cognitive processes can amplify or dampen sympathoadrenal responses to internal or external stimuli. Thus, the perception of stress is relayed via the appropriate cortical structures through the thalamus to the locus ceruleus and sympathoadrenal components of the acute stress response. Stimulation of the medial forebrain bundle, the second major norepinephrine pathway in the brain, elicits increased levels of goal-directed and reward-seeking behavior. Sustained stress also eventually results in decreased levels of norepinephrine in the medial forebrain bundle, which may account for anergia, anhedonia, and diminished libido in depression. Increased noradrenergic output also stimulates inhibitory a 2-adrenergic heteroreceptors on serotonergic neurons. Serotoninergic Systems Serotoninergic neurons project from the brainstem dorsal raphe nuclei to the cerebral cortex, hypothalamus, thalamus, basal ganglia, septum, and hippocampus (Fig. 14.4-2). Serotonin pathways have both inhibitory and facilitatory functions in the brain. For example, much evidence suggests that 5-HT is an important regulator of sleep, appetite, and libido. Serotonergic neurons projecting to the suprachiasmatic nucleus of the hypothalamus help to regulate circadian rhythms (e.g., sleep-wake cycles, body temperature, and hypothalamic-pituitary-adrenocortical axis function). Serotonin also permits or facilitates goal-directed motor and consummatory behaviors in conjunction with norepinephrine and dopamine. Moreover, serotonin inhibits aggressive behavior across mammalian and reptilian species.

FIGURE 14.4-2 A lateral view of the brain demonstrates the course of the major serotonergic pathways. Although the raphe nuclei form a fairly continuous collection of cell groups throughout the brain stem, they are graphically illustrated here as two groups, one rostral and one caudal. (Reprinted with permission from Kandel ER, Schwartz JH, Jessell TM, editors: Principles of Neural Science, ed 3. Appleton & Lange, Stanford, CT, 1991.)

There is some evidence that serotonin neurotransmission is partly under genetic control. Nevertheless, acute stress increases serotonin release transiently, whereas chronic stress eventually will deplete serotonin stores. Chronic stress may also increase synthesis of 5-HT 1A autoreceptors in the dorsal raphe nucleus, which further decrease serotonin transmission. Elevated glucocorticoid levels tend to enhance serotonergic functioning and thus may have significant compensatory effects in chronic stress. Dopaminergic Systems There are four relatively discrete dopamine pathways in the brain ( Fig. 14.4-3). The tuberoinfundibular system projects from cell bodies in the hypothalamus to the pituitary stalk, exerting inhibitory control over prolactin secretion. The nigrostriatal system originates from cell bodies in the substantia nigra and projects to the basal ganglia, regulating involuntary motor activity. The cell bodies of the mesolimbic pathway are located in the ventral tegmentum and project to almost all limbic regions: the nucleus accumbens, amygdala, hippocampus, medial dorsal nucleus of the thalamus, and cingulate gyrus. The mesolimbic dopamine pathway modulates emotional expression, learning and reinforcement, and hedonic capacity. The fourth dopamine pathway, also originating in the ventral tegmentum's mesocortical pathway, which projects to the orbitofrontal and the prefrontal cortical regions, helping to regulate motivation, concentration, initiation of goal-directed and complex, executive cognitive tasks. Decreases in mesocortical and mesolimbic dopamine activity have obvious implications in the cognitive, motor, and hedonic disturbances associated with depression. Moreover, dopamine activity appears to be potentiated by nicotinic inputs and glucocorticoids, and dopamine concentrations are correlated with brain serotonin activity.

FIGURE 14.4-3 A lateral view of the brain demonstrates the course of the four major dopaminergic tracts. (Reprinted with permission from Kandel ER, Schwartz JH, Jessell TM, editors: Principles of Neural Science, ed 3. Appleton & Lange, Stanford, CT, 1991.)

Biogenic Amine Function After nearly 30 years of research it can be concluded that subsets of depressed people manifest one or more abnormalities of monoamine neurotransmission. Decreased central norepinephrine activity can be inferred, in part, from decreased urinary excretion of the metabolite 3-methoxy-4-hydroxyphenylglycol. A partly overlapping subgroup of patients has elevated circulating levels of norepinephrine and its metabolites. This suggests a dissociation of norepinephrine activity in the brain's medial forebrain bundle and the sympathomedullary systems peripheral activities. Increased noradrenergic activity also is reflected by blunted a 1, b, and b-coupled second messenger (i.e., cyclic adenosine monophosphate) responses. Further, an acute response to noradrenergically active antidepressants (i.e., desipramine, nortriptyline, or bupropion) may be transiently reversed by the norepinephrine synthesis inhibitor a-methyl-paratyrosine. Serotonin dysfunction has been documented in overlapping subgroups of patients using a variety of methods, ranging from low cerebrospinal fluid (CSF) levels of 5-HIAA to decreased cerebral metabolism. Serotonin dysfunction also is reflected by blunted responses to specific serotonin (5-hydroxytryptamine [5-HT]) HT 1A subtype 1A (5-HT1A) agonists (e.g., ipsapirone) and nonselective agonists (e.g., L-tryptophan or dex-fenfluramine), decreased neuroendocrine responses, and decreased serotonin uptake sites on blood platelets. Decreased serotonin neurotransmission can be inferred from the findings of cortical-hypothalamic-pituitary-adrenocortical and EEG sleep studies. In functional terms, a state of a relative hypofrontality of cerebral blood flow and glucose metabolism in the brain is fully consistent with decreased neurotransmission by 5-HT neurons projecting from the dorsal raphe nuclei. In support of this observation, dietary depletion of L-tryptophan will induce this abnormality in a subset of vulnerable patients. Tryptophan depletion also reverses acute responses to selective serotonin reuptake inhibitors. Increased sensitivity to dopamine, perhaps mediated by elevated glucocorticoid levels, may contribute to the development of delusions and hallucinations. Other Neurotransmitters Cholinergic neurons containing acetylcholine are distributed diffusely throughout the cerebral cortex, and have reciprocal or interactive relationships with all three monoamine systems. Abnormal levels of choline, which is a precursor to acetylcholine, are seen in the brains of some depressed patients, perhaps reflecting abnormalities in cell phospholipid composition. Cholinergic agonist and antagonist drugs have differential clinical effects on depression and mania. Agonists can produce lethargy, anergia, and psychomotor retardation in normal subjects; exacerbate symptoms in depression; and reduce symptoms in mania. These effects generally are not sufficiently robust to have clinical applications and adverse effects limit their clinical utility. Via their serotonergic or adrenergic effects, antidepressant drugs may decrease cholinergic function, although direct anticholinergic effects are unrelated to antidepressant activity. In an animal model of depression, a strain of mice that is supersensitive to cholinergic effects has been found to develop learned helplessness more quickly and cholinergic supersensitivity has been shown to be attenuated by manipulation of adrenergic activity. Conversely, cholinergic agonists can induce changes in cortical-hypothalamic-pituitary-adrenocortical activity and sleep EEG studies that mimic those associated with severe depression. Indeed, some remitted patients with bipolar or depressive disorders, as well as their never-ill first-degree relatives, have a trait-like increased sensitivity to cholinergic agonists. GABA has an inhibitory effect on ascending monoamine pathways, particularly the mesocortical and mesolimbic systems. Reductions of GABA have been observed in plasma, CSF, and brain GABA concentrations in depression. Animal studies have also found that chronic stress can reduce or deplete GABA levels and, by contrast, GABA receptors can be upregulated by antidepressants. The amino acids glutamate and glycine appear to be the major excitatory neurotransmitters in the central nervous system. Glutamate and glycine bind to sites associated with the N-methyl-D-aspartate (NMDA) receptor and, in excess, can have neurotoxic effects. The hippocampus has a high concentration of NMDA receptors; it is thus possible that glutamate in conjunction with hypercortisolemia mediate the neurocognitive effects of chronic stress. There is emerging evidence that drugs that antagonize NMDA receptors have antidepressant effects. The binding of a neurotransmitter and postsynaptic receptor triggers a cascade of chemical processes that include the second messenger systems. Receptors interact with the intracellular environment via guanine nucleotide-binding proteins (G proteins). The G proteins, in turn, connect to various intracellular enzymes and effectors (e.g., adenylate cyclase, phospholipase C, and phosphodiesterase) that stimulate the formation of second messengers, such as cyclic nucleotide [e.g., cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP)], phosphatidylinositols (e.g., inositol triphosphate and diacylglycerol), and calcium-calmodulin. These second messengers regulate the function of neuronal membrane ion channels, neurotransmitter synthesis and release, and protein kinase activity. Protein kinase, for example, catalyzes phosphorylation, an anergy-liberating process involved in synthesis and degradation of neuroreceptors, ion channels, G proteins, and DNA transcription and messenger-RNA translation factors that regulate gene expression. Recent studies have reported abnormalities in platelet adenylate cyclase activity, phosphoinositide hydrolysis, intracellular calcium metabolism, and G-protein function in depressive disorders. Moreover, antidepressant medications may initiate a series of intracellular reactions that “turn down” synthesis of corticotropin-releasing hormone and monoamine receptors and “turn on” peptides such as neuronal growth factors. There is also increasing evidence that mood-stabilizing drugs (e.g., lithium) act upon G proteins or other second messengers. Alterations of Hormonal Regulation Cortical-Hypothalamic-Pituitary-Adrenal Cortical Activity Elevated glucocorticoid activity is a hallmark of the mammalian stress response. Evidence of increased cortisol secretion is apparent in 20 to 40 percent of depressed outpatients and 40 to 60 percent of depressed inpatients. Rates are highest among older patients, particularly those with highly recurrent or psychotic depressive disorders. Hypercortisolism is thus one of the most common correlates of melancholic depressions. A variety of methods can be used to study elevated cortical-hypothalamic-pituitary-adrenal cortical activity: excretion of urinary free cortisol, 24-hour (or shorter time segments) intravenous collections of glucocorticoid plasma cortisol levels, salivary cortisol levels, and tests of the integrity of feedback inhibition. Methods of testing feedback inhibition usually involve administration of the potent synthetic glucocorticoid dexamethasone, which in 0.5-, 1-, or 2-mg doses normally suppresses cortical-hypothalamic-pituitary-adrenal cortical axis activity for 24 hours. Impaired feedback inhibition is reflected by nonsuppression of cortisol secretion at 8 AM the following morning or subsequent escape from suppression at 4 PM or 11 PM. A more recent development is the pairing of dexamethasone suppression with an infusion of corticotropin-releasing hormone. The sensitivity and specificity of these various tests of feedback inhibition are not sufficient for use and adrenocortical hyperactivity is observed in many other psychiatric disorders, albeit usually at a lower prevalence. Nonsuppression usually implicates a premature loss of inhibitory hippocampal glucocorticoid receptors, which also may account for the age dependence of cortisol nonsuppression. Hypercortisolemia associated with early trauma also may permanently decrease synthesis of glucocorticoid receptors or actually lead to atrophy of these vulnerable neurons. Hypersecretion of cortisol and dexamethasone nonsuppression are imperfectly correlated (about 60 percent concordance). Elevated cortical-hypothalamic-pituitary-adrenal cortical activity in depression is typically not associated with the physical stigmata of Cushing's disease, but it is sufficient to induce a reversible cortical atrophy and is implicated in the genesis of neurocognitive disturbances. Starvation and protracted sleep deprivation also can induce hypercortisolism. Patients with increased cortical-hypothalamic-pituitary-adrenal cortical activity are typically less responsive to attention placebo and psychosocial treatments. However, hypercortisolism does typically resolve with effective treatment and, when persistent, conveys a high risk of relapse. This is presumed to be a consequence of incomplete resolution of the depressive episode at the level of the brain. Dexamethasone and the cortisol synthesis inhibitor ketoconazole (Nizoral Ò) are sometimes used to externally suppress the hypothalamic-pituitary-adrenocortical axis of hypercortisolemic patients with more refractory depressive disorders.

Beyond failure of feedback inhibition, a deficit of 5-HT activity and an increase in norepinephrine or acetylcholine activity have been shown to increase cortical-hypothalmic-pituitary-adrenal cortical activity. Thyroid Axis Activity About 5 to 10 percent of people evaluated for depression have previously undetected or subclinical thyroid dysfunction, as reflected by an elevated basal thyroid-stimulating hormone (TSH) concentration or an increased TSH response to a 500-µg infusion of the hypothalamic neuropeptide thyrotropin-releasing hormone (TRH). Such abnormalities are often associated with elevated antithyroid antibody levels and, unless corrected with thyroid hormone replacement therapy, may compromise response to treatment. These findings are especially relevant to women with rapid-cycling bipolar disorder. More commonly, depressed patients receiving a TRH challenge test show a blunted TSH response. This abnormality, which may be state-independent, has been associated with a heightened relapse risk following pharmacotherapy or ECT. The TSH response may represent pituitary downregulation consequent to a prolonged elevation of TRH secretion. In turn, increased TRH secretion could result from a homeostatic response intended to enhance noradrenergic neurotransmission. Some researchers further speculate that the therapeutic benefit of liothyronine (Cytomel) augmentation therapy is the result of correction of this failed homeostatic response. Growth Hormone Growth hormone secretion from the anterior pituitary is stimulated by norepinephrine and dopamine and inhibited by CRH and somatostatin, a hypothalamic neuropeptide. Somatostatin also inhibits CRH secretion. Secretion of growth hormone follows a 24-hour circadian rhythm, with a characteristic secretory surge during the first few hours of sleep. The most consistent finding in depression is a blunted growth hormone response to clonidine, an a 2 receptor agonist. The onset of sleep and nonselective adrenergic agonists such as desipramine also elicit a blunted growth hormone response. Somatostatin Although the hypothalamus has the highest concentrations of somatostatin, significant concentrations are also found in the amygdala, hippocampus, nucleus accumbens, prefrontal cortex, and locus ceruleus. In addition to inhibition of growth hormone and release of corticotropin-releasing hormone, somatostatin inhibits GABA, adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone. Somatostatin levels are lower in the cerebrospinal fluid of people with depression as compared to those with schizophrenia or normals, and increased levels have been observed in mania. Prolactin Prolactin release from the pituitary is stimulated by serotonin and inhibited by dopamine. Most studies have not found significant abnormalities of basal or circadian prolactin secretion in depression, although a blunted prolactin response to various serotonin agonists has been frequently reported. This response is less likely to be abnormal in premenopausal women, suggesting that estrogen has a moderating effect. Alterations of Sleep Neurophysiology People prone to depression tend to have a premature loss of deep, slow (delta) wave sleep, and an early onset of the first episode of rapid eye movement (REM) sleep (Fig. 14.4-4). Results of family and twin studies suggest that these related abnormalities are at least partly heritable. Consistent with the expected behavior of a heritable trait, reduced REM latency and deficits of slow-wave sleep typically persist following recovery from a depressive episode. A blunted growth hormone response following sleep onset or administration of adrenergic agonists is correlated with a slow-wave sleep deficit and shows similar state-independent or trait-like behavior.

FIGURE 14.4-4 The all night electroencephalographic (EEG) sleep profiles of a healthy young woman and a 63-year-old woman with melancholia. (Reprinted with permission from Thase ME, Howland: Biological Processes in Depression: An Updated Review and Integration. In Handbook of Depression, ed 2, EE Beckham, WR Leber, editors. Guilford, New York, 1995.)

More severe depressions are associated with age-dependent decreases in sleep maintenance (i.e., the capacity to sleep without awakenings) and an increase in the phasic intensity of REM sleep, particularly during the first several REM periods. These changes correlate with clinical measures of severity of depression and tend to normalize during times of remission. Other state-dependent abnormalities are hypercortisolemia, dexamethasone nonsuppression, and elevated levels of peripheral catecholamine metabolites. A deficit of slow-wave sleep and reduced REM latency can be induced and may be caused by a decrease in 5-HT neurotransmission or an increase in central cholinergic activity. Serotoninergic neurons from the dorsal raphe-nuclei project to cholinergic cells in the pons to tonically inhibit REM sleep. During non-REM (NREM) sleep, these cholinergic neurons are inactive. L-tryptophan depletion results in an increase in REM time and a decrease in REM latency. Serotoninergic neurons projecting rostrally to the thalamus and prefrontal cortex also mediate slow-wave activity, as do drugs that antagonize 5-HT CSF concentrations of 5-HIAA is correlated with diminished slow-wave sleep, an effect mimicked by acute serotonin depletion.

2

receptors. Low

Prefrontal cortical metabolism is normally decreased during nREM sleep, a time of physical and metabolic rest. By contrast, REM sleep is normally associated with an increase in glucose metabolism in the limbic system. In depression there is relatively increased prefrontal glucose metabolism during nREM sleep, corresponding to the diminution of restorative slow wave sleep. REM sleep is associated with an even greater increase in limbic glucose utilization. The sleep profiles of younger, hypersomnolent patients can be remarkably normal, particularly if laboratory routines do not permit an extended morning sleep period. Such patients may actually have increased slow-wave sleep and an increase in REM time associated with a greater total sleep time. Reduced REM latency, however, has been reported in juvenile depressives by at least one group of investigators. The combination of reduced REM latency, increased REM density, and decreased sleep maintenance identifies about 40 percent of depressed outpatients, 80 percent of depressed inpatients, and 10 percent of age-matched normal controls. These sleep abnormalities also have been reported in a subset of dysthymic disorder patients. Sleep studies are too expensive and inconvenient to be used routinely for diagnostic purposes in depression and, like dexamethasone nonsuppression, false-positive cases are common in other psychiatric disorders. Nevertheless, current data indicate that patients manifesting this constellation of disturbances are less responsive to psychotherapies and may benefit preferentially from pharmacotherapy. It remains to be seen if those normal individuals with false-positive studies have an increased vulnerability to future episodes of depression. Successful nonpharmacological treatment of the depressive episode results in normalization of this profile in about 50 percent of cases. Pharmacotherapy with most antidepressant agents has an overcorrective effect characterized by prolongation of REM latency and suppression of REM sleep; such medications have variable effects on sleep maintenance. REM suppression may reflect activation of postsynaptic 5-HT 1A receptors or enhanced norepinephrine neurotransmission. Both desipramine (Norpramin) and the SSRIs for example, produce a rapid REM suppression in normal patients as well as in patients with depression. The efficacy of antidepressant medications that do not suppress REM sleep, such as nefazodone (Serzone), and bupropion (Wellbutrin) in patients with pathologically increased REM sleep suggests that these formulations may not apply to all depressions. Alterations of Circadian Rhythms In addition to sleep disturbances, depressed patients often show a blunting of circadian rhythms of cortisol secretion, growth hormone secretion, and body temperature. These changes were originally thought to represent a phase advance of the sleep-wake cycle, although stronger evidence now suggests that circadian rhythms may be disorganized by heightened nocturnal arousal. Increased CRH, increased somatostatin, hypercortisolemia, and decreased 5-HT could all be implicated in this process. By contrast, in some cases of depressive disorders with seasonal (winter) pattern there is evidence of a phase delay of the sleep-wake cycle in relation to the nocturnal onset of melatonin secretion. The role of melatonin in the pathophysiology of mood disorders remains

unclear. Brain Structure and Function Structural Lesions Computed axial tomography and magnetic resonance imaging scans provide sensitive, noninvasive methods to assess the brain, including cortical and subcortical tracts, as well as white matter lesions. The most consistent abnormality observed in the depressive disorders is increased frequency of abnormal hyperintensities in subcortical regions, especially the periventricular area, basal ganglia, and thalamus ( Fig. 14.4-5). More common in bipolar I disorder and among the elderly, these hyperintensities appear to reflect the deleterious neurodegenerative effects of recurrent mood episodes. Ventricular enlargement, cortical atrophy, and sulcal widening also have been reported in patients with mood disorders as compared to normal controls. In addition to age and illness duration, structural abnormalities are associated with increased illness severity, bipolar status, and increased cortisol levels. Some depressed patients also may have reduced caudate nucleus volumes, suggesting a defect in the mesocorticolimbic system. Cerebrovascular factors, including strong, often involve subcortical frontal and basal ganglia structures, and appear particularly relevant to late-life depression.

FIGURE 14.4-5 This magnetic resonance imaging (MRI) scan of a patient with late onset major depressive disorder illustrates extensive periventricular hyperintensities associated with diffuse cerebrovascular disease.

Cerebral Metabolic Alterations Positron emission tomography (PET) scanning is currently the most powerful method for visualizing brain metabolism during rest and various states of activation. Normal sadness is associated with an increase in cerebral blood flow to the thalamus and medial prefrontal cortex. This appears to be a nonspecific change associated with diverse emotional responses. More specific activation is seen in the left amygdala, hippocampal formation, and parahippocampal gyrus. Sadness generated by one's own thoughts (as opposed to a video scenario) also is associated with a relative increase in cerebral blood flow to the anterior insular cortex, as is anticipatory anxiety. Direct activation of limbic structures by intravenous infusions of procaine hydrochloride also has been studied in normal controls. Such activation is characterized by reliable, bilateral increases in cerebral blood flow in the amygdala, parahippocampal gyri, insula, and anterior cingulate cortex. These changes are associated with a wide range of emotions, ranging from euphoria to severe anxiety. The most widely replicated PET finding in depression is decreased anterior brain metabolism, which is generally more pronounced on the left side. This abnormality appears to be state dependent and has been observed in both depressive and bipolar disorders ( Fig. 14.4-6), as well as in depression associated with obsessive-compulsive disorder. There is a reversal of hypofrontality following shifts from depression into hypomania, such that there are greater left-hemisphere reductions in depression compared to greater right-hemisphere reductions in mania.

FIGURE 14.4-6 Composite coronal and sagittal sections of positron emission tomography (PET) scans show areas where cerebral glucose metabolism is decreased in depressed patients relative to matched health controls. (Reprinted with permission from Drevets WC: Nature 386:824–827, 1997. Ó 1997 MacMillan Magazine Limited.)

Other studies have observed more specific reductions of reduced cerebral blood flow and metabolism in the dopaminergically innervated tracts of the mesocortical and mesolimbic systems in depression. There is evidence that antidepressant agents at least partially normalize some of these changes. In addition to a global reduction of anterior cerebral metabolism, increased glucose metabolism has been observed in several limbic regions. The best evidence of this abnormality comes from studies of patients with relatively severe recurrent depression and a family history of mood disorder ( Fig. 14.4-7). This abnormality was found to be reversible with effective pharmacotherapy, but persistent when recently remitted patients were studied again when they were off medication. During episodes of depression, increased glucose metabolism is correlated with intrusive ruminations. If truly state-independent, such amygdalar hypermetabolism could represent the emotional “amplifier” that helps to distort the signal of relatively minor stressors in vulnerable people.

FIGURE 14.4-7 A lateral composite positron emission tomogram (PET) illustrating increased blood flow to the amygdala of patients with pure familial depressive disease as compared to healthy controls. (Reprinted with permission from Drevets WC: Exploring the Functional Anatomy of Depressive Disorder—Part I. In Masters in Psychiatry, Cliggott Communications, 1994.)

Magnetic resonance spectroscopy has recently been used to study brain phosphorus metabolism in mood disorders. These studies focus on phosphorus metabolites because they reflect metabolic activity of several second messengers, such as cAMP, cyclic guanine monophosphate, and phosphatidylinositol. An asymmetrical abnormality of phosphorus metabolism has been observed in the frontal lobes of patients with bipolar disorder compared to normal controls, as well as the left frontal lobe and basal ganglia of patients with depression.

IMMUNOLOGICAL DISTURBANCE Depressive disorders are associated with several immunological abnormalities, including decreased lymphocyte proliferation in response to mitogens and other forms of impaired cellular immunity. These lymphocytes produce neuromodulators such as corticotropin-releasing factor and cytokines, which are peptides known as interleukins. There appears to be an association with clinical severity, hypercortisolism, and immune dysfunction and the cytokine interleukin-1 may induce gene activity for flucocorticoid synthesis. The precise clinical relevance of these findings requires further investigation.

SEX DIFFERENCES There is no compelling evidence that a single, sex-related factor accounts for the increased risk of depression in women. Certainly, alterations of sex hormones or hypothalamic gonadotropins in depression have not been documented consistently. Prior to menopause, estrogen and its metabolites may actually “protect” depressed women from developing hypercortisolemia. Although probably not a specific causal factor in depression, menopause may thus represent a point of transition from less severe depressions characterized by reverse vegetative symptoms to melancholia. There are, however, a multitude of risk factors that may contribute to the “gender gap,” including greater risk of early sexual abuse and current spousal abuse, higher rates of thyroid disease, oral contraceptive use, and premenstrual or postpartum-onset mood disorders. Alternatively, gender differences in emotional expressivity may interact with sociocultural factors and the texture of modern life to create the increased risk of depression for women. Conversely, use of external coping strategies and greater traditional social role expectations to achieve competence outside of the home (and the resultant economic power) may provide men relatively greater protection against depression. Gender differences in rates of depression are not well documented in nonindustrialized cultures and, in the United States, no differences in men's and women's rates of depression were found in the old-order Amish of Pennsylvania.

FUTURE DIRECTIONS Major depressive disorder is associated with a myriad of neurobiological disturbances, perhaps as varied as the range of effective treatments and clinical presentations. Broadly viewed as traits (either inherited or acquired) or states (abnormalities only apparent during illness), these disturbances begin to show some psychobiological coherence. State-dependent abnormalities, for example, tend to coaggregate in patients with more severe syndromes and, especially past ages 40 to 50, are associated with the more classic endogenous or melancholic manifestations. These changes include increased phasic REM sleep, poor sleep maintenance, hypercortisolism, impaired cellular immunity, global reductions of anterior cerebral blood flow and glucose metabolism, elevated peripheral noradrenergic metabolites, and possibly increased glucose metabolism in the left amygdala. Such changes suggest, almost without exception, the consequences of an exaggerated and sustained stress response. Once manifest in this fashion, the depressive episode tends to be longer, more disabling, more prone to relapse, and more likely to benefit from pharmacotherapy or ECT. Trait-like abnormalities include reduced slow-wave sleep, reduced REM latency, blunted nocturnal growth hormone response, and various indicators of decreased serotonin neurotransmission. Heritability of these abnormalities is inferred from family studies and other at-risk paradigms. These abnormalities are associated with an early age of onset and perhaps with increased vulnerability to recurrent illness. They may also increase the likelihood of state-dependent biological changes during depressive episodes, probably by reflecting impairments in the ability to dampen or lower stress responses. Examples of more persistent but “acquired” abnormalities may include global and focal changes, cortical atrophy, hypertrophy of the adrenal cortex, periventricular hyperintensities, and alterations in CRH synthesis. Blunted response of thyroid-stimulating hormone to an infusion of thyrotropin-releasing hormone and dexamethasone nonsuppression may represent “hybrids,” in that these abnormalities can be slow to normalize and, when persistent after remission, convey a high risk of relapse. Although specific genes have not yet been identified, vulnerability to mood disorders is heritable for some people. This type of heritability is most likely polygenetic and, in all likelihood, will be best understood through models that include gene-environment interactions. Nevertheless, increased heritability is associated with an earlier age of onset, greater comorbidity, increased risk of recurrent illness, and an increased likelihood of hypomanic or manic episodes. Two of the more heritable forms of depression, early-onset chronic depression and bipolar depression, are commonly nonmelancholic in clinical presentation and relatively less likely to manifest state-dependent neurobiological disturbances. Both different genetic vulnerabilities and age-dependent changes in the brain's response to depression might explain this apparent paradox. Hypersomnolence and hyperphagia may thus reflect an episodic yet age-dependent homeostatic response to enhance serotoninergic dysfunction. In contrast, the sharp rise of mania post-pubescently may be related to maturational effects of catecholaminergic systems in the brain. Aging and an accumulating risk of recurrent episodes are inextricably connected, although the diseases of aging that ravage brain function definitely increase the risk of depression, and these syndromes often prove to be resistant to treatment. The late-onset form of depression associated with periventricular hyperintensities also illustrates a more subtle interplay between vascular disease, brain damage, and mood disorder. Ultimately, depression remains the most human of the Axis I disorders, partly because everyone can relate to sadness, grief, and the heartbreak of lost love and partly because the cognitive world of animals subjected to prolonged, inescapable stress is inaccessible. Even if their mental equivalents of “Why did this happen to me?” “Why bother—nothing I try will help?” and “I wish I was dead” could be identified, however, the incidence, prevalence, disability, and tragedy of depression in humans cannot be generalized to rodents or primates. Strong, sustaining affective bonds and an enduring sense of self-worth and competence are all-important and assaults on these fundamental aspects of human well-being are so frequent that many individuals succumb to depression. Some individuals are more vulnerable than others, and the association between severe depression and numerous, reproducible changes in brain function are well documented. Understanding the mechanisms of adaptation and brain dysfunction that predispose, initiate, distort, and maintain depressive disorders represents our best hope to prevent and relieve the misery and suffering of tens of millions of people.

SUGGESTED CROSS-REFERENCES Monoamine neurotransmitters are discussed in Section 1.4, and the contributions of the neural sciences in general are the focus of the other sections of Chapter 1. Biological therapies are covered in Chapter 31. SECTION REFERENCES Akiskal HS: Interaction of biologic and psychologic factors in the origin of depressive disorders. Acta Psychiatr Scand 319:131, 1985. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M: ‘Vascular depression' hypothesis. Arch Gen Psychiatry 54:915, 1997. *Anand A, Darnell A, Miller HL, Berman RM, Cappiello A, Oren DA, Woods SW, Charney DS: Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder. Biol Psychiatry 45:972, 1999. Avissar S, Nechamkin Y, Roitman G, Schreiber G: Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression. Am J Psychiatry

154:211, 1997.

Barden N: Modulation of glucocorticoid receptor gene expression by antidepressant drugs. Pharmacopsychiatry 29:12, 1996. Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal JH, Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS: Positron emission tomography

measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. Arch Gen Psychiatry 54:364, 1997. *Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, ed 3. Oxford University Press, New York, 1996. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR: Serotonin function and the mechanism of antidepressant action: Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 47:411, 1990. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME: A functional anatomical study of unipolar depression. J Neurosci 12:3628, 1992. *Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597, 1997. Higley JD, Thompson WW, Champoux M, Goldman D, Hasert MF, Kraemer GW, Scanlan JM, Suomi S, Linnoila M: Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rheusus monkeys (Macaca mulatta). Arch Gen Psychiatry 50:615, 1993. Holsboer F: Neuroendocrinology of mood disorders. In Psychopharmacology: The Fourth Generation of Progress. FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. Kapur S, Mann JJ: Role of the dopaminergic system in depression. Biol Psychiatry 32:1, 1992. Karege F, Bovier P, Rudolph W, Gaillard JM: Platelet phosphoinositide signaling system: An overstimulated pathway in depression. Biol Psychiatry 39:697, 1996. Kupfer DJ, Ehlers CL: Two roads to rapid eye movement latency. Arch Gen Psychiatry 46:945, 1989. Maes M, Meltzer HY: The serotonin hypothesis of major depression. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. *Manji HK, Potter WZ, Lenox RH: Signal transduction pathways. Arch Gen Psychiatry 52:531, 1995. Mayberg HS: Limbic-cortical dysregulation: A proposed model of depression. J Neuropsychiatry 9:471, 1997. *Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT: Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness. Am J Psychiatry 156:675, 1999. Nemeroff CB: New vistas in neuropeptide research in neuropsychiatry: Focus on corticotropin-releasing factor. Neuropsychopharmacology 6:69, 1992. Petty F: GABA and mood disorders: A brief review and hypothesis. J Affect Disord 34:275, 1995. Plotsky PM, Owens MJ, Nemeroff CB: Neuropeptide alterations in mood disorders. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. *Rajkowska G, Miguel-Hidaglgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA: Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085, 1999. Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, Yun L-S, Chen K: Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 154:918, 1997. Renshaw PF, Lafer B, Babb SM, Fava M, Stoll AL, Christensen JD, Moore CM, Yurgelun-Todd DA, Bonello CM, Pillay SS, Rothschild AJ, Nierenberg AA, Rosenbaum JF, Cohen BM: Basal ganglia choline levels in depression and response to fluoxetine treatment: An in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 41:837, 1997. Ribeiro SCM, Tandon R, Grunhaus L, Greden JF: The DST as a predictor of outcome in depression: A meta-analysis. Am J Psychiatry 150:1618, 1993. *Sapolsky RM: Stress, glucocorticoids, and damage to the nervous system: The current state of confusion. Stress 1:1, 1996. Schatzberg AF, Schildkraut JJ: Recent studies on norepinephrine systems in mood disorders. In Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer, editors. Raven Press, New York, 1995. Servan-Schreiber D, Perlstein WM: Pharmacologic activation of limbic structures and neuroimaging studies of emotions. J Clin Psychiatry 58(suppl):13, 1997. Soares JC, Mann JJ: The anatomy of mood disorder—review of structural neuroimaging studies. Biol Psychiatry 41:86, 1997. *Swann AC, Katz MM, Bowden CL, Berman NG, Stokes PE: Psychomotor performance and monoamine function in bipolar and unipolar affective disorders. Biol Psychiatry 45:979, 1999. *Teasdale JD, Howard RJ, Cox SG, Ha Y, Brammer MJ, Williams SCR, Checkley SA: Functional MRI study of the cognitive generation of affect. Am J Psychiatry

156:209, 1999.

Thase ME, Buysse DJ, Frank E, Cherry CR, Cornes CL, Mallinger AG, Kupfer DJ: Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal electroencephalographic sleep profiles. Am J Psychiatry 154:502, 1997. Thase ME, Dubé S, Bowler K, Howland RH, Myers JE, Friedman E, Jarrett DB: Hypothalamic-pituitary-adrenocortical activity and response to cognitive behavior therapy in unmedicated, hospitalized depressed patients. Am J Psychiatry 153:886, 1996. *Thase ME, Howland RH: Biological processes in depression: An updated review and integration. In Handbook of Depression, EE Beckham, WR Leber, editors. Guilford, New York, 1995. Weiss JM: Stress-induced depression: Critical neurochemical and electrophysiological changes. In Neurobiology of Learning, Emotion, and Affect, JIV Madden, editor. Raven Press, New York, 1991.

Textbook of Psychiatry

14.5 MOOD DISORDERS: PSYCHODYNAMIC ASPECTS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.5 MOOD DISORDERS: PSYCHODYNAMIC ASPECTS GLEN O. GABBARD, M.D. Psychodynamic Theories of Depression Psychodynamic Psychotherapy Mania Other Psychological Theories Suggested Cross-References

A contemporary psychodynamic approach to mood disorders takes into account the strong biological underpinnings of these disorders. The domain of meanings is central to psychodynamic thought. Even when psychiatric illnesses can be traced to alternations in neurotransmitters, the symptomatology may acquire specific meanings for the patient. Moreover, psychosocial stressors and interpersonal events appear to trigger certain neurophysiological and neurochemical changes in the brain that significantly alter the balance of neurotransmitters. In other words, the development of an episode of depression or mania is generally regarded as a final common pathway of a complex mixture of psychosocial, genetic, and biological influences. Clinically significant depression has long been linked to psychosocial stressors, such as the loss of a spouse. In addition, the loss of a parent before age 11 places adults at a higher than usual risk of depression. Some investigators have linked early childhood losses or separations to changes in neuronal receptor sites in the brain. This mechanism, known as kindling, is postulated to work in the following manner. Environmental stressors in childhood (e.g., loss or separation) so sensitize the receptor sites that relatively minor stressors in later life may suffice to trigger an episode of affective disorder. Chronic stress and deprivation of environmental origin may produce alterations in the catecholaminergic system in response to stimulation from the corticotrophin-releasing hormone–adrenocorticotropic hormone (ACTH) axis. Primate studies have lent some support to the hypothesis that psychosocial influences have permanent effects on neurophysiological factors. Infant squirrel monkeys who are separated from their mothers experience long-lasting and, in some cases, permanent neurobiological changes. The changes include lasting alterations in the sensitivity of noradrenergic receptors, changes in hypothalamic serotonin secretion, and persistently elevated plasma cortisol concentrations. The sensitivity and number of brain opioid receptors are also significantly affected by repeated separation. Some changes are reversible if the infant monkeys are reunited with their mothers or siblings; other changes are not. Moreover, the separations appear to be more or less damaging during certain developmental periods, possibly because of the correlation with myelinization in the nervous system. Although depression was once divided into endogenous and reactive subgroups, recent research has rendered these distinctions obsolete. Most depression is triggered by stressors, although at times relatively mild to an outside observer, and all depression involves endogenous biochemical factors. In this regard, every case of depression and mania can be regarded as having both a psychosocial and a biological dimension. Similarly, most depressions, except those of extreme severity, respond equally well to psychotherapy and medication. One of the most sophisticated efforts to define the relative contributions of psychological vulnerability, genetics, and environmental stressors in major depressive disorder was a prediction study involving female twins. Multiple assessments of 680 female-female twin pairs of known zygosity were made over time, and the findings allowed the investigators to develop an etiological model to predict major depressive episodes. One of the most influential predictors was the presence of recent stressful events. Genetic factors were also important in predicting depression. Two other factors, neuroticism and interpersonal relations, also played substantial etiological roles. Neuroticism seemed to contribute in part by reducing the level of social support for an individual. Interpersonal dimensions of social support, recent difficulties, and parental warmth were all involved in predicting a major depressive episode. Kenneth Kendler and his colleagues expanded on their twin study by examining information about stressful life events and the onset of major depressive episodes in a population base sample of 1082 female-female twin pairs. They interviewed members of the sample on two different occasions separated by a mean time of 17.3 months. They again found that stressful events significantly predicted onset of major depression in the month of occurrence. The most severe stressors included death of a close relative, serious marital problems, assault, and divorce or breakup. Genetic liability also had a significant impact on the risk of onset of depression. In individuals at lowest genetic risk (i.e., monozygotic twins with an unaffected cotwin), the probability of having a major depression in a particular month was 0.5 percent if unexposed to a severe life event. However, if the individual did experience such an event, the probability went up to 6.2 percent. An even more dramatic difference was found by looking at individuals at the highest genetic risk (i.e., monozygotic twins with an affected cotwin). In these cases, the probability of having a major depression in a particular month was only 1.1 percent if no stressor was involved. However, if these individuals were exposed to a severe event, their risk of having a depressive episode skyrocketed to 14.6 percent. The investigators described the best model for the joint effect of genetic liability and stressful life events on the onset of major depression as follows: genetic factors influence the risk of onset of major depression, at least in part, by altering the sensitivity of individuals to the depression-inducing effect of stressful life events. They emphasized that an individual's genetic endowment is not static. It interacts with the environment and reacts to psychosocial stressors. One factor not captured by research using large samples is the role of the meaning of a particular stressor. What may seem a relatively mild psychological stressor may have conscious or unconscious meanings to an individual patient that greatly magnify its impact. In examining research on the role of stressful events in the course of unipolar and bipolar disorders, Constance Hammen concluded, “The field has reached considerable consensus that it is not the mere occurrence of a negative life event but rather the person's interpretation of the meaning of the event and its significance in the context of its occurrence.” In a longitudinal study of the link between depressive reactions and stressors, Hammen and her colleagues found that stressors whose content matched the patient's area of self-definition were particularly likely to precipitate depressive episodes. In other words, in someone whose sense of self is partly defined by social connectedness, loss of significant interpersonal contacts may precipitate a depressive episode. On the other hand, someone whose self-worth is linked to achievement and efficacy might be more likely to have a depressive episode in response to a perceived failure in the workplace. Psychodynamic theories of etiology have accumulated over years of clinical experience. These psychodynamic theories must be viewed within a broad dialogue with the neuroscientific data regarding brain changes in affective disorders. The following theories may also be regarded as psychodynamic themes that emerge in the treatment of depressed patients and may assist the clinician in understanding the patient's inner experience.

PSYCHODYNAMIC THEORIES OF DEPRESSION Anger Turned Inward A common finding in depressed patients is profound self-depreciation. Sigmund Freud, in his classic 1917 paper “Mourning and Melancholia,” attributed that self-reproach to anger turned inward, which he related to object loss, which may or may not be real. A fantasied loss may suffice to trigger a severe depression. Moreover, the patient may actually be unaware of any specific feelings of loss, since the fantasied loss may be entirely unconscious. Freud drew an analogy between serious melancholic states and normal grief. Both may be time limited, but Freud cited two principal differences. In cases of grief, there is an actual object loss in external reality; in depression the lost object is more likely to be emotional than real. The second difference is that persons with depression experience profound loss of self-esteem, but the self-regard of persons engaged in a mourning process is not diminished. The observational differences between grief and depression were pivotal in Freud's theory. He reasoned that one way of dealing with the loss of a beloved person is to become like the person. Freud defined that process as introjection, a defense mechanism central to the psychodynamics of depression, in which the patient internalizes the lost object so that it becomes an internal presence. Freud later noted that introjection is the only way that the ego can give up a valued and loved object. Because depressed persons perceive the departed love object as having abandoned them, feelings of hatred and anger are intermingled with feelings of love. Freud

suggested that ambivalence involving the coexistence of love and hate is instrumental in the psychodynamics of depression. As a result of introjecting the lost object, the negative part of the depressed patient's ambivalence—the hatred and anger—is directed inward and results in the pathognomonic picture of self-reproach. In that manner a suicidal act may have the unconscious meaning of murder. Karl Abraham, one of Freud's early colleagues, shared Freud's view of depression but also extended and elaborated it. Abraham viewed the process of introjection as a defense mechanism that takes two forms. First, he thought that the introjection of the original love object is the basis for building one's ego-ideal, so that the role of the conscience is eventually taken over by the introjected object. In that conceptualization much pathological self-criticism is seen as emanating from the introjected love object. In the second form of introjection, more in keeping with Freud's idea, the content of self-reproach is merciless criticism directed at the object. In other words, Abraham viewed the two processes of introjection as instrumental in creating the superego. Abraham also linked depression to early fixations at the anal and the oral levels of psychosexual development. He viewed oral sadistic tendencies as the primary source of self-punishment in depressed patients, and he inferred that inadequate mothering during the oral stage of development was involved. The psychodynamic understanding of depression defined by Freud and expanded by Abraham is known as the classical view of depression. That theory involves four key points: (1) disturbances in the infant-mother relationship during the oral phase (the first 12 to 18 months of life) predispose to subsequent vulnerability to depression; (2) depression can be linked to real or imagined object loss; (3) introjection of the departed object is a defense mechanism invoked to deal with the distress connected with the object loss; and (4) because the lost object is regarded with a mixture of love and hate, feelings of anger are directed inward at the self. Depressive Position Although Melanie Klein understood depression as involving the expression of aggression toward loved ones, much as Freud did, the developmental theory on which her view was based is quite different from Freudian theory. During the first year of life, Klein believed, the infant progresses from the paranoid-schizoid position to the depressive position. In the first few months of life, according to Klein, the infant projects highly destructive fantasies into its mother and then becomes terrified of the mother as a sadistic persecutor. That terrifying “bad” mother is kept separate from the loving, nurturing “good” mother through the defense mechanism of splitting. In that manner the infant's blissful feeding experience remains uncontaminated and undisturbed by persecutory fears of attack by the “bad” mother. In the course of normal development, according to Klein, the positive and negative images of the mother are integrated into a more ambivalent view. In other words, the infant recognizes that the “bad” mother it fears and hates is the same mother as the “good” mother it loves and adores. The recognition that one can hurt loved ones is the essence of the depressive position. Klein connected clinical depression with an inability to successfully negotiate the depressive position of childhood. She regarded depressed persons as fixated or stuck at a developmental level in which they are extraordinarily concerned that loved good objects have been destroyed by the greed and destructiveness they have directed at them. In the absence of those good objects, depressed persons feel persecuted by the hated bad objects. In short, Klein's view was that depressed patients are longing or pining for the lost love objects while being persecuted by bad objects. In that theoretical framework the feelings of self-depreciation are linked to the fear that one's good parents have been transformed into violent persecutors as a result of one's own destructive tendencies. Also, the bad internal objects are internalized into the superego, which then makes sadistic demands on the patient. Hence, in the kleinian view, the self-reproaches experienced by depressed patients are directed against the self and internal impulses, rather than toward an introjected object, as in Freud's view. Tension Between Ideals and Reality Whereas most psychodynamic theories of depression incorporate the superego as a significant part of the conceptual understanding, Edward Bibring viewed depression as tension arising from within the ego itself, rather than between the ego and the superego. According to Bibring, the ego has three highly invested narcissistic aspirations—to be good and loving, to be superior or strong, and to be loved and worthy. Those ideals are held up as standards of conduct. Depression sets in when a person becomes aware of the discrepancy between those ideals and reality. Helplessness and powerlessness result from the feeling that one cannot measure up to such high standards. Any blow to the self-esteem or any frustration of the strivings toward those aspirations precipitates depression. Bibring's theory, unlike Freud's and Klein's, does not regard aggression as playing a primary role in depression. The depressed person may ultimately experience anger turned inward, resulting from the awareness of helplessness; however, such expressions of aggression are secondary, rather than primary. The essence of depression, in Bibring's view, is a primary affective state arising within the ego and is based on the tension between what one would like to be and what one is. Ego as Victim of Superego Edith Jacobson compared the state of depression to a situation in which the ego is a powerless, helpless child, victimized by the superego, which becomes the equivalent of a sadistic and powerful mother who takes delight in torturing the child. Like Freud, Jacobson assumed that depressed persons have identified with ambivalently regarded lost love objects. The self is experienced as identified with the negative aspects of the object, and ultimately the sadistic qualities of the lost love object are transformed into the cruel superego. Hence, depressed persons feel that they are at the mercy of a sadistic internal tormentor that is unrelenting in its victimization. Jacobson also noted that the boundary between self and object may disappear, resulting in a fusion of the bad self with the bad object. Dominant Other Silvano Arieti studied the psychodynamic underpinnings of depression in severely ill patients who were unresponsive to most somatic treatments. He observed a common psychological theme in those patients that involved living for someone else, rather than for themselves. He referred to the person for whom depressed patients live as the dominant other. In most cases the dominant other is the spouse or a parent, but Arieti also noted that sometimes a principle, an ideal, or an organization serves a similar psychodynamic function. In such cases he referred to the entity as the dominant ideology or the dominant goal. Depression often sets in when patients realize that the person for whom they have been living is never going to respond in a manner that will meet their expectations. The goal of their lives is regarded as unattainable, and a profound feeling of helplessness sets in. In Arieti's conceptualization of depression, he stressed a marked rigidity in the thinking of depressed persons, so that any alternative to living for the dominant other or the dominant ideology is viewed as unacceptable and even unthinkable. Depressed patients feel locked into an inflexible perspective on how they should live their lives and how gratification or fulfillment can be obtained. Even though they are depressed because living for someone or something other than themselves has been a failure, they nevertheless feel paralyzed and unable to shift their approach to life. If the dominant other will not respond to them in the way they have longed for, they feel that life is worthless, and that rigidity is often involved in a decision that suicide is the only alternative. A 19-year-old college student consulted a psychiatrist after one semester in school. He told the psychiatrist that he was depressed and discouraged with college and with himself. College was not what he had expected, and he had not performed up to his expectations. He was seriously questioning whether he should return for the second semester, and he had a sense of hopelessness about changing his feelings. Suicidal thoughts had occasionally crossed his mind, although he was not planning to act on them. His sleep was disturbed by awakening in the middle of the night and ruminating about what he should do. He felt a significant diminution in his energy level, and he commented that things he used to find enjoyable no longer gave him pleasure. The patient attended a prestigious college on the West Coast, but he indicated that he had actually wanted to get into Harvard. His application to Harvard had resulted in his being placed on the waiting list, but he had not been accepted. The psychiatrist he consulted commented that the college he had chosen to attend was certainly highly regarded. The patient responded, “It's not Harvard.” When the psychiatrist asked the patient how he had done academically during the first semester, the patient appeared embarrassed and replied, “I only got a 3.25 grade-point average—one A and three Bs.” The psychiatrist asked him why he seemed embarrassed to reveal such a solid academic record. The patient explained that he had wanted to make the dean's list but that he had fallen short of it, since the list required a 3.5 grade-point average. The psychiatrist asked the patient if he hoped to be in a different situation after one semester of college. The patient's answer revealed that he had an extraordinarily high internal expectation of himself. He had wanted to be “a star,” a straight-A student at Harvard. He explained that his father had gone to Harvard, and he hoped that, by being a standout there, he would finally achieve the praise and recognition from his father that he had always longed for but had never received. His father seemed disappointed that his son had not been accepted at Harvard, and the patient was convinced that his father was ashamed of him for not making the dean's list. The above case example illustrates the psychodynamic theories of both Arieti and Bibring. The patient was living his life for a dominant other—his father. He tried to perform beyond his abilities to extract an approving and loving response from his father that was never forthcoming. That longed-for response was rigidly construed as the only thing that mattered in life. Even though he was succeeding at a highly competitive college, his success did not make him feel good about himself. Moreover, the patient's depression can also be linked to his awareness of the disparity between his idealized expectations of himself and the reality of his situation, as described by Bibring. Being a straight-A student at Harvard was his aspiration; the reality was that he was a B + student at a college that did not measure up to Harvard. The vignette also reflects two other key elements in the psychodynamic etiology of depression. First, in accord with the psychoanalytic notion of multiple causation,

more than one psychodynamic theory may be pertinent in understanding an individual patient's depression. Clearly, both the dominant other and the tension between ideals and realities were significant determinants in causing the patient's depression. Second, the precipitating factors that produce depression do not have to be catastrophic events involving obvious external disasters. To a casual observer the college student had no apparent reason to be depressed, since he was performing successfully at a highly regarded college. Nonetheless, the intrapsychic meaning of his academic performance was such that the patient felt hopeless and despairing as a result. In assessing the psychodynamic factors in depression, clinicians must always attend to idiosyncratic personal meanings of events to understand fully the effects they have on the patient. Otherwise, clinicians run the risk of responding in the same unempathic manner that often characterizes the responses of family members. In the absence of objective evidence of any disastrous events in the depressed person's life, loved ones often react by saying: “You have no reason to be depressed. Everything is going so well in your life.” Selfobject Failure The ego and the superego do not figure in Heinz Kohut's conceptualization of depression. Kohut's theory, known as self psychology, rests on the assumption that the developing self has specific needs that must be met by parents to give the child a positive sense of self-esteem and self-cohesion and that similar responses are required from others throughout the course of the life cycle. He referred to those needs as mirroring, twinship, and idealization. The mirroring responses required by the self are equated with the gleam in the mother's eye when the child exhibitionistically shows off for her. Admiration, validation, and affirmation are responses that are included in the category of mirroring. Twinship responses refer to the child's need to be like others. A small boy who is outside playing with his toy lawn mower while his father is mowing the lawn is meeting important psychological needs in asserting his commonality with his father. Finally, the need for idealization is an important aspect of the development of the self. Children who grow up with parents they can respect and idealize develop healthy standards of conduct and morality. Kohut referred to those three needs collectively as selfobject needs. In other words, the responses demanded from others are required by the self, and the needs of the object as a separate person are not taken into account. The other person serves as an object who meets the needs of the self. Selfobject needs essentially refer to certain functions that persons in the environment provide rather than to those persons themselves. Kohut felt that selfobject responses continue to be needed throughout life and are as necessary for emotional health as oxygen is for physical health. Within that conceptual framework, depression involves the failure of selfobjects in the environment to provide the self of the depressed person with mirroring, twinship, or idealizing responses necessary for the self to feel whole and sustained. The massive loss of self-esteem seen in depression is regarded by Kohut and the self psychologists as a serious disruption of the self-selfobject connection or bond. Depression as Affect and Compromise Formation Some contemporary ego psychologists believe that depression is not truly a psychiatric disorder or illness. Instead, depression is regarded as an affect reflecting conflict and compromise formation. Charles Brenner, the principal architect of that view, suggested that concern about such childhood calamities as object loss, loss of love, castration, and punishment are associated with two kinds of unpleasure. One form of unpleasure is anxiety, which involves an anticipated calamity or danger. The other form of unpleasure, depressive affect, involves a calamity that has already happened. That theory of depressive affect differs sharply from the classical views of Freud and Abraham. Brenner pointed out that depression is not always related to object loss or to oral wishes. He also asserted that identification with a lost object is found in some depressed persons but not in all and that anger turned inward is a result of depression, rather than a cause. Depressive affect, in Brenner's view, can be linked to any of the childhood calamities, rather than uniquely to object loss. People can experience depressive affect because they feel unloved, because they feel castrated, or because they feel punished in a variety of ways. Depressive affect is a normal and universal part of the human condition. A critical feature in Brenner's formulation is the idea of compromise formation, in which a symptom is viewed as simultaneously expressing an unconscious wish or drive and a defense against that wish or drive. A particular compromise formation may be more or less successful in eradicating depressive affect in the same manner as it may succeed to varying degrees in dealing with anxiety. A dog phobia, for example, is a symptomatic compromise formation that succeeds in eliminating anxiety as long as dogs are avoided. Similarly, certain forms of compromise formation may eradicate depressive affect while others do not. The central point of Brenner's psychodynamic theory is that depressive affect is a universal feature in every pathological conflict, whether it is apparent on the surface or buried in the depths of the compromise formation. Depressive affect is a universal factor in all cases of psychiatric illness. From that standpoint, Brenner believed that classifying certain forms of mental illness as depression simply because depressive affect is part of the conscious symptoms does not make sense. The conscious experience of depression provides information about the efficacy and the nature of a patient's defensive maneuvers and compromise formations, in Brenner's view, but it does not reveal much about the underlying causes of the patient's illness. Early Trauma and Deprivation Several investigators have noted that consistent, loving, nurturant parental involvement appears to have some value in preventing the development of depression. Conversely, separation from parents early in life or the actual loss of a parent may predispose one to depression. Edith Zetzel observed that adverse experiences in the formative years of childhood, particularly those involving separation and loss, make it difficult for children to tolerate depressive affects without resorting to primitive defensive operations. If caretakers fail to assist children in identifying and tolerating painful feelings that result from an adverse life experience, the child will grow up with inadequate coping mechanisms. That impaired adaptation may contribute to the subsequent development of depression. Empirical research has provided some corroboration for the view that early deprivation is relevant to the cause of depression. René Spitz demonstrated that infants separated from their mothers during the second 6 months of life have overt signs of depression. In some cases the infants in Spitz's studies wasted away and died in response to the separation. Margaret Mahler and her colleagues, who studied the interactions between normal and abnormal mother-infant pairs, found that children's emotional dependence on their parents is instrumental in the development of their capacity to grieve and mourn. That capacity, in turn, influences children's feelings of self-esteem and helplessness. Although the development of depression may involve genetic and constitutional factors, as well as environmental stressors, most theorists agree that the early relationship between child and parent plays a significant role in causing depression. One elegantly designed study documented an increased risk for major depressive disorder in those women who had experienced maternal or paternal separation in childhood or adolescence. A prospective study from the United Kingdom found that women with a history of childhood abuse or neglect are twice as likely to have negative relationships and low self-esteem in adulthood. Those abused or neglected women who have these negative relationships and low self-esteem in adulthood are then ten times more likely to experience depression. One of the clinical implications of this finding is that exploration of the impact of childhood trauma or neglect may be crucial in the psychodynamic therapy of depressed patients. These empirical findings suggest a stress-diathesis model for mood disorders. In other words, a genetic substrate might serve to diminish monoamine levels in synapses or to increase reactivity of the hypothalamic-pituitary-adrenal axis to stress. Corticotropin-releasing factor (CRF), which induces the pituitary to secrete ACTH, is consistently elevated in the cerebrospinal fluid of depressed patients when compared with normal controls. When the brains of laboratory animals are given additional CRF, they have exhibited behavior similar to depression in humans. In keeping with the stress-diathesis model, some investigators have postulated that if there is no serious stress on the individual, the genetically determined threshold is not necessarily sufficient to induce depression. However, experiences of neglect or abuse in childhood may activate the stress response and induce elevated activity in CRF-containing neurons, which are known to be stress responsive and to be excessively active in depressed people. These cells can become supersensitive in certain individuals and then react dramatically to even mild stressors. Premorbid Personality Factors A comprehensive psychodynamic understanding of depression must include premorbid personality factors in the equation. All persons may become depressed, given sufficient environmental stress, but certain personality types or traits appear to dispose one to depression. For example, the harsh, perfectionistic superego characteristic of persons with obsessive-compulsive personality disorder may lead them to feel that they are always falling short of their own excessive expectations of themselves. That intrapsychic constellation may be critical in the development of a major depressive episode. Similarly, Axis II personality disorders involving dependent yearnings for care—such as dependent, histrionic, and borderline personality disorders—may also be more vulnerable to depression. Personality disorders that use projection and other externalizing defense mechanisms, such as antisocial and paranoid personality disorders, are less likely to decompensate into depression. No particular premorbid personality type has been associated with the development of bipolar disorder. Evidence is accumulating that an Axis II diagnosis of a personality disorder may complicate the course and treatment of depression. Depressed patients with personality disorders generally have poorer outcomes in the area of social functioning than those without personality disorders. Furthermore, residual depressive symptoms are more likely to present in recovering depressed patients with an Axis II diagnosis. Psychoanalytic clinicians have observed that personality factors frequently serve to maintain a depressed state once it has occurred. In clinical practice the complicating factors of a comorbid personality disorder diagnosis are quite common. One study found that 42 percent of persons with major depressive disorder and 51 percent of patients with dysthymic disorder have an accompanying Axis II diagnosis. In an 18-year follow-up study of 89 depressed patients, the investigators found that the personality measure of neuroticism led to poorer outcomes in patients with melancholia. Similarly, an examination of the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Project data found that patients with personality disorders who were also depressed had poorer outcomes in social functioning and a much greater likelihood of residual depressive

symptoms than those who did not have personality disorders. In a third study 76 depressed outpatients were treated with interpersonal psychotherapy. The only significant predictor of time to remission was the degree of personality pathology. Even though patients with the most-severe personality disorders, borderline and antisocial, were excluded from the study, those who had other Axis II conditions responded more slowly to psychotherapy or not at all. Characterological Depression Many patients encountered in clinical practice report feelings of depression even though they lack symptoms of a well-defined Axis I disorder, such as major depressive episode. Many of those patients have a primary diagnosis of a personality disorder on Axis II and experience characterological depression, a feeling of pervasive loneliness or emptiness associated with the perception that others are not meeting one's emotional needs. They can be distinguished from patients with an Axis I diagnosis of major depressive episode by the absence of vegetative symptoms (e.g., psychomotor retardation, loss of libido, diminished appetite, lack of energy, and sleep disturbance) and by the presence of certain qualitative features of their complaint of depression. Loneliness, emptiness, and boredom are often chronic complaints in characterological depression but are much less common in Axis I illnesses. In addition, a conscious sense of rage at not having their needs met may be present. The patients often describe childhood experiences in which they felt deprived of appropriate emotional nurturance from their patients. As a result, they continue to seek parental substitutes in adult life. Characterological depression is differentiated from Axis II personality disorders by the fact that it is an affective state occurring within the context of certain personality disorders, rather than a constellation of traits forming an overarching personality type. A 29-year-old woman came to psychotherapy complaining that she was “empty” inside and “needed to be filled up” by a positive experience with a psychotherapist. She said that, while she was growing up, her mother never had time for her and that her mother loved her two sisters more than her. The patient had had a series of romantic relationships with men, but she never felt that she was getting the kind of attention and love that she needed from any of them. The men often ended the relationship because they felt that she was too demanding and that they could not possibly meet all her needs. Her last therapist had “given up” on her because he, too, felt that he was unable to be of help to her. The patient also indicated that she had called her previous therapist almost every night because she would begin to feel lonely and need his reassurance that he still cared. She feared that she had turned off her therapist by being too demanding. She also described several angry outbursts directed at him when he would not talk with her for lengthy periods of time on the phone during the evening. She wondered if her outbursts made him hate her. The patient had taken four different antidepressive medications with no improvement. She did not meet the diagnostic criteria for an Axis I dysthymic disorder or major depressive episode. However, she did have characteristics in keeping with two different Axis II diagnoses dependent personality disorder and borderline personality disorder. Other Clinical Entities In addition to the existence of characterological depression and the presence of other Axis II diagnoses, another clinical entity gaining increased acceptance is depressive personality disorder. In Appendix B of the fourth edition of Diagnostic and Statistical Manuel of Mental Disorders (DSM-IV) the criteria for the disorder emphasize a constellation of personality traits, while the criteria for dysthymia focus on somatic symptoms. These traits include a mood dominated by unhappiness, dejection, and gloominess; a self-concept centered on worthlessness and low self-esteem; a proneness to feel guilt or remorse; a tendency to blame and criticize oneself; a negativistic and judgmental stance toward others; a pessimistic attitude; and a tendency to worry and to brood. Although this diagnostic entity has a long-standing psychoanalytic tradition, there has been controversy regarding whether or not it is truly distinct from dysthymic disorder. Data are emerging suggesting that the distinction between the two is valid and clinically useful. In a study of 54 patients with early onset long-standing mild depressive features, Katherine Phillips and her collaborators identified 30 subjects with and 24 without depressive personality disorder. Sixty-three percent of the subjects with depressive personality disorder did not have dysthymic disorder, while 60 percent did not have current major depressive disorder. The depressive personality disorder patients were more likely than the comparison group to have another personality disorder, but 40 percent of them had no such disorder. Those who were comorbid for another personality disorder tended to have anxious or Cluster C personality disorder, suggesting that defenses and conflicts at a neurotic level were most prominent, in keeping with the psychoanalytic conceptualization of depressive personality disorder. Finally, the duration of psychotherapy was significantly longer for subjects who had depressive personality disorder when compared to those who did not. Antidepressant drugs may be combined with psychotherapy in the treatment of characterological depression. Clinicians must remember that depression spans the entire spectrum of pathology and health. In addition to being a discrete psychiatric disorder, depression refers to an emotional state that can occur in normal persons at certain times as well as in persons with characterological or psychotic conditions. Moreover, simply because the patient does not have sufficient symptoms to be given an Axis I diagnosis of a mood disorder does not mean that the depression is benign. In one study, employees with minor forms of depression that did not meet Axis I criteria had 51 percent more disability days than did persons with a diagnosis of major depressive episode.

PSYCHODYNAMIC PSYCHOTHERAPY Although brief psychodynamic psychotherapy has been shown in meta-analyses to be no better or worse than other forms of psychotherapy, there are few controlled trials of the modality with depressed patients. Even more problematic is the fact that few of the trials that exist have been carried out by advocates of the technique who actively practice it. In most studies brief dynamic therapy was used on a comparison or control group to contrast with the different psychotherapies that the investigators favored. Most studies testing brief dynamic therapy were also done in a group format, even though individual therapy is much more widely practiced by psychodynamic clinicians. A number of the trials involving brief dynamic therapy, in which the investigators favored other therapies, found it significantly less effective than the other interventions. More recently, well-designed studies show promising results from brief dynamic therapy. In an investigation of depressed caregivers of elderly family members, random assignment was made to one of two treatment cells: brief psychodynamic therapy or cognitive-behavioral therapy. After 20 sessions, 71 percent of the caregivers were no longer clinically depressed. Overall, no differences were found between the two treatment groups. Symptom-oriented measures suggested that those who had been caregivers for more than 3.5 years improved more with cognitive-behavioral therapy, whereas those who had been caregivers for shorter periods showed more improvement from brief psychodynamic therapy. In the British study known as the second Sheffield Psychotherapy Project, similar findings were obtained in a randomized, controlled trial. Some 120 depressed patients were assigned to either 8 or 16 sessions of cognitive-behavioral therapy or psychodynamic-interpersonal therapy. Both treatments were found equally effective, and their effects equally rapid. Patients with only mild or moderate depression had the same outcome whether they were treated with 8 or 16 weeks of therapy. However, significantly better outcomes were noted in the severely depressed group when 16 weeks of therapy were provided, whether cognitive-behavioral or psychodynamic-interpersonal. At 1-year follow-up no overall differences were found in outcome or maintenance of gains between those receiving the two types of therapy. However, longer periods of therapy appeared to be associated with better long-term outcomes, particularly in the case of psychodynamic-interpersonal therapy. Systematic controlled studies using randomized assignment are not available for extended psychodynamic psychotherapy and psychoanalysis. Most therapists would agree that these modalities are not indicated as exclusive treatment for patients in the acute phase of major depressive disorder. However, a subgroup of patients who do not respond to medication or brief psychotherapy may benefit from more-extended psychodynamic exploration. Sidney Blatt and his associates reanalyzed the data from the NIMH Treatment of Depression Collaborative Research Project and found that highly perfectionistic and self-critical patients did not respond well to any of the treatment cells, which included 16 weeks of cognitive therapy, 16 weeks of interpersonal therapy, 16 weeks of imipramine (Tofranil) plus clinical management, and 16 weeks of placebo plus clinical management. In two other naturalistic follow-along studies of extended psychotherapy on such patients, self-critical and perfectionistic traits appeared to respond well to intensive psychoanalytic psychotherapy. Hence a subgroup of depressed patients may be particularly well suited to more-extended psychoanalytic therapy. Depressed patients with significant Axis II pathology may also respond poorly to brief therapies or medication and require intensive psychotherapy over a long time. However, no data from controlled trials are available to confirm this clinical impression. In any depressed patient, certain psychodynamic principles may be useful, no matter which treatment modality is selected. For example, the American Psychiatric Association practice guidelines for depression suggest that psychotherapeutic management should be part of every treatment for depression. Psychodynamic concepts such as therapeutic alliance, transference, resistance, and countertransference apply to all patients, regardless of the type of treatment. The role of the therapeutic alliance may be particularly important in terms of outcome in both psychotherapy and pharmacotherapy. A team of investigators led by Janice Krupnick looked at 225 cases of depressed patients in the NIMH Treatment of Depression Collaborative Research Program. Clinical raters scored videotapes made of the treatments in all four cells. When outcomes were assessed on these cases, the therapeutic alliance was found to significantly affect clinical outcomes of both psychotherapies, placebo treatment, and the imipramine group. In fact, the patient contribution to the therapeutic alliance accounted for 21 percent of the outcome variance on standardized outcome measures, with more of the variance in outcome attributed to alliance than to the treatment method itself. Among the four cells,

none showed significant group differences in terms of the relationship between therapeutic alliance and outcome. Hence attention to the psychotherapeutic relationship is of central importance in all treatment of depression. Sydney Blatt has suggested that the psychodynamic psychotherapeutic approach must be tailored to the underlying type of depression. His research has delineated two distinct categories of depressed patients: anaclitic and introjective. Anaclitic depression is characterized by feelings of helplessness, loneliness, and weakness related to chronic fears of being abandoned and unprotected. These individuals have longings to be nurtured, protected, and loved. They have a vulnerability to having interpersonal relationships disrupted. These types of patients require a therapy that emphasizes the therapeutic relationship rather than interpretation or insight. By contrast, introjective depression is characterized by feelings of unworthiness, failure, guilt, and inferiority. These individuals are also highly self-critical and suffer from a chronic fear of criticism and disapproval from others. They are highly perfectionistic and competitive and are often driven to achieve in work and school. They have a characteristic vulnerability to disruptions of a positive and effective sense of self, and their depression is manifested primarily by dysphoric feelings of guilt, worthlessness, failure, and by a sense that one's autonomy and control have been lost. Interpretive interventions that provide insight seem to be more helpful with this category of depressed patients.

MANIA Almost all researchers who have studied bipolar disorders have concluded that psychosocial interventions may be crucial in concert with pharmacotherapy for the prevention of relapse. Relapse rates as high as 60 percent over a period of 2 years have been reported, even when maintenance therapy on lithium carbonate (Eskalith) has achieved adequate plasma concentrations. Work status deteriorates in about two-thirds of patients, while social function deteriorates in one-half of patients. In addition, there is a 45 percent separation or divorce rate, compared with 18 percent in controls. In fact, the average 25-year-old female patient can expect to lose nearly 9 years of life, 14 years of effective major activity (work or school), and 12 years of normal health. A psychodynamic understanding can be extraordinarily helpful in identifying the nature of stressors likely to precipitate episodes. In one 2-year study of 61 outpatients, patients with the highest levels of stress had a 4.53 times greater risk of relapse than patients without stress. In a 10-year follow-up study, two different groups of treatment failures were identified in a cohort of patients with bipolar disorder. One group of patients relapsed because the treating psychiatrist had failed to increase the lithium dosage in response to increased physiological activation before the onset of a manic episode. In the other group of treatment failures, psychological issues that were clearly involved in precipitating manic episodes had not been given appropriate attention by the responsible psychiatrists, and manic episodes had resulted from the stress of those psychosocial factors. In one study investigators examined both individual differences in stress reactivity and psychological characteristics of a group of 58 patients with bipolar disorders followed for at least 1 year. The stress level predicted relapse, but personality variables, particularly introversion and obsessionality, were also significant predictors. Hence a psychodynamic perspective on the bipolar disorder patient may help both in identifying psychological and environmental stressors and in dealing with characterological issues that may complicate the treatment. There is an increasing recognition that with refined diagnostic methods, a high degree of comorbidity may exist between bipolar disorders and Axis II disorders. In a study of 66 outpatients with a Research Diagnostic Criteria diagnosis of hypomania and a lifetime diagnosis of bipolar disorder, each patient was interviewed during the hypomanic episode and after recovery. Knowledgeable informants were also interviewed at both times. The researchers found that hypomania was associated with higher levels of maladaptive personality traits than the euthymic state, but even when euthymic, 50 percent of the cohort had at least one personality disorder. They also found that the alleged decrease in maladaptive personality traits following recovery was much greater in the reports by patients than in those by informants. Some of these characterological features of the personality disorder may contribute to compliance problems with medications designed to stabilize mood. They also may alienate family members who then become more critical and more distant, producing an increased risk of relapse. Often these character traits may require individual dynamic psychotherapy in which they can be addressed in the transference-countertransference dimensions of the treatment. Even in bipolar disorder patients without a personality disorder, compliance is a major problem. At least half of bipolar disorder patients stop taking medication at least once in the course of their illness. Frederick Goodwin and Kay Jamison found that the most important reasons for noncompliance listed by patients were dislike of having medication control their moods, dislike of the idea of having a chronic illness, aversion to feeling depressed, and dislike of adverse effects. The combination of medication and individual psychotherapy is required for comprehensive treatment and optimal compliance. Patients with bipolar disorder have been studied from the perspective of ongoing psychoanalysis and psychoanalytic psychotherapy, and those clinical investigations have revealed specific psychodynamic factors at work in the onset of manic episodes. In one series of patients, unconscious sexual urges and fantasies seemed to overpower ego defense mechanisms, leading to a clinical picture of hypersexuality and other symptoms of mania. Increasing the lithium dosage decreased the sexual behavior and reinstituted the ego defense mechanisms present before the manic episode. In the course of continued psychotherapeutic or psychoanalytic treatment, the patients became consciously aware of their unconscious sexual desires and of the defenses elicited to deal with those desires. This conscious awareness enabled the patients to identify early warning signals of increased sexual impulses, so that future manic episodes could be avoided by increasing their lithium dosage. These studies reflect how a psychodynamic understanding of patients with bipolar disorder may be crucial to the effective treatment of the disorder. Most manic patients cannot make use of psychotherapy interventions in the midst of a full-blown manic episode because the essence of mania is a denial of psychological problems. However, after the patient has become euthymic as a result of pharmacological stabilization, psychotherapeutic interventions may have value both in preventing subsequent episodes and in dealing with the feelings of shame and guilt associated with embarrassing behavior that took place during the manic episode. Psychodynamic Theories of Mania The psychodynamic understanding of mania is usefully applied to clinical instances of hypomania because the differences between the two entities are quantitative, rather than qualitative. Just as mania and depression have been linked from a neurophysiological standpoint, they are similarly connected from a psychodynamic perspective. Karl Abraham Most theories of mania view manic episodes as defensive against underlying depression. Abraham, for example, believed that manic episodes may reflect an inability to tolerate childhood depression in reaction to a developmental tragedy, such as the loss of a parent. The manic state, in Abraham's view, is understood as a way of removing the shackles of a tyrannical superego by merging the ego and the superego. Self-criticism is then replaced by euphoric self-satisfaction. Bertram Lewin Lewin regarded the hypomanic patient's ego as a purified pleasure ego. The defense mechanism of denial is appropriated by the ego to disregard unpleasant perceptions and affects as well as distressing psychic realities that may result in self-punishment or self-criticism. Melanie Klein Klein also viewed mania and hypomania as defensive reactions to depression, but she linked the mechanism to the depressive position, rather than to an overriding of the superego. The essence of the depressive position is intense anxiety that one's own aggression has resulted in the destruction of important love objects, such as parents. In Klein's own words, “Persecution (by ‘bad' objects) and the characteristic defenses against it, on the one hand, and pining for the loved (‘good') object, on the other, constitute the depressive position.” She thought that manic defenses are necessary both to control and to master the dangerous bad objects and to restore and to save the loved good objects. Manic defenses include omnipotence, denial, idealization, and contempt. Omnipotence serves to deny the need for good objects, to delude oneself into feelings of self-containment and grandiosity, and to help one feel insulated and protected from assault by internal persecutors. Idealization and denial work together so that idealization of self and others serves to deny any destructiveness or aggression in relationships. The euphoric disposition of the manic or hypomanic patient reflects the tendency to gloss over any unpleasant aspects of reality and to treat everything with a sense of humor and a striking disregard for the tragic dimensions of reality, even if the situation is tragic. Idealization, however, may rapidly give way to contempt, which is also linked to denial because it is a way of disregarding the importance of love objects and, therefore, denying the concern that damage has been done to them and reparation is needed. Moreover, the manic patient can then minimize any distressing feelings of sorrow or regret that may arise in connection with concerns about having destroyed love objects. Klein also observed that a wish to triumph over parents is often an integral part of the manic defensive posture. She noted that a frequent childhood fantasy is to reverse the child-parent relationship and that the fantasy produces feelings of guilt and anxieties of a depressive nature related to the wish to destroy and replace the parents. Feelings of depression may develop after a job promotion or other professional success because the person's unconscious wish to triumph over and to

surpass one's parents has been fulfilled. The kleinian conceptualization of mania as defensive against feelings of depression is useful in understanding the phenomenon of dysphoria in manic patients when depression breaks through a manic episode, requiring a resurgence of manic denial. This formulation is also useful in understanding the commonly observed phenomenon of elation after the death of a loved one. A patient received a phone call that informed him of his mother's death. Rather than feeling grief-stricken or shocked, be noted a sense of expansiveness and power. As he discussed the odd reaction with his psychotherapist, he was able to recognize that the high feeling he experienced was related to a sense that he was finally liberated from feelings of slavish dependence on a tyrannical mother. Other Theories Other views of mania include Bibring's conceptualization that manic elation is essentially a compensatory reaction secondary to severe depression or an unconscious fulfillment of a person's narcissistic aspirations to be loved, worthy, superior, and virtually flawless. Jacobson understood mania as a transformation of the sadistic superego figure from a punitive tormentor into a loving and forgiving object who is thoroughly idealized. This dramatically altered superego is then projected into persons in the outside world with whom the manic patient establishes idealized relationships that are free from any negative characteristics, such as hatred and anger.

OTHER PSYCHOLOGICAL THEORIES Adolf Meyer Meyer viewed depression as a person's reaction to a distressing life experience, such as a financial setback, the loss of a job, the death of a loved one, or a serious physical illness. He believed that depression must always be understood in the context of the patient's life history, as an event with psychic causality. Karen Horney Horney believed that children raised by rejecting and unloving parents are prone to feelings of insecurity and loneliness. In her view, children need to be loved but fear criticism and rejection, which make them susceptible to feelings of depression and helplessness. Sandor Rado Rado linked depression to a profound feeling of helplessness. He believed that anhedonia, the inability to experience pleasure, is a central phenomenon in depression that develops when persons are not aware of their capacities or cannot provide feelings of emotional self-gratification. Rado connected severe depression with a punitive superego that punishes the patient for unconscious hostility toward a deceased loved one. John Bowlby Bowlby saw depression from an ethological perspective that emphasized disturbances of the mother-infant attachment bond. He believed that separation of infants from mothers (or other caregivers) early in life leads to feelings of depression and hopelessness that may in some cases continue throughout the life cycle. Harry Stack Sullivan Although Sullivan concentrated his efforts more on schizophrenia than on mood disorders, his interpersonal perspective applies to both. He thought that adverse interactions between persons and their psychosocial environments were critical to the development of depression. Cognitive-Behavioral Theory According to the theory developed by Aaron Beck, depression results from specific cognitive distortions present in persons prone to depression. Those distortions, referred to as depressogenic schemata, are cognitive templates that perceive both internal and external data in ways that are altered by early experiences. These schemata are associated with four systematic errors in logic: overgeneralization, magnification of negative events with a simultaneous minimization of positive events, arbitrary inference, and selective abstraction. Learned Helplessness The learned helplessness theory of depression connects depressive phenomena to the experience of uncontrollable events. For example, when dogs in a laboratory were exposed to electrical shocks from which they could not escape, they showed behaviors that differentiated them from dogs who had not been exposed to such uncontrollable events. After exposure to the shocks, they would not cross a barrier to stop the flow of electric shock when put in a new learning situation. According to the learned helplessness theory, the dogs learned that outcomes were independent of responses, so they had both cognitive motivational deficit (i.e., they would not attempt to escape the shock) and emotional deficit (indicating a decreased reactivity to the shock). In the reformulated view of learned helplessness as applied to human depression, internal causal explanations are thought to produce a loss of self-esteem after adverse external events. Behaviorists who subscribe to the theory stress that improvement of depression is contingent on the patient's learning a sense of control and mastery of the environment. Psychodynamic Treatment Clinicians who combine pharmacotherapy with a mood stabilizer and individual dynamic therapy focus to a large extent on preventing relapse through greater medication compliance, through detailed understanding of problematic stressors, and through careful examination of relationship difficulties, some of which may relate to Axis II psychopathology. Several major psychodynamic themes are often present in bipolar patients, all of which may be relevant at one time or another in the ongoing treatment of the condition. Denial of illness is one of the major defensive postures encountered with these patients. Many argue that their manic or hypomanic symptoms are not part of an illness but rather a reflection of who they really are. Hence when their collaboration is enlisted in a medication regimen or other component of the treatment plan, they frequently deny having a problem that requires treatment. Patients with bipolar illness are notoriously lacking in insight. In one study of 28 manic patients treated on an inpatient unit, insight was measured at admission and discharge. Even when all other symptoms of mania had improved or remitted, insight remained notably absent. The investigators concluded that poor insight is a prominent characteristic of a bipolar disorder regardless of illness phase. Often related to denial is another psychodynamic theme—splitting or psychic discontinuity. Many bipolar I disorder patients continue to deny the significance of their prior manic episodes when they are euthymic. They may claim that the behavior was simply a result of being exhausted and not taking care of themselves. They also assert that nothing like that will ever happen again. This involves a form of splitting the self-representation so that the self involved in a manic episode is considered entirely disconnected from the self in the euthymic phase. The discontinuity between the different versions of the self may be regarded with bland denial or indifference. A 35-year-old dentist was admitted to an inpatient unit with pressured speech, flight of ideas, and extreme hyperactivity. He had been engaging in extensive sexual activity in the days preceding the admission, and he had been spending all of his savings on a variety of outlandish investment schemes. When he finally arrived on the hospital unit, he was singing and dancing around the lounge area to such an extent that he had to be placed in the seclusion room to try to settle him down long enough to conduct a psychiatric interview. The female psychiatric resident who was on call entered the seclusion room with her attending psychiatrist. The patient abruptly stopped his singing and said, “I have a plan.” He then pointed to the female resident and said, “I'll screw her, and you watch.” The patient was told that his plan was not tenable and that he needed to take medication. With considerable coaxing, he finally agreed to take lithium and an antipsychotic agent. Seven days later his manic episode had subsided. He was calm, polite, and generally socially appropriate. A teaching conference for residents was held in which the patient was interviewed. The attending psychiatrist asked him about his reasons for hospitalization and the nature of his problems. He went on at some length about how he was experiencing “burnout” on his job because people were always telling dentists their problems. He continued to say that he had gotten rather tired and found his job less than fulfilling. He also said that his marriage was troubled because of his long work hours. The impression he created was that of a hardworking professional who was suffering mild stress as a result of occupational difficulties. At no time did he mention anything to the group of residents attending the conference that reflected his bizarre behavior associated with his recent manic episode. The attending psychiatrist interviewing the patient finally interrupted him and said that he wondered why he was not bringing up any of the behaviors that had brought him into the hospital 7 nights ago, such as singing and dancing, spending vast sums of money on unwise investments, staying up all night, and engaging in extensive sexual activity. The patient stared at the interviewer blandly and said, “Oh, that? Well, that's not a problem now.” This vignette clearly illustrates how the manic self and the euthymic self are maintained in separate compartments so that no continuity of the self is apparent. This form of compartmentalization is a major contributor to compliance difficulties. If patients can maintain this kind of discontinuity, they can deny the need for medication or even vulnerability to a subsequent episode. The clinician needs to assemble the self-fragments into a continuous narrative of the patient's life so that maintenance treatment becomes more compelling. Tape recording manic episodes (with the patients' permission) and then playing the recordings back to patients

when they are in a euthymic state may be a useful technique. Another reason for this form of splitting is a wish to avoid the work of mourning and grief that becomes necessary when the manic self and the euthymic self are connected. There may be mourning of the healthy premorbid self, which seems to be forever gone. Also, following a manic episode, patients may become acutely aware of their own destructiveness and feel intense remorse about the harm they have caused others during the manic phase. Splitting it off and denying its significance spares them the pain of this awareness. If the therapist can gently confront them with this defensive maneuver, they can then acknowledge the harm they have done and attempt to make reparation. Another relevant psychodynamic theme is ego-syntonic attachment to hypomania. Many patients insist that they are more creative, more full of life, and more engaging when they are in a hypomanic or manic episode. They do not want to comply with their mood-stabilizer medication because they feel it interferes with their creativity and their enjoyment of life. Helping them to see that their behaviors clearly had a negative impact on others may help them deal with the attachment and make it more ego dystonic. Lithium or other mood stabilizers may take on special meanings to bipolar patients. These agents may come to represent something that is taken away from them. If they comply, they have to resign themselves to no longer experiencing the euphoria of their manic periods, and their denial of their illness is challenged. Maintenance medication may have the meaning of having a severe mental illness that requires lifelong treatment. Integrating this notion into their sense of self also requires the work of mourning. Clinicians must always keep in mind that there is a psychological function of mania that runs in parallel with the biological alteration of the brain—namely, manic denial serves to defend against depression and loss. Medication may also have the meaning of identification with specific family members who have had bipolar illness. To take the medication may unconsciously mean that the course of their illness will be the same as their relative's. The cornerstone of the psychotherapeutic strategy with bipolar disorder patients is to build a therapeutic alliance. Arguing with the patient about whether or not a bipolar disorder is a correct diagnosis is of little value. Psychotherapeutic exploration, empathy, and education are generally more effective. Creation of a mood chart that helps the patient track highs and lows may also be helpful. Transference tends to shift from idealization to devaluation, often in parallel with shifts in mood. The therapist must also be wary of countertransference acting out in response to anger and frustration with the patient's refusal to cooperate with the treatment plan. Most clinicians now treating bipolar disorders consider the combination of psychotherapy and pharmacotherapy essential. Jamison, who wrote a vivid personal account of her struggles with bipolar illness, described it as follows: Ineffably, psychotherapy heals. It makes some sense of the confusion, reins in the terrifying thoughts and feelings, returns some control and hope and possibility of learning from it all.... No pill can help me deal with the problem of not wanting to take pills; likewise, no amount of psychotherapy alone can prevent my manias and depressions. I need both.

SUGGESTED CROSS-REFERENCES Further discussion of psychoanalytic theory can be found in Section 6.1. For additional material on characterological depression, see the discussion of borderline personality disorder in Chapter 24. SECTION REFERENCES Abraham K: Notes on the psycho-analytical investigation and treatment of manic-depressive insanity and allied conditions. In Selected Papers of Karl Abraham, M.D. Basic Books, New York, 1953. American Psychiatric Association: Practice guidelines for major depressive disorder in adults. Am J Psychiatry 150(Suppl):126, 1993. *Barkham M, Shapiro DA, Hardy GE, Rees A: Psychotherapy in two-plus-one sessions: Outcomes of a randomized controlled trial of cognitive-behavioral and psychodynamic-interpersonal therapy for subsyndromal depression. J Consult Clin Psychol 67:201, 1999. Bearden C, Lavelle N, Buysse D, Karp JF, Frank E: Personality pathology and time to remission in depressed outpatients treated with interpersonal psychotherapy. J Pers Disord 10:164, 1996. *Bibring E: The mechanism of depression. In Affective Disorders: Psychoanalytic Contributions to Their Study. P. Greenacre, editor. International Universities Press, New York, 1953. Bifulco A, Brown GW, Moran P, Ball C, Campbell C: Predicting depression in women: The role of past and present vulnerability. Psychol Med 28:39, 1998. *Blatt SJ: Contributions of psychoanalysis to the understanding and treatment of depression. J Am Psychoanal Assoc 46:723, 1998. Blatt SJ, Quinlan DM, Pilkonis PA, Shea MT: Impact of perfectionism and need for approval on the brief treatment of depression: the National Institute of Mental Health Treatment of Depression Collaborative Research Program revisited. J Consult Clin Psychol 63:125, 1995. Broadhead WE, Blazer DG, George LK, Tse CK: Depression, disability days, and days off from work in a prospective epidemiologic survey. JAMA 264:2524, 1990. Coe CL, Wiener SG, Rosenberg LT, Levine S: Endocrine and immune responses to separation and maternal loss in nonhuman primates. In The Psychobiology of Attachment and Separation, M Reite, T Field, editors. Academic Press, Orlando, FL, 1985. Depression Guideline Panel: Depression in Primary Care, vol 2, Treatment of Major Depression. U.S. Department of Health and Human Services, Rockville, MD, 1993. Duggan CF, Lee AS, Murray RM: Do different subtypes of hospitalized depressives have different long-term outcomes? Arch Gen Psychiatry 48:308, 1991. Ellicott A, Hammen C, Gitlin M, Brown G, Jamison K: Life events in the course of bipolar disorder. Am J Psychiatry 147:1194, 1990. Feinstein SC, Wolpert EA: Juvenile manic-depressive illness: Clinical and therapeutic considerations. J Am Acad Child Psychiatry 12:123, 1973. Freud S: The ego and the id. In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 19. Hogarth Press, London, 1961. *Freud S: Mourning and melancholia. In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 14. Hogarth Press, London, 1963. Gabbard GO: Psychodynamic Psychiatry in Clinical Practice: The DSM-IV Edition. American Psychiatric Press, Washington, DC, 1994. Gabbard GO: Psychodynamic psychiatry in the decade of the brain. Am J Psychiatry 149:991, 1992. *Gallagher-Thompson D, Steffen AM: Comparative effects of cognitive-behavioral and brief psychodynamic psychotherapies for depressed family caregivers. J Consult Clin Psychol

62:543, 1994.

Ghaemi SN, Stoll AL, Pope HG: Lack of insight in bipolar disorder: The acute manic episode. J Nerv Ment Dis 183:464, 1995. Gold PW, Goodwin FK, Chrousos GP: Clinical and biochemical manifestations of depression: Relation to the neurobiology of stress, part I. N Engl J Med 319:348, 1988. Gold PW, Goodwin FK, Chrousos GP: Clinical and biochemical manifestations of depression: Relation to the neurobiology of stress, part II. N Engl J Med 319:413, 1988. *Goldberg JF, Harrow M, editors: Bipolar Disorders: Clinical Course and Outcome. American Psychiatric Press, Washington, DC, 1999. Hammen C, Marks T, Mayol A, DeMayo R: Depressive self-schemas, life stress, and vulnerability to depression. J Abnorm Psychol 94:308, 1985. Hammen CL: Stress and the courses of unipolar and bipolar disorders. In Does Stress Cause Psychiatric Illness? CM Mazure, editor. American Psychiatric Press, Washington, DC, 1995. Jacobson E: Psychotic identifications. In Depression: Comparative Studies of Normal, Neurotic, and Psychotic Conditions. International Universities Press, New York, 1971. Jacobson E: Transference problems in depressives. In Depression: Comparative Studies of Normal, Neurotic, and Psychotic Conditions. International Universities Press, New York, 1971.

Jamison KR: An Unquiet Mind: A Memoir of Moods and Madness. Vintage Books, New York, 1995. Kendler KS, Kessler RC, Neale MC, Health AC, Eaves LJ: The prediction of major depression in women: Toward an integrated etiological model. Am J Psychiatry 150:1139, 1993. Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC, Eaves LJ: Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry 152:833, 1995. Klein M: Mourning and its relation to manic-depressive states. In Love, Guilt, and Reparation and Other Works 1921–1945. Free Press, New York, 1975. Klerman GL, Weissman MM, editors: New Applications of Interpersonal Therapy. American Psychiatric Press, Washington, DC, 1993. Kohut H: The Analysis of the Self: A Systematic Approach to the Psychoanalytic Approach of Narcissistic Personality Disorders. International Universities Press, New York, 1971. Kohut H: How Does Analysis Cure? A Goldberg, editor. University of Chicago Press, Chicago, 1984. Krupnick JL, Sotsky SM, Simmens S, Moyer J, Elkin I, Watkins J, Pilkonis PA: The role of the therapeutic alliance in psychotherapy and pharmacotherapy outcome: Findings in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J Consult Clin Psychol 64:532, 1996. Lewin BD: The Psychoanalysis of Elation. Norton, New York, 1950. Loeb FF, Loeb LR: Psychoanalytic observations on the effect of lithium on manic attacks. J Am Psychoanal Assoc 35:877, 1987. Nemeroff CB: The neurobiology of depression. Sci Am 278:42, 1998. Phillips KA, Gunderson JG, Hirschfeld RMA, Smith LE: A review of the depressive personality. Am J Psychiatry 147:830, 1990. Phillips KA, Gunderson JG, Triebwasser J, Kimble CR, Faedda G, Lyoo IK, Renn J: Reliability and validity of depressive personality disorder. Am J Psychiatry 155:1044, 1998. *Salzman C: Integrating pharmacotherapy and psychotherapy in the treatment of a bipolar patient. Am J Psychiatry 155:686, 1998. Shapiro DA, Rees A, Barkham M, Hardy G: Effects of treatment duration and severity of depression on the effectiveness of cognitive-behavioral and psychodynamic-interpersonal psychotherapy. Society for Psychotherapy Research (1994, York, England). J Consult Clin Psychol 63:378, 1995. Shea MT, Pilkonis PA, Beckham E, Collins JF, Elkin I, Sotsky SM, Docherty JP: Personality disorders and treatment outcome in the NIMH Treatment of Depression Collaborative Research Program. Am J Psychiatry 147:711, 1990. Slavney PR: The mind-brain problem, epistemology, and psychiatric education. Acad Psychiatry 17:59, 1993. Solomon DA, Keitner GI, Miller IW, Shea MT, Keller MB: Course of illness and maintenance treatments for patients with bipolar disorder. J Clin Psychiatry 56:5, 1995. Suomi SJ: The development of affect in rhesus monkeys. In The Psychobiology of Affective Development, N Fox, R Davidson, editors. Erlbaum, Hillsdale, NJ, 1984. Suomi SJ: Early stress and adult emotional reactivity in rhesus monkeys. In Childhood Environment and Adult Disease: Symposium No. 156, Ciba Foundation Symposium Staff, editors. Wiley, Chichester, England, 1991. Swendsen J, Hammen C, Heller T, Gitlin M: Correlates of stress reactivity in patients with bipolar disorder. Am J Psychiatry 152:795, 1995.

Textbook of Psychiatry

14.6 MOOD DISORDERS: CLINICAL FEATURES Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.6 MOOD DISORDERS: CLINICAL FEATURES HAGOP S. AKISKAL, M.D. Heterogeneity of Mood Disorders Affects, Moods, Temperaments, and Morbid Mood States Psychopathology Diagnostic Classification Depressive Disorders Bipolar Disorders Mood Disorders not otherwise Specified Differential Diagnosis ICD-10 Suggested Cross-References

HETEROGENEITY OF MOOD DISORDERS Terminology Mood disorders are characterized by pervasive dysregulation of mood and psychomotor activity and by related biorhythmic and cognitive disturbances. The rubric of “affective disorder,” which in some European classifications also subsumes morbid anxiety states, is increasingly being replaced by the nosologically more delimited concept of “mood disorder.” Thus mood disorder is now the preferred term in both the World Health Organization's (WHO's) 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) and the American Psychiatric Association's (APA's) fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Official mood disorder categories in current use include bipolar disorders (with manic or hypomanic, depressive, or mixed episodes) and major depressive disorders and their respective attenuated variants known as cyclothymic and dysthymic disorders. Conditions that in earlier editions of these manuals were categorized as “endogenous depression,” “involutional melancholia,” and “psychotic depressive reaction” have been incorporated into major depressive disorder, whereas “depressive neurosis” has been largely absorbed by dysthymic disorder. Although the neurotic-endogenous distinction has been officially deleted, the term “melancholic features” is now used to qualify major depressive disorders in which biological concomitants predominate. While both the American and international classifications recognize the common occurrence of mixed anxiety-depressions, whether they should be classified with mood disorders or with anxiety disorders remains unresolved. It is equally uncertain how to classify the classic neurasthenic conditions, which have recently reemerged and overlap to some extent with the so-called chronic fatigue syndrome. Destigmatization The reshuffling and reclassification of various affective conditions into the mood disorders chapter of the third edition of DSM (DSM-III) and DSM-IV has, on balance, considerably broadened their boundaries. This change reflects, in part, new developments in pharmacotherapy that have resulted in considerable alleviation of suffering for persons whose illnesses fall short of and sometimes beyond the boundaries of classic mood disorders. As a result, many persons with recurrent mood disorders who would have been disabled can now lead productive lives. Such gratifying results have, in turn, helped to destigmatize this group of disorders. Destigmatization has been further facilitated by published self-revelations of famous persons with depressive and bipolar disorders. Spectrum of Mood Disorders As often happens when new therapeutic interventions prove successful, the past two decades have witnessed an increased readiness to diagnose mood disorders and their variants. These developments should not be dismissed as mere therapeutic fad, however. External validating strategies, such as familial-genetic studies and prospective follow-up, can now be used to buttress the broadened concept of mood disorders. New research comparing monozygotic and dizygotic twins has demonstrated that the genetic propensity to mood disorders embraces entities that extend beyond endogenous depression (melancholia in DSM-IV) to subsume a larger variety of depressions, including some encountered in persons in the community who have never received psychiatric treatment. Although such data might seem counterintuitive to those who would restrict depression to a core primary biological disease, they suggest that the constitutional predisposition for affective dysregulation occurs in as many as one of every three persons. That ratio is similar to the proportion of those who progress to a full depressive syndrome following bereavement, of rhesus monkeys developing depressive-like behavior following a separation paradigm, and of dogs who develop learned helplessness after inescapable shock. The fact that these rates are considerably higher than one observes in clinical populations suggests that many subjects possess protective factors against major depressive episodes; alternatively, the data suggest that other factors determine which person with emotional distress will become a clinical case. A great deal might therefore be revealed about the nature of pathological affective processes through study of self-limiting affective conditions on the border of mood disorders. The suffering and dysfunction resulting from mood disorders are among the most common reasons for consulting psychiatrists and other physicians. In fully developed cases, all activity stops—including creative powers—and life is grim and in total disarray (as portrayed in Dürer's masterpiece, Fig. 14.6-1).

FIGURE 14.6-1 Melancholia (1514) by Albrecht Dürer.

All great physicians of the past, beginning with Hippocrates, have devoted considerable space in their general medical texts to the clinical characterization of melancholic and manic states, as well as alternations in the same patient. Greco-Roman medicine recognized a broad spectrum of affective disturbances, ranging from the relatively mild temperamental variants (represented in the official nosology by dysthymic and cyclothymic disorders) to their severest forms (including what today is considered mood disorder with mood-congruent and mood-incongruent psychotic features). The ancients also recognized the intimate relation of morbid states of fear to melancholia. Furthermore, they noted that melancholia and certain physical diseases shared seasonal incidence and described the common occurrence of alcohol indulgence, especially in those prone to mania. Boundaries The boundaries between temperament (personality) and mood disorder, grief and melancholia, anxiety and depressive states, depressive and bipolar disorders, mood-congruent and mood-incongruent psychotic features, and other (schizophrenic) psychotic conditions remain unresolved. Mood disorders have long been known to be highly comorbid with alcohol use and somatic disease; these trends continue today, with the addition of substance use disorders.

AFFECTS, MOODS, TEMPERAMENTS, AND MORBID MOOD STATES Ethological Considerations Affects and moods refer to different aspects of emotion. Affect is communicated through facial expression, vocal inflection, gestures, and posture and (according to current ethological research) is intended to move human beings and other primates to appraise whether a person is satisfied, distressed, disgusted, or in danger. Thus joy, sadness, anger, and fear are basic affects that serve a communicative function in primates as well as many other mammalian species. Affects tend to be short-lived expressions, reflecting momentary emotional contingencies. Moods convey sustained emotions; their more-enduring nature means that

they are experienced long enough to be felt inwardly. Moods are also manifested in subtle ways, and their accurate assessment often requires empathic understanding by the interviewer. The words that subjects use to describe their inner emotions may or may not coincide with the technical terms used by researchers or clinicians and often vary from one culture to another. Furthermore, the inward emotion and the prevailing affective tone may be discordant. This conflict could be due to deliberate simulation (i.e., the subject does not wish to reveal his or her inner emotion) or it could result from a pathological lesion or process that has altered the emotions and their neural substrates. Thus, evaluating moods and affective expression requires considerable clinical experience. Sadness and Joy The normal emotions of sadness and joy are part of everyday life and should be differentiated from major depressive disorder and mania. Sadness, or normal depression, is a universal human response to defeat, disappointment, or other adversities. The response may be adaptive, in an evolutionary sense, by permitting withdrawal to conserve inner resources, or it might signal the need for support from significant others. Transient depressive periods also occur as reactions to certain holidays or anniversaries, as well as during the premenstrual phase and the first week postpartum. Termed, respectively, “holiday blues,” “anniversary reactions,” “premenstrual tension disorder” and “maternity blues,” they are not psychopathological per se, but those predisposed to mood disorder may develop clinical depression during such times. Premenstrual Dysphoric Mood Changes In view of the higher prevalence of depressive disorders in women, premenstrual affective changes—dysphoria, tension, irritability, hostility, and labile mood—have received both clinical and research attention. The attempt to establish a specific premenstrual dysphoric disorder has neglected the not uncommon occurrence of premenstrual eutonia, increased energy, and sexual drive. The not uncommon occurrence of these positive emotions, along with the labile mixed affective manifestations, tend to point toward a “bipolar” phenomenon. Although women with severe premenstrual complaints appear to have higher rates of lifetime major mood disorders, a recent twin study found that genetic and environmental factors contributing to premenstrual depression and major depressive disorders are largely distinct. Furthermore, events such as migraine, epileptic attacks, and panic states may, in some instances, be associated with the premenstrual phase. The foregoing considerations suggest the hypothesis that premenstrual psychobiological changes exacerbate different neuropsychiatric disorders to which women are otherwise predisposed. Whether the exaggerated premenstrual variability in emotional equilibrium constitutes a variant of mood disorder must await more definitive studies. Grief Normal bereavement or grief, considered the prototype of reactive depression, occurs in response to significant separations and losses such as death, divorce, romantic disappointment, leaving familiar environments, forced emigration, or civilian catastrophes. DSM-IV tends to limit the concept of normal grief to loss due to death. However, the work of Elie Karam and colleagues showed that losses associated with the civil war in Lebanon served as potent forces in depression formation. In addition to depressed affect appropriate to the loss, bereavement reactions are characterized by the prominence of sympathetic arousal and restlessness, believed to represent (from an evolutionary perspective) physiological and behavioral mechanisms to facilitate the search for the lost object. Like other adversities, bereavement and loss do not generally seem to cause depressive disorder, except in those predisposed to mood disorder. Elation The positive emotion of elation is popularly linked to success and achievement. However, paradoxical depressions may also follow such positive events, possibly because of the increased responsibilities that often have to be faced alone. Elation is conceptualized psychodynamically as a defense against depression or as a denial of the pain of loss, as exemplified by the so-called maniacal grief, a rare form of bereavement reaction in which elated hyperactivity may replace the expected grief. Other pseudomanic states include the brief energetic and unusually lucid periods encountered in dying patients or in those who need to take superhuman action in the face of unusual duress, both of which have been conceptualized as “flight into health.” In predisposed persons such reactions might be the prelude to a genuine manic episode. Sleep deprivation, which commonly accompanies major stressors, might represent one of the intermediary mechanisms between stressor and adverse clinical outcome. Affective Temperaments Another mediating factor between normal and pathological moods is temperament. Most persons have a characteristic pattern of basal affective oscillations that defines their temperament. For instance, some are easily moved to tears by sad or happy circumstances, whereas others tend to remain placid. Normally oscillations in affective tone are relatively minor, tend to resonate with day-to-day events, and do not interfere with functioning. Some exhibit greater variability of emotional responses whereby, with no obvious provocation, the person alternates between normal mood and sadness or elation, or both. Temperaments tend to cluster into basic types, four of which are of the greatest relevance to mood disorders. The depressive temperament, in which the person easily swings into the sad direction, occurs in 3 to 6 percent of the general population; the hyperthymic temperament, in which the person is naturally inclined toward cheerful moods has been reported in 4 to 8 percent and the cyclothymic temperament swinging between cheerful and sad moods characterizes 4 to 6 percent of young adults. All three types have an early insidious onset and tend to persist throughout adult life. An irritable-explosive type occurs in 2 to 3 percent of young subjects and tends to attenuate by middle age. An examination of the traits associated with these temperaments can provide the rationale for Ernst Kretschmer's hypothesis about the social functions they served. Thus, the person with a depressive temperament is hard working, dependable, and suitable for jobs that require long periods of devotion to meticulous detail ( Table 14.6-1). Such persons shoulder the burdens of existence without experiencing its pleasures. A person with the hyperthymic temperament, endowed with high levels of energy, extroversion, and humor (Table 14.6-1), will assume leadership positions in society or excel in the performing arts or entertainment. In talented persons the cyclothymic temperament, which alternates between sadness and elation, could provide the inspiration and the intensity needed for composing music, painting, or writing poetry. One with the irritable temperament, probably a variant of the cyclothymic type, might be best suited for a military career or even revolutionary action. The danger with such temperaments is that they could swing too far in one or the other direction, or in both directions (i.e., major depressive, manic, or mixed episodes). Use of such substances as alcohol, caffeine, and other stimulants might further destabilize affective regulation in persons with those attributes. Some adolescent girls with the irritable temperament might develop the extreme emotional disequilibrium that in contemporary psychiatry is considered borderline personality disorder.

Table 14.6-1 Attributes, Assets and Liabilities of Depressive and Hyperthymic Temperaments

Morbid Mood States Mood disorders represent abnormal or extreme variations of mood and associated manifestations and are characterized by the following features. Pathological Mood Change Pathological moods are distinguished from heir normal counterparts by being out of proportion to any concurrent stressor or situation; being unresponsive to reassurance; being sustained for weeks, months, and sometimes years; and having a pervasive effect on the person, such that judgment is seriously influenced by the mood. Endoreactive Moods Depression and mania are diagnosed, respectively, when sadness or elation is overly intense and continues beyond the expected impact of a stressful life event. Indeed the morbid mood might arise without apparent or significant life stress. The pathological process in mood disorders is thus partly defined by the ease with which an intense emotional state is released and especially by its tendency to persist autonomously even when the offending stressor is no longer operative. Rather than being endogenous (i.e., occurring in the absence of precipitants), mood disorders are best conceptualized as endoreactive (i.e., once released, they tend to persist autonomously). The homeostatic dyscontrol of mood, which is part of a more pervasive mood dysregulation, resists reversal to the habitual baseline affective tone. DSM-IV, which tends to disparage theory and adhere to a descriptive level of operationalization, gives insufficient weight to this fundamental

characteristic of mood disorders. Recurrence In a more descriptive vein, what sets mood disorders apart from their normal emotional counterparts is the clustering of signs and symptoms into discrete syndromes that typically recur on an episodic basis or pursue an intermittent, subthreshold course over the span of many years, if not a lifetime. Cyclic course and in some cases regular recurrence, or periodicity, are other signs of mood dysregulation particularly relevant to bipolar disorder. Impairment Normative reactions to adversity and stress, including biological stress, typically consist of transient admixtures of anxiety and dysphoria that are best captured under the DSM-IV rubric of adjustment disorder with mixed emotional features. That is, the self-limiting reactions are best qualified broadly as normal affective states that produce little, if any, impairment in the main areas of functioning. Although anxiety, irritability, and anger do occur in various types of mood disorders, pathologically sustained mood states of depression and elation characterize those disorders. Morbid mood states (mood disorders) then consist of protracted emotional reactions that deepen or escalate, respectively, into clinical depression or mania, with a tendency to recur or evolve into unremitting chronicity in 15 to 20 percent of cases. The contribution of temperamental peculiarities to such outcomes should be apparent. The impaired functioning characteristic of mood disorders is thus based on a combination of factors, including severity, autonomy, recurrence, and chronicity of the clinical features. To recapitulate, dysregulation in mood disorders can take different forms. It could be expressed as a single severe episode that persists autonomously for many months and sometimes years or it might recur with episodes of varying severity, years apart or in rapid succession, with or without interepisodic remission. In general, the earlier the age at onset, the more likely are recurrences, especially those of bipolar nature. Thus, depending on the course of the illness, impairment could be state dependent and occur during an episode or it could extend into the interepisodic period. According to National Institute of Mental Health (NIMH) estimates, on average, a woman with bipolar disorder spends 12 years in florid episodes (often hospitalized), loses 14 years from a productive career and motherhood, and has her life curtailed by 9 years. Recent observations have also revealed another pattern of impairment. In dysthymic and cyclothymic disorders, which represent an intensification of temperamental instability, impairment is not due to the severity of the mood disturbance per se, but to the cumulative impact of the dysregulation beginning in the juvenile or early adult years and continuing unabated or intermittently over long periods; hence the frequent confusion with character pathology. Here the impairment is more subtle but nonetheless pervasive. Persons with cyclothymic disorder tend to be dilettantes, whereas those with dysthymic disorder often lead morose and colorless lives.

PSYCHOPATHOLOGY Depressive Syndrome Like other illnesses, depressive disorder clusters into signs and symptoms that constitute what DSM-IV and ICD-10 term major depressive episode (Tables 14.6-2). These criteria attempt to set an operational threshold for depressive disorder based on a specified number of items and their temporal patterns. The diagnosis of clinical depression cannot be accomplished by a checklist: The DSM-IV diagnostic criteria for major depressive disorder provide only a general guide. Only after an in-depth phenomenological approach can a clinician ascertain diagnosis of a depressive disorder. Disturbances in all four spheres (mood, psychomotor activity, cognitive, and vegetative) should be ordinarily present for a definitive diagnosis of major depressive disorder, although that is not specified in DSM-IV.

Table 14.6-2 DSM-IV Criteria for Major Depressive Episode

Mood Disturbances Mood change, usually considered the sine qua non of morbid depression, appears in a variety of disturbances, including (1) painful arousal, (2) hypersensitivity to unpleasant events, (3) insensitivity to pleasant events, (4) insensitivity to unpleasant events, (5) reduced anticipatory pleasure, (6) anhedonia or reduced consummatory pleasure, (7) affective blunting, and (8) apathy. The phenomenology and psychometric properties of this broad range of mood disturbances are under investigation at the Salpêtrière Hospital in Paris. Our focus here is primarily on painfully aroused mood (depression) and diminished capacity for pleasure (anhedonia), two mood disturbances given selective weight in DSM-IV and ICD-10. DEPRESSED MOOD The term “depressed mood” refers to negative affective arousal, variously described as depressed, anguished, mournful, irritable, or anxious. These terms tend to trivialize a morbidly painful emotion, typically experienced as worse than the severest physical pain. Thus depressed mood has a somatic quality that in the extreme is indescribably painful. Even when not so severe, depressive suffering is qualitatively distinct from its neurotic counterparts, taking the form of groundless apprehensions with severe inner turmoil and torment. This description is particularly apt for middle-aged and elderly persons, who were once considered to be suffering from “involutional melancholia.” The sustained nature of the mood permits no respite, although it tends to lift somewhat in the evening. Suicide may represent an attempt to find deliverance from such unrelenting psychic torment; death can be experienced as comforting ( Fig. 14.6-2).

FIGURE 14.6-2 Death Giving Comfort by Kaethe Kollwitz (1867–1945).

Patients with a milder form of the malady typically seen in primary care settings might deny experiencing mournful moods and instead complain of physical agony from headache (Fig. 14.6-3), epigastric pain, precordial distress, and so on, in the absence of any evidence of diagnosable physical illness. Such conditions have been described as “depressio sine depressione,” or “masked depression.” In such cases, commonly observed in older patients, the physician should corroborate the presence of mood disturbance by the depressed affect in the patient's facial expression, voice, and overall appearance.

FIGURE 14.6-3 Headache by Honoré Daumier (1808–1879).

ANHEDONIA AND LOSS OF INTEREST Paradoxically, the heightened perception of pain in many persons with depressive disorder is accompanied by an inability to experience normal emotions. Patients exhibiting the disturbance may lose the capacity to cry, a deficit that is reversed as the depression is lifting. In evaluating anhedonia inquiring whether the patient has lost the sense of pleasure is not enough; the clinician must document that the patient has actually given up previously enjoyed pastimes. When mild, anhedonia evidences with decreased interest in life. Later, patients complain that they have lost all interest in things. This is best illustrated by William Shakespeare in Hamlet's disgust: “How weary, stale, flat, and unprofitable seem to me all the uses of the world” (Act I, Scene II). In the extreme, patients lose their feelings for their children or spouses, who once were a source of joy. Thus the hedonic deficit in clinical depression might represent a special instance of a more pervasive inability to experience emotions. Patients with severe depression may complain of being emotionally cut off from others and experience depersonalization and a world that seems strange to them (derealization). The impact of the loss of emotional resonance can be so pervasive that patients may denounce values and beliefs that had previously given meaning to their lives. For instance, members of the clergy might present with the complaint that they no longer believe in the Church, that they have lost God. The inability of the person with depressive disorder to experience normal emotions (commonly observed among young depressed patients) differs from the schizophrenic patient's flat affect in that the loss of emotions is itself experienced as painful; that is, the patient suffers immensely from the inability to experience emotions. Psychomotor Disturbances In depression psychomotor changes consist of abnormalities in the motor expression of mental and emotional activity. In severe cases, these changes manifest in specific facial features ( Fig. 14.6-4).

FIGURE 14.6-4 The Swiss neuropsychiatrist Otto Veraguth described a peculiar triangle-shaped fold in the nasal corner of the upper eyelid. The fold, often associated with depression, is referred to as Veraguth's fold. The photograph illustrates this physiognomic feature in a 50-year-old man during a major depressive episode. Veraguth's fold may also be seen in persons who are not clinically depressed, usually while they are harboring a mild depressive affect. Distinct changes in the tone of the corrugator and zygomatic facial muscles accompany depression, as shown on electromyograms. (Courtesy of Heinz E. Lehmann, M.D.)

PSYCHOMOTOR AGITATION Although agitation (pressured speech, restlessness, hand wringing, and hair pulling) is the more readily observed abnormality, it appears to be less specific to the illness than retardation (slowing of psychomotor activity). Psychophysiological studies have documented that such slowing often coexists with agitation. PSYCHOMOTOR RETARDATION Underlying many of the deficits seen in clinical depression, some authorities believe psychomotor retardation to be the core, or primary, pathology in mood disorders. Morbid depression—what patients describe as being “down”—can be understood in terms of moderate-to-extreme psychomotor slowing. The patient experiences inertia, being unable to act physically and mentally. Recent brain imaging research that has revealed subcortical (extrapyramidal system) disturbances in mood disorders tends to support the centrality of psychomotor dysfunction in these disorders. Long neglected in psychopathological research, psychomotor retardation, can be measured with precision. The Salpêtrière Retardation Scale developed by Daniel Widlöcher and colleagues places special emphasis on the following disturbances: (1) paucity of spontaneous movements; (2) slumped posture with downcast gaze (Fig. 14.6-5); (3) overwhelming fatigue (patients complain that everything is an effort”); (4) reduced flow and amplitude of speech and increased latency of responses, often giving rise to monosyllabic speech; (5) a subjective feeling that time is passing slowly or has stopped; (6) poor concentration and forgetfulness; (7) painful rumination—thinking that dwells on a few (usually unpleasant) topics; and (8) indecisiveness, or an inability to make simple decisions.

FIGURE 14.6-5 A 38-year-old woman during a state of deep retarded depression (A) and 2 months later, after recovery (B). Note the turned-down corners of her mouth, her stooped posture, her drab clothing, and her hairdo during the depressed episode. (Courtesy of Heinz E. Lehmann, M.D.)

DSM-IV places greater emphasis on the more easily observable objective or physical aspects of retardation. For the patient, however, the subjective sense of slowing is as pervasive and disabling. This more psychological dimension of retardation is most reliably elicited from depressed persons with good verbal skills.

Ms. A, a 34-year-old literature professor, presented to a mood clinic with the following complaint: “I am in a daze, confused, disoriented, staring. My thoughts do not flow, my mind is arrested... I seem to lack any sense of direction, purpose...I have such an inertia, I cannot assert myself. I cannot fight, I have no will.” Less linguistically sophisticated patients would simply complain of an inability to perform household chores or difficulty in concentrating on their studies. Such psychomotor deficits in turn underlie depressed patients' diminished efficiency or their inability to work. PSEUDODEMENTIA The slowing of mental functions can be so pronounced in elderly persons that they experience memory difficulties, disorientation, and confusion. STUPOR Psychomotor slowing in young persons is sometimes so extreme that patients might slide into a stupor, unable to participate even in such basic biological functions as feeding themselves. Such an episode is often the precursor of bipolar disorder, which later declares itself in a manic episode. Today depressive disorder is diagnosed in its earlier stages, and subtle stupor is much more likely to be encountered clinically. A 20-year-old male college student seen in the emergency room spoke of “being stuck—as if I have fallen into a black hole and can't get out.” Further evaluation revealed that the patient was metaphorically describing his total loss of initiative and drive and was engulfed by the disease process. A clinician without the requisite phenomenological training, might consider such a patient bizarre and perhaps even psychotic. Yet the patient responded dramatically to fluoxetine (Prozac) and in 2 weeks was back in school. Cognitive Disturbances The cognitive view of depression considers negative evaluations of the self, the world, and the future (the negative triad) central to understanding depressed mood and behavior, but it is equally likely that the depressed mood colors perceptions of the self and others or that disturbed psychomotor activity leads to negative self-evaluations. Therefore, instead of being considered causal, the cognitive triad in depression is best approached empirically as a psychopathological manifestation of depression. Those faulty thinking patterns are clinically expressed as (1) ideas of deprivation and loss; (2) low self-esteem and self-confidence; (3) self-reproach and pathological guilt; (4) helplessness, hopelessness, and pessimism; and (5) recurrent thoughts of death and suicide. The essential characteristic of depressive thinking is that the sufferer views everything in an extremely negative light. The self-accusations are typically unjustified or are blown out of proportion, as in the case of a middle-aged woman who was tormented by guilt because as a child she had not repaid 5 cents she had borrowed from a classmate. Some of the thoughts may verge on the delusional. For instance, an internationally renowned scientist complained that he was “nothing.” Self-evaluations that indicate an extremely low image of self might nonetheless reflect an accurate perception of one's impairment from psychomotor retardation. MOOD-CONGRUENT PSYCHOTIC FEATURES In depressive disorder with psychotic features ( Table 14.6-3), negative thinking acquires grossly delusional proportions and is maintained with such conviction that the thoughts are not amenable to change by evidence to the contrary. According to Kurt Schneider, delusional thinking in depression derives from humankind's four basic insecurities, those regarding health, financial status, moral worth, and relationship to others. Thus, severely depressed patients may have delusions of worthlessness and sinfulness, reference, and persecution: They believe they are being singled out for their past mistakes and that everyone is aware of their errors. Persecutory ideation in depression is often prosecutory in that it derives from the belief that the person deserves punishment for such transgressions. A severely depressed man may feel so incompetent in all areas of functioning, including the sexual sphere, that he may suspect his wife of having an affair (delusion of infidelity).

Table 14.6-3 DSM-IV Criteria for Severity/Psychotic/Remission Specifiers for Current (or Most Recent) Major Depressive Episode

Other depressed persons believe that they have mismanaged their finances and their children will starve (delusions of poverty) or that they harbor an occult illness, such as cancer or the acquired immune deficiency syndrome (AIDS) (delusions of ill health) or that parts of their bodies are missing (nihilistic delusions). In more severe illness the patient might feel that the world has changed and that calamity and destruction await everyone. In rare instances a parent with such delusions might kill his or her young children to save them from moral or physical decay and then commit suicide. Finally, a minority of depressed persons have fleeting auditory or visual hallucinations with extremely unpleasant content along the lines of their delusions (e.g., hearing accusatory voices or seeing themselves in coffins or graveyards). All of these psychotic experiences are genuine affective delusions or hallucinations. They are mood congruent in the sense that they are phenomenologically understandable in light of the prevailing pathological mood. MOOD-INCONGRUENT PSYCHOTIC FEATURES Sometimes so-called first-rank or schneiderian-type symptoms can arise in the setting of a major depressive episode. A 42-year-old civil servant said she was so paralyzed by depression that she felt that she had no personal initiative and volition left; she believed some malignant force had taken over her actions, and it would comment on every action that she would undertake. The patient recovered fully with thymoleptic medication. There is no reason to believe that in this patient the feelings of somatic passivity and running commentary indicated a schizophrenic process. Thus, with proper phenomenological probing, certain classes of apparently mood-incongruent psychotic experiences listed in DSM-IV can be understood as arising from the pathological mood and the profound changes in psychomotor activity that accompany them. (In other instances, the clinician must seek a history of alcohol or substance use disorder or withdrawal as a putative explanation for mood incongruence in psychotic depression.) In brief, incidental schneiderian first-rank symptoms should not distract from the diagnosis of an affective disorder if otherwise typical signs and symptoms are present. HOPELESSNESS AND SUICIDE Given that most, if not all, clinically depressed patients find themselves locked in the private hell of their negative thoughts, it is not surprising that up to 15 percent of untreated or inadequately treated patients give up hope of ever recovering and kill themselves. The suicide attempt is not, however, undertaken in the depth of melancholia. One severely depressed patient asked if she had any suicide plans, replied, “Doctor, I don't exist—I am already dead.” Thus the risk of suicide is less pronounced during acute severe depression. Emil Kraepelin observed that it is when psychomotor activity is improving, and yet mood and thinking are still dark, that the patient is most likely to muster the requisite energy to commit the suicidal act. Hopelessness on mental status evaluation in a patient recovering from depression should alert the clinician to the possibility of such an outcome. There is no basis for the common belief that inquiring about suicide provokes such behavior. On the contrary, patients are often relieved that the physician appreciates the magnitude of their suffering. Suicidal ideation is commonly expressed indirectly (e.g., in a wish not to wake up or to die from a malignant disease). Some depressed persons are tormented with suicidal obsessions and are constantly resisting unwanted urges or impulses to destroy themselves. Others might yield to such urges passively (e.g., by careless driving or by walking into high-speed traffic). A third group harbors elaborate plans, carefully preparing a will and taking out insurance. Deliberate planning indicates a very high suicidal risk. The foregoing examples are not exhaustive; they are meant to remind clinicians in charge of depressed patients to be always alert to the possibility of suicide. Vegetative Disturbances The Greeks considered depression a somatic illness and ascribed it to black bile; hence the term “melancholia.” The mood change in

depressive disorder is accompanied by measurable alterations of biorhythms that implicate midbrain dysfunction. Once the changes occur, they tend to be independent of the environment throughout much of the episode, and as a consequence, they do not respond to interpersonal feedback of a pleasant and upbeat nature. The biological concomitants of melancholia include profound reductions in appetite, sleep, and sexual functioning as well as alterations in other circadian rhythms, especially matinal worsening of mood and psychomotor performances. These disturbances are central to the DSM-IV concept of melancholia ( Table 14.6-4), a form of depression in which such biological concomitants predominate. A smaller subgroup of depressed persons exhibits a reversal of the vegetative and circadian functions, with increases in appetite and sleep—and sometimes in sexual functioning—and an evening worsening of mood; in this atypical pattern ( Table 14.6-5), patients characteristically exhibit mood reactivity and sensitivity to rejection.

Table 14.6-4 DSM-IV Criteria for Melancholic Features Specifiers

Table 14.6-5 DSM-IV Criteria for Atypical Features Specifier

ANOREXIA AND WEIGHT LOSS The most reliable somatic indicators of depressive disorder include anorexia and weight loss. In addition to the presumed hypothalamic disturbance of depression, anorexia might be secondary to blunted olfactory or taste sensations or a decreased enjoyment of food, or (rarely) it might result from a delusional belief that the food has been poisoned. If weight loss is severe, especially after the age of 40, the psychiatrist should first use appropriate medical consultation to rule out the likelihood of an occult malignancy. Inanition, especially in elderly persons, can lead to malnutrition and electrolyte disturbances that represent medical emergencies. WEIGHT GAIN Overeating, decreased activity, or both may result in weight gain. In middle-aged patients it may aggravate preexisting diabetes mellitus, hypertension, or coronary artery disease. In younger patients, especially women, weight problems may conform to a bulimic pattern that is sometimes the expression of the depressive phase of a bipolar disorder with infrequent hypomanic periods (bipolar II disorder). INSOMNIA Sleep disturbance, a cardinal sign of depression, often is characterized by multiple awakenings, especially in the early hours of the morning, rather than by difficulty falling asleep. The light sleep of a depressed person, in part a reflection of the painful arousal of the disorder, tends to prolong the depressive agony over 24 hours. Thus, deep stages of sleep (3 and 4) are either decreased or deficient. The attempt to overcome the problem by drinking alcohol may initially succeed but ultimately aggravates the sleep patterns and insomnia. This is also true for sedative-hypnotic agents, which are often prescribed by the busy general practitioner who has not spent enough time diagnosing the depressive condition. Although sedatives (including alcohol) effectively reduce the number of awakenings in the short term, they are not effective in the long run because they further diminish stage 3 and stage 4 sleep. They are not antidepressants, and they tend to prolong the depression. HYPERSOMNIA Young depressed patients, especially those with bipolar tendencies, often exhibit excessive sleep and have difficulty getting up in the morning. Kevin, a 15-year-old boy, was referred to a sleep center to rule out narcolepsy. His main complaints were fatigue, boredom, and a need to sleep all the time. Although he had always started the day somewhat slowly, he now could not get out of bed to go to school. That alarmed his mother, prompting sleep consultation. Formerly a B student, he had been failing most of his courses in the 6 months before referral. Psychological counseling, predicated on the premise that his family's recent move from another city had led to Kevin's isolation, had not been beneficial. Extensive neurological and general medical workup had also proven negative. He slept 12 to 15 hours a day but denied cataplexy, sleep paralysis, and hypnagogic hallucinations. During psychiatric interview he denied being depressed but admitted that he had lost interest in everything except his dog. He had no drive, participated in no activities, and had gained 30 pounds in 6 months. He believed he was “brain damaged” and wondered whether it was worth living like that. The question of suicide disturbed him as it was contrary to his religious beliefs. These findings led to the prescription of desipramine (Norpramin) in a dosage that was gradually increased to 200 mg a day over 3 weeks. Not only did desipramine reverse the presenting complaints, but it also pushed him to the brink of a manic episode. The affective nature of the disorder in such patients is often unrecognized, and their behavior is attributed to “laziness.” The vignette also illustrates the emergence of manic behavior during antidepressant treatment. Such shifts in polarity are common in major depressive disorder and necessitate revising the diagnosis to a bipolar disorder (contrary to the admonitions of DSM-IV). CIRCADIAN DYSREGULATION Many circadian functions, such as temperature regulation and cortisol rhythms, are disrupted in major depressive disorder. Disturbances of sleep rhythms, however, have received the greatest research focus. These include deficits in stage 4 or delta sleep, as well as more intense rapid eye movement (REM) activity in the first third of the night. More specific to depressive disorders—and whether suffering from insomnia or hypersomnia—nearly two-thirds of patients exhibit a marked shortening of REM latency, the period from the onset of sleep to the first REM period. This abnormality is observed throughout the depressive episode and may also be seen during relatively euthymic periods in persons with recurrent depression. The occurrence of short REM latency in the younger “well” relatives of the affectively ill suggests that neurophysiological abnormalities might precede the overt psychopathological manifestations of the illness; upon closer scrutiny, these well relatives will often be found to meet criteria for subthreshold mood conditions such as dysthymic disorder, intermittent depression or labile temperament. Few data exist on the consistency of sleep electroencephalographic (EEG) abnormalities in patients from episode to episode. However, clinical experience suggests that a patient observed over time (even during the same episode) may exhibit insomnia and morning worsening of mood and activity during one period of the disorder and hypersomnia extending to late morning hours during another period. In either case, persons with depressive disorder are characteristically tired in the morning, which means that even prolonged sleep is not refreshing for them. The propensity to exhibit such divergent patterns of sleep disturbance is more likely in bipolar disorders. Patients with major depressive disorder tend to exhibit insomnia more stereotypically episode after episode; despite extreme fatigue, they rarely oversleep. Such fatigue coexisting with negative affective arousal is even more exhausting.

SEASONALITY Another classic biorhythmic disturbance in mood disorders is seasonal (especially autumn-winter) accentuation or precipitation of depression. Most of those patients experience increased energy and activation, if not frank hypomania, in the spring. In the fall and winter, they complain of fatigue, tend to crave sugars, and overeat and oversleep. The hypersomnia in some of these patients is associated with delayed (rather than short) REM latencies. These data suggest dysregulation of circadian rhythms in depressive disorders rather than mere phase advance. Although autumnal-winter depression has received the greatest attention, there also exist summer depressions; the former appear related to reduction of daylight (photoperiods), and the latter to increased temperature. The DSM-IV criteria for seasonal pattern specifiers are listed in Table 14.6-6.

Table 14.6-6 DSM-IV Criteria for Seasonal Pattern Specifier

SEXUAL DYSFUNCTION Decreased sexual desire is seen in both depressed men and women. In addition, some women experience temporary interruption of their menses. Depressed women are typically unresponsive to lovemaking or are disinclined to participate in it, a situation that could lead to marital conflict. Psychotherapists might mistakenly ascribe the depression to the marital conflict and devote unnecessarily zealous psychotherapeutic attention to conjugal issues. Decreased or lost libido in men often results in erectile failure, which may prompt endocrinological or urological consultation. Again, depression may be ascribed to the sexual dysfunction rather than the reverse, and definitive treatment may be delayed by the physician's focus on the sexual complaint. Tragically, some men with depressive disorder have been subjected to permanent penile implants before receiving more definitive treatment for their depression. This is less likely to occur in the sildenafil (Viagra) era, but even treatment with such agents would not necessarily resolve the impotence in clinically depressed patients without competent treatment of the mood disorder. A small subgroup of persons with depressive disorder may exhibit increased sexual drive or activity of a “compulsive” nature. These patients tend to have other atypical features as well; hence the increased sexual drive can be considered the “fifth reverse vegetative sign” (after evening or morning worsening of mood, initial insomnia, hypersomnia, and weight gain). In these depressed persons, increased sexual drive may indicate a mixed episode of bipolar disorder. Further scrutiny in such cases will often reveal a premorbid cyclothymic or hyperthymic temperament. Manic Syndrome As with clinical depression, the psychopathology of mania ( Table 14.6-7) can be conveniently discussed under mood, psychomotor, circadian, and cognitive disturbances. The clinical features of mania are generally the opposite of those of depression. Thus, instead of lowered mood, thinking, activity, and self-esteem, there is elevated mood, a rush of ideas, psychomotor acceleration, and grandiosity. Despite those contrasts, the two disorders share such symptoms as irritability, anger, insomnia, and agitation. Actually, an excess of such symptoms of escalating intensity suggests a mixed phase or mixed episode ( Table 14.6-8) of mania and depression occurring simultaneously. Manic and mixed episodes represent the hallmark of what was once termed manic-depressive psychosis and is currently termed bipolar I disorder.

Table 14.6-7 DSM-IV Criteria for Manic Episode

Table 14.6-8 DSM-IV Criteria for Mixed Episode

Although milder mania (hypomania [Table 14.6-9]) can contribute to success in business, leadership roles, and the arts, recurrences of even mild manic symptomatology are typically disruptive. The elated mood tends to produce overoptimism concerning one's abilities, which coupled with the impulsivity characteristic of mania, often leads to disaster. Thus, accurate and early diagnosis is paramount.

Table 14.6-9 DSM-IV Criteria for Hypomanic Episode

Classic mania as formulated in the DSM-IV operationalization of manic episode ( Table 14.6-7) is relatively easy to recognize. Misdiagnosis was once rampant in North American practice as clinicians confused severe mania with schizophrenia, and its milder variants with normality or with narcissistic and sociopathic personality disorders. Like the misdiagnosis of depressive conditions, such errors of clinical judgment are due to a lack of familiarity with the phenomenology of the classic illness. Again, DSM-IV criteria provide only a guideline. The actual diagnosis requires careful history and phenomenologic understanding. The manic patient lifts the observer's mood, makes the examiner smile and even laugh, and can often be irritating. The patient's speech is fast and may even appear “loose,” but it also can often be witty. Finally, the behavior is typically dramatic, expansive, and jesting. For the experienced clinician, the overall gestalt experienced in the presence of such patients is emotionally and qualitatively distinct from that of persons with schizophrenia or frontal lobe diseases; the latter conditions tend to leave the examiner “cold.” These considerations become clearer when the clinical observer systematically examines the psychopathology of mania in the areas of mood, behavior, and thinking. Mood Disturbance Mood disturbance in mania represents a contrast to that observed in depression, but not entirely. MOOD ELEVATION The mood in mania is classically one of elation, euphoria, and jubilation, typically associated with laughing, punning, and gesturing. LABILITY AND IRRITABILITY The prevailing positive mood in mania is not stable, and momentary crying or bursting into tears is common. Also, the high is so excessive that many patients experience it as intense nervousness. When crossed, patients can become extremely irritable and hostile. Thus, lability and irritable hostility are as much features of the manic mood as is elation. Psychomotor Acceleration Accelerated psychomotor activity, the hallmark of mania, is characterized by overabundant energy and activity and rapid, pressured speech. Subjectively, the patient experiences an unusual sense of physical well-being (eutonia). FLIGHT OF IDEAS Thinking processes are accelerated, experienced as flight of ideas, and thinking and perception are unusually sharp. The patient may speak with such pressure that associations are difficult to follow; such clang associations are often based on rhyming or chance perceptions and can be lightning fast. The pressure to speak may continue despite development of hoarseness. IMPULSIVE BEHAVIOR Manic patients are typically impulsive, disinhibited, and meddlesome. They are intrusive in their increased involvement with others, leading to friction with family members, friends, and colleagues. They are distractible and move quickly, not only from one thought to another, but also from one person to another, showing heightened interest in every new activity that strikes their fancy. They are indefatigable and engage in various activities in which they usually display poor social judgment. Examples include preaching or dancing in the street; abuse of long distance calling; buying new cars, hundreds of records, expensive jewelry, or other unnecessary items; paying the bills of total strangers in bars; giving away furniture; impulsive marriages; engaging in risky business ventures; gambling; and sudden trips. Such pursuits can lead to personal and financial ruin. DELIRIOUS MANIA An extremely severe expression of mania (once known as “Bell's mania”), delirious mania involves frenzied physical activity that continues unabated and leads to a life-threatening medical emergency. This complication, the manic counterpart of stupor, is rare today. (There is no need to invoke here the concept of catatonic features as advocated by DSM-IV ( Table 14.6-10). The DSM-IV position is terminologically confusing and phenomenologically imprecise).

Table 14.6-10 DSM-IV Criteria for Catatonic Features Specifier

Vegetative Disturbances Vegetative disturbances are more difficult to evaluate in mania than in depression. HYPOSOMNIA The cardinal sign is decreased need for sleep—the patient sleeps only a few hours but feels energetic on awakening. Some patients may actually go sleepless for several days. This practice could lead to dangerous escalation of manic activity, which might continue despite signs of physical exhaustion. INATTENTION TO NUTRITION There does not seem to be a clinically significant level of appetite disturbance as such, but weight loss may occur because of increased activity and neglect of nutritional needs. SEXUAL EXCESSES The sexual appetite is typically increased and may lead to sexual indiscretion. Married women with previously unblemished sexual lives may associate with men below their social status. Men typically overindulge in alcohol, frequent bars, and squander their savings on prostitutes. The sexual misadventures of manic patients result in marital disasters and hence the multiple separations or divorces that are almost pathognomonic of the disorder. Such sexual impulsivity is even more problematic now, in view of the specter of AIDS. Cognitive Distortions Manic thinking is overly positive, optimistic, and expansive. GRANDIOSITY, LACK OF INSIGHT, AND DELUSION FORMATION The patient exhibits inflated self-esteem and a grandiose sense of confidence and achievements. Behind that facade, however, may be a vague and painful recognition that the positive self-concepts do not represent reality. However, such insight (if present at all) is transient, and manic patients are notoriously refractory to self-examination and insight. Denial and lack of insight, cardinal psychological derangements of mania, are not listed in the DSM-IV criteria for manic episode or bipolar disorders. This is a serious omission because this lack of insight leads manic patients to engage in activities that harm themselves and their loved ones. It also explains, in part, their noncompliance with medication regimens during the manic phase. Finally, because of their lack of insight, mania nearly always reaches delusional proportions, including delusions of exceptional mental and physical fitness and exceptional talent; delusions of wealth, aristocratic ancestry, or other grandiose identity; delusions of assistance (i.e., well-placed persons or supernatural powers are assisting their endeavors); or delusions of reference and persecution, based on the belief that enemies are observing or following them out of jealousy at

their special abilities. At the height of mania patients may even see visions or hear voices congruent with their euphoric mood and grandiose self-image (e.g., they might see images of heaven or hear cherubs chanting songs to praise them). The denial characteristic of mania—and the frequently psychotic nature of episodes—means that clinicians must routinely obtain diagnostic information about past episodes from significant others. (Lack of insight also unfortunately means that hospitalization must usually be arranged on an involuntary basis). MOOD-INCONGRUENT PSYCHOSIS Psychosis in the setting of mania and mixed manic episodes is typically mood congruent. The sense of physical well-being and mental alacrity is so extraordinary that it is understandable why manic patients believe that they possess superior powers or perhaps are great scientists or famous reformers. Moreover, their senses are so vivid that reality appears richer and more exotic, and can be easily transformed into a vision. Likewise, their thoughts are so rapid and vibrant that they feel they can hear them. Thus, certain first-rank schneiderian-type symptoms that have been traditionally considered mood incongruent can be understood phenomenologically to arise from the powerful mental experiences of mania. A 37-year-old engineer, had experienced three manic episodes for which he had been hospitalized; all three episodes were preceded by several weeks of moderate psychomotor retardation. Although he had responded to lithium (Eskalith, Lithobid) each time, once outside the hospital he had been reluctant to take it and eventually refused to do so. Now that he was euthymic, following his third and most disruptive episode during which he had badly beaten his wife, he could more accurately explain how he felt when manic. Mania, he felt, was “like God implanted in him,” so he could serve as “testimony to man's communication with God.” He elaborated as follows: “Ordinary mortals will never, never understand the supreme manic state which I'm privileged to experience every few years. It is so vivid, so intense, so compelling. When I feel that way, there can be no other explanation: To be manic is, ultimately, to be God. God himself must be supermanic: I can feel it, when mania enters through my left brain like laser beams, transforming my sluggish thoughts, recharging them, galvanizing them. My thoughts acquire such momentum, they rush out of my head, to disseminate knowledge about the true nature of mania to psychiatrists and all others concerned. That's why I will never accept lithium again—to do so is to obstruct the divinity in me.” Although he was on the brink of divorce, he would not yield to his wife's plea to go back on lithium. The vignette illustrates the possibility that even some of the most psychotic manifestations of mania represent explanatory delusions, the patient's attempt to make sense of the experience of mania. The DSM-IV criteria for severity/psychotic specifiers for manic and mixed episode ( Table 14.6-11 and Table 14.6-12) are more concerned with operational rigor than with the phenomenological sophistication needed to understand such core manic experiences. (Many manic patients abuse alcohol and stimulants to enhance their mental state; mood incongruence can sometimes be explained on that basis).

Table 14.6-11 DSM-IV Criteria for Severity/Psychotic/Remission Specifiers for Current (or Most Recent) Manic Episode

Table 14.6-12 DSM-IV Criteria for Severity/Psychotic/Remission Specifiers for Current (or Most Recent) Mixed Episode

MANIA VERSUS HYPOMANIA Nonpsychotic and nondisruptive variants of mania are much more common and are recognized by DSM-IV as hypomanic episodes. Diagnostically, history of a partial manic syndrome is preferably obtained from significant others who have observed the patient; the experience is often pleasant, and the subject may either be unaware of it or tend to deny it. DSM-IV stipulates a minimum duration of 4 days for hypomania; however, the Memphis and Zurich studies found a modal duration of 2 days. Finally, although DSM-IV states that treatment-emergent hypomania in a depressed patient does not count toward a diagnosis of bipolarity, prospective observations show that nearly all such episodes are followed eventually by spontaneous hypomania (or mania).

DIAGNOSTIC CLASSIFICATION P>The classification of mood disorders in DSM-IV subsumes a large variety of patients seen in private and public, ambulatory and inpatient settings. The main demarcation in that large clinical terrain is between bipolar and depressive (unipolar) disorders. Thus, bipolar disorders range from the classic manic and depressive episodes of psychotic intensity (bipolar I disorder) through recurrent major depressive episodes, alternating with hypomanic episodes (bipolar II disorder), and cyclothymic mood swings. Likewise, depressive disorders include those with psychotic severity, melancholia, atypical features, and dysthymic variants. Major and specific attenuated subtypes are distinguished on the basis of severity and duration. In dysthymic and cyclothymic disorders a partial mood syndrome—consisting of such subthreshold features as subdepressive and hypomanic periods—is maintained, intermittently or continuously, for at least 2 years. Subdepressive periods dominate in dysthymia; in cyclothymia, they alternate with hypomania. The onset is typically in adolescence or childhood, and most persons with these diagnoses seen in young adulthood have had low-grade mood symptoms for 5 to 10 years. Major mood disorders, which generally begin much later in life, require the presence of either a full manic episode or a full depressive episode—sustained for at least 1 or 2 weeks, respectively—and an episodic course, typically permitting recovery or remission from episodes. DSM-IV recognizes that a significant minority of persons with major depressive disorders fails to achieve full symptomatic recovery and should thus be qualified as chronic or in partial remission. They are no longer considered dysthymic (the misleading convention in DSM-III). Dichotomy or Continuum? Although, in the extreme, bipolar and depressive (unipolar) disorders can be discriminated clinically and therapeutically ( Table 14.6-13), clinical observations testify to a vast overlap between those extremes. Thus the distinctions between the various affective subtypes are not as hard and fast as DSM-IV attempts to portray. For instance, full-blown bipolar disorder can be superimposed on cyclothymic disorder that tends to persist after the resolution of manic or major depressive episodes. Even more common is major depressive disorder complicating cyclothymic disorder, which should be reclassified as an important course variant of bipolar II disorder. Likewise, recent evidence indicates that dysthymic disorder may precede major depressive disorder in as many as a third of cases. Moreover, one in four persons with major depressive disorder subsequently develops hypomanic or manic episodes and so should be reclassified as having bipolar disorder. Finally, unexpected crossing from dysthymic disorder to hypomanic or manic episodes has also been described, suggesting that some forms of dysthymic disorder are subaffective precursors of bipolar disorder. Such observations are in line with Kraepelin's historic attempt to bring all mood disorders under one rubric. Epidemiological studies in the community have also shown much fluidity between various subthreshold and major mood disorders.

Table 14.6-13 Differentiating Characteristics of Bipolar and Unipolar Depressions

Heterogeneity undoubtedly exists among mood disorders; however, the foregoing observations suggest that much of the unipolar terrain might be “pseudo-unipolar” (i.e., soft bipolar). The clinical significance of these considerations lies in the fact that many DSM-IV subtypes of mood disorders are not pure entities, and considerable overlap and switches in polarity take place. They also provide some rationale, for instance, for why lithium (or lithium augmentation) may be effective in some apparently unipolar depressions; such patients do not experience spontaneous hypomanic episodes, but instead often exhibit a high baseline level of hyperthymic traits. Finally, several studies have shown that bipolar patients with cyclothymic premorbid adjustment and interepisodic adjustment are at considerable risk for antidepressant-induced rapid cycling, defined as a rapid succession of major episodes with few or no intervals of freedom. Such considerations further testify to the wisdom of supplementing major mood diagnoses with temperamental attributes. DSM-IV only makes subtle or oblique hints concerning this, and instead provides the practitioner with an unwieldly, if not useless, array of episode and course specifiers. The DSM-IV criteria for longitudinal course specifiers are given in Table 14.6-14.

Table 14.6-14 DSM-IV Criteria for Longitudinal Course Specifiers

As Kraepelin illustrated in his monograph, course is best captured graphically. DSM-IV only provides examples of this for depressive disorders ( Fig. 14.6-6) and limits itself to four patterns. Kraepelin, after diagramming 18 illustrative patterns for the entire spectrum of manic-depressive illness, declared that the illness pursued an indefinite number of courses.

FIGURE 14.6-6 Graphs depicting prototypical courses. A, Course of major depressive disorder, recurrent, with no antecedent dysthymic disorder and a period of full remission between the episodes. This pattern predicts the best future prognosis. B, Course of major depressive disorder, recurrent, with no antecedent dysthymic disorder but with prominent symptoms persisting between the two most recent episodes (i.e., partial remission is attained). C, Rare pattern (present in fewer than 3 percent of persons with major depressive disorder) of major depressive disorder, recurrent with antecedent dysthymic disorder but with full interepisode recovery between the two most recent episodes. D, Course of major depressive disorder, recurrent, with antecedent dysthymic disorder and no period of full remission between the two most recent episodes. This pattern, commonly referred to as double depression, is seen in about 20 to 25 percent of persons with major depressive disorder. (Reprinted with permission from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Copyright, American Psychiatric Association, Washington, DC, 1994.)

DEPRESSIVE DISORDERS The broad category of depressive disorders includes major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Major Depressive Disorder Episodes usually begin over a prodromal period of weeks to months. The DSM-IV diagnosis of major depressive disorder requires (1) dysphoric mood or decreased interest in usual activities and (2) at least four additional classic depressive signs and symptoms, (3) which must be sustained for at least 2 weeks, and (4) cannot be explained by another process known to cause depressive symptoms, such as normal bereavement, certain physical conditions commonly associated with depression, or another mental disorder. It can be single and, more commonly, recurrent. ( Table 14.6-15 and Table 14.6-16).

Table 14.6-15 DSM-IV Diagnostic Criteria for Major Depressive Disorder, Single Episode

Table 14.6-16 DSM-IV Diagnostic Criteria for Major Depressive Disorder, Recurrent

Comorbid Physical Disease Those considerations raise the question whether major depressive disorder should be limited to depressions of unknown etiology (i.e., those without documented physical causes). The DSM-IV approach has basically been that when the cause is known, the condition should be diagnosed as mood disorder due to a general medical condition ( Table 14.6-17) which must be specified, or substance-induced mood disorder ( Table 14.6-18). The problem with this approach is that many common medical factors historically associated with depression (e.g., use of certain antihypertensive agents) do not seem to be causative in the etiological sense, but rather are triggering agents in otherwise predisposed persons. This is analogous to the situation with life events, which no longer are used in making distinctions between reactive and endogenous subtypes of depression. A more troubling implication is that major depressive disorders without demonstrable physical disease are not medical or otherwise biological. More importantly there appears to be no reliable or valid way for a clinician to decide that a depressive condition is due to a specified medical condition. For this reason it is generally more practical to diagnose the depressive disorder on Axis I and specify the contributing physical condition on Axis III. In brief, the designation “due to a general medical condition” is both cumbersome and redundant. The author considers major depressive disorder to represent the final common pathway of multifactorial interacting factors—both physical and psychological—a syndrome that should be diagnosed irrespective of presumed cause.

Table 14.6-17 DSM-IV Diagnostic Criteria for Mood Disorder Due to a General Medical Condition

Table 14.6-18 DSM-IV Diagnostic Criteria for Substance-Induced Mood Disorder

Diagnostic Threshold Another question concerning the DSM-IV definition of major depressive disorders relates to the threshold at which a constellation of depressive features becomes a condition distinct from the ordinary blues. According to the current definition, a person who responds to a setback with lowered spirits and self-doubt, difficulty in sleeping and concentration, and decreased sexual interest for 14 days qualifies for a diagnosis of a major depressive disorder of mild intensity. Many clinicians would consider such a condition a relatively minor departure from normality, probably no more than an adjustment disorder. Obviously, criteria other than signs, symptoms, and duration are necessary to differentiate a depressive disorder from adjustment reactions to life situations. The presence of the following characteristics might assist in such a differentiation. By definition, a major depressive disorder should be incapacitating. Previously, much attention was paid to the interpersonal consequences of depression. Recent evidence indicates that measurable deficits in work performance are often early manifestations. Afflicted persons also do not benefit from taking leisure time, and hence prescribing vacations is futile. Depressive disorder is usually perceived as a break from a person's usual or premorbid self, which can be so striking that sufferers may feel as though they are losing their minds. The important point is that both the patient and significant others can usually relate the onset of the illness to a given month or quarter of a year, which is not true, for instance, for dysthymic disorder. Depressive disorder is often experienced by the sufferer as qualitatively distinct from grief or other understandable reactions to loss or adversity. William James

described it as follows: There is a pitch of unhappiness so great that the goods of nature may be entirely forgotten, and all sentiment of their existence vanish from the mental field. For this extremity of passion to be reached, something more is needed than adversity; the individual must in his own person become the prey of pathological melancholy. Such sensitiveness and susceptibility of mental pain is a rare occurrence where the nervous constitution is entirely normal: one seldom finds it in a healthy subject even where he is the victim of the most atrocious cruelties of outward fortune; it is an active anguish, a sort of psychical neuraglia wholly unknown to healthy life. Two additional features, when present, would further validate the diagnosis of major depressive disorder. History of past episodes. Consecutive-generation family history of mood disorder—especially when a large number of family members are afflicted with depression or mood disorder—is characteristic of clinical depression. For instance, one study that prospectively followed persons with minor or neurotic depression found that such pedigrees predicted the development of future major episodes. DSM-IV makes no provision for considering such familial factors in diagnostic decisions. In clinical practice these factors often strongly influence whether depression is taken seriously. Single Episode and Recurrent Subtypes About a third of all major depressive episodes do not recur ( Table 14.6-15). Such patients tend to be older and less likely to have a positive family history for mood disorders, and have a more protracted (1 to 2 years) course of the disorder. Patients with major depressive disorder, single episode should be distinguished from those experiencing their first episodes of major depressive disorder, recurrent ( Table 14.6-16). The latter group tends to be younger, and the disorder is more likely to have been preceded by a depressive temperament or dysthymic disorder. Research has established that recurrent major depressive disorders are more familial than their single-episode counterparts. The average length of episodes is 6 months, whereas the mean interval between episodes tends to vary (typically years). The mean number of major episodes over a lifetime, according to retrospective and prospective studies, is five to six, in contrast to an average of eight to nine major episodes in bipolar disorder. Melancholic Features In DSM-III the neurotic-endogenous distinction was deleted. Neurotic depression was largely absorbed by dysthymic disorder and the major depressive disorders that complicate it; endogenous depression became “melancholic features,” a qualifying phrase for major depressive disorders in which anhedonia, guilt, and psychomotor-vegetative disturbances dominate the clinical picture ( Table 14.6-4). DSM-IV retains these conventions. Although the foregoing conventions have received much criticism, they are based on solid data from independent studies in the United States and Germany. Thus neurotic depression, defined as a reactive (i.e., precipitated) nonpsychotic depression of mild to moderate intensity with predominant anxiety and characterologic pathology, does not seem to constitute a distinct nosological entity. Although such a presentation is common in clinical practice, well-conducted studies in the United States and Europe have shown that the prospective follow-up course of those patients is heterogeneous, including melancholic and even psychotic depressions and, in some instances, bipolar transformation. The progression of a precipitated, relatively mild depression (reactive illness) to severe psychotic depression—or one with melancholic autonomy—during prospective observation suggests that so-called endogenous depressions may have their onset in milder depressions, that neurotic and psychotic depressions do not necessarily refer to distinct disorders but to disorders that differ in severity, and that the presence of precipitating stress carries little diagnostic weight in differentiating subtypes of depression (although the absence of such stress might be used to support a melancholic level of major depressive disorder). At the heart of the concept of morbid depression is its autonomy from stresses that may have precipitated it and its general unresponsiveness to other environmental input. This is embodied in Donald Klein's concept of endogenomorphic depression, which could be precipitated and mild (endoreactive) while exhibiting disturbances of hedonic mechanisms refractory to current interpersonal contexts. Many authorities believe that such features dictate the need to use somatic approaches to reverse the maladaptive autonomy and restore response to interpersonal feedback; that is, psychotherapeutic approaches are deemed largely ineffective until the autonomy is somatically lysed. Given the somatic connotation of the ancient concept of melancholia, the APA classification has officially adopted it as the preferred nosological term for the revised concept of endogeneity; hence the prominence of the vegetative and biorhythmic features accorded to it in both DSM-III and DSM-IV. However, the APA diagnostic schema risks confusing endogeneity with another classic concept of mood disorder, that of “involutional melancholia.” Psychotic Features About 15 percent of major depressive disorders, usually from the rank of those with melancholic features, develop into delusional depressions. In young persons they tend to be retarded, even stuporous, and are best considered initial episodes of a bipolar disorder. More typically, psychotic depression that develops for the first time after the age of 50 often presents with severe agitation, delusional guilt, hypochondriacal preoccupations, early-morning awakening, and weight loss. The premorbid adjustment of such patients is classically characterized as “obsessoid.” Their mournful-anxious mood and agitation are autonomous, being refractory to psychological interventions, and they endure great psychic suffering. Except for the fact that generally one to two episodes occur in late-onset (so-called involutional) depressions, they represent a severe variant of DSM-IV melancholia. Kraepelin's postulation of a cerebrovascular basis for such cases makes the ventricular enlargement and white matter opacities reported in psychotic depressions of some interest. Their etiological specificity for persons with late-onset psychotic depression has been controversial, however, since younger (more bipolar) persons with psychotic depression exhibit similar findings. Brain imaging findings tend to be correlated with the neurocognitive deficits observed in psychotic depressions. Those features do not seem to define a distinct depressive subtype, but one of greater severity. Finally, despite attempts to suggest a neurochemical uniqueness based largely on the need for antipsychotic treatment in the acute phase of many of those patients, familial and other external validators have failed to support psychotic depression as a separate entity; hence the decision in DSM-IV to use psychotic features merely as a specifier for major depressive episode ( Table 14.6-3). Emerging data, nonetheless, might eventually force a change in this convention. For instance, William Coryell and collaborators in the NIMH collaborative study of depression have shown psychotic depression to be the most consistent unipolar subtype across episodes. Alan Schatzberg's work, originally conducted at Harvard, likewise underscores the uniqueness of psychotic depression based on neuroendocrine and putative neurochemical considerations. Chronic Depression The DSM-IV criteria for chronic specifier appear in Table 14.6-19. The clinical situation, however, is much more complex than these conventions. For instance, the symptom profile in chronic depressions usually displays low-grade intensity rather than severe syndromal chronicity. Severe depressive disorder in its psychotic forms is so agonizing that the sufferer is at risk of committing suicide before the disorder has a chance to become chronic. More commonly, the psychotic symptoms respond to medication or to electroconvulsive therapy (ECT), but residual depressive symptoms may linger for a long time. In other persons with chronic depressions the chronicity arises from more mundane (nonpsychotic) major depressive episodes, depressive residua following one or several clinical episodes that fail to remit fully. Instead of the customary remission within a year, the patients are ill for years. The level of depression varies, fluctuating between syndromal illness and milder symptoms. The patients often show a sense of resignation, generalized fear of an inability to cope, adherence to rigid routines, and inhibited communication.

Table 14.6-19 DSM-IV Diagnostic Criteria for Chronic Specifier

Rather than exhibiting a frankly depressive mood, many persons with chronic depression suffer from deficits in their ability to enjoy leisure and display an attitude of

irritable moroseness. The leisure deficits and irritable humor tend to affect their conjugal lives: their marriages are typically in a state of chronic deadlock, leading neither to divorce nor to reconciliation. In other patients the residual phase is dominated by somatic features, such as sleep and other vegetative or autonomic irregularities. Thus, self-treatment with ethanol or iatrogenic benzodiazepine dependence is common. That these interpersonal, conjugal, and autonomic manifestations represent unresolved depression is shown by persistent sleep EEG (especially REM and delta phase) abnormalities that are indistinguishable from their acute counterparts. Failure to recover from major depressive disorder is associated with increased familial loading for depression, disabled spouses, deaths of immediate family members, concurrent disabling medical disease, use of depressant pharmacologic agents, and excessive use of alcohol and sedative-hypnotic agents. Social support is often eroded in persons with residual depression, through either the death or illness of significant others. Therefore, a thorough medical evaluation and socially supportive interventions should be essential ingredients of the overall approach to those patients. Interpersonal disturbances in such patients are usually secondary to the distortions produced by long-standing depression. Therefore, observed pathological characterological changes—clinging or hostile dependence, demandingness, touchiness, pessimism, and low self-esteem—are best considered as “postdepressive personality” changes. A dangerous stereotypical thinking holds that because a patient has not responded adequately to standard treatments (the illness has become chronic), the disorder must have a characterological substrate. The long duration of the disorder often leads the patient to identify with the failing functions of depression, producing the self-image of being a depressed person. This self-image itself represents a malignant cognitive manifestation of the depressive disorder and dictates vigorous treatment targeted at the mood disorder. Dysthymic Disorder Dysthymic disorder (Table 14.6-20) is distinguished from chronic depressive disorder by the fact that it is not a sequel to well-defined major depressive episodes. Instead, in the most typical cases, patients complain that they have always been depressed. Thus, most cases are of early onset, beginning in childhood or adolescence and certainly by the time patients reach their 20s. A late-onset subtype, much less prevalent and not well characterized clinically, has been identified among middle-aged and geriatric populations, largely through epidemiological studies in the community.

Table 14.6-20 DSM-IV Diagnostic Criteria for Dysthymic Disorder

Although the dysthymic disorder category in DSM-IV can occur as a secondary complication of other psychiatric disorders, the core concept of dysthymic disorder refers to a subaffective disorder with (1) low-grade chronicity for at least 2 years, (2) insidious onset with origin often in childhood or adolescence, and (3) persistent or intermittent course. Although not part of the formal definition of dysthymic disorder, the family history is typically replete with both depressive and bipolar disorders, which is one of the more robust findings supporting its link to primary mood disorder. Social Adjustment Dysthymic disorder is typically an ambulatory disorder compatible with relatively stable social functioning. However, the stability is precarious; recent data document that many patients invest whatever energy they have in work, leaving none for leisure and family or social activities, which results in marital friction. These empirical findings on the work orientation of persons with dysthymic disorder echo earlier formulations in the German and Japanese literature. For instance, Kraepelin described such persons as follows: “Life with its activity is a burden which they habitually bear with dutiful self-denial without being compensated by the pleasure(s) of existence.” The dedication of persons with dysthymic disorder to work has been suggested to be an overcompensation and a defense against their battle with depressive disorganization and inertia. Nevertheless, Kretschmer suggested that such persons are the “backbone of society,” dedicating their lives to jobs that require dependability and great attention to detail. Epidemiological studies have demonstrated that some persons with protracted dysthymic complaints, extending over many years, have never experienced clear-cut depressive episodes. Some of them may seek outpatient counseling and psychotherapy for what some clinicians might consider “existential depression,” with feelings of being empty and lacking any joy in life outside their work. Such persons have been described as leading monocategorical existences. Others present clinically because their low-grade dysphoria has intensified into a major depression disorder. Course An insidious onset of depression dating back to late childhood or the teens, preceding any superimposed major depressive episodes by years or even decades, represents the most typical developmental background of dysthymic disorder. A return to the low-grade depressive pattern is the rule following recovery from superimposed major depressive episodes, if any; hence the designation “double depression” as a prominent course pattern illustrated in DSM-IV for depressive illness (Fig. 14.6-6). This pattern, commonly seen in clinical practice, consists of the baseline dysthymic disorder fluctuating in and out of depressive episodes. The more prototypical patients with dysthymic disorder often complain of having been depressed since birth or of feeling depressed all the time. They seem, in the apt words of Kurt Schneider, to view themselves as belonging to an “aristocracy of suffering.” Such descriptions of chronic gloominess in the absence of more objective signs of depression earn such patients the label of “characterological depression.” The description is further reinforced by the fluctuating depressive picture that merges imperceptibly with the patient's habitual self and thus raises uncertainty as to whether dysthymic disorder belongs in Axis I or Axis II. Clinical Picture The profile of dysthymic disorder overlaps with that of major depressive disorder but differs from it in that symptoms tend to outnumber signs (more subjective than objective depression). This means that marked disturbances in appetite and libido are uncharacteristic, and psychomotor agitation or retardation is not observed. This all translates into a depression with attenuated symptomatology. However, subtle endogenous features are not uncommonly observed: inertia, lethargy, and anhedonia that are characteristically worse in the morning. Because patients presenting clinically often fluctuate in and out of a major depression, the core DSM-IV criteria for dysthymic disorder tend to emphasize vegetative dysfunction, whereas the alternative criterion B for dysthymic disorder ( Table 14.6-21) in a DSM-IV appendix lists cognitive symptoms.

Table 14.6-21 DSM-IV Alternative Research Criterion B for Dysthymic Disorder

Although dysthymic disorder represents a more restricted concept than its parent, neurotic depression, it is still quite heterogeneous. Anxiety is not a necessary part of its clinical picture, yet dysthymic disorder is often diagnosed in patients with anxiety and neurotic disorders. That clinical situation is perhaps to be regarded as a secondary or “anxious dysthymia” or, in the framework of Peter Tyrer, as part of a “general neurotic syndrome.” For greater operational clarity it is best to restrict dysthymic disorder to a primary disorder, one that cannot be explained by another psychiatric disorder. The essential features of such primary dysthymic disorder include habitual gloom, brooding, lack of joy in life, and preoccupation with inadequacy. Dysthymic disorder then is best characterized as long-standing fluctuating low-grade depression, experienced as part of the habitual self and representing an accentuation of traits observed in the depressive temperament ( Table 14.6-1). Dysthymia then can be viewed as a more symptomatic form of that temperament (introduced in a DSM-IV appendix as a depressive personality disorder). Sleep EEG data indicate that many persons with dysthymic disorder at baseline exhibit the sleep patterns of those with acute major depressive disorder, providing support for the constitutional nature of the disorder. Further evidence for that position comes from studies demonstrating high rates of familial affective disorder in dysthymic disorder, depressive temperament, or both. The clinical picture of dysthymic disorder that emerges from the foregoing description is quite varied, with some patients proceeding to major depression, while others manifest the pathology largely at the personality level. The foregoing considerations suggest that a clinically satisfactory operationalization of dysthymia must include symptomatic, cognitive, and trait characteristics. A 27-year-old, male, grade-school teacher presented with the chief complaint that life was a painful duty that had always lacked luster for him. He said he felt enveloped by a sense of gloom that was nearly always with him. Although he was respected by his peers, he felt “like a grotesque failure, a self-concept I have had since childhood.” He stated that he merely performed his responsibilities as a teacher and that he had never derived any pleasure from anything he had done in life. He said he had never had any romantic feelings; sexual activity, in which he had engaged with two different women, had involved pleasureless orgasm. He said he felt empty, going through life without any sense of direction, ambition, or passion, a realization that itself was tormenting. He had bought a pistol to put an end to what he called his “useless existence” but did not carry out suicide, believing that it would hurt his students and the small community in which he lived. Dysthymic Variants Dysthymia is not uncommon in patients with chronically disabling physical disorders, particularly among elderly adults. Dysthymia-like clinically significant subthreshold depression lasting 6 or more months has also been described in neurological conditions, including stroke. According to a recent WHO conference, this condition aggravates the prognosis of the underlying neurological disease and, therefore, deserves pharmacotherapy. Ongoing studies should provide more explicit clinical recommendations on this topic. Prospective studies on children have revealed an episodic course of dysthymia with remissions, exacerbations, and eventual complications by major depressive episodes, 15 to 20 percent of which might even progress to hypomanic, manic, or mixed episodes postpuberty. Persons with dysthymic disorder presenting clinically as adults tend to pursue a chronic unipolar course that may or may not be complicated by major depression. They rarely develop spontaneous hypomania or mania. However, when treated with antidepressants, some of them may develop brief hypomanic switches that typically disappear when the antidepressant dose is decreased. Although DSM-IV would not allow the occurrence of such switches in dysthymia, systematic clinical observation has verified their occurrence in as many as a third of dysthymic patients. In this special subgroup of persons with dysthymic disorder, the family histories are often positive for bipolar disorder. Such patients represent a clinical bridge between depressive disorder and bipolar II disorders. Depressive Disorder Not Otherwise Specified The DSM-IV criteria for depressive disorder not otherwise specified, are presented in Table 14.6-22. What follows are descriptions of conditions that are commonly used in the epidemiological, clinical, or pharmacological literature but do not easily fit into the official nosology of depressive disorders. Some represent complex interweaving of depression with personality constructs. For instance, community studies have revealed a prevalent pattern of intermittent depressive manifestations with brief episodes, below the 2-week duration threshold for major depressive disorder. In so-called minor depressive disorder (Table 14.6-23), observed in primary care settings, the depression is subthreshold, milder than major depression and yet not protracted enough to be considered dysthymic. These varied manifestations of depression argue for a continuum model ( Fig. 14.6-7) as originally envisaged by Kraepelin. Lewis Judd and collaborators at the University of California at San Diego have suggested that subthreshold depressive symptoms—without necessarily meeting the criterion for mood change—might actually represent the most common expressions of a depressive diathesis. From such a subsyndromal symptomatic depressive base, individuals predisposed to depressive illness are said to fluctuate in and out of the various DSM-IV and subthreshold subtypes of depressive disorders. This viewpoint is presently most cogent for subsyndromal symptomatic depression that follows major depressive disorder, a strong predictor of subsequent frequent relapse or chronic course. There is an important message for the clinician here: treat subsyndromal symptomatic depression residual to major depressive disorder.

Table 14.6-22 DSM-IV Diagnostic Criteria for Depressive Disorder Not Otherwise Specified

Table 14.6-23 DSM-IV Research Criteria for Minor Depressive Disorder

FIGURE 14.6-7 Relation of various depressive conditions supporting a spectrum concept. (Reprinted with permission from Akiskal HS: Dysthymia: Clinical and external validity. Acta Psychiatr Scand 89(Suppl):19, 1994.)

Recurrent Brief Depressive Disorder Now in a DSM-IV appendix (Table 14.6-24), recurrent brief depressive disorder derives from British work on young adults with frequent suicide attempts and epidemiological studies conducted in a young adult cohort in Zurich. It is described as short-lived depressions that usually recur on a monthly basis but are not menstrually related. They could coexist with major depressive disorder and dysthymic disorder. Such patients are believed to be more prevalent in primary care than in psychiatric settings. Those seen in psychiatric settings are likely to be given Axis II diagnoses such as borderline personality disorder.

Table 14.6-24 DSM-IV Research Criteria for Recurrent Brief Depressive Disorder

The current nosological status of those patients is uncertain, but they testify to Kraepelin's observation that many transitional forms link the depressive temperament to affective episodes: A permanent gloomy stress in all the experiences of life usually perceptible already in youth, and may persist without essential change throughout the whole of life (or) there is actually an uninterrupted series of transitions to periodic melancholia in which the course is quite indefinite with irregular fluctuations and remissions. Reactive Depression Classically, reactive depression is defined as resulting from a specific life event. In an ideal case the depression would not have occurred without the event (e.g., love loss) to which it is a reaction. It continues as long as the event is present, and it terminates with the reversal of the event (e.g., return of the lover). Depressions exhibiting all of those features are almost never seen in clinical practice. With interpersonal support most people can face life's reverses, which explains why reactive depression tends to be self-limiting. Hence, adjustment disorder is the more appropriate diagnosis for most cases of reactive depression. Conceptually, however, one can envision chronically unsatisfactory life situations that might lead to chronic demoralization. However, such a condition, which could warrant the designation of chronic reactive depression, is a contradiction in terms. The question often raised is why a person would continue to stay in the situation. Sometimes psychodynamic authors invoke the concept of masochism to explain why certain persons cannot rid themselves of painful life situations, implying that they somehow contribute to their maintenance. Current thinking is that some of those presumed self-defeating traits are more situation specific than previously believed and might resolve with the elimination of the situation. So-called self-defeating features then are best considered psychodynamic mechanisms rather than indicators of a specific personality. At the present stage of knowledge, they do not deserve to be raised to the level of a nosological entity (hence, their disappearance from DSM-IV). Chronic adjustment disorder might describe the chronic demoralization observed among some individuals stuck in chronically unsatisfactory life situations. Many more might fulfill the criteria for dysthymia. Neurasthenia A century-old term developed by the American neuropsychiatrist George Beard, neurasthenia refers to a more chronic stage of anxious-depressive symptomatology. The anxiety generated by overstimulation is so excessive that it is replaced by a chronic disposition to irritability, fatigue (especially mental fatigue), lethargy, and exhaustion. It is as if the sufferer's mind refuses to take on new stresses. The clinical picture described by Beard suggests that anxious manifestations were preeminent in his time. They included headache, scalp tenderness, backache, heavy limbs, vague neuralgias, yawning, dyspepsia, palpitations, sweating hands and feet, chills, flushing, sensitivity to weather changes, insomnia, nightmares, pantaphobia, asthenopia, and tinnitus. Although the diagnosis of neurasthenia is now used more in China than in the rest of the world, the recent worldwide popularity of the concept of chronic fatigue syndrome attests to the clinical acumen of classic physicians. Despite much energy invested in finding a viral or immunological cause, current descriptions tend to suggest an anxiety or mood disorder basis for some (but not all) of those with the syndrome. However, what circumstances would lead anxiety or depression to manifest primarily in fatigue is as elusive as it was 100 years ago. Like many other patients presenting to primary care settings with somatic complaints, those with chronic fatigue tend to denounce psychiatric diagnoses as inadequate explanations for their ills. Postpsychotic Depressive Disorder of Schizophrenia DSM-IV describes postpsychotic depressive disorder of schizophrenia as follows: The essential feature is a Major Depressive Episode that is superimposed on, and occurs only during, the residual phase of Schizophrenia. The residual phase of Schizophrenia follows the active phase (i.e., symptoms meeting Criterion A) of Schizophrenia. It is characterized by the persistence of negative symptoms or of active-phase symptoms that are in an attenuated form (e.g., odd beliefs, unusual perceptual experiences). The superimposed Major Depressive Episode must include depressed mood (i.e., loss of interest or pleasure cannot serve as an alternate for sad or depressed mood). Most typically, the Major Depressive Episode follows immediately after remission of the active-phase symptoms of the psychotic episode. Sometimes it may follow after a short or extended interval during which there are no psychotic symptoms. Mood symptoms due to the direct physiological effects of a drug of abuse, a medication, or a general medical condition are not counted toward postpsychotic depressive disorder of Schizophrenia. According to DSM-IV, persons whose presentation meets those research criteria ( Table 14.6-25) would be diagnosed as having depressive disorder not otherwise specified. As already pointed out, mood or depressive disorder not otherwise specified represents such a hodgepodge of clinical situations that the designation not otherwise specified is at best meaningless and at worst countertherapeutic. In all postpsychotic depressions, one must first exclude a missed bipolar diagnosis. Negative symptoms due to classic antipsychotics—especially depot phenothiazines and those due to the residium of schizophrenia once positive symptoms are brought under control—should be distinguished from the depressive episodes that complicate the course of schizophrenia in young, intelligent patients.

Table 14.6-25 DSM-IV Research Criteria for Postpsychotic Depressive Disorder of Schizophrenia

BIPOLAR DISORDERS Four bipolar disorders are included in DSM-IV: bipolar I disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder not otherwise specified. Bipolar I Disorder Typically beginning in the teenage years, the 20s, or the 30s, the first episode could be manic, depressive, or mixed. One common mode of onset is mild retarded depression, or hypersomnia, for a few weeks or months, which then switches into a manic episode. Others begin with a severely psychotic manic episode with schizophreniform features; only when a more classic manic episode occurs is the affective nature of the disorder clarified. In a third group several depressive episodes take place before the first manic episode. A careful history taken from significant others often reveals dysthymic or cyclothymic traits that antedated the frank onset of manic episodes by several years. According to DSM-IV, bipolar I disorder, single manic episode ( Table 14.6-26) describes patients having a first episode of mania (most such patients eventually develop depressive episodes). The remaining subcategorization is used to specify the nature of the current or most recent episode in patients who have had recurrent mood episodes (Table 14.6-27, Table 14.6-28, Table 14.6-29, Table 14.6-30 and Table 14.6-31. For clinicians and researchers alike it is more meaningful to chart a patient's course in color over time—for example using red rectangles for manic, blue for depressive, and violet for mixed episodes, with hypomanic, dysthymic, and cyclothymic periods drawn in the appropriate colors on a smaller scale between the major episodes. Life events, biologic stressors, and treatment can be indicated by arrows on the time axis. This approach, originally championed by Kraepelin, is routinely used in mood clinics. Robert Post at the NIMH has developed this approach into systematic clinical science.

Table 14.6-26 DSM-IV Diagnostic Criteria for Bipolar I Disorder, Single Manic Episode

Table 14.6-27 DSM-IV Diagnostic Criteria for Bipolar I Disorder, Most Recent Episode Manic

Table 14.6-28 DSM-IV Diagnostic Criteria for Bipolar I Disorder, Most Recent Episode Hypomanic

Table 14.6-29 DSM-IV Diagnostic Criteria for Bipolar I Disorder, Most Recent Episode Mixed

Table 14.6-30 DSM-IV Diagnostic Criteria for Bipolar I Disorder, Most Recent Episode Depressed

Table 14.6-31 DSM-IV Diagnostic Criteria for Bipolar I Disorder, Most Recent Episode Unspecified

On average, manic episodes predominate in youth, and depressive episodes in later years. Although the overall sex ratio is about one to one, men on average undergo more manic episodes and women experience more mixed and depressive episodes. Bipolar I disorder in children is not as rare as previously thought; however, most reported cases are in boys, and mixed-manic (dysphoric-explosive) presentations are the mode. Childhood-onset depression must also be considered a major risk for ultimate bipolar transformation. This is based on the following characteristics: (1) early age of onset; (2) even sex ratio; (3) prominence of irritability, labile moods, and explosive anger, suggesting mixed episodes; (4) questionable response to antidepressants, hypomanic switches, or both; (5) high recurrence rate after depression; and (6) familial affective loading. Mania can also first appear after age 65, though a diligent search often reveals a past mild, forgotten, or untreated depressive episode in earlier years. Acute Mania Mania typically escalates over a period of 1 to 2 weeks; more-sudden onsets have also been described. The DSM-IV criteria ( Table 14.6-7) stipulate (1) a distinct period that represents a break from premorbid functioning, (2) a duration of at least 1 week, (3) an elevated or irritable mood, (4) at least three to four classic manic signs and symptoms, and (5) the absence of any physical factors that could account for the clinical picture. The irritable mood in mania can deteriorate to cantankerous behavior, especially when the person is rebuffed. Such patients are among the most aggressive seen in the emergency room. Florid grandiose psychosis with paranoid features, a common presentation of mania, further contributes to the aggression. Alcohol use, observed in at least 50 percent of bipolar I patients (often during the manic phase), further disinhibits the patient and might lead to a dangerous frenzy. Such patients may attack loved ones and hurt them physically. So-called crimes of passion have been committed by patients harboring delusions of infidelity on the part of spouses or lovers, usually when under the influence of alcohol. The genesis of delusional, hallucinatory, even first-rank, psychotic experiences in mania has been described. Recent research has documented that most types of formal thought disorders are common to both schizophrenic and mood psychoses; only poverty of speech content (vagueness) emerges as significantly more common in schizophrenia. Finally, posturing and negativism occur in mania (and, in the author's view, do not warrant the designation of catatonic features as advocated by DSM-IV). Although not specifically mentioned in the DSM-IV definition, confusion, even pseudodemented presentations, can occur in mania. Mania is most commonly expressed as a phase of bipolar type I disorder, which has strong genetic determinants. Available evidence does not permit separating recurrent mania without depressive episodes from that type as a distinct nosological entity. Secondary Mania Although there is some suggestion that postpartum mania without depression is distinct from familial bipolar I disorder (in which depressive, manic, and especially mixed manic episodes occur in the postpartum period), the evidence for a distinct puerperal mania is not compelling at this time (hence the decision in DSM-IV to include the postpartum-onset specifier [see Table 13.4-3], rather than a separate mood disorder diagnosis). Mania without prior bipolarity can arise in the setting of such somatic illnesses as thyrotoxicosis, systemic lupus erythematosus or its treatment with steroids, rheumatic chorea, multiple sclerosis, Huntington's disease, cerebrovascular disorder, diencephalic and third ventricular tumors, head trauma, complex partial seizures, syphilis, and (most recently) AIDS. The family history is reportedly low in such cases, suggesting a relatively low genetic predisposition and thus a lower risk of recurrence. These patients do not easily fit into the DSM-IV category of mood disorder due to a general medical condition ( Table 14.6-17) because most of the conditions appear to be cerebral. Such factors must always be diligently sought in manias of late life. Less well defined forms of mania are the so-called reactive manias. Personal loss and bereavement are hypothesized to be triggering factors, and the reaction is conceptualized psychodynamically as a denial of loss. Although such explanations may be plausible in individual cases, no systematic data suggest that these patients differ in family history from persons with other manias. The same is generally true for depressed patients who switch to hypomania or mania after abuse of stimulant drugs, treatment with antidepressants, or sleep deprivation. In all of these situations a bipolar diathesis is usually manifest either in a family history of mania or in spontaneous excited episodes during prospective observation. First-onset manic episodes can also occur in persons who abruptly abstain from alcohol after one or more decades of chronic use and then develop classic bipolar I disorder. Chronic Mania DSM-IV does not specifically address the diagnostic questions posed by the 5 percent of bipolar I patients who have a chronic manic course. These cases commonly represent deterioration of course dominated by recurrent manic episodes grafted on a hyperthymic baseline. Noncompliance with pharmacological treatment is the rule. Recurrent excitement is personally reinforcing, subjective distress is minimal, and insight is seriously impaired. Thus the patient sees no reason to adhere to treatment. Episodic or chronic alcohol abuse, prevalent in such patients, has been suggested as a contributory cause of the chronicity. Some authorities

further consider comorbid cerebral pathology responsible for nonrecovery (and increased mortality) from manic excitements occurring in late life. Grandiose delusions (e.g., delusions of inventive genius or aristocratic birth) are not uncommon in chronic mania and may lead to the mistaken diagnosis of paranoid schizophrenia. Because of their social deterioration, Kraepelin subsumed such patients under the category “manic dementia.” Organic factors such as head trauma and chronic alcohol abuse may contribute to the deterioration. Nonschizoid premorbid adjustment, a family history of bipolar I disorder, and the absence of flagrant formal thought disorder can be marshaled in establishing the affective basis of these poor-prognosis manic states. Bipolar Mixed Phase Momentary tearfulness and even depressed mood are commonly observed at the height of mania or during the transition from mania to retarded depression. These transient labile periods, which occur in most bipolar I disorder patients, must be contrasted with mixed episodes proper. The latter, variously referred to as “mixed mania” or “dysphoric mania,” are characterized by dysphorically excited moods, irritability, anger, panic attacks, pressured speech, agitation, suicidal ideation, severe insomnia, grandiosity, and hypersexuality, as well as persecutory delusions and confusion. Severely psychotic mixed states that involved hallucinations and schneiderian symptoms risk being labeled “schizoaffective.” A correct diagnosis is mandatory because conventional antipsychotic drugs tend to exacerbate the depressive component and failure to use mood stabilizers can prolong the patient's misery. New research data from mood centers worldwide on mixed mania suggest that dysphoric mania—mania and full-blown depression occurring simultaneously—is relatively uncommon. Two to four depressive symptoms from the list of depressed mood, helplessness, hopelessness, fatigue, anhedonia, guilt, and suicidal ideation, or impulses, or both, in the setting of a manic syndrome, appear to suffice for the diagnosis of mixed manic states, which occurs in 50 percent of patients with bipolar disorder sometime during their lives. Mixed states occur predominantly in females in whom mania is superimposed on a depressive temperament or a dysthymic baseline. These considerations suggest that the DSM-IV concept of mixed episode ( Table 14.6-8) as a cross-sectional mixture of mania and depression is simplistic and phenomenologically naive. The emerging conceptualization of mixed mania is a manic state intruding upon long-term depressive traits. Depressive Phase Psychomotor retardation, with or without hypersomnia, marks the uncomplicated depressive phase of bipolar I disorder. Onset and offset are often abrupt, though onset can also occur gradually over several weeks. Patients may recover into a free interval or switch directly into mania. Switching into an excited phase is particularly likely when antidepressants have been used. However, not all patients develop mania after antidepressant treatment of bipolar depression. Some develop a mixed agitated depression; indeed, patients may be stuck for many months in a severe depressive phase with some manic admixtures such as racing thoughts and sexual arousal. DSM-IV does not specifically recognize a mixed depressive phase with few manic symptoms occurring during full-blown depression. Such recognition is necessary because these patients don't need continued aggressive antidepressant therapy but mood stabilizers, ECT, or both. Delusional and hallucinatory experiences are less common in the depressive phase of bipolar I disorder than in the manic and mixed manic phases. Stupor is the more common psychotic presentation of bipolar depression, particularly in adolescents and young adults. Pseudodemented organic presentations appear to be the counterpart of stupor in elderly adults. Cyclothymic Disorder An attenuated bipolar disorder that typically begins insidiously before the age of 21, cyclothymic disorder is characterized in DSM-IV by frequent short cycles of subsyndromal depression and hypomania ( Table 14.6-32). The author's research has revealed alternating patterns of moods, activity, and cognition (Table 14.6-33), which are more explicit than the DSM-IV criteria. The course of cyclothymia is continuous or intermittent, with infrequent periods of euthymia. Shifts in mood often lack adequate precipitants (e.g., sudden profound dejection with social withdrawal for a few days switching into cheerful, gregarious behavior). Circadian factors may account for some of the extremes of emotional lability, such as the person's going to sleep in good spirits and waking up early with suicidal urges. The mood changes of cyclothymia are best described as “endoreactive” in the sense that endogenous overreactivity seems to determine the sudden shifts in mood and behavior (e.g., falling in love with a person one has just met and as quickly falling out of love).

Table 14.6-32 DSM-IV Diagnostic Criteria for Cyclothymic Disorder

Table 14.6-33 Clinical Features of Cyclothymic Disorder

Mood swings in these ambulatory patients are overshadowed by the chaos that the swings produce in their personal lives. Repeated romantic breakups or marital failures are common because of interpersonal friction and episodic promiscuous behavior. Uneven performance at school and work is also common. Persons with cyclothymic disorder are dilettantes; they show great promise in many areas, but rarely bring any of their efforts to fruition. As a result, their lives are often a string of improvident activities. Geographical instability is a characteristic feature; easily attracted to a new locale job, or love partner, they soon lose interest and leave in dissatisfaction. Polysubstance abuse which occurs in as many as 50 percent of such persons, is often an attempt at self-treatment. Bipolar II Disorder (and the Soft Bipolar Spectrum) Research conducted during the past three decades showed that between the extremes of classic manic-depressive illness defined by at least one acute manic episode (bipolar I disorder) and strictly defined major depressive disorder without any personal or family history of mania (pure unipolar disorder), exists an overlapping group of intermediary forms characterized by recurrent major depressive episodes and hypomania. Table 14.6-34 summarizes the author's observations in defining the clinical subtypes within this intermediary realm best described as “soft bipolarity.” The most accepted of the subtypes is bipolar II disorder (with spontaneous hypomania), elevated to the status of a nosological entity in DSM-IV ( Table 14.6-35). Current data worldwide indicate that bipolar II disorder is actually more prevalent than bipolar I disorder. This certainly appears true in the outpatient setting, where 30 to 50 percent of persons with major depressive disorder have been reported to conform to the bipolar II pattern.

Table 14.6-34 Spectrum of Bipolar Disorders Compared With Unipolar Depression

Table 14.6-35 DSM-IV Diagnostic Criteria for Bipolar II Disorder

The following self-description provided by a 34-year-old poet illustrates the pattern: I have known melancholy periods, lasting months at a time, when I would be literally paralyzed: All mental activity comes to a screeching halt, and I cannot even utter one word. I become so dysfunctional that I was once hospitalized. Although the paralysis creeps into me insidiously—often lasting months—it typically reverses within hours. I am suddenly alive and vibrant, I cannot turn off my brain neither during the day nor at night; I usually go on celebrating like this for many weeks, needing no more than few hours of slumber each day. This vignette is nearly identical to the autobiographical description provided by the British poet William Cowper three centuries earlier: I have known many a lifeless and unhallowed hour ... long intervals of darkness interrupted by short returns of peace and joy ... For many succeeding weeks to rejoice day and night was all my employment. Too happy to sleep much, I thought it was lost time that was spent on slumber. The hypomania at the end of depressive episodes in most bipolar II patients does not persist long; it is usually measured in days. The modal duration of hypomania found in Memphis and Zurich studies was 2 days. Another common form of bipolar II disorder is major depressive disorder superimposed on cyclothymic disorder, in which hypomania precedes and follows major depression, the entire interepisodic period characterized by cyclothymic mood instability. As a result, these are difficult bipolar II patients to manage in clinical practice. Hypomania in bipolar II disorder can be defined as minimanic episodes occurring spontaneously. Bipolar II disorder—especially when major depressions are superimposed on cyclothymia—is thus best characterized as cyclical or “cyclothymic depression.” The depressive episodes of patients with bipolar disorder often have admixtures (e.g., flight of ideas, increased drives and impulsivity in sexual and other domains). The phenomenon of lithium augmentation is perhaps best explained by the high prevalence of pseudounipolar depressions with subtle hypomania either during or following a depressive episode, as well as the mixed simultaneous presence of depressive and hypomanic symptoms. The latter are not as severe as dysphoric mixed states, but are refractory to antidepressants nonetheless. Hypomania The common denominator of the soft spectrum of bipolar disorders is the occurrence of hypomania. Hypomania ( Table 14.6-9) refers to a distinct period of at least a few days of mild elevation of mood, sharpened and positive thinking, and increased energy and activity levels, typically without the impairment characteristic of manic episodes. It is not merely a milder form of mania. Hypomania occurring as part of bipolar II disorder rarely progresses to manic psychosis; distractibility is uncommon in hypomania, and insight is relatively preserved. Hypomania is distinguished from mere happiness in that it tends to recur (happiness does not) and can sometimes be mobilized by antidepressants. In cyclothymic disorder it alternates with minidepressions; in hyperthymic temperament it constitutes the person's habitual baseline. These definitions then recognize three patterns of hypomania: brief episodes heralding the termination of a retarded depressive episode (bipolar II disorder), cyclic alternation with minidepressions (cyclothymic disorder), and an elevated baseline of high mood, activity, and cognition (hyperthymic or chronic hypomanic traits). Because hypomania is experienced either as a rebound relief from depression or as pleasant, short-lived, ego-syntonic mood state, persons with bipolar II disorder rarely report it spontaneously. Skillful questioning is thus required to make the diagnosis of soft bipolar conditions; as in mania, collateral information from family members is crucial. In interviewing the patient the following probes have been found useful to elicit hypomania: “Have you had a distinct sustained high period (1) when your thinking and perceptions were unusually vivid or rapid, (2) your mood was so intense that you felt nervous, and (3) you were endowed with such energy that others could not keep up with you?” The hypomanic manifestations for hypomania in the DSM-IV scheme basically list the signs and symptoms of mania in criterion A and B for mania (Table 14.6-9) but require fewer items and shorter duration. Clinical and epidemiological studies in the United States and Europe have revealed a richer range of manifestations including an increase in cheerfulness and jocularity; gregariousness and people seeking; greater interest in sex; talkativeness, self-confidence, and optimism; and decreased inhibitions and sleep need. The clinician must ascertain that those experiences were not due to stimulant or alcohol withdrawal. Depressive and hypomanic periods are often not easily discerned because chronic caffeinism, stimulant abuse, or both complicate the depression. In such instances, diagnosis should be based on clinical observation for 1 month after detoxification. When in doubt, direct clinical observation of hypomania—sometimes elicited by antidepressant pharmacotherapy—provides definitive evidence for the bipolar nature of the disorder. Unfortunately DSM-IV denies bipolar status to treatment-emergent hypomanic episodes. Follow-up studies in juvenile and young adults with pharmacological hypomania have demonstrated that nearly all such individuals progress to spontaneous hypomanic (or manic) episodes. Although DSM-IV stipulates a minimum duration of 4 days for hypomania, any recurrent hypomania coupled with major depression should count toward the diagnosis of bipolar II. Seasonal Patterns Seasonality is observed in many cyclic depressions, often with autumn or winter anergic depression and energetic periods in the spring. This natural propensity explains why phototherapy may provoke mild hypomanic switches. Although not specifically identified by DSM-IV, seasonal depressions conform, in large measure, to the bipolar II or III pattern. Furthermore, preliminary evidence suggests that treatment with classic antidepressants disrupts the baseline seasonality, with the depressive phase appearing in the spring and summer. The changes antidepressants induce in seasonal depressions probably represent a special variant of the rapid-cycling phenomenon. Temperament and Polarity of Episodes New systematic clinical observations have revealed that bipolar II disorder (characterized predominantly by depressive attacks) arises more often from a hyperthymic or cyclothymic baseline, whereas bipolar I disorder (defined by manic attacks) not uncommonly arises from the substrate of a depressive temperament. When the hyperthymic temperament occurs in bipolar I disorder, it is usually associated with a recurrent mania, which is an

uncommon bipolar course. A prospective 11-year NIMH study of major depressive disorder patients who switched to bipolar II disorder showed that “mood-labile” (cyclothymic) and “energetic-active” (hyperthymic) temperament traits were highly specific and reasonably sensitive predictors of such an outcome. Bipolarity is conventionally defined by the alternation of manic (or hypomanic) and depressive episodes. The foregoing data on temperaments suggest hat a more fundamental characteristic of bipolarity is the reversal of temperament into its “opposite” episode (in the case of the bipolar II spectrum, from cyclothymia and hyperthymia to major depression). Such findings suggest that the intrusion of cyclothymic and hyperthymic traits into a depressive episode may underlie the instability of the bipolar II subtype and could partly explain why bipolar II depression often has mixed features. These considerations may have important implications for preventing recurrence. For instance, a prospective study of the onset of bipolar disorder in the offspring or sibs of adults with the disorder found that children with depressive onsets as their first episode (and which were usually treated with antidepressants) had significantly higher rates of recurrence than those with manic or mixed onsets (treated with lithium) during a 3-year prospective observation. It appears that temperamental instability in the depressive group might have predisposed them to the cycling effect of antidepressants. Alcohol, Substance Abuse, and Suicide New evidence supports the high prevalence of alcohol and substance abuse in mood disorder subtypes, especially those with interepisodic cyclothymia and hyperthymia. The relation appears particularly strong in the teenage and early adult years, when the use of such substances often represents self-medication for the mood instability. It is not just self-treatment for selected symptoms associated with the down or up phases (e.g., alcohol to alleviate the insomnia and nervousness characteristic of both phases), it also augments certain desired ends (e.g., stimulants to enhance high-energy performance and sexual behavior associated with hypomania). How many display alcohol and substance abuse secondary to an underlying bipolar diathesis remains to be determined. But in view of findings suggesting a link between polysubstance abuse and suicide in adolescents with bipolar familial backgrounds, the use of mood stabilizers in these adolescents should be strongly considered. Although alcohol and stimulant use continues into adult years in a considerable number of bipolar disorder patients, such use is often unrelated to familial alcoholism, and frequently tends to dwindle during long-term follow-up, which supports the self-medication hypothesis. To complicate matters, in a substantial minority of cases, bipolar mood swings appear for the first time after abrupt cessation of long-term alcohol use; it is not uncommon for such mood swings to escalate into full-blown bipolar syndromes. Rapid-Cycling Bipolar Disorder Rapid cycling is defined as the occurrence of at least four episodes—both retarded depression and hypomania (or mania)—a year (Table 14.6-36). Thus rapid cyclers are rarely free of affective symptoms and suffer serious vocational and interpersonal incapacitation. Lithium is often only modestly helpful to those patients, as are traditional antipsychotic agents; most antidepressants readily induce excited episodes and thus aggravate the rapid-cycling pattern. A balance among mood stabilizers, antipsychotic drugs, and antidepressants may be difficult to achieve. Many such patients require frequent hospitalization because they develop explosive excitement and precipitous descent into severe psychomotor inhibition. The disorder is a roller coaster nightmare for the patient, significant others, and the treating physician. Treating these patients is an art.

Table 14.6-36 DSM-IV Diagnostic Criteria for Rapid Cycling Specifier

As expected, rapid cycling commonly arises from a cyclothymic substrate, which means that most rapid cyclers have bipolar II disorder. Factors favoring its occurrence include (1) female gender; (2) borderline hypothyroidism; (3) menopause; (4) temporal lobe dysrhythmias; (5) alcohol, minor tranquilizer, stimulant, or caffeine abuse; and (6) long-term, aggressive use of antidepressant medications. Most clinically identified patients are bipolar II women in middle age or upper social classes. Rapid cycling is uncommon from a bipolar I base. Leadership and Creativity Persons with hyperthymic temperament and soft bipolar conditions in general possess assets that permit them to assume leadership roles in business, the professions, civic life, and politics. Increased energy, sharp thinking, self-confidence and eloquence represent the virtues of an otherwise stormy life. Creative achievement is relatively uncommon among those with the manic forms of the disorder, which is too severe and disorganizing to permit the necessary concentration and application. Notable artistic achievements are found among those with soft bipolar disorders, especially cyclothymic disorders. Psychosis, including severe bipolar swings, is generally incompatible with creativity. That conclusion, based on recent systematic studies, tends to refute the romantic tendency to idolize insanity as central to the creative process. As talent is the necessary ingredient of creativity, how might soft bipolarity contribute? The simplest hypothesis is that depression might provide insights into the human condition, and the activation associated with hypomania helps in producing the artistic work. A more profound interpretation suggests that the repeated self-doubt that comes with recurrent depression might be an important ingredient of creativity, because original artistic or scientific expression is often initially rejected, and the self-confidence that accompanies repeated bouts of hypomania can help in rehearsing such ideas or expressions until they are perfected. Finally, the tempestuous object relations associated with bipolarity in the parent's or the patient's life often create the unique biographical landmarks that might be immortalized in an artistic medium. Bipolar Disorder Not Otherwise Specified The criteria for bipolar disorder not otherwise specified are listed in Table 14.6-37.

Table 14.6-37 DSM-IV Diagnostic Criteria for Bipolar Disorder Not Otherwise Specified

Recurrent hypomanic episodes without intermittent depressions (example 2 in the DSM-IV criteria for bipolar disorder not otherwise specified are almost never observed clinically. Recurrent Brief Hypomania Recurrent brief depressive disorder as a transitional form between dysthymia and major depression or brief hypomanic episodes often have been missed during evaluations performed by nonclinicians. Some patients who meet the Zurich description might therefore belong in the soft bipolar spectrum. Indeed, subsequent evaluation and analyses have revealed high rates of comorbidity between recurrent brief depression and brief hypomania. Thus, some recurrent brief depressive cases appear to be variants of bipolar disorder. The subtle bipolar nature of recurrent brief depressive disorder is clinically supported by the fact that

the very few such patients the author has encountered in his own practice did poorly with antidepressant monotherapy but benefited from mood stabilizers used alone or combined with antidepressants. The recurrent hypomanic counterpart of recurrent brief depressive disorder is described under soft bipolar conditions. By DSM-IV criteria, it represents an instance of bipolar disorder not otherwise specified. Hysteroid Dysphoria The category hysteroid dysphoria combines reverse vegetative signs with the following characteristics: (1) giddy responses to romantic opportunities and an avalanche of dysphoria (angry-depressive, even suicidal responses) upon romantic disappointment; (2) impaired anticipatory pleasure, yet the capability to respond with pleasure when such is provided by others (i.e., preservation of consummatory reward); (3) craving for chocolate and sweets, which contain phenylethylamine compounds and sugars believed to facilitate cellular and neuronal intake of the amino acid L-tryptophan, hypothetically leading to synthesis of endogenous antidepressants in the brain. The use of the epithet “hysteroid” was used to convey that the apparent character pathology was secondary to a biological disturbance in the substrates governing affect, drives, and reward. The intense, giddy, unstable life of the patient with hysteroid dysphoria suggests links to cyclothymic disorder or bipolar II disorder. This suggestion is further supported by the Columbia group's tendency to subsume those patients under atypical depressions (some of which, as indicated, have bipolar affinities). Like patients with bipolar depression, they respond preferentially to monoamine oxidase inhibitors (MAOIs). In brief, hysteroid dysphoria appears to be a variant of bipolar II with cyclothymic-irritable traits. Other variants of bipolar II disorder with hyperthymic-narcissistic traits are described under soft bipolar disorder and represent instances of bipolar disorder not otherwise specified. Bipolar III Disorder In bipolar III disorder (which is not an official nosological term but can be subsumed under bipolar disorder not otherwise specified) evidence of bipolarity is softer, such as a single brief episode of an antidepressant-mobilized switch. In a related subgroup of cryptic bipolar disorders, strong evidence for familial bipolarity raises the possibility that some phenotypically “unipolar” depressed patients are nonetheless constitutionally bipolar; in such cases, history for hypomania occurring in discrete episodes is not obtained; instead the patient's habitual temperamental baseline is sunny, overenergetic, and overoptimistic (hyperthymic). Depending on the threshold of traits used in determining the presence of hyperthymia, bipolar III patients may constitute 10 to 20 percent of those with major depressive disorder. Thus, many patients with so-called unipolar depression are actually “pseudounipolar.” The presence of marked narcissistic traits is a helpful clinical clue that a clinically depressed patient might belong to the group of those with hyperthymic depressions.

MOOD DISORDERS NOT OTHERWISE SPECIFIED After all diagnostic information has been obtained, some depressed and bipolar or otherwise affective patients do not meet the specific criteria for the mood conditions described thus far. Mood disorders not otherwise specified is a statistical concept for filing purposes and not a clinical description. The author prefers to consider such cases as undiagnosed mood disorders rather than using the DSM-IV categories of depression disorder not otherwise specified, bipolar disorder not otherwise specified or mood disorder not otherwise specified. What follows are descriptions of conditions that commonly appear in the psychiatric literature but do not easily fit into the official nosology of mood disorders. They represent hybrids between mood and anxiety disorders. Mixed Anxiety-Depressive Disorder The inclusion of anxious depressive states in a DSM-IV appendix acknowledges the simultaneous occurrence of anxious (e.g., the threat loss represents) and depressive (e.g., the despair of loss) cognition in a person confronted with a major aversive life situation. The admixture implies that the psychopathology progresses from anxiety to depression, that the patient's mental state is still in flux, and that the ongoing dynamics partly explains the subacute or chronic nature of the disorder. Anxious depression serves to point to the common presence of anxiety in depressive states, especially its greater visibility when the depression is less prominent. Patients with the latter presentation are reportedly most prevalent in general medical settings. This should not come as a surprise, because depressive symptoms that motivate medical consultation commonly complicate generalized anxiety states with a subthreshold level of symptomatology. Some authorities argue that neurotic depressions arise as maladaptive responses to anxiety and on that basis suggest retaining the “neurotic depression” rubric. Recent preliminary genetic data indirectly support the contention that certain (unipolar) depressive and (generalized) anxiety states are related. However, more research is needed before such an entity can be unequivocally accepted as an official nosological category. The difficulty is that as currently defined, anxious depressions are heterogeneous. In patients refractory to anxiolytic or antidepressant treatment or both, practitioners must entertain the diagnosis of a complex bipolar II disorder with mixed features. Indeed, recent genetic investigations suggest that bipolar II disorder with panic attacks might represent a special form of bipolar disorder. Atypical Depression Although a delimited version of atypical depression was incorporated into DSM-IV as “atypical features ( Table 14.6-5) to qualify the cross-sectional picture of depressive disorders, this construct is much broader in the clinical research literature. Originally developed in England and currently under investigation at Columbia University in New York, atypical depression refers to fatigue superimposed on a history of somatic anxiety and phobias, together with reverse vegetative signs (mood worse in the evening, insomnia, tendency to oversleep and overeat). Sleep is disturbed in the first half of the night in many persons with atypical depressive disorder, so irritability, hypersomnolence, and daytime fatigue would be expected. The temperaments of these patients are characterized by inhibited-sensitive traits. The MAOIs and serotonergic antidepressants seem to show some specificity for such patients, which is the main reason that atypical depression is taken seriously. Other research suggests that reverse vegetative signs can be classified as either (1) the anxious type just described or (2) a subtle bipolar subtype with protracted hyperphagic-hypersomnic-retarded dysthymic disorder with occasional brief extroverted hypomanic-type behavior, often elicited by antidepressants. Increasing evidence indicates considerable affinity between atypical depression and bipolar II and III disorders. Furthermore, many patients with dysthymic disorder exhibit atypical features at various times. Actually, atypical depression might be an artifact of the DSM-IV definition of hypomania of 4 or more days. Recent Italian research suggests that many patients with atypical depressive meet criteria for brief hypomania or cyclothymic disorder. The categories of not otherwise specified in the DSM-IV mood disorders schema largely reflect inadequacies of the operational approach to capture patients whose symptomatology falls between or on the boundaries of more classic diagnoses.

DIFFERENTIAL DIAGNOSIS A missed mood disorder diagnosis means that the disorder does not receive specific treatment, which has serious consequences. Many such persons drop out of school or college, lose their jobs, get divorced, or may commit suicide. Those with unexplained somatic symptoms are frequent users of the general health system. Others are unwell despite interminable psychotherapy. Some, treated with dopamine receptor antagonists develop tardive dyskinesia unnecessarily. As with other medical disorders for which specific treatments are available, accurate diagnosis and early treatment are within the purview of all physicians and mental health professionals. Psychiatrists, in particular, should develop the competence to detect the entire spectrum of mood disorders. Despite massive educational efforts, underdiagnosis and undertreatment of mood disorders remain serious problems worldwide. Although much enthusiasm was generated a decade ago about the potential use of certain biologic markers (e.g., REM latency, dexamethasone (Decadron) suppression test, and the thyrotropin-releasing-hormone test) to corroborate the differentiation of mood disorder from adjacent disorders, no definitive progress justifies their routine use in clinical practice. Faced with unusual or confusing presentations, a systematic clinical approach is still the best method in differential diagnosis (1) to detail all clinical features of the current episode, (2) to elicit a history of more typical major mood episodes in the past, (3) to assess whether the presenting complaints recur periodically or cyclically, (4) to substantiate adequate social functioning between periods of illness, (5) to obtain a positive family history for classic mood disorder and to construct a family pedigree, and (6) to document a history of unequivocal therapeutic response to thymoleptic medication or ECT in either the patient or the family. Using the foregoing validating approach, one can examine the affective links of many DSM-IV disorders currently listed under mood disorders not otherwise specified, as well as controversial nosological entities currently categorized as nonmood disorders. The latter include conduct disorders; borderline personality disorder; impulse-control disorders; polysubstance abuse; psychotic disorder not otherwise specified; pain disorder; hypochondriasis; hypoactive sexual desire disorder; circadian rhythm sleep disorder, delayed sleep phase type; bulimia nervosa; and adjustment disorder (with work inhibition). These conditions place special emphasis on selected affective features, such as disinhibited behavior, temperamentality, mood lability, vegetative disturbances, and psychomotor anergia. What follows is a systematic examination of the differential diagnosis of mood disorders with their more classic boundaries. Alcohol and Substance Use Disorders The high comorbidity of alcohol and substance use disorders with mood disorders cannot be explained as merely the chance

occurrence of two prevalent disorders. Self-medication for mood disorders is insufficiently appreciated by both psychiatrists and other professionals who deal with addiction. Given the clinical dangers of missing an otherwise treatable disorder, mood disorder should be seriously considered as the primary diagnosis if marked affective manifestations persist or escalate after detoxification (e.g. 1 month). This consideration also pertains to cyclothymic disorder and dysthymic disorder, which appear particularly likely to invite self-medication. The clinical validating strategies listed above can further buttress a mood disorder diagnosis. The DSM-IV category of substance-induced mood disorder ( Table 14.6-18) is difficult to validate clinically because in the absence of an affective diathesis, detoxification should, in principle, rapidly clear affective disturbances in persons whose primary problem is that of substance abuse. In the author's view, a dual diagnosis of both a mood disorder and a substance use disorder is a more realistic clinical approach to this group of patients. Bipolarity, particularly bipolar II disorder, should be sought in the interface of mood and substance use disorders. A 27-year-old married businessman employed in an international family venture owned by his father presented with a court-ordered request for psychiatric treatment. He had been found “bringing” cocaine across the U.S.-Mexican border and was briefly jailed. He had used stimulants since his late teens to enhance his already high level of energy. His family was rich, and he had no difficulty affording cocaine. During the previous year, he had needed more cocaine because of greater moodiness and fleeting suicidal ideation, which he linked to increasing tensions between him and his father: “My father was never satisfied with me and demanded greater and greater performance from me.” His arrest by police was a major embarrassment for him and his family and motivated his compliance with psychiatric hospitalization to detoxify him. He had not had cocaine for 10 days, exhibited marked lability of mood, and gradually sank into a severe hypersomnic-retarded depression of stuporous proportions. He was treated with tranylcypromine (Parnate) 20 mg twice a day, and within 10 days he switched into hypomania, his mind “exploding with creativity and confidence,” marked jocularity and witticisms that entertained other patients, and marked seductiveness toward the nurses. His wife recalled that the patient previously had had several such periods naturally (i.e., “off cocaine”), which had strained their marriage due to “brief sexual liaisons.” Reducing the tranylcypromine dosage by 50 percent did not eliminate the hypomanic behavior and lithium 900 mg a day was added. He has since been maintained on a combination of tranylcypromine and lithium for 4 years; he has not relapsed into cocaine use, and following few psychoeducational sessions involving father and spouse, relationships with family and spouse have been less tempestuous. (Since consultation was sought by the patient's 60-year-old mother, an attractive, sophisticated woman, who confessed that for years she had been engaging in “love relationships” with young artists, with apparently her husband's “silent consent”; since at least her mid-20s, she by history would meet the criteria for bipolar II, only treated “on the couch,” and both her sister and brother had received treatment for “alcohol excesses.”) Patient states that pharmacotherapy—which did require adjustment now and then—has helped in balancing the “rough edges” of his “high-nervous temperament” and his “periodic lapse into paralyzing fatigue states that occurred at stressful times.” If clinicians had assumed that primarily due to cocaine withdrawal, they would have never treated the patient's bipolar II disorder. DSM-IV conventions in this regard unfortunately bias diagnosis in favor of substance use disorders and, more tragically, against the realistic chance of cure from substances. There is emerging interest in treating dually diagnosed patients with mood stabilizers, especially anticonvulsants. The intention is to attenuate any withdrawal phenomena from substances of abuse, while treating any underlying or emerging soft bipolar disorders. Personality Disorders The state dependency of most personality measures is well documented. Accordingly, as exhorted by DSM-IV, clinicians should refrain from using personality disorder labels in describing patients with active affective illness and should focus instead on competent treatment of the mood disorder. Even in those with chronic or subthreshold mood disorders, personality maladjustment is best considered postaffective, arising from the distortions and conflicts that affective disturbances produce in the life of the sufferer. The most problematic of the personality labels used in those with mood disorders is borderline personality disorder, usually applied to teenage and young adult females. The DSM-IV diagnostic criteria for the disorder indicate a liberal mélange of low-grade affective symptoms and behavior. Table 14.6-38 shows that the overlap between borderline personality and mood disorders is extensive, so that giving a “borderline” diagnosis to a person with mood disorder is redundant. Use of personality disorder diagnoses may lead to neglect of the mood disorder or perhaps half-hearted treatment of the mood disorder; failure to respond would then be blamed on the patient's “self-defeating character” or “resistance to getting well,” thus exculpating the clinician.

Table 14.6-38 Overlap of Borderline Personality Disorder and Mood Disorders

Although more-systematic research is needed on the complex interface of personality and mood disorders, clinically they are often inseparable. As with alcohol and substance use disorders, it is generally preferable to diagnose mood disorders at the expense of personality disorders, which should not be difficult to justify in most cases that satisfy the validating strategies outlined above. When features of personality and mood disorders coexist, it is good practice to defer Axis II diagnoses and embark upon competent treatment of the concurrent mood disorder. Although not all personality disturbances recede with the competent treatment of mood disorders, so many experienced clinicians have seen such disturbances melt away with the successful resolution of the mood disorder that erring in favor of mood disorders is justified. A 19-year-old single woman presented with the chief complaint that “all men are bastards.” Since her early teens, with the onset of her menses, she had complained of extreme variability in her moods on a nearly daily basis; irritability with hostile outbursts was her main affect, though more protracted hypersomnic depressions with multiple overdoses and wrist slashings had led to at least three hospitalizations. She also suffered from migrainous headaches that, according to the mother, had motivated at least one of those overdoses. Despite her tempestuous and suicidal moods that led to these hospitalizations, she complained of “inner emptiness and a bottomless void.” She had used heroin, alcohol, and stimulants to overcome this troubling symptom. She also gave history of ice-cream craving and frequent purging. She was talented in English and wrote much-acclaimed papers on the American confessional poet, Anne Sexton. She said she was mentally disturbed because of a series of stepfathers who had all forced “oral rape” between the ages of 11 and 15. She subsequently gave herself sexually to any man she met in bars, no longer knowing whether she was a “prostitute” or a “nice little girl.” On two occasions she had inflicted cigarette burns on her vagina “to feel something.” She had also engaged in a “brief lesbian relationship” that ultimately left her “emptier” and guilt-ridden; nonetheless, she now believed that she should burn in hell, because she could not get rid of “obsessing” about the excitement of mutual cunnilingus with her much older female partner. The patient's mother, who owned an art gallery, had been married five times and gave history of unmistakable hypomanic episodes; a maternal uncle had died from alcohol-induced cirrhosis. The patient's father, a well-known lawyer known for his “temper and wit,” had committed suicide. The patient was given phenelzine (Nardil), eventually raised to 75 mg a day, at which point the mother described her as “the sweet daughter she was before age 13.” At her next premenstrual phase, patient developed insomnia, ran away from home at night, started “dancing like a go-go girl,” met an “incredibly handsome man” of 45 years (actually, a pornography shop owner) and got married. Lithium augmentation controlled this excited episode. After many dosage adjustments, she is maintained on a combination of lithium (900 mg a day) and divalproex (Depakote) (750 mg a day). The patient now attends college and has completed four semesters in art history. In addition to control of her irritable and suicidal moods, bulimic and migraine attacks have abated considerably. Her marriage has been annulled on the basis that she was not mentally competent at the time of the wedding. She is no longer promiscuous and now expresses fear of intimacy with men she is attracted to. She is receiving individual psychotherapy for this problem. The author often hears the complaint that even when a mood disorder is diagnosed in a “borderline” patient, response to antidepressants is disappointing. The problem is that affective disorders in these patients usually conform to bipolar II disorder—often complicated by ultrarapid cycling—and many clinicians, including

some with biological orientation, may lack sufficient experience in the art of pharmacologically managing patients who markedly deviate from classic bipolar I disorder. The interface of mood disorders and behavioral disturbances (conduct and attention-deficit/hyperactivity disturbances) in children is even more problematic than in adult psychiatry. Nonetheless, progress has occurred in clinically recognizing certain behavioral manifestations as possible signs of depression in juvenile subjects, including periodic marked decline in school performance; restlessness and pulling or rubbing hair, skin, or clothing; outbursts of complaining, shouting, or crying; and aggressive or antisocial acts (such as kicking the mother, shoplifting) out of character to the child; as well as other acute personality changes ranging from defiant attitudes to negativism and avoidant behavior. Examined carefully, children and pubescent youth with these characteristics often meet the specific criteria for the diagnosis of major depressive disorder or dysthymic disorder. However, most children do not complain of subjective dysphoria; instead, the clinician can observe the depressed affect in the child's facial expressions or overall demeanor. After much resistance, many child clinicians now accept the existence of childhood mood disorders. Bipolar disorder in children, even in adolescents, is still grossly underdiagnosed at the expense of so-called externalizing disorders. Table 14.6-39 lists those and related conditions often confused with bipolar disorders in juvenile patients. Many children express bipolar disorder in explosive outbursts of irritable mood and behavior (i.e., as a mixed or dysphoric manic state); another pattern is intermittent hypomania and cyclothymia. Children with bipolar disorder are distinguished from those with so-called externalizing disorders by the fact that they are often, though not always, considered charming and likeable, yet overconfident or delusionally grandiose, and may exhibit age-inappropriate sexual behavior, such as lecherous advances toward adult women (e.g., their elementary school teachers): Moreover, they often get worse on stimulant medication. Correct diagnosis depends on the index of suspicion of a clinician who is convinced that bipolarity exists in juvenile subjects. Depression with first onset before age 18 has an extremely high rate of switching into both bipolar I and bipolar II disorders.

Table 14.6-39 Misdiagnosis in the Affectively Ill Juvenile Kin of Adults With Bipolar Disorder

Normal Bereavement Bereaved persons exhibit many depressive symptoms during the first 1 to 2 years after their loss, so how can the 5 percent of bereaved persons who have progressed to a depressive disorder be identified? Grieving persons and their relatives perceive bereavement as a normal reaction, while those with depressive disorder often view themselves as sick and may actually believe they are losing their minds. Unlike the melancholic person, the grieving person reacts to the environment and tends to show a range of positive affects. Marked psychomotor retardation is not observed in normal grief. Although bereaved persons often feel guilty about not having done certain things that might have saved the life of the deceased loved one (guilt of omission), they typically do not experience guilt of commission. Delusions of worthlessness or sin and psychotic experiences in general point toward mood disorder. Active suicidal ideation is rare in grief but common in major depressive disorder. Mummification (i.e., keeping the belongings of the deceased person exactly as they were before his or her death) indicates serious psychopathology. Severe anniversary reactions should alert the clinician to the possibility of psychopathology. In another form of bereavement depression, the sufferer simply pines away, unable to live without the departed person, usually a spouse. Although not necessarily pathological by the foregoing criteria, such persons do have a serious medical condition. Their immune function is often depressed, and their cardiovascular status is precarious. Death can ensue within a few months of that of a spouse, especially among elderly men. Such considerations (highlighted in the work of Sidney Zisook and his San Diego colleagues at the University of California) suggest that it would be clinically unwise to withhold antidepressants from many persons experiencing an intensely mournful form of grief. A 75-year-old widow was brought by her daughter because of severe insomnia and total loss of interest in daily routines following her husband's death 1 year before. She had been agitated for the first 2 to 3 months and thereafter “sank into total inactivity—not wanting to get out of bed, not wanting to do anything, not wanting to go out.” According to her daughter, she was married at 21, had four children, and had been a housewife until her husband's death from a heart attack. Past psychiatric history was negative; premorbid adjustment had been characterized by compulsive traits. During the interview she was dressed in black, appeared moderately slowed, and sobbed intermittently, saying “I search everywhere for him ... I don't find him.” When asked about life, she said “everything I see is black.” Although she expressed no interest in food, she did not seem to have lost an appreciable amount of weight. Her dexamethasone suppression test result was 18 µg/dL. The patient declined psychiatric care, stating that she “preferred to join her husband rather than get well.” She was too religious to commit suicide but by refusing treatment she felt she would “pine away ... find relief in death and reunion.” Anxiety Disorders Anxiety symptoms including panic attacks, morbid fears, and obsessions are common during depressive disorders, and depression is a common complication of anxiety states. Systematic British studies have shown that early-morning awakening, psychomotor retardation, self-reproach, hopelessness, and suicidal ideation are the strongest clinical markers of depression in that differential diagnosis. On follow-up of depressed patients, the manifestations tend to remit, whereas those with anxiety states continue to exhibit marked tension, phobias, panic attacks, vasomotor instability, feelings of unreality, and perceptual distortions as well as hypochondriacal ideas. A predominance of such anxiety features antedating the present disorder suggests the diagnosis of an anxiety disorder. Since anxiety disorders rarely first appear after the age of 40, late appearance of marked anxiety features strongly favors the diagnosis of melancholia. The clinical picture is often one of morbid groundless anxiety with somatization, hypochondriasis, and agitation. The depressive nature of the illness is further supported by a superior response to ECT. Periodic monosymptomatic phobic and obsessional states exist that can be regarded as affective equivalents on the basis of a family history of mood disorders and their response to thymoleptic agents. Recent data from a large clinical series suggests that 15 percent of patients with obsessive-compulsive disorders develop unmistakable hypomanic symptoms; these patients are best considered to have bipolar II disorder and treated with lithium salts. Social phobias exist that usher in adolescent depression, even a bipolar disorder. The psychopathological differentiation of anxiety and depressive states has not been entirely resolved. Cognitive factors may differentiate them best ( Table 14.6-40). Although recurrent (especially retarded) major depressive disorder is a distinct disorder from anxiety states, at least some forms of depression may share a common diathesis with anxiety disorders, particularly generalized anxiety disorders. Before assigning patients to such a putative mixed anxiety-depressive group (not yet an official nosological entity), the clinician must note that anxiety that arises primarily during depressive episodes is best considered as epiphenomenal to depressive disorder. The same is generally true for anxiety symptoms that occur in a person with depressive disorder who is using alcohol or sedative-hypnotic or stimulant drugs. Finally, anxiety symptoms could be prominent features of mixed bipolar states as well as of complex partial seizures.

Table 14.6-40 Unique Cross-Sectional Profiles of Clinical Anxiety and Depression

Physical Disease Somatic complaints are common in depressive disorders. Some, such as vegetative disturbances, represent the hypothalamic pathology that is believed to underlie a depressive disorder. Autonomic arousal, commonly associated with depression, could explain such symptoms as palpitations, sweating, and headache. In some instances the physical symptoms might reflect delusional experiences. The clinician must be vigilant about the likelihood that somatic complaints in depression can also reflect an underlying physical illness. Table 14.6-41 lists the most common medical conditions that have been associated with depression. When depressive symptoms occur in the setting of physical illness, it is not always easy to determine whether they constitute a genuine depressive disorder. Before diagnosing depression, psychiatrists must ensure that they are not dealing with pseudodepression: (1) functional loss due to physical illness; (2) vegetative signs, such as anorexia and weight loss, as manifestations of such an illness; (3) stress and demoralization secondary to the hospitalization; (4) pain and discomfort associated with the physical illness; and (5) medication adverse effects. On the other hand, nonpsychiatric physicians who manage such patients must consider the diagnosis of depression in the presence of persistent anhedonia; observed depressed mood with frequent crying; observed psychomotor retardation or agitation; indecisiveness; convictions of failure, worthlessness, or guilt; and suicidal ideation. The physician should also suspect clinical depression in all patients who refuse to participate in medical care.

Table 14.6-41 Pharmacological Factors and Physical Diseases Associated with Onset of Depression

Diagnosing depression in medically ill elderly patients can be particularly difficult. This task should be undertaken diligently because it was recently reported that (especially in those with cardiovascular disease) mortality is accelerated by depression. Depressed elderly adults often deny being “depressed” but complain of anxiety, fatigue, and worsening memory. Hypochondriacal symptoms and pain are common. Patients may exhibit extreme negativism and querulousness when invited to participate in medical procedures; others develop poor fluid and food intake out of proportion to their physical conditions. Another important diagnostic problem at the interface of mood disorder and physical disease is the rare development of malignancy in patients with an established mood disorder. Patients who had responded well to a given antidepressant during previous episodes now have an unsatisfactory response to the same medication. Even a small dose may cause such alarming symptoms as agitation, dizziness, depersonalization, and illusions, which might indicate an occult malignancy, perhaps in the abdomen or the brain. The psychiatrist should always be vigilant about the development of life-threatening physical diseases in patients with preestablished depressive disorder. A 55-year-old woman had suffered from four previous episodes of severe depression that had responded to ECT or amitriptyline (Elavil) or both in her native city of Cairo, Egypt. She immigrated to the United States at age 43 and encountered several major stresses; including unfamiliarity with English, daughter dating a man of Japanese extraction, and a complicated series of operations for uterine prolapse. Then her husband confessed he had had an affair with a much younger woman. For months the patient had complained of intermittent fatigue and expressed anger toward her husband. Her ensuing fifth depressive episode appeared fully “understandable,” but her physician's prescription of 25 mg of amitriptyline resulted in dizzy spells that culminated in syncope. Paroxetine (Paxil) 10 mg did not fare any better. An extensive medical workup revealed a retroperitoneal lymphoma. She died 6 months later. Stupor Although less common today, stupor still raises a diagnostic problem in differentiating between a mood disorder and somatic disease as well as other psychiatric disorders. Depressive stupor is relatively easy to distinguish from so-called hysterical mutism; in the latter, behavior is meaningfully directed to significant others in the patient's environment. The rubric of catatonic stupor is best reserved for a phase of schizophrenia; in such patients the schizophrenic origin of the catatonia might be apparent from the patient's history. Otherwise, most acute-onset stupors are probably of affective origin. The main differential diagnosis here is from organic stupor (due to drugs or acute intracranial events); the physical and neurological examination is not always decisive in such cases, and diagnosis depends on a high index of suspicion of possible somatic factors. Depressive Pseudodementia The geriatric equivalent of semistupor in younger persons with depressive disorder, depressive pseudodementia is distinguished from primary degenerative dementia by its acute onset without prior cognitive disturbance; a personal or family history of past affective episodes; marked psychomotor retardation with reduced social interaction; self reproach; diurnal cognitive dysfunction (worse in the morning); subjective memory dysfunction in excess of objective findings; circumscribed memory deficits that can be reversed with proper coaching; and a tendency to improve with sleep deprivation. Chronic Fatigue Syndrome Chronic fatigue syndrome is a complex differential diagnostic problem in view of the subtle immunological disturbances presumably associated with it. The following self-report by such a patient illustrates many of the uncertainties marking the present knowledge of the interface between the syndrome and mood disorders.

I am a 39-year-old, never-married woman, trained as a social worker, but currently on disability. I have experienced extreme lethargy and fatigue for many years. I have always felt foggy headed and had trouble thinking and concentrating. My complaint is of fatigue, not of depression. My body feels like lead and aches all over. My brain feels achy and sore. I feel much worse in the morning and I can't get out of bed; I feel better at night. I feel bad every day. I ache all over, as though someone had beaten me up. Exercise has been prescribed to me, but it makes me worse. Also, I am very sensitive to hot and cold. My sexual drive is low. I have a general feeling of anhedonia. As far back as I remember—in junior high school—I was always exhausted. I always complained about fatigue, not depression, because that has been the overwhelming problem. I feel the depression is secondary to the fatigue. In high school I was a compulsive overeater and I was bulimic for a few years, but it was never severe and I was only about 10 pounds overweight. In those days I would sleep 10 or 12 hours a night on the weekend and still feel exhausted; I could not get up for school on Monday. As an adolescent, I felt inferior. I couldn't make decisions, I didn't want to go to camp or leave home for long periods of time—I felt so insecure. Recently I had a sleep study done, which showed a short latency to stage REM sleep (49 minutes). I was diagnosed as having dysthymic disorder and began taking antidepressants. When I took tranylcypromine, it was the first time in my life that I felt like a normal person. I could play sports, I had a sex drive, I had energy, and I was able to think clearly. But the benefits lasted for barely 2 months. My response was equally short-lived to phenelzine, imipramine (Tofranil), selegiline (Eldepryl), and bupropion (Wellbutrin). I have not responded to serotonin-specific reuptake inhibitors (SSRIs) at all. I also wish to point out that I had never experienced high periods before I took antidepressants. My main problem has always been one of exhaustion. When I responded to medications, they worked very quickly (within a few days) and I felt great, but they all stopped working after a short time. The dose would be raised, and again I would feel better. Eventually, when I got to high doses, I either could not tolerate the high dose or the drug would no longer help. I have taken different combinations of drugs for 10 years and I haven't been able to feel well for more than 6 weeks at a time. Recently, I went to an immunologist. He said I have an abnormality in regulating antibody production and recommended gammaglobulin shots. They did not help. When I first started working, I always felt tired and foggy headed, so it was difficult to be sharp while at work. At times I would close the door to my office and put my head down. Working has become increasingly difficult for me. I had two great jobs, which I blew. As of last year I had to go on disability. I am desperate for relief, as my condition has drastically affected my life. Disability has been hard for me. I am single and have no other financial resources. I am very despondent, as I feel that my life is passing by without the hope of my ever really improving. The foregoing clinical picture is compatible with a pseudounipolar or bipolar III disorder as described by the author. Some virologists and immunologists as well as some psychiatrists believe that abnormal substances circulate in the bloodstream supplying the brains of such patients. Industrial toxins have also been suggested. While awaiting more definitive research on the etiology of chronic fatigue syndrome, the psychiatrist can cautiously consider certain patients for thymoleptic trials. That decision can be bolstered by the following considerations: the patient wakes up with fatigue and dread of facing the day; fatigue is part of a more generalized psychomotor inertia or lack of initiative; fatigue is associated with anhedonia, including sexual anhedonia; and fatigue coexists with anxious and pessimistic ruminations. Although none of the foregoing alone is pathognomonic for depression, in aggregate they point in that direction. The occurrence of hypomanic-like periods (as in the above vignette) further supports the link between some cases of chronic fatigue and mood disorder. Use of antidepressants without sedative effects, given in gradually increasing doses as tolerated, is a rational strategy; lithium and valproate, though not formally tested in such patients, are rational augmentation choices. Several recent neuroendocrine challenge studies suggest that some chronic fatigue patients might have a strong anxiety substrate and could be managed accordingly. This is not to say that chronic fatigue is largely a matter of missed affective diagnoses; yet it would be a pity to miss potentially treatable diagnoses. A family or past personal history of classic affective illness or episodes should strongly weigh in this direction. Obviously definitive data are lacking on the essential nature of chronic fatigue, and practitioners should be guided by their own clinical experience, while awaiting new research developments. Schizophrenia Cross-sectionally, young patients with bipolar disorder might seem psychotic and disorganized and thus schizophrenic. Their thought processes are so rapid that they may seem loose, but, unlike those with schizophrenia, they display expansive and elated affect, which is often contagious. By contrast, the severely retarded bipolar depressive person, whose affect may superficially seem flat, almost never exhibits major fragmentation of thought. The clinician, therefore, should place greater emphasis on the pattern of symptoms than on individual symptoms in the differential diagnosis of mood and schizophrenic psychoses. No pathognomonic differentiating signs and symptoms exist. Differential diagnosis should be based on the overall clinical picture, phenomenology, family history, course, and associated features. Because the two groups of disorders entail radically different pharmacological treatments on a long-term basis, the differential diagnosis is of major clinical importance. Table 14.6-42 summarizes the author's clinical experience in the area and lists the most common pitfalls in diagnosis. In the past many bipolar patients, especially those with prominent manic features at onset, were labeled as having “acute schizophrenia” or “schizoaffective schizophrenia.” Such misdiagnoses (which typically led to long-term treatment with antipsychotic agents) has been costly in terms of tardive dyskinesia, vocational and social decline, and even suicide. For instance, some patients with postpsychotic depressive disorder of schizophrenia in the DSM-IV scheme ( Table 14.6-25) have postmanic depressions that were treated with neuroleptic monotherapy without the benefit of more definitive thymoleptic agents.

Table 14.6-42 Misdiagnosis of Mood Disorder as Schizophrenia

Modern treatments, which tend to keep many persons with schizophrenia out of the hospital, do not seem to prevent an overall downhill course. By contrast, the intermorbid periods in bipolar illness are relatively normal or even supernormal, yet over time some social impairment may result from the accumulation of divorces, financial catastrophes, and ruined careers. (Although rapid-cycling disorders, which have sharply risen during the past two decades, cause considerable social impairment, mood symptoms are so prominent that differentiation from schizophrenia is generally not difficult; also such patients usually display more classic bipolar phases before the rapid cycling). Postpsychotic depressions in persons with established schizophrenia are sometimes due to inadequate control of schizophrenic symptomology. In other patients, especially more intelligent young schizophrenic patients, they reflect the experience of losing one's ego and sanity. It would be more meaningful to give such patients a diagnosis of both schizophrenia and a depressive disorder and treat the patient accordingly. Schizoaffective Disorder As the above considerations suggest, depression in the setting of a schizophrenic disorder does not necessarily constitute a distinct nosological entity. The concept of schizoaffective (or cycloid) psychosis should be restricted to recurrent psychoses with full affective and schizophrenic symptoms occurring nearly simultaneously during each episode. This diagnosis should not be considered for a mood psychosis in which mood-incongruent psychotic features (e.g., schneiderian and bleulerian symptoms) can be explained on the basis of one of the following: (1) affective psychosis superimposed on mental retardation, giving rise to extremely hyperactive and bizarre manic behavior; (2) affective psychosis complicated by concurrent brain disease, substance abuse, or substance withdrawal, known to give rise to numerous schneiderian symptoms; or (3) mixed episodes of bipolar disorder (which are notorious for signs and symptoms of psychotic disorganization). Official diagnostic systems such as DSM-IV use the category of schizoaffective disorder broadly. Thus patients with clear-cut manic episodes receive a schizoaffective diagnosis if delusions or hallucinations occur in the interepisodic period, in the absence of prominent affective symptoms. Many psychotic symptoms in mood disorders are often explanatory (albeit delusional), whereby the patient tries to make sense of the core experiences of the affective illness. In patients with recurrent episodes, delusional thinking can be carried over into the interepisodic period. Such patients are thus delusional in the absence of prominent mood symptoms and technically (i.e., by research diagnostic or DSM-IV criteria) might be considered schizoaffective. The author does not concur with that convention. Affective illness is typically a lifelong process, and limiting its features to discrete episodes is artificial. Although neuroleptic agents might be prescribed on an as needed basis to reduce the strong affective charge of those interepisodic delusions, they do not effectively eliminate the affect-laden experiences. Continued thymoleptic treatment (resorting to ECT, if necessary) and an empathic psychotherapeutic approach are more rewarding in

the long run. A 29-year-old female college graduate, mother of two children and married to a bank president, had experienced several manic and retarded depressive episodes that had responded to lithium carbonate. She was referred to the author, because she had developed the delusion that she had been involved in an international plot. Careful probing revealed that the delusion represented further elaboration, in a rather fantastic fashion, of a grandiose delusion she had experienced during her last postpartum manic episode. She believed she had played an important role in uncovering the plot, thereby becoming a national hero. Nobody knew about it, she contended, as the affair was top secret. She further believed that she had saved her country from the international scheme and suspected that she was singled out for persecution by the perpetrators of the plot. At one point she had even entertained the idea that the plotters sent special radio communications to intercept and interrupt her thoughts. As is typical in such cases, she was on a heavy dosage of a lithium-antipsychotic combination. The consultation was requested because the primary mood symptoms were under control and yet she had not given up her grandiose delusion. She flippantly remarked that one must be “crazy” to believe in her involvement in an international plot, but she could not help but believe in it. Over several months, seen typically in 60-minute sessions weekly, the patient had developed sufficient trust that the author could gently challenge her beliefs. She was in effect told that her self-professed role in the international scheme was highly implausible and that someone with her superior education and high social standing could not entertain a belief, to use her own words, “as crazy as that.” She eventually broke into tears, saying that everyone in her family was so accomplished and famous that to keep up with them, she had to be involved in something grand; in effect, the international scheme, she said, was her only claim to fame: “Nobody ever gives me credit for raising two kids, and throwing parties for my husband's business colleagues. My mother is a dean, my older brother holds high political office, my sister is a medical researcher with five discoveries to her credit [all true] and who am I? Nothing. Now, do you understand why I need to be a national hero?” As she alternated, over subsequent months, between such momentary flashes of insight and delusional denial, antipsychotic medication was gradually discontinued. Maintained on lithium, she now only makes passing reference to the grand scheme. She was encouraged to pursue her career goal toward a master's degree in library science. The vignette illustrates how phenomenological understanding, rational pharmacotherapy, and practical psychotherapeutic or vocational guidance can be fruitfully combined in the approach to patients with psychotic mood disorders. At a more fundamental level it suggests that clinical diagnoses in psychiatry cannot be based entirely on operational criteria; one's opinion of patient's illnesses is not infrequently changed by their response to treatment. In the author's view, DSM-IV represents something good (operationalization of diagnostic criteria) carried to extreme (arbitrary precision often divorced from clinical reality).

ICD-10 The ICD-10 criteria for mood disorders, which are used throughout the world, are listed in Table 14.6-43. Although these criteria derive in part from DSM-III-R, they are more flexible and clinician-friendly: they do not pretend to impose arbitrary precision on the clinical universe of psychiatry.

Table 14.6-43 ICD-10 Diagnostic Criteria for Mood [Affective] Disorders

SUGGESTED CROSS-REFERENCES Diagnosis and psychiatry are discussed in Chapter 7, the clinical manifestations of psychiatric disorders are covered in Chapter 8, and the classification of mental disorders is presented in Chapter 9. Schizophrenia is the subject of Chapter 12. The somatic treatment of mood disorders is discussed in Section 14.7 and Section 14.8. Psychotherapy is covered in Section 14.9. Mood disorders and suicide in children are the topic of Chapter 45. Anxiety disorders are presented in Chapter 15, and mood disorders in geriatric psychiatry are discussed in Section 51.3d. Somatoform disorder including neurasthenia and chronic fatigue syndrome is covered in Chapter 16. SECTION REFERENCES Akiskal HS, Hantouche EG, Bourgeois ML, Azorin JM, Sechter D, Allillaire JP, Lancrenon S, Fraud JP, Châtenet-Duchêne L: Gender, temperament, and the clinical picture in dysphoric mixed mania: Findings from a French National Study (EPIMAN) J Affect Disord 50:175, 1998. *Akiskal HS: The prevalent clinical spectrum of bipolar disorders: Beyond DSM-IV. J Clin Psychopharmacol 16(Suppl):4S, 1996. Akiskal HS, Cassano GB, editors: Dysthymia and the Spectrum of Chronic Depressions. Guilford Press, New York, 1997. Akiskal HS, Puzantian VR: Psychotic forms of depression and mania. Psychiatr Clin North Am 2:419, 1979. Angst J: The emerging epidemiology of hypomania and bipolar-II disorder: The Zurich study. J Affect Disord 50:143, 1998. Barefoot JC, Schroll M: Symptoms of depression, acute myocardial infarction and total mortality in a community sample. Circulation 93:1976, 1996. *Baschetti R: Psychological factors and chronic fatigue. NZ Med J 112:58, 1999. Bauer MS, Calabrese JR, Dunner DL, Post RP, Whybrow PC, Gyulai L, Tay LK: Multi-site data reanalysis: Validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry 151:506, 1994. Beard GM: A Practical Treatise on Nervous Exhaustion (Neurasthenia): Its Nature, Sequences, and Treatment. Wood, New York, 1881. Clayton PJ: The sequelae and nonsequelae of conjugal bereavement. Am J Psychiatry 136:1530, 1979. Coryell W, Winokur G, Shea T, Maser J, Endicott J, Akiskal HS: The long-term stability of depressive subtypes. Am J Psychiatry 151:701, 1994. Davidson JR, Miller RD, Turnbull CD, Sullivan JL: Atypical depression. Arch Gen Psychiatry 39:527, 1982. Dunner DL, Kai Tay L: Diagnostic reliability of the history of hypomania in bipolar II patients with major depression. Compr Psychiatry 34:303, 1993. Hantouche E, Akiskal HS, Lancrenon S, Allilaire JF, Sechter D, Azorin JM, Bourgeois M, Fraud JP, Châtenet-Duchêne L: Systematic clinical methodology for validating bipolar II disorder: Data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 50:163, 1998. James W: The Varieties of Religious Experience. Random House, New York, 1902.

*Judd LL, Akiskal HS, Maser JD, Zelle PJ, Endico HJ, Corey W, Parks MP, Kenovac JL, Leon AC, Mueller TJ, Rice JA, Keller MB: A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 55:694, 1998. Karam EG: The nosological status of bereavement-related depressions. Br J Psychiatry 165:48, 1994. Kendler KS, Karkowski LM, Corey LA, Neale MC: Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry 155:1234, 1998. Klein DF: Endogenomorphic depression. A conceptual and terminological revision. Arch Gen Psychiatry 31:447, 1974. *Kraepelin E: Manic-Depressive Insanity and Paranoia, GM Robertson, editor, RM Barclay, translator. Livingstone, Edinburgh, 1921. Manning JS, Haykal RF, Connor PD, Akiskal HS: On the nature of depressive and anxious states in a family practice setting: The high prevalence of bipolar II and related disorders in a cohort followed longitudinally. Compr Psychiatry 38:102, 1997. McElroy SL, Keck PE, Pope HGJ, Hudson JI, Faedda GL, Swann AC: Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry 149:1633, 1992. MacKinron DF, Xu J, McMahon FJ, Simpson SG, Stine OC, McInnis MG, De Paulor JR: Bipolar disorder and panic disorder in families: An analysis of chromosome 18 data. Am J Psychiatry 1998.

155:629,

*Pagani M, Lucini D: Cronic fatigue syndrome: A hypothesis focusing on the autonomic nervous syndrome. Clin Science 96:117, 1999. Perugi G, Akiskal HS, Lattanzi L, Cecconi D, Mastrocinque C, Patronelli A, Vignoli S: The high prevalence of soft bipolar (II) features in atypical depression. Compr Psychiatry 39:73, 1998. Reynolds CF, Hoch CC, Kupfer DJ, Buysse DJ, Houck PR, Stack JA, Campbell DW: Bedside differentiation of depressive pseudodementia from dementia. Am J Psychiatry 145:1099, 1988. Rosenthal NE: Winter Blues. Guilford, New York, 1993. Roth M, Gurney C, Garside RF, Kerr TA: Studies in the classification of affective disorders: The relationship between anxiety states and depressive illness I. Br J Psychiatry 121:147, 1972. Schatzberg AF, Rothschild AJ: Psychotic (delusional) major depression: Should it be included as a distinct syndrome in DSM-IV? Am J Psychiatry 149:733, 1992. *Widlocher DJ: Psychomotor retardation: Clinical, theoretical, and psychometric aspects. Psychiatr Clin North Am 6:27, 1983. Winokur G, Turvey C, Akiskal HS, Coryell W, Solomon D, Leon A, Mueller T, Endicott J, Maser J, Keller M: Alcoholism and drug abuse in three groups—Bipolar 1, unipolars, and their acquaintances. J Affect Disord 50:81, 1998.

Textbook of Psychiatry

14.7 MOOD DISORDERS: TREATMENT OF DEPRESSION Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 14. MOOD DISORDERS

14.7 MOOD DISORDERS: TREATMENT OF DEPRESSION A. JOHN RUSH, M.D. Strategies Tactics Strategic Choices Combined Treatment Electroconvulsive Therapy Other Treatments Strategic Issues Tactical Issues Continuation Treatment Maintenance Treatment Patient Preference Suggested Cross-References

Many available options now exist for treatment of mood disorders. Depressive disorders have enjoyed major therapeutic advances during the past decade, and the plethora of new options confronts clinicians with the problem of tailoring them to individual patients. Which strategies (types of treatment), applied in what order (strategic planning), and delivered by which methods (tactics) (e.g., dosage, duration) produce the best results for most patients in the shortest period of time? Specifying the objectives of each phase of treatment and careful, timely reappraisal of whether they are met, optimize patient outcomes. Specific objectives of each treatment phase (i.e., acute, continuation, maintenance) provide a strategic map for managing these patients. For mood disorders, initial treatment objectives include (1) symptom remission (acute phase) and restoration of psychosocial functioning (acute and continuation phases), (2) prevention of a relapse (continuation phase), and (3) prevention of recurrences, or new episodes in patients with recurrent depressions (maintenance phase).

STRATEGIES When initiating acute-phase treatment, practitioners decide where the patient should be treated (e.g., outpatient, day hospital, or inpatient). Treatment location is dictated by factors such as (1) the imminent risk of suicide, (2) the capacity of the patient to recognize and follow instructions or recommendations (adherence, psychosis), (3) the level of psychosocial resources, (4) the level of psychosocial stressors, and (5) the level of functional impairment. Next, one chooses among the four common acute-phase treatments (medication, psychotherapy, the combination of medication and psychotherapy, or electroconvulsive therapy [ECT]). For some, light therapy alone or in combination with medications may also be an option. In general, patients who respond to acute-phase medication (alone or combined with psychotherapy) receive continuation-phase medication at the same dosage. Continuation-phase ECT may be indicated for acute-phase ECT responders if continuation-phase medication does not prevent relapse or if prior medications have been ineffective, although the efficacy of this approach rests on open case series rather than randomized controlled trials of continuation-phase ECT. While no randomized controlled trials of continuation-phase psychotherapy alone are available, a few open studies suggest that patients responding to acute-phase psychotherapy alone may further benefit from continuation-phase psychotherapy at less frequent intervals for the subsequent 6 to 8 months. The comparative efficacy of the combination of medication and formal psychotherapy during the continuation phase versus continuing medication only has not been investigated.

TACTICS Tactics are devised to ensure an adequate treatment trial (e.g., adequate dosage and duration of treatment). Adequate implementation is required to determine whether any strategic choice was correct. Adherence is the most important tactical issue. Low adherence may be due to adverse effects, the conscious or unconscious meaning of taking medication, or the desire to leave treatment once improved (perhaps because of the shame and stigma that still surround psychiatric disorders). A second key tactical issue is adequate evaluation of whether the objective (i.e., symptom remission) was met. Symptom severity may be gauged by careful interviewing or by use of a rating scale. For mood disorders, a serious difficulty is accepting a partial response in place of a full remission, a risk for any acute-phase treatment. A full remission carries a better prognosis and minimal residual symptoms.

STRATEGIC CHOICES Medication The available antidepressants differ in their pharmacology, drug-drug interactions, and short- and long-term adverse effects. They do not differ in overall efficacy, speed of response, or long-term effectiveness. Substantial evidence shows that failure to tolerate or respond to one medication does not imply failure with other medications. In fact, a shift from one medication class to another carries 1 in 2 chance of response to both the initial medication and to the next medication if the first fails to provide a satisfactory response. Psychotherapy Formal psychotherapy aims at particular objectives. General clinical management, part of any treatment, includes explaining the diagnosis, treatment plan, treatment objectives, anticipated treatment period, counseling, management of both adherence and adverse effects, and a regular assessment of whether or not the treatment objectives are being met. It may involve consulting both the patient and significant others. The objectives of formal psychotherapy used alone to treat mood disorders are identical to those for medication: (1) symptom remission; (2) psychosocial restoration; and (3) prevention of relapse or recurrence. When used in combination with medication, psychotherapies can achieve such additional objectives as reducing the secondary psychosocial consequences of the disorder (e.g., marital discord, occupational difficulties) or increasing medication adherence. Clinical management aims to increase adherence, but formal psychotherapy can also be beneficial. Individuals who may need more-formal adherence counseling include those with significant prior or current adherence difficulties and those with relatively fixed negative attitudes toward a clearly indicated treatment. Formal psychotherapy to address the psychosocial consequences of the disorder may include individual, family, couples, or occupational approaches. Evidence suggests that used in combination with medication to control symptoms, such treatments improve the targeted difficulty (e.g., marital counseling improves marriages). Psychotherapy as monotherapy for symptom remission has shown greater efficacy than wait-listing controls in studies of less severely or chronically ill, nonpsychotic, depressed outpatients. In addition, while some evidence suggests that psychotherapy alone as a maintenance treatment has some benefit in prolonging the well interval, in general, when maintenance treatment is anticipated, medications (alone or combined with psychotherapy) are preferred, given the larger number of medication maintenance studies supporting efficacy. Choosing Among Psychotherapies No established clinical predictors exist to guide selection of a psychotherapy. Cognitive therapy may be slightly less effective in those with more-dysfunctional attitudes, while interpersonal psychotherapy may be somewhat less effective in those with more-interpersonal problems. However, these predictors lack clinical utility. Time-limited therapies are usually preferred over time-unlimited therapies for symptom reduction because they have established efficacy (time-unlimited therapies do not) and because medication is an effective alternative if psychotherapy alone fails. Some believe that reconstructive (time-unlimited) psychotherapies are more useful in the treatment of Axis II disorders, while reeducative therapies may be more useful with Axis I conditions. No evidence favors use of psychotherapy alone over medication when a concurrent Axis II disorder exists. On the other hand, psychotherapeutic tactics may benefit the medication management of depressed patients with Axis II conditions by ensuring adherence. Logically, psychotherapy, if

used alone, should be tried for a finite time period and outcome should be evaluated, just as with medication. Declaration of psychotherapy failures is largely based on lack of efficacy, although a few patients discontinue treatment unilaterally. When to declare psychotherapy a failure is a complex problem. Some patients respond early, while others may take 8 to 10 weeks. The premature discontinuation rate may be higher in actual practice than it is in efficacy trials. Just as with medication, if a symptomatic patient inappropriately discontinues treatment, one should actively attempt to reengage them since the depression has not remitted and, consequently, the prognosis is poor. What treatment should follow if psychotherapy alone is ineffective? Medication, given its established efficacy, is the next best logical step. The psychotherapy may be continued or discontinued when medication is begun. Whether a different form of psychotherapy would be effective if the initial psychotherapeutic approach has not been tested.

COMBINED TREATMENT Medication and formal psychotherapy are often combined in practice, yet data from randomized controlled trials suggest that the combination does not predictably add to the symptom-reducing effects of either treatment alone, at least in less complex, chronically ill patients. Conversely, the combination may result in both symptom reduction and psychosocial restoration, which is an additional rationale for using the combined approach. There are basically three ways to develop a combined treatment: (1) initiate the combination as acute-phase treatment, (2) add formal psychotherapy to medication that has elicited a partial response (particularly when there are residual cognitive, psychological, or interpersonal symptoms or difficulties), or (3) add medication after a partial response to psychotherapy alone. Using the combination of medication and formal psychotherapy at the outset of acute-phase treatment is called for if either (1) formal psychotherapy is used to increase adherence, while medications are used for symptom control or (2) if the targets of each treatment were somewhat distinct and both needed early remediation (e.g., medication for the depressive symptoms and psychotherapy for marital problems). In addition, clinical experience suggests that combination treatment may be preferable to either treatment alone with (1) a coexisting Axis II disorder, (2) a chronic and recurrent pattern with poor interepisode recovery, or (3) a patient who is discouraged and demoralized as well as clinically depressed. Diagnosis and medication management must allow time for patients with little prior treatment to collaborate in the optimal use of medication. Thus, it is often simpler to initiate medication and clinical management and then determine whether formal psychotherapy is indicated either for complete symptomatic remission or to address psychosocial problems unrelieved by medication. For example, psychotherapy might be added after a partial medication response (e.g., persistence of cognitive and interpersonal difficulties). When to add psychotherapy to medication is unclear. Evidence suggests that psychosocial and occupational improvements follow response. Thus, routine use of both treatments initially may not be necessary for psychosocial restoration. The need for adjunctive psychotherapy to redress psychosocial difficulties becomes clearer the longer symptom remission obtains and psychosocial problems persist. A history of long-standing psychosocial difficulties, even during remission of chronic depression, may suggest either beginning with combined treatment or adding psychotherapy shortly after symptoms are controlled with medication. When combined treatment does not produce a full response, a switch of medication classes with continued psychotherapy is logically the next step, since evidence indicates that switching medication classes is effective.

ELECTROCONVULSIVE THERAPY ECT is effective, even in patients who have failed to respond to one or more medications or combined treatment. It is effective in both psychotic and nonpsychotic forms of depression. Usually, 8 to 12 treatments are needed. Bilateral ECT is somewhat more effective than unilateral ECT, but it appears to have more cognitive adverse effects.

OTHER TREATMENTS Light therapy has been most clearly evaluated in mood disorder with seasonal pattern, either as monotherapy or in combination with medication. Patients who respond do so within 2 to 4 weeks.

STRATEGIC ISSUES Role of Diagnosis in Treatment Selection Maintenance medication effectively prevents recurrences of dysthymic disorder, complicated by recurrent major depressive episodes or not. Psychotic depression usually requires both an antidepressant and an antipsychotic agent. Alternatively, ECT is useful in psychotic depression, either as a first-line treatment or after medication has proven ineffective. For those with atypical features, strong evidence indicates that tricyclic drugs are less effective than the monoamine oxidase inhibitors (MAOIs). There is some suggestion of efficacy for the selective serotonin reuptake inhibitors (SSRIs) in atypical depression. The concurrent presence of another disorder may also affect initial treatment selection. Presence of nonmood Axis I disorder favors use of medications with demonstrated efficacy in both the mood and nonmood disorder. For example, effective treatment of obsessive-compulsive disorder with depressive symptoms usually results in remission of the depression. Similar findings have been reported for anorexia nervosa and bulimia. When panic disorder co-occurs with major depressive disorder, medications with demonstrated efficacy in each condition are preferred (e.g., tricyclic drugs, SSRIs). In general, the nonmood disorder dictates the choice of treatment. Concurrent substance abuse raises the possibility of a substance-induced mood disorder, which must be evaluated by history or after several weeks of abstinence, since abstinence results in remission of depressive symptoms in substance-induced mood disorders. If significant depressive symptoms continue, even with abstinence, an independent mood disorder is diagnosed and treated. Axis II disorders frequently accompany mood disorders, but diagnosis of Axis II disorders remains tentative in the presence of a clinical depression. An Axis II disorder should not be mistaken for recurrent major depressive disorder with poor interepisode recovery, since the treatment objectives and strategies differ. An Axis II disorder does not contraindicate treating the mood disorder, but its presence may prolong the time to acute-phase treatment response, interfere with adherence, or even preclude full symptomatic remission. In general, the presence of Axis II disorders suggests a less optimistic prognosis, because circumstantial evidence suggests that Axis II disorders are risk factors for subsequent relapse or recurrence. Axis II disorders raise other tactical issues, such as adherence, establishing a therapeutic alliance, or long-term management. In addition, the response to either medication or time-limited psychotherapy is slower, less complete, or both in the presence of an Axis II disorder. General medical conditions commonly accompany mood disorders and are established risk factors in their development. Recent evidence indicates that a major depressive episode is associated with increased morbidity or mortality of some associated general medical conditions. Principles that apply to the treatment of depression without a general medical condition generally apply when these conditions are present. However, treatment strategies and tactics are more complex. The initial choice of treatment is influenced by prior response to antidepressant treatments, the relative medical safety of medications, and clinical judgment about whether psychotherapeutic methods might particularly benefit some of these patients. The tactical choice of medications is affected by drug interactions, the pharmacological profile of the compound, the general medical condition, and drug dosing requirements. Complex, ongoing, stressful life events or social contextual issues (often profoundly disturbing to patients) should not influence whether or not medication is used. Often, patients in major depressive episodes whose symptoms are reduced by medication become less disabled from the mood disorder and are better able to manage these complex life circumstances. On the other hand, chronic, disturbing, life circumstances (e.g., chronic marital discord, spousal abuse) argue for stronger consideration of combined treatment, either initially or sequenced, to obtain both symptom remission and psychosocial restoration. Table 14.7-1 summarizes the

relation between clinical diagnoses and treatment selection.

Table 14.7-1 Relation of Diagnosis to Treatment Selection

Selecting Initial Treatment In general, about 45 to 60 percent of all outpatients with nonpsychotic major depressive disorder who begin treatment with medication, psychotherapy, or the combination respond. Consequently, roughly one-half of patients should anticipate a second treatment trial if the initial treatment selected is either intolerable or ineffective. Selection of the initial treatment depends on the chronicity of the condition, the history of recurrences (which predicts the likelihood of future recurrences), family history of illness, symptom severity, associated comorbid general medical or other psychiatric conditions, prior treatment responses to other acute-phase treatments, and patient preference. In general, the less severe, less chronic, and less complex the depression (i.e., less current comorbidity), the greater the role for patient preference, since evidence for selecting between time-limited, depression-targeted psychotherapy and medication is lacking. Furthermore, it is believed that the combination of medication and formal psychotherapy is less likely to be needed for milder, uncomplicated depressions. Moderate-to-severe mood disorders with prominent chronicity or prior recurrences generally require maintenance treatment. Since medications are the maintenance treatments with established efficacy, medication treatment (alone or combined with psychotherapy) is recommended. The evidence for the efficacy of medication alone in more-severe depressions is clear; psychotherapy alone is less well studied. Psychotherapy alone appears to be less predictably effective than medication in outpatients with endogenous or melancholic symptom features. Whether psychotherapy alone is effective in depressions with atypical symptom features is under study. However, the MAOIs and SSRIs have established efficacy in this group. Selecting Second Treatment Options If the first treatment fails (e.g., due to intolerance or lack of efficacy), a strategic decision on the second treatment after the differential diagnosis (including occult general medical condition or substance abuse) has to be reconsidered. For those receiving medication initially, dose adjustments, extending the trial period, switching to an alternative treatment (either medication or psychotherapy), or adding a second treatment to the initial one are common options. Factors recommending dose escalations are (1) no adverse effects, (2) a prior history consistent with rapid drug metabolism, or (3) low therapeutic blood concentrations. However, blood concentrations of newer-generation medications are related to outcome although they are for desipramine (Norpramin, Pertofrane), imipramine (Tofranil), and nortriptyline (Pamelor). Extending the initial trial is indicated if (1) it has been less than 6 weeks, (2) there is a partial response by 6 weeks, or (3) prior medication trials were unsuccessful and shorter than 6 weeks. Likewise, partial response to psychotherapy by week 6 argues for extending the trial period. Nonresponse by 8 weeks often predicts an ultimate poor response. Extending a trial of light therapy beyond 3 weeks in nonresponders has not been evaluated. Clinical experience suggests that extending ECT beyond 10 trials with complete nonresponse is unlikely in most cases to elicit a subsequent response, although careful studies are lacking. The choice to switch from the initial single treatment to a new single treatment (as opposed to adding a second treatment) depends on the philosophy guiding the clinician, the patient's prior treatment history, and other clinical issues. The best-documented augmentation strategies involve inexpensive medicines (e.g., lithium or thyroid hormones) and response, if it occurs, is often within 2 weeks. Conversely, a switching strategy sometimes involves a washout period (e.g., switching from fluoxetine [Prozac] to an MAOI) for safety reasons as well as the need to wait longer than 2 weeks for a full effect. Alternatively, how long to continue augmentation is not clear, and lithium augmentation entails some expense and inconvenience (i.e., blood concentration monitoring). If the initial trial is the patient's first treatment and other clinical or economic reasons favor monotherapy, switching rather than augmenting is preferred. On the other hand, augmentation strategies, particularly the use of two different medications, seem effective in patients who have failed one or more well-conducted single medication trials. Thus, switching might be preferable for those with only one or two prior treatment attempts, while augmentation is preferable for those who have failed several single-treatment trials. Recent reviews indicate that if the initial medication is ineffective or cannot be tolerated, it is reasonable to switch medication classes. In psychiatric settings, augmentation may be preferable, since more psychiatric patients have failed several adequate prior single treatments. The value of augmenting medication with psychotherapy is not well evaluated. Many clinicians believe that if the residual symptoms after a partial response to medication are largely cognitive or psychological, either augmentation with psychotherapy or prolonging the initial medication trial are preferred to switching medications or augmenting with another medication, based on the assumption that these symptoms represent residual psychosocial sequelae. On the other hand, if anhedonia persists after an initial medication trial, switching or augmentation with another medication rather than psychotherapy is often preferred since such symptoms suggest ongoing limbic/paralimbic system dysfunction. However, these suggestions are largely based on clinical experience rather than scientific evidence.

TACTICAL ISSUES The strategic choices of treatment focus on selection of the initial therapy, or for those who fail the initial therapy, the selection of a second treatment option. Implementation of these strategies requires (1) careful attention to adherence, (2) careful evaluation of outcome, (3) proper dosing and duration of the trial, and (4) timely declaration of treatment failure. Adherence Treatment adherence is increased if patients understand anticipated objectives and common strategies, if fewer daily doses are required (e.g., once-a-day versus three-times-a-day dosing), and no personality disorder is present. Evidence also suggests more-frequent early visits (e.g., weekly versus monthly) improve adherence. Whether other current psychiatric conditions affect adherence is unclear; it is not related to gender, educational level, or socioeconomic status. The best predictor of future adherence is prior adherence. Thus, general clinical management of medication treatment should include discussions with patients (and, potentially, significant others) about the objectives of treatment, anticipated treatment period, and adherence obstacles. It is best to anticipate and identify obstacles to adherence prior to prescribing medication or initiating psychotherapy and to make adherence checks a routine part of each visit. Initially, visits should be frequent enough to ensure adherence and permit timely intervention for adverse effects. Several brief telephone contacts during the initial weeks of treatment help adherence by reassuring patients, ensuring that adverse effects are avoided, countering demoralization and pessimism that impairs adherence, and providing information to overcome short-term concentration and recall problems that are part of depressive episodes. Choosing Among Medications If medication (alone or in combination with psychotherapy) is part of the first step, the practitioner must select from a variety of available compounds. Medications differ in their short- and long-term adverse effects and spectrum of action but not in overall efficacy or speed of response. If maintenance medication is anticipated, long-term adverse effects are more important than short-term effects in selection (e.g., tertiary tricyclic drugs are associated with greater weight gain than SSRIs over the long run). Table 14.7-2 lists commonly used antidepressant agents presently available in the United States and groups them on the basis of their presumed mechanisms of action (e.g., presynaptic or postsynaptic activity). However, as basic neuroscientific knowledge expands, further actions will likely be discovered. For example, the

number of serotonin receptor types has increased faster than our understanding of their physiological roles. Further, the actions of some (e.g., venlafaxine [Effexor]) are affected by the dosages used or levels attained in the central nervous system (CNS). Venlafaxine exerts proportionally more serotonin than norepinephrine reuptake blockade at lower dosages than at higher dosages.

Table 14.7-2 Antidepressant Medications*

Table 14.8-2 lacks two commonly used drug combination treatments (lithium plus antidepressants and liothyronine [Cytomel] augmentation of tricyclic drugs). A Table 14.8-2 provides selected clinical caveats. This list is not exhaustive. Drug-drug interactions, at either the neuronal level (pharmacodynamics) or at the level of absorption, metabolism, and excretion (pharmacokinetics) affect selection of agents, their dosing, and ultimately the risk-benefit equation for individual patients. Patients should be advised what adverse effects to anticipate and encouraged to report them as early as possible. Management of adverse effects may include lowering the dosage, switching medications, or treating the adverse effects with an additional medication. The MAOIs (tranylcypromine [Parnate] and phenelzine [Nardil]) still have a role in the treatment of depression, the depressed phase of bipolar disorders, and in depressions unresponsive to other treatments. However, because of the necessity of regulating diet ( Table 14.7-3) and evaluating concomitant medications (Table 14.7-4), the MAOIs are not used as first-line drugs.

Table 14.7-3 MAOI Dietary Restrictions

Table 14.7-4 MAOI Drug Incompatibilities

Among the tricyclic medications, the secondary amines (desipramine or nortriptyline) have fewer adverse effects than the tertiary amines. Since nortriptyline has a well-established therapeutic window, drug concentration monitoring can ensure that patients who need minimal medication exposure obtain a therapeutic concentration. Conversely, the upper limit of the nortriptyline window may be a disadvantage when deciding to switch or augment treatments, as the blood concentrations may be used to declare a nonresponse. Choosing more-sedating antidepressants (e.g., amitriptyline [Elavil, Endep]) for more-anxious depressed patients, or more-activating agents (e.g., desipramine) for those more psychomotor retarded is not based on evidence of differential efficacy. However, some clinicians believe that such choices based on adverse-effect profiles increase adherence in the initial weeks of treatment. That is, patients with marked insomnia and anxiety obtain some immediate relief from these associated symptoms before the full antidepressant effect of the drug appears and thus are more likely to comply with acute-phase treatment. These clinical observations are not supported by empirical data, however. In fact, attrition associated with paroxetine (Paxil) or fluoxetine (less-sedating drugs) is lower in acute-phase treatment than that with imipramine or amitriptyline (more-sedating drugs). In addition, the longer-term cost of a possibly beneficial short-term adverse effect advantage must be considered. For example, initially sedating antidepressants often continue to be sedating in the longer run, which may lead patients to prematurely discontinue continuation or maintenance phase treatment, thus increasing the risk of relapse or recurrence. Some practitioners combine adjunctive medications (e.g., hypnotics or anxiolytics) with antidepressants to provide more immediate symptom relief either routinely from the outset or when the need for such adjunctive medications arises in an individual patient. Adjunctive medications used briefly to cover adverse effects to which most patients ultimately adapt can be useful. Conversely, discontinuing adjunctive medications can result in some return of symptoms or adverse effects to which the patient has not adapted. Several disadvantages are associated with the routine use of adjunctive medications: (1) the potential risk, inconvenience and expense of unnecessary medications (i.e., many patients may not require them); (2) difficulty identifying the cause of medication intolerance or adverse effects (e.g., an allergic rash) when treatment with an antidepressant and an adjunctive medication is begun at the same time; (3) difficulty in judging response to the antidepressant medication alone if adjunctive medication addresses critical symptoms used to gauge the success of acute-phase treatment, (discontinuing the adjunctive medication to see if the apparent response holds on the antidepressant alone may unnecessarily increase the number of visits or delay a timely revision in the treatment plan); and (4) adjunctive medications may cover adverse effects that if observed would lead to either a dose reduction or to switching treatments. For example, a sedative-hypnotic agent used in conjunction with an SSRI may inappropriately delay a strategic decision to either decrease the dosage or switch to an alternative agent.

In addition to adverse effects, medication choice is affected by prior history of response, cross-sectional symptom features, patient preference, dosing convenience (which affects adherence), drug interactions (if patients are, or will be, taking other medications), current general medical conditions (making one adverse-effect profile preferred over another), and a family history of response. A patient's prior treatment history is important because prior response typically predicts current response. In addition, a documented failure on a properly conducted trial of a particular antidepressant class (e.g., SSRIs, tricyclics, or MAOIs) suggests choosing an agent from an alternative class. Switching classes for those who fail on one class appears to be associated with roughly a 50 percent response rate with the second class of drugs. History of a first-degree relative responding to a tricyclic drug or an MAOI is associated with a better response to the same class of agents in the patient. Whether family history of response predicts response to the newer antidepressant compounds is not known. Dosage and Duration Tactical issues surrounding medication use include dosing steps, drug metabolism, pharmacokinetics, drug interactions, and adverse effects. The tricyclic drugs typically are initially given at low dosages and increased to the maximally tolerated dosage or (in the case of nortriptyline) until a therapeutic concentration is obtained. Gradual dose escalations are important to ensure adherence and avoid severe initial adverse effects. Thus, the tricyclic drugs require visits roughly once a week for outpatients as dosages are adjusted. Tricyclic blood concentration monitoring may reduce dosage adjustment time. Dosing is less complicated for the SSRIs than for the tricyclic drugs; fewer dose increments are needed, and the proper dosage is attained earlier because of their better adverse-effect profiles. Some newer agents (e.g., SSRIs, bupropion [Wellbutrin]) need fewer dosage adjustments, but with others (e.g., venlafaxine and nefazodone [Serzone]), raising the dosage increases the likelihood of response, so several adjustments are often helpful. Safety in overdose is an issue, especially early in treatment. Thus, a 1-week prescription is recommended (without refills) so patients return for frequent medication visits when adverse effects and dosage levels are managed. Tricyclic drugs account for a greater percent of completed suicides than the newer agents, which are far safer in overdose. Evaluation of Outcome The objective of acute-phase treatment (medication, psychotherapy, their combination, or ECT) is symptom remission, not just symptom reduction. Partial response is associated with a stormier prognosis. Thus, careful interviewing for criterion symptoms at each visit is essential. Self-reported or clinician-rated instruments can facilitate this assessment. Often the patient is slower to recognize the early therapeutic effect of the treatment than the clinician. Thus, a clinician-rated scale may be preferred to a self-reported instrument. Timely Declaration of Treatment Failures Growing evidence indicates that acute phase medication trials should last 6 (and preferably 8) weeks to determine the full extent of symptom reduction attainable, although most (but not all) patients who ultimately respond fully show at least a partial response by weeks 3 or 4 if the dose is adequate during the initial weeks of treatment. Clinical impression and recent reports suggest that no response by 3 to 4 weeks (e.g., a2-heteroreceptors located on serotonergic neurons. GH response to clonidine challenge is blunted while remaining intact with GH-releasing hormone challenge, suggesting possible subsensitivity of a 2-adrenergic receptors. Neuroendocrine Systems Several abnormalities in baseline and challenge response have been found with hypothalamic-pituitary hormones. Increased CSF oxytocin concentrations were found in a subgroup of OCD patients without a personal or family history of tic disorder, and the oxytocin concentration correlated with the current severity of OCD. Concentration of the GH negative-regulator, somatostatin, is higher in the CSF of OCD patients, which may explain the blunted GH response to clonidine. Recently CSF CRF concentrations have come under investigation. Though mostly negative, one study did find that male OCD patients have higher CSF CRF concentrations than panic disorder or generalized anxiety disorder patients and normal controls. Also, cytokine interleukin-6 (IL-6) concentration, known to

increase in the peripheral blood in response to CRF stimulation, correlates with the severity of compulsive (but not obsessive) symptoms in OCD. Baseline elevations in plasma cortisol have also been found in OCD patients as a group, and one small study showed increased circadian secretion of cortisol that was not altered after 8 weeks of symptom-remitting fluoxetine (Prozac) therapy. Neuroimmunology Interest has developed in a possible link between streptococcal infection and OCD. Group A b-hemolytic streptococcal infection can lead to rheumatic fever about 2 to 3 percent of the time, and approximately 10 to 30 percent of patients with rheumatic fever develop Sydenham's chorea. It has been reported that over 70 percent of patients with Sydenham's chorea manifest obsessive-compulsive symptoms. A monoclonal antibody to B lymphocytes, D8/17, developed using mice immunized with B lymphocytes from a patient with rheumatic carditis, has been used to measure B-cell D8/17 antigen in a small sample of patients with childhood onset of OCD or Tourette's syndrome. All 31 patients, 29 percent of whom had pure OCD, showed an elevated percentage of D8/17 antigen, contrasted with only 1 of 21 controls. Thus this antigen may serve as a marker for vulnerability to some forms of childhood OCD. Further, infectious or immune-mediated factors may play a role in at least a subgroup of OCD patients.

SUGGESTED CROSS-REFERENCES Neurotransmitters are discussed in Section 1.4 and Section 1.5, and the contributions of the neural sciences in general are the focus of the other sections of Chapter 1. The biological therapies are discussed in Chapter 31. SECTION REFERENCES *Biber B, Alkin T: Panic disorder subtypes: Differential response to CO 2 challenge. Am J Psychiatry 156:739, 1999. *Brawman-Mintzer O, Lydiard RB: Biological basis of generalized anxiety disorder. J Clin Psychiatry 58(Suppl):16, 1997. Charney DS, Grillon C, Bremner JD: The neurobiological basis of anxiety and fear: Circuits, mechanisms, and neurochemical interactions (Part I). Neuroscientist 4:35, 1998. Charney DS, Grillon C, Bremner JD: The neurobiological basis of anxiety and fear: Circuits, mechanisms, and neurochemical interactions (Part II). Neuroscientist 4:122, 1998. Coplan JD, Klein DF: Pharmacologic probes in panic disorder. In Advances in the Neurobiology of Anxiety Disorders, HGM Westenberg, JA Den Boer, DL Murphy, editors. Wiley, New York 1996. *Coplan JD, Pine DS, Papp LA, Gorman JM: A view on noradrenergic, hypothalamic-pituitary-adrenal axis and extrahypothalamic corticotrophin-releasing factor function in anxiety and affective disorders: The reduced growth hormone response to clonidine. Psychopharmacol Bull 33:193, 1997. *Dolberg OT, Iancu I, Sasson Y, Zohar J: The pathogenesis and treatment of obsessive-compulsive disorder. Clin Neuropharmacol 19:129, 1996. Goddard AW, Charney DS. Toward an integrated neurobiology of panic disorder. J Clin Psychiatry 58(Suppl):4, 1997. Graeff FG, Guimaraes FS, DeAndrade TGCS, Deakin JFW: Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 54:129, 1996. Gray TS: Amygdaloid CRF pathways: Role in autonomic, neuroendocrine, and behavioral responses to stress. Ann NY Acad Sci 697:53, 1993. *Grillon C, Southwick SM, Charney DS: The psychobiological basis of posttraumatic stress disorder. Mol Psychiatry 1:278, 1996. Halgren E: Emotional neurophysiology of the amygdala within the context of human cognition. In The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction, JP Aggleton, editor. Wiley-Liss, New York, 1992. Handley SL: 5-Hydroxytryptamine pathways in anxiety and its treatment. Pharmacol Ther 66:103, 1995. Johnson MR, Lydiard RB: The neurobiology of anxiety disorders. Psychiatr Clin North Am 18:681, 1995. Katz L, Fleisher W, Kjernisted K, Milanese P: A review of the psychobiology and pharmacotherapy of posttraumatic stress disorder. Can J Psychiatry 41:233, 1996. Klein DF: False suffocation alarms, spontaneous panics, and related conditions: An integrative hypothesis. Arch Gen Psychiatry 50:306, 1993. Krystal JH, Deutsch DN, Charney DS: The biological basis of panic disorder. J Clin Psychiatry 57(Suppl):23, 1996. LeDonx JE: The Emotional Brain. Simon & Schuster, New York, 1996. Miner CM, Davidson JR: Biological characterization of social phobia. Eur Arch Psychiatry Clin Neurosci 244:304, 1995. Papp LA, Coplan J, Gorman JM: Anxiety disorders. In Review of Psychiatry, vol 13, JM Oldham, MB Riba, editors. American Psychiatric Press, Washington, DC, 1994. *Potts NL, Book S, Davidson JR: The neurobiology of social phobia. Int Clin Psychopharmacol 11(Suppl):43, 1996. Rauch SL, Jenike MA: Neurobiological models of obsessive-compulsive disorder. Psychosomatics 34:20, 1993. Shekhar A, Keim SR: The circumventricular organs form a potential neural pathway for lactate sensitivity: Implications for panic disorder. J Neurosci 17:9726, 1997. Southwick SM, Krystal JH, Bremner JD, Morgan CA III, Nicolaou AL, Nagy LM, Johnson DR, Heninger GR, Charney DS: Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch Gen Psychiatry 54:749, 1997. Tancer ME: Neurobiology of social phobia. J Clin Psychiatry 54(Suppl):26, 1993. Trivedi MH: Functional neuroanatomy of obsessive-compulsive disorder. J Clin Psychiatry 57(Suppl):26, 1996. Yehuda R: Sensitization of the hypothalamic-pituitary-adrenal axis in posttraumatic stress disorder. Ann NY Acad Sci 821:57, 1997.

Textbook of Psychiatry

15.4 ANXIETY DISORDERS: GENETICS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 15. ANXIETY DISORDERS

15.4 ANXIETY DISORDERS: GENETICS ABBY J. FYER, M.D. Panic Disorder and Agoraphobia Generalized Anxiety Disorder Social Phobia Specific Phobias Obsessive-Compulsive Disorder Posttraumatic Stress Disorder Suggested Cross-References

What is currently known about the contribution of genetic factors to the development of anxiety disorders is based on data of six types of studies. Twin, adoption, and deoxyribonucleic acid (DNA) marker (linkage or association) studies can provide definite evidence of a genetic contribution. In the case of twin studies genetic influence is demonstrated if monozygotic (MZ) twins (who share 100 percent of their genetic material) are more often alike (concordant) with respect to a trait than are dizygotic (DZ) twins (who, like sibs, share only 50 percent of their DNA). Adoption studies indicate a genetic contribution if adopted offspring are more similar to their biological parents than to the adoptive parents who are raising them. DNA marker studies, not yet successful in psychiatry, offer the possibility of using molecular genetic methods to identify chromosomal loci or actual genes associated with clinical syndromes. Important corroborative evidence of genetic influence is provided by family and segregation analytic studies as well as animal models. Family studies can indicate intergenerational transmission and are helpful identification of heritable phenotypes; however, they do not distinguish between genetic and environmental influences. Segregation analysis can demonstrate that familial prevalence patterns are consistent with a particular mode of genetic transmission (e.g., major dominant locus, polygenic). Although this does not prove that genes are responsible, identifying the correct genetic model may be critical to the success of linkage studies. Animal models of fear and anxiety may provide more neurophysiologically specific hypotheses concerning the origin of pathology. Many functional gene families are conserved across species, and this in turn may provide clues about genetic mechanisms. The classification of anxiety disorders has become increasingly specific since the late 1970s. In 1968 the second edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-II) included three anxiety disorders (anxiety, phobic and obsessional neuroses) while the current fourth edition of DSM (DSM-IV) includes six: panic disorder with or without agoraphobia, generalized anxiety disorder, simple and social phobias, obsessive-compulsive disorder, and posttraumatic stress disorder. Heritability refers to the proportion of the liability for a disorder that is estimated to be due to genetic factors. Disorders (or traits) in which genetic influences dominate (e.g., Huntington's disease, cystic fibrosis) have high heritabilities >.6). Moderate heritability (.3 to .5) suggests that the studied phenotype (1) results from a more even interaction between genetic and nongenetic influences; or (2) contains several genetically different syndromes, some with high and others with low or no heritability. Examples of this latter situation are common in other areas of medicine in which actual genetic mechanisms have been identified (e.g., diabetes, breast cancer, Alzheimer's disease).

PANIC DISORDER AND AGORAPHOBIA Panic disorder is the best studied anxiety disorder with respect to intergenerational transmission. Accumulated data strongly suggest a genetic contribution to its etiology. However, heritability estimates are variable (from .3 to .6 percent) and the mode of transmission is unknown. Although several DNA marker studies are now under way, no positive results have been reported. Twin Studies Four twin studies of panic disorder have been reported. Three indicate greater concordance for the diagnosis for MZ twin pairs than for DZ twin pairs, supporting a genetic contribution to the disorder. The fourth study indicates a genetic role in the predisposition to anxiety symptoms but not to any of the specific revised third edition of DSM (DSM-III-R) anxiety disorders. When 1033 twin pairs from the Virginia Twin Registry were studied, diagnosis of panic disorder was made in 5.8 percent of the 2163 interviewed twins. Assessments were done using a semi-structured clinician-administered interview. Probandwise concordance for DSM-III-R panic disorder was 24 percent in MZ twin pairs and 11 percent in DZ twin pairs. The highest heritability (46 percent) was found using a narrow (strict adherence to the DSM-III-R criteria) definition of panic disorder. The heritability (and by extention the estimate of strength of genetic contribution) was lower when the criteria were broadened to include cases that did not meet full criteria (e.g., recurrent panic attacks with only three rather than four associated symptoms). Contrasting results were reported in a smaller sample of twins drawn from the Norwegian Twin registry (32 MZ and 53 DZ). Concordance for strict third edition of DSM (DSM-III) panic disorder was 1 of 5 in MZ and 0 of 6 in DZ pairs. However, if the phenotype was broadened to include an anxiety disorder that included recurrent unexpected panic the concordance pattern (4 of 13 versus 0 of 16;31 percent vs 0 percent P < 0.05) indicated a strong genetic contribution. A study using a larger but overlapping sample reported similar results; concordance for panic disorder in MZ versus DZ pairs was 42 percent versus 17 percent. A subset of Australian twin registry was studied using clinical interviews. In 34 twin pairs at least one twin had panic disorder. No difference in concordance for panic disorder was found in MZ versus DZ pairs. Family Studies Six direct-interview family studies of panic disorder have been reported—all indicate that panic disorder is highly familial. Rates of panic disorder in the relatives of panic disorder patients are 4 to 10 times as high as those in the relatives of never–mentally-ill or community controls. With the exceptions of social phobia and alcohol abuse, excess risk for disorders other than panic was not seen. Several studies have also used the family study method to investigate possible heterogeneity within the DSM-IV category. This approach is based on the principle that if two syndromes are associated with different patterns of familial aggregation, they may differ with respect to some aspect of their etiology. For example, one investigation divided panic disorder patients into those with early- (at or before 20 years old) versus; later- (after age 20) onset panic disorder. Significantly higher rates of panic disorder were found in relatives of the early-onset patients as compared to the relatives of later-onset patients or controls. A second study using the family history method found that panic disorder patients who reported at least one relative affected with panic disorder also had an earlier onset of panic disorder than did patients who had no affected relatives. These data are of interest in that they suggest that early-onset panic disorder may be a more severe or etiologically different form of the illness; however, further investigations are needed. Another interesting area of current research concerns response to carbon dioxide. A number of studies indicate that individuals with panic disorder are significantly more likely than well individuals to become anxious or panic during exposure to carbon dioxide (5 to 35 percent). Two recent studies have extended this work by studying never–mentally-ill relatives of panic disorder patients, patients with depression, and never–mentally-ill controls. Mentally healthy relatives of panic patients have significantly higher rates of panic during carbon dioxide exposure than either of the other groups. This finding suggests that carbon dioxide sensitivity may be a familially transmitted marker of an inherited susceptibility to panic disorder. Family and follow-up studies to clarify these findings are now under way. Some individuals with panic disorder also develop agoraphobia while some do not and the reasons for this variation are not known. It is possible that panic disorder with agoraphobia is a more severe form of panic disorder. Alternatively, the development of agoraphobia may be related to separate inherited or environmental factors; or some mixture of these. Two studies have addressed these questions. Rates of panic disorder with and without agoraphobia in relatives of three groups of individuals patients with panic disorder and no agoraphobia, patients with panic disorder and agoraphobia, and nonanxious controls were compared; results indicated that relatives of the agoraphobia patients had higher rates of both panic disorder (7.0 versus 3.5) and agoraphobia (14.9 versus 3.5) than the relatives of the controls, although the difference reached the .05 level of significance only in the latter group. In contrast, the relatives of the panic disorder patients had significantly higher rates of panic disorder (14.9 versus 3.5, P < .005) but not agoraphobia (1.7 versus 3.5, not significant) as compared to relatives of controls. These data may be interpreted as indicating that with respect to intergenerational transmission agoraphobia (with panic attacks) is either a more severe form of panic disorder or possibly

a different but partially overlapping illness. A twin study tested the fit of their data with several genetic models in which panic disorder with avoidance was hypothesized to be a more genetically severe form of panic disorder without avoidance and good fit was found in three out of four cases; heritability estimates ranged from .34 to .40. Segregation Analyses Several segregation analytic studies of panic disorder have been reported. Results are consistent with genetic transmission but inconclusive as to the genetic model. Support was found for a single major locus dominant model. Another study found equal support for the single major dominant or recessive models in two independent samples; however, in none of these cases could polygenic transmission be excluded. DNA Marker Linkage and Association Studies of Panic Disorder Although there is significant evidence for a genetic contribution to panic disorder, at this point there is no data indicating association between a specific chromosomal location or mode of transmission and this disorder. Two large genomic screening studies are in progress and both have reported only negative findings. One study has reported exclusion of linkage between the DSM-III-R panic disorder phenotype for over 95 percent and 60 percent of sites in the human genome under the dominant and recessive models of transmission respectively. Other researcher have excluded linkage between panic disorder and several candidate genes including: five adrenergic receptors, a-haptoglobin, and several components of the g-aminobutyric acid (GABA) receptor system. Accumulated twin and family study data indicate that panic disorder does not follow a Mendelian mode of transmission and is therefore considered a complex disorder in terms of genetic studies. Experience with complex disorders in other areas of medicine indicates that multiple genes may be involved in determination of a single aspect of clinical pathology. Moreover, both pleiotropy (different clinical syndromes associated with the same genetic underpinnings) and genetic heterogeneity (different genes can lead to the same clinical phenotype) are ubiquitous. In this setting it is not surprising that the current effort to identify a gene for panic disorder has not yet been successful. Genetic heterogeneity can greatly impair the power of linkage analyses by introducing inadvertent false positives. Similarly, pleiotropy can lead to inadvertent exclusion of genetically affected individuals and consequent reduction in power to identify linkage. Current efforts to resolve these difficulties are directed at: (1) using epidemiological biological, and family study data to identify phenotypes that may be closer to the gene; (2) enlarging samples to provide sufficient power to identify smaller gene effects; and (3) improvement of molecular genetic technologies.

GENERALIZED ANXIETY DISORDER In 1980 DSM-III subdivided anxiety neurosis into panic disorder and generalized anxiety disorder depending on the presence or absence of recurrent spontaneous panic attacks. Although several earlier studies suggested a genetic contribution to anxiety neurosis, their relevance to the residual category of generalized anxiety disorder is unclear. This section focuses on work using the DSM-III and subsequent criteria for generalized anxiety disorder. Several twin and family studies indicate a genetic role in the etiology of this syndrome. However, the extent of the relationship between the disorder and depression as well as the symptom and duration boundaries of generalized anxiety disorder itself require further study. Adoption and DNA marker studies of this disorder have not been reported. Twin Studies Six twin studies have examined heritability of DSM-III or DSM-III-R generalized anxiety disorder. Although results are mixed, taken as a whole these data suggest a moderate genetic contribution to this disorder. Three of the six studies used epidemiological twin samples and bivariate genetic modeling to investigate both the genetic contribution to generalized anxiety disorder and its relation to major depressive disorder. One study evaluated subjects by direct semistructured interview, the other two by questionnaire. Similar results were found across the three samples. Generalized anxiety disorder was found to be moderately heritable (heritability ~.4 to .5). However, according to this model the genetic factors that make an individual vulnerable to this disorder completely overlap with those that predispose an individual to major depressive disorder. Whether an individual with this genetic loading develops generalized anxiety disorder, major depressive disorder, or both depends on individual-specific environmental factors. No significant effect was found for common family environment. The remaining three twin studies of generalized anxiety disorder used direct interview procedures in smaller samples derived from a combination of population and hospital registries. Genetic contribution was examined by contrasting probandwise concordance for generalized anxiety disorder in MZ versus DZ twin pairs. One study found no difference in rates of concordance for the disorder in monozygotic and dizygotic pairs (0/12 versus 1/20). Major depressive disorder did not aggregate in the cotwins of generalized anxiety disorder probands. The two remaining studies found somewhat higher concordance rates in the MZ pairs. However, these differences did not reach the .05 level of significance. The relationship between generalized anxiety, disorder and major depressive disorder was not systematically examined. One hundred and forty-four twin pairs from a geographical subsample of the Australian Twin Registry in which the index twin met DSM-III criteria for generalized anxiety disorder were interviewed. Concordance for the disorder was 21.5 percent (13/63) in the MZ versus 13 percent (11/81) in the DZ pairs (NS). A sample of 49 twin pairs, which included 12 index twins with generalized anxiety disorder, were found to have MZ versus DZ concordance rates of 3/5 versus 1/7 (NS). Family Studies Two family studies of generalized anxiety disorder have been reported. In both, psychiatric disorder in relatives of probands with the disorder is compared to that in the relatives of not-ill controls as well as patients with panic disorder or major depressive disorder or both. One hundred and twenty-three relatives of 20 both generalized anxiety disorder probands with similarly evaluated relatives of 20 control, 40 panic disorder, and 40 agoraphobic probands ( N = 113, 241, and 236 respectively) were compared. Significantly higher rates of generalized anxiety disorder were found in the relatives of the probands compared to those of the other groups (19.5 percent versus 3.5 percent versus 5.4 percent versus 3.9 percent; P < .001) The two-way contrast between the relatives of the subjects with generalized anxiety disorder versus control patients was significant at P < .001 (chi squared = 14.37). There were no significant differences between rates of other anxiety and mood disorders (7.3 percent versus 7.1 percent) in the relatives of the anxiety disorder patients versus relatives of controls. The latter argues against the overlap in heritability of generalized anxiety disorder and major depressive disorder reported by the twin studies cited previously. Panic disorder was significantly elevated in relatives of panic patients versus controls. The absence of an excess of panic disorder in the relatives of the generalized anxiety disorder patients versus controls (4.5 versus 3.5 percent) supports the DSM-III separation of these two syndromes. The second family study compared relatives of four proband groups: generalized anxiety disorder, major depressive disorder, panic disorder, and controls. Rates of the anxiety disorder were higher in relatives of the probands but did not differ significantly across groups (8.9 versus 4.9 versus 4 versus 1.9 percent). There was no evidence of a shared familial diathesis between generalized anxiety disorder and either panic disorder or major depressive disorder.

SOCIAL PHOBIA Data on genetic contributions to social anxiety are drawn from three sources: (1) twin and family studies of DSM-III-R social phobia; (2) twin studies of irrational social fears in adults; and (3) studies of childhood temperament. Twin and Family Studies of Social Phobia Of 2163 twins (1033 pairs) drawn from the Virginia Twin Registry, 11.5 percent met criteria for social phobia. Probandwise concordance for social phobia was 24 percent in monozygotic versus 15 percent in dizygotic pairs. The best-fitting model suggested that genetic and environmental factors contribute respectively 30 and 70 percent of the liability for social phobia. Two thirds of the genetic liability is made up of factors specific to social phobia and the remaining one third comes from genetic liability that contributes to all phobias (e.g., phobia proneness). One direct-interview family study and one family history study of social phobia have been reported. Each found moderate, specific familial aggregation of this disorder. One study compared rates of psychiatric disorders in the directly interviewed relatives of social phobia ( N = 105), specific phobia (N = 49), agoraphobia with panic ( N = 164), and never-ill controls ( N = 231). Rates of social phobia but not of other anxiety disorders were significantly elevated in the relatives of the social phobia probands as compared to the relatives of the other groups. Relatives of social phobia probands had an almost threefold increased risk for social phobia as compared to relatives of controls (16 versus 6 percent, P < .05). Similar results were found using the family history method (in this method the data on relatives came from interviewing patients about their relatives). Relatives of social phobia patients were reported to have a higher risk for social phobia (6.6 percent) as compared to both the relatives of panic disorder patients (.4 percent, P < .001) and not ill controls (2.2 P < .1). The DSM-III-R and DSM-IV have divided social phobia into two subtypes: generalized (most social situations) and nongeneralized. If these represent two causally different syndromes they would be expected to be associated with different patterns of intergenerational transmission. For example, relatives of patients with generalized social phobia would be expected to have an elevated rate of generalized but not nongeneralized social phobia and vice versa. A 1998 direct interview family study addressed one aspect of this question. Rates of generalized and performance social phobia were compared in relatives ( N = 111) of generalized social phobia patients and controls ( N = 74). Significantly higher rates of generalized (24 versus 4 percent, odds ratio = 7.6) but not performance (15 versus 14 percent, NS) social phobia were found in the relatives of the generalized social phobia patients. This finding suggests a possible causal distinction between the two subtypes. However, since the study did not include a proband group of performance social phobia patients, it was not possible to determine whether this group would transmit an increased risk for generalized social phobia to their relatives. If so, this would suggest a partial overlap between the subtypes. Further studies in samples that

include larger numbers of nongeneralized social phobia probands are needed to clarify the relationship of these subtypes with respect to heritability. Twin Studies of Irrational Social Fears A series of twin studies indicate a moderate genetic contribution to irrational social fears and shyness. It is not possible to determine the exact proportion of individuals in these studies who would meet criteria for DSM-IV social phobia. However, the consistency of these data makes a strong argument that genetic factors play an important if partial role in this area of human behavior. Two reports have been published on a large twin-family study of individuals recruited through university registries in Indiana and the Indiana University Twin panel. A survey questionnaire was used to assess existence and severity of 51 commonly seen irrational fears, several related to social anxiety, in this population. Seven factors accounted for 45 percent of the variance in fear survey responses. Two of these (Negative Social Interactions/Social Criticism and Social Responsibility) are made up of fears that are considered to be part of social phobia. Negative social interactions included fears of making mistakes, looking foolish, or being criticized. Items loading on the social responsibility factor included public speaking, being a leader, and meeting new people. The 1983 report by these investigators included 222 MZ and 132 DZ twin pairs. The heritability of the Negative Social Interactions and Social Responsibility factors in this sample was .44 and .60, respectively. This is interpreted as indicating that 44 percent of the liability to have irrational fears of negative social interaction and 60 percent of the liability to fears of social responsibility items is determined by genetic factors. The second report included 341 families (250 twin families and 91 sib families); the overlap between this and the 1983 sample is unclear. A multivariate path analysis was used to examine the relative fit of various genetic models. The best fitting model indicated: (1) moderate heritability of the two social fear factors; (2) a single genetic factor that accounted for most of the genetic liability for all 51 fears; (3) smaller genetic contributions that were specific to each of the fear factors; and (4) a moderate contribution from the common twin environment. A similar study was conducted in 99 same-sex twin pairs (50 MZ and 49 DZ) from the Norwegian National Twin Register. However, in this case fear survey answers were elicited during a face-to-face clinical interview. Five factors accounted for over 50 percent of the variance in fear responses. Heritability of the social fears factor was .50 (fears of eating with strangers; being watched writing, working, or trembling). Using a slightly different approach a study was conducted of 99 MZ and DZ twin pairs using the California Personality Inventory (CPI). Forty-one of the 82 items in the inventory showed differences between MZ and DZ pairs, indicating genetic influence. A factor analysis of the 41 items revealed two factors related to social behavior (conversational poise and social ease). Items in these factors included: fear of finding anything to talk about with people, difficulty talking to or meeting new people, and fear of public speaking. Childhood Temperaments Related to Social Behavior Two well-studied childhood temperaments (behavioral inhibition and shyness) may also contribute to the understanding of the development of social phobia. Each shares some clinical features with social anxiety and has been shown to have a genetic contribution to its etiology. However, there are also clear differences between each of these syndromes and social phobia. Moreover, as longitudinal studies have not been carried out, there is as yet no prospective evidence that either of these childhood syndromes increases the risk for adult social phobia. Extensive studies have been conducted on the childhood temperament behavioral inhibition, which is found to occur in approximately 10 to 15 percent of white children and is characterized by timid, fearful, and withdrawn behavior on encountering unfamiliar people or situations. Another 10 to 15 percent of children show an opposite temperament (behaviorally uninhibited), which is characterized by outgoing, active, and exploratory behavior in new situations. More recent work indicates that these temperaments are distinguishable at as early as 4 months of age and are stable in 50 to 75 percent of individuals over the first 7 years of life. The suggestion that behavioral inhibition is linked to social phobia comes from both the observation of overlap in certain clinical symptoms and a family study that indicated higher rates of social phobia were found in the parents of behaviorally inhibited versus behaviorally uninhibited children versus controls (18 versus 0 versus 3 percent, P < .05). A recent twin study of behavioral inhibition carried out in connection with a larger study of childhood temperaments reported the heritability at .49 (i.e., about 50 percent of the liability to develop behavioral inhibition comes from genetic factors). This moderate genetic contribution is consistent with those found in other studies of social anxiety. A second piece of evidence on genetic contribution to behavioral inhibition comes from breeding and cross-fostering (i.e., adoption) studies using animal models. There are several animal models of variation in reactivity to the unfamiliar; in each of these cases the more reactive strain shows the timid behavior and increased arousal that characterize Kagan's behaviorally inhibited children. That these behaviors can be bred in strains even if offspring are raised by unaffected individuals suggests a genetic contribution. For example, in a breeding study of rhesus monkeys it was found that the similarity with regard to extent of high reactive (i.e., behaviorally inhibited) behavior was proportional to degree of biological relatedness. High reactivity also persisted in monkeys who were cross-fostered (i.e., adopted) by low reactive mothers, suggesting that pedigree rather than mothering style is the predominant determinant of this trait. A second set of developmental studies have focused on shyness. In this context shyness is defined as timid, avoidant, and passive behavior when confronted with an unfamiliar person. The Institute for Behavioral Genetics in Colorado has carried out several twin and adoption studies of this temperament in children. The results of the twin studies indicate significantly greater correlation of shyness scale scores between MZ versus DZ twins, supporting a genetic contribution to variation in this behavior. For example, 21 MZ and 25 DZ twin pairs aged 22 months were studied by observing their social response to structured situations involving their mothers and the research rater in their own homes. The types of social situations included: how long it takes the child to engage and interact with the researcher and how the child reacts to playing alone with the researcher or being separated from the mother. Correlation of scores between members of MZ pairs were in the range of .40 to .67 and were higher than those between members of DZ (–.05 to .34) pairs for all but one situation (time to smiling MZ .08 versus DZ .25). Similar results were found for children ranging from 4 to 10 years using both parental rating and direct observation. In contrast to the twin data, the Colorado Adoption Project data were equivocal with respect to the possibility of a genetic contribution to shyness. This project included 182 adoptive and 164 nonadoptive families. Parents rated infant shyness at 12 and 24 months using a specially developed social ability-and-shyness scale. Typical items included: “child tends to be shy,” child takes a long time to warm up to strangers.” Parental shyness was measured using three self-report adult temperament scales. There were small but significant correlations between infant shyness and parental self-ratings on all three scales in the nonadoptive families (i.e., families in which biological parents raised their biological children) suggesting some degree of familial transmission of these behaviors. A genetic contribution would be indicated by high correlations between biological mothers and their adopted-away children and low correlations between adoptive parents and their adopted children. In actuality, in this sample there were very few strong correlations among any of these groups. Social ease in biological mothers was negatively correlated with shyness in their adopted-away 24-month-old infants (–15, P < .05). Correlations of similar strength were seen between this measure in adoptive mothers and fathers and shyness in their adopted (i.e., nonbiological) children. Twin and family studies of social phobia and social fears indicate a moderate genetic contribution to these behaviors. Two childhood temperaments (shyness and behavioral inhibition), which also have a moderate genetic basis, show symptomatic overlap with social phobia. However, further studies of the adult outcome of these temperaments are needed to clarify their relationship to social phobia. Systematic DNA marker studies have not been reported.

SPECIFIC PHOBIAS Although specific irrational fears and phobias had often been thought to originate completely through learned conditioning, there is significant evidence that genetic factors also play a definite (though partial) role in their development. However, neither adoption, DNA marker, nor segregation analytic studies have been reported. In addition to the obvious unanswered questions concerning mode and mechanism of transmission, two issues have been the subject of discussion in this field. These are: (1) the extent to which one inherits a susceptibility to a particular phobia versus a general phobia proneness; and (2) whether the genetic factors that influence irrational fears and phobias are the same. Irrational fears are distinguished from phobias by the fact that they do not involve either impairment or distress about the fear and therefore do not meet the DSM-III-R criteria for phobic disorder. Twin Studies of Specific Fears and Phobias The Virginia Twin Registry study assessed heritability of two specific phobia subtypes: animal and situational (e.g., fears of tunnels, closed places, bridges, airplanes, high places). Each was found to have moderate heritability, although the genetic modeling analyses indicated different mechanisms of transmission. Animal phobias occurred in 11 percent of the sample. Probandwise concordance was 26 percent for MZ and 12 percent for DZ pairs. The best-fitting genetic model suggested that the major contributions to heritability of animal phobias were genetic factors common to all phobias (35 percent) and specific environmental events (59 percent; e.g., getting stuck in a tunnel). A completely different pattern was seen for situational phobias. Here probandwise concordance was similar in MZ versus DZ twin pairs (22 versus 24 percent). The best-fitting model indicated that 53 percent of the liability to these phobias comes from specific environmental events, 20 percent from specific, and 9 percent from common genetic factors. Several additional twin studies have used the fear survey method to assess specific irrational fears. Subjects were asked to rate the severity of their fear of a variety of different situations on an ordinal scale (e.g., 0 = no fear, 5 = extremely anxious) As fear-related impairment and distress were not assessed, this methodology identified a mixed group some of whom will and some of whom will not meet the DSM-III-R or DSM-IV criteria for specific phobic disorder. These data must be

interpreted in light of this limitation. Irrational fears were studied in a large twin sample recruited from university students and their families throughout Indiana. The first investigation included 222 MZ and 132 DZ same-sex twin pairs who were assessed for severity of fear of 51 commonly feared situations. Seven factors were found to account for 45 percent of the variance in fear response; two were related to social anxiety. The remaining five factors include irrational fears that are commonly the subject of specific phobic disorders. Each of these five fear factors was found to be influenced by genetic factors; however, the magnitude of heritability varied considerably. Relatively high heritabilities (indicating a large genetic contribution) were found for irrational fears of dangerous places (.58) for example, closed places, crowded places, heights; small organisms (.66) for example, snakes, mice, spiders; and personal death (.72), for example, death, untimely or early. Moderate heritabilities were found for the factors including fears of deep water (.32), including boating, swimming, deep water, and loved one's misfortunes (.28), for example, death, illness or injury of a loved one). In a second study path analytic methods were applied to genetic analysis of 341 families (250 twin pairs, 91 sib pairs, and their parents). Assessment and data reduction methodology were similar to that used in the previous work. Seven factors accounted for over 50 percent of response variance. Two factors were comprised of social and four of specific irrational fears. The specific fear factors were similar to those identified in the earlier investigation. A seventh factor that is not clearly related to a particular DSM-IV phobia diagnosis included fears of death and illness of loved ones. A single genetic factor accounted for 80 percent of the variance in all fear responses in this sample and contributed to the development of each of the types of fears. In addition, specific genetic factors of varying strength were found for each fear type. Overall heritability was moderate. Heritabilities of each of the irrational fear types were: heights (.22), water (.20), dangerous places and organisms (.39), morbid settings (e.g., cemeteries, dead bodies, needles; .34). Ninety-nine twin pairs from the Norwegian Twin Registry were studied using a fear survey administered during a clinical interview. Five factors, three of which are relevant to specific phobia, were found to account for over 50 percent of the variation in fear responses. For each of the three specific phobia factors the correlation of fear scale scores was significantly greater between MZ as compared to DZ twins, supporting a genetic contribution. Although the factors largely overlap with those identified in earlier research, the heritabilities were slightly higher. The three factors and their heritabilities were as follows: fears of animals (rats, mice, insects) .47; mutilation (blood, injury, medical procedures) .48; and nature (e.g., bridges, high places, closed places, tunnels, sharp objects, the ocean, fire). These data indicate a genetic contribution to both irrational fears and phobias but do not address the question of their interrelationship with respect to intergenerational transmission. Two smaller studies provide some preliminary information on this issue. Both suggest that the transmitted component may be a susceptibility to a particular irrational fear whereas the possible consequence of avoidance or impairment is determined by other factors. However, further studies in larger and more well-defined samples are needed to further explore this question. Forty-nine twin pairs from the Maudesly Twin Registry were studied. Twenty-one index twins had a phobia diagnosis. There was little difference between MZ versus DZ pairs in concordance for treatment of a phobia (13 percent in MZ versus 8 percent in DZ). However, when the diagnostic criteria were broadened to include phobic symptoms with or without treatment, concordance rates for MZ twins were substantially higher although not significantly different from those for DZ twins (88 versus 33 percent). A subset of the Virginia Twin Registry study participants (541 MZ and 388 DZ twin pairs) were called back a year later to assess presence of phobias and irrational fears of blood, needles, hospitals, and illness. The best-fitting model indicated a genetic contribution to irrational fears of the first three items. However, occurrence of the DSM-IV disorder blood injury phobia (i.e., irrational fear of any of these situations, which interfered with the subject's life) was best explained by environmental factors. Family Studies Several family and family history studies indicate a greater risk for phobic disorders among the relatives of phobia patients as compared to the relatives of controls. However, these data are somewhat difficult to interpret because most have used mixed proband groups that include patients with both social phobia and agoraphobia. The one direct interview family study of DSM-III-R simple phobia found a threefold increased rate of simple phobia among relatives ( N = 49) of simple phobia probands as compared to relatives (119) of never–mentally-ill controls (31 versus 11 percent, P < .005, relative risk = 3.3). There was no evidence of familial aggregation of subdisorder irrational fears. Although this study is consistent with the twin data it requires replication in a larger sample. Animal Models One striking feature of phobias is that they are irrational. That is, individuals with phobias are fearful of objects or situations that are not, from most people's point of view, realistically dangerous. This observation has led to the hypothesis that at least some phobias are acquired through conditioning. Conditioning is a process by which the animal acquires fear of a previously neutral stimulus through its repeated association with a noxious stimulus (e.g., shock). In a typical experiment a rat would be trained to fear a soft tone (conditioned stimulus) by repeated exposure to the tone followed by an electric shock (unconditioned stimulus). When conditioning takes place the rat will react to the tone as though it were the shock (i.e., with fear), even if the shock is no longer given. Animal models of conditioned fear are used to study the neurobiology of fear as well as of learning and memory. Experiments with fear conditioning have indicated that: (1) it is possible to breed strains of animals who are more or less fearful of specific stimuli and (2) there is genetic variability between strains in the strength and persistence of conditioned fear. Although this work is not directly applicable to the case of specific phobias in humans, it may provide starting points for development and testing of molecular genetic models. These data indicate that genes contribute to the development of specific irrational fears and phobias. However, their role is moderate, leaving substantial influence to environmental factors (e.g., interpersonal, chance events). Most studies also indicate complexity in the structure of the genetic contribution. That is, there may be two types of genetic factors involved: those which influence an individual's likelihood to develop any phobia and those that are specific to fears or phobias of a particular situation. This suggestion of genetic heterogeneity within and across the DSM-IV categories is consistent with the diversity seen in studies of onset and course of specific phobias. Recent findings in animal models offer the possibility of dissecting phenotypes that may be more amenable to successful application of molecular genetic techniques.

OBSESSIVE-COMPULSIVE DISORDER Data on the heritability of obsessive-compulsive disorder are inconclusive. Most but not all modern family studies have been positive, suggesting that there is intergenerational transmission of susceptibility to at least some subset of these cases. However, a genetic contribution to this disorder has not been well documented and there are no large systematic twin studies of this disorder. Recent findings in neuroimaging and treatment studies indicate that some cases of obsessive-compulsive disorder may be associated with specific autoimmune, receptor, or neuroanatomical abnormalities. These data suggest etiologic heterogeneity within the DSM-IV category; they have also increased interest in and provided some clues for understanding the possible genetic underpinnings of obsessive-compulsive disorder. Twin and Family Studies Only one systematic twin study has assessed obsessive-compulsive symptoms and its results are suggestive but inconclusive concerning a genetic contribution to the disorder. Thirty (15 MZ and 15 DZ) of 49 twin pairs admitted to the Maudesly Twin Register had an index twin with obsessional symptoms. Probandwise concordance for treated obsessional symptoms that met DSM-III criteria was higher but not significantly different in MZ versus DZ twin pairs (33 versus 7 percent) When the diagnostic criteria were broadened to include either obsessive-compulsive disorder or untreated subclinical obsessional features, concordance rates were higher but still not significantly different (MZ versus DZ: 87 versus 47 percent). Diagnostic evaluations were not blind to diagnosis of cotwin. Thirteen family studies of obsessive-compulsive disorder have been reported; however, only three employed state-of-the-art research methods (i.e., controls, blind assessment of relatives, and operational diagnostic criteria). Of these three studies two indicate familial aggregation in relatives of patients with obsessive-compulsive disorder versus relatives of normal controls, the third did not. One study found the disorder in 10.3 percent of the first-degree relatives of patients with obsessive-compulsive disorder as compared to only 1.9 percent of the relatives of psychiatrically well controls ( P < .005). In one study the disorder was diagnosed in 7 percent of relatives of patients with the disorder as compared to 2 percent of relatives of controls ( P < .050). In contrast, the third study found an increased rate of generalized anxiety disorder and any anxiety disorder among the relatives of patients with obsessive-compulsive disorder as compared to relatives of nonpsychiatrically ill controls. However, rates of the disorder did not differ between groups (2.5 percent versus 2.3 percent). Interestingly, this mixed pattern of results is similar to that seen in earlier, less methodologically rigorous work. For example, of two earlier controlled (but not blind) studies, one reported a significantly higher rate of obsessive-compulsive disorder in relatives of probands with the disorder as compared to relatives of controls while the other study did not. A third study reported on families of early-onset obsessive-compulsive disorder (mean onset 10 years ± 3) using blind diagnostic ratings and DSM-III criteria, but no control group. Considerably higher rates of the disorder (13 percent) and subdisorder of the disorder symptoms (17 percent) among relatives

of childhood-onset probands with obsessive-compulsive disorder than are expected in the general population. It has been suggested that these mixed findings on familial aggregation of the disorder reflect differences in methodology as well as etiologic heterogeneity within the diagnostic category. That is, some cases of obsessive-compulsive disorder have a heritable contribution whereas others do not. If so, then whether a study shows familial aggregation or not depends on the proportion of familial cases that are included in its sample. To investigate this hypothesis several recent studies have began to subtype patients by such variables as age at onset, presence of neurological symptoms, and symptom patterns of the disorder. Relation Between Obsessive-Compulsive Disorder and Tourette's Disorder One interesting set of findings concerns the possible relationship between a subset of these cases and certain types of motor tic syndromes (i.e., Tourette's disorder and chronic motor tics). Increased rates of obsessive-compulsive disorder, Tourette's disorder, and chronic motor tics were found in the relatives of Tourette's disorder patients as compared to relatives of controls whether or not the patient had obsessive-compulsive disorder. However, most family studies of probands with obsessive-compulsive disorder have found elevated rates of Tourette's disorder and chronic motor tics only among the relatives of probands with obsessive-compulsive disorder who also have some form of tic disorder. Taken together these data suggest that there is a familial and perhaps genetic relationship between Tourette's disorder and chronic motor tics and some cases of obsessive-compulsive disorder. Cases of the latter in which the individual also manifests tics are the most likely to be related to Tourette's disorder and chronic motor tics. As there is considerable evidence of a genetic contribution to Tourette's disorder this finding also supports a genetic role in a subset of cases of obsessive-compulsive disorders.

POSTTRAUMATIC STRESS DISORDER Posttraumatic stress disorder (PTSD) is the least studied anxiety disorder with respect to heritable or genetic contributions to etiology; only one twin and a few family studies have been reported. However, the data are intriguing and suggest further investigation in this area will both help clarify the causes of PTSD, and also improve the overall understanding of the multiple ways in which genes and environment can interact in the development of pathology. The major indication of a genetic contribution to PTSD comes from a large twin study whose subjects were drawn from the Vietnam era veterans registry. Approximately two thirds of the registry twins ( N = 4042 male twin pairs) responded to a mailed questionnaire. Independent genetic effects were found to influence both exposure to combat and development of PTSD symptoms. Within-pair correlation for most of the DSM-III-R PTSD symptoms was twice as high for MZ as compared to DZ twins. Although the prevalence of PTSD symptoms increased in proportion to extent of combat exposure, the MZ versus DZ twin pair difference held true even among veterans who did not serve in combat zones. Using a quantitative genetic model, genetic factors were estimated to account for approximately one third of the variance in liability to develop each of the DSM-III-R PTSD clusters in the overall sample (arousal cluster 28 to 32 percent, reexperiencing cluster 30 to 34 percent, and avoidance cluster 13 to 30 percent). These findings must be considered with caution because the diagnoses are based completely on self-report rather than clinical evaluation and only two thirds of the sample responded. However, the suggestion of genetic influence on both (1) variation in response to stress; and (2) likelihood to expose oneself to situations leading to greater probability of trauma is consistent with several previous findings in epidemiological, personality, and animal model research. In contrast to these twin study findings, several reported family history studies have not found increased rates of PTSD relatives of PTSD probands as compared to relatives of normal and psychiatrically ill controls. However, the significance of these results is difficult to interpret because the family information or sample sizes were insufficient to examine PTSD rates in relatives who were exposed versus not exposed to trauma. One study yielded family history data indicating an increased rate of anxiety disorders among relatives of PTSD probands compared to relatives of combat-exposed non-PTSD probands. This finding would suggest a heritable relationship between PTSD and other anxiety disorders. However, it was not confirmed in a subsequent direct interview family study and no adoption studies on PTSD have been reported. Another interesting approach to this problem is reported by researchers who studied the occurrence of PTSD in adolescent Cambodian refugees and their parents. Although subjects were currently living in the United States, all had had significant exposure to war trauma before immigration. Within each family the trauma exposure of the parent and adolescent was similar. Assessments were by direct interview. Significantly higher rates of DSM-III-R PTSD were found among adolescents whose parents had versus those who did not have PTSD (16/60 versus 4/58, 27 versus 7 percent, P < .05). This effect was independent of socioeconomic status, amount of reported war trauma, living arrangements, or treatment. The data summarized above indicate that genetic factors play an important role in the development of anxiety disorders. However, as the heritability of these syndromes is only moderate, nongenetic factors are equally crucial. In addition, as the patterns of intergenerational transmission do not follow Mendelian rules, anxiety disorders fall into the ever-enlarging category of genetically complex disorders. Future research will have to take into account the high probability that there is widespread pleiotropy (i.e., different clinical syndromes associated with the same genetic underpinnings) and genetic heterogeneity (i.e., different genes can lead to the same clinical phenotype). It will also need to focus not only on genetic mechanisms that underlie susceptibility to pathological anxiety states, but also on nongenetic contributions and how (and if) there is interaction between several different genes as well as between genetic and nongenetic causes. The classification of anxiety disorders has become increasingly specific. Overall the family study and genetic data are supportive of these new distinctions. For several anxiety disorders there is evidence of specific genetic contributions that increase susceptibility to that illness but not to the other anxiety syndromes. However, there are also data that indicate the existence of genetic factors that increase an individual's likelihood for any anxiety disorder; at least one investigation finds that both types of genetic effects (general and disorder specific) are important. These data are completely consistent with the current knowledge of the etiological heterogeneity seen in genetically complex disorders. However, taken together they suggest that the actual genetics of anxiety disorders may be much more complicated than suggested by previous etiological theories.

SUGGESTED CROSS-REFERENCES Population genetics in psychiatry is discussed in Section 1.17 and genetic linkage analysis of psychiatric disorders is in Section 1.18. Epidemiology is covered in Section 5.1. SECTION REFERENCES Black DW, Noyes R Jr, Goldstein RB, Blum N: A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 49:362, 1992. Brown FW: Heredity in the psychoneuroses. Proc R Soc Med. 35:785, 1942. Carey G, Gottsman II: Defining cases by genetic criteria. In What is a Case? JK Wing, P Bebbington, LN Robins, editors. Grant McIntyre, London, 1981. *Carey G, Gottesman II: Twin and family studies of anxiety, phobic, and obsessive disorders. In Anxiety New Research and Changing Concepts, DF Klein, JG Rabkin, editors. Raven, New York, 1981. Cohen ME, Badal DW, Kilpatrick A, Reed EW, White PD: The high familial prevalence of neurocirculatory asthenia (anxiety neurosis, effort syndrome). Am J Hum Genet

3:126, 1951.

Coryell W: Hypersensitivity to carbon dioxide as a disease-specific trait marker. Biol Psychiatry 41:259, 1997. *Crowe RR, Noye R, Pauls DL, Slymen DJ: A family study of panic disorder. Arch Gen Psychiatry 40:1065, 1983. Fyer AJ, Mannuzza S, Chapman T, Liebowitz MR, Klein DF: A direct interview family study of social phobia. Arch Gen Psychiatry 50:286, 1993. Fyer AJ, Mannuzza S, Chapman TF, Martin LY, Klein DF: Specificity in familial aggregation of phobic disorders. Arch Gen Psychiatry 52:564, 1995. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684, 1990. Henikoff S, Greene EA, Pietrokousk S, Bork P, Attwood TK, Hood L: Gene families the taxonomy of protein paralogs and chimeras. Science 278:609, 1997. Kagan J, Snidman N: Temperamental factors in human development. Am Psychol 46:856, 1991. *Katsuragi S, Kunugi H, Sano A, Tsutsumi T, Isogawa K, Nanko S, Akiyoshi J: Association between serotonin transporter gene polymorphism and anxiety-related traits. Biol Psychiatry 45:368, 1999.

Kendler KS, Heath AC, Martin NG, Eaves LJ: Symptoms of anxiety and symptoms of depression: Same genes, different environments? Arch Gen Psychiatry 44:451, 1987. *Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: The genetic epidemiology of phobias in women: The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry 49:273, 1992. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: Panic disorder in women: A population-based twin study. Psychol Med 23:397, 1993. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA, Haghighi F, De Jesus GM, Rassnick H, Preud'homme-Rivelli X, Autsin T, Cunjak J, Mick S, Fine JD, Woodley KA, Das K, Maier W, Adams PB, Freimer NB, Klein DF, Gilliam TC: Results of a genome-wide genetic screen for panic disorder. Am J Med Genetic 81:139, 1998. *Lander ES, Schork NJ: Genetic dissection of complex traits. Science 265:2037, 1994. Lyons MJ, Goldberg J, Eisen SA, True W, Tsuaung MT, Meyer JM, Henderson WG: Do genes influence exposure to trauma: A twin study of combat. Am J Med Genet 48:22, 1993. Noyes R Jr, Clarkson C, Crowe RR, Yates WR, McChesney CM: A family study of generalized anxiety disorder. Am J Psychiatry 144:1019, 1987. Ohman A: Face the beast and fear the face: Animal and social fears as prototypes for evolutionary analyses of emotion. Psychophysiology 23:123, 1986. Pauls DL, Alsobrook JP, Goodman W, Rasmussen S, Leckman JF: A family study of obsessive-compulsive disorder. Am J Psychiatry 152:76, 1995. Perna G, Cocchi S, Bertani A, Arancio C, Bellodi L: Sensitivity to 35% CO

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in healthy first-degree relatives of patients with panic disorder. Am J Psychiatry 152:623, 1995.

Phillips K, Fulker DW, Rose RJ: Path analysis of seven fear factors in adult twin and sibling pairs and their parents. Genet Epidemiol 4:345, 1987. Plomin R, Daniels D: Genetics and shyness. In Shyness, WH Jones, M Cheek, SR Briggs, editors. Plenum, New York, 1986. Rose RJ, Miller JZ, Pogue-Gelle MF, Cardwell GF: Twin-family studies of common fears and phobias. In Twin Research 3: Intelligence, Personality, and Development. Liss, New York, 1981. P>Rosenbaum JF, Biederman J, Hirshfeld DR, Bolduc EA, Faraone SV, Kagan J, Snidman N, Reznick JS: Further evidence of an association between behavioral inhibition and anxiety disorders: Results from a family study of children from a nonclinical sample. J Psychiatr Res 25:49, 1991. Sack WH, Clarke GN, Seeley J: Posttraumatic stress disorder across two generations of Cambodian refugees. J Am Acad Child Adolesc Psychiatry 34(9):1160, 1995. *Stein MB, Chartier MJ, Hazen AL, Kozak MA, Tancer ME, Lander S, Furer P, Chubaty D, Walker JR: A direct-interview family study of generalized social phobia. Am J Psychiatry

155:1, 1998.

Suomi SJ: Genetic, maternal, and environmental influences on social development in rhesus monkeys. In Primate Behavior and Social Biology, AB Chiarelli, RS Corruccini, editors. Springer, New York, 1987. Suomi SJ, Kraemer GW, Baysinger CM, DeLizio RD: Inherited and experiential factors associated with individual differences in anxious behavior displayed by rhesus monkeys. In Anxiety, New Research and Changing Concepts, Klein DR, Rabkin J, editors. Raven, New York, 1981. Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport JL, Dow SP, Kanter ME, Chapman F, Zabriskie J: Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 154:110, 1997. Tatusov RL, Koonin EV, Lipman DJ: A genomic perspective on protein families. Science 278:631, 1997. Torgersen S: Genetic factors in anxiety disorders. Arch Gen Psychiatry 40:1085, 1983. Torgersen S: The nature and origin of common phobic fears. Br J Psychiatry 134:1979. True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, Nowak J: A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 50:257, 1993. Vieland VJ, Hodge SE, Lish JD, Adams P, Weissman MM: Segregation analysis of panic disorder. Psychiatr Genet 3:63, 1993. Weissman MM, Warner V, Wickramaratne P, Moreau D, Olfson M: Offspring of depressed parents. 10 years later. Arch Gen Psychiatry 54:932, 1997. Weissman MM, Wickramaratne P, Adams P, Lish JD, Horwath E, Charney D, Woods SW, Leeman E, Frosch E: The relationship between panic disorder and major depression: A new family study. Arch Gen Psychiatry 50:767, 1993.

Textbook of Psychiatry

15.5 ANXIETY DISORDERS: PSYCHODYNAMIC ASPECTS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry

CHAPTER 15. ANXIETY DISORDERS

15.5 ANXIETY DISORDERS: PSYCHODYNAMIC ASPECTS GLEN O. GABBARD, M.D Freud’s Theory of Anxiety Klein's Views of Anxiety Self Psychological Views of Anxiety Hierarchy of Anxiety Contemporary Views of Anxiety Panic Disorder Phobias Obsessive-Compulsive Disorder Posttraumatic Stress Disorder Acute Stress Disorder Generalized Anxiety Disorder Suggested Cross-References

FREUD'S THEORY OF ANXIETY Sigmund Freud placed anxiety at the core of neurosis; hence the history of the development of psychoanalytic theory can be linked to the evolution of Freud's understanding of anxiety. In 1895 he put forth his original theory of anxiety, which postulated a biologically based cause. Specifically Freud believed that the accumulation of undischarged libido was transformed into anxiety. In his view the “dammed-up” libido could either result from external obstacles to its appropriate discharge or from internal inhibitions related to unconscious conflicts about sexual gratification. Freud did not fully explain how the transformation of accumulated libido into symptomatic anxiety occurred—he merely suggested that such a transformation must occur. Freud referred to this form of anxiety as actual neurosis, and this designation clearly referred to a pathological type of overwhelming fear. It was directly linked to drive energy and associated with a number of physiological symptoms, including manifestations of autonomic discharge, such as profuse sweating, diarrhea, and increased respiratory and heart rates. He also connected it with an overwhelming sense of panic and terror. This rather nonpsychological formulation of anxiety was retained until 1926, when Freud wrote his classic monograph Inhibitions, Symptoms, and Anxiety. This publication appeared 3 years after The Ego and the Id, which suggested that the tripartite structural model of id, ego, and superego, was the key to understanding mental phenomena. His 1926 monograph was essentially a new theory of anxiety based on his understanding of interagency conflict in the structural model. Although he had now abandoned the original idea that undischarged libido is transformed into anxiety, he nevertheless continued to regard anxiety as having a biological or genetic basis. He recognized that there was clearly a Darwinian survival value in reacting to external threats with anxiety; hence he believed that every human organism must be congenitally endowed with this capacity to respond to danger situations both physiologically and psychologically. However, Freud's theory of anxiety was not designed to identify the origin of anxiety as a human phenomenon; instead, its emphasis was on how to understand the role of anxiety in the individual's mental life. Traumatic situations were regarded as central to the development of anxiety according to Freud's new theory. The prototype of the traumatic situation was the experience of birth, when the infant is overwhelmed by a flood of stimuli arising from external sources as well as from internal sensations. Freud believed that this prototypical model could be used to understand anxiety in other situations in the course of development where individuals are overwhelmed by an influx of stimuli that they are incapable of mastering. The emphasis in his theory was primarily on stimuli arising from the id, specifically aggressive and sexual wishes that had been repressed and are striving to make their presence known. A second aspect of Freud's new theory on anxiety involved “danger” situations. Freud suggested that as children develop they learn to anticipate a traumatic situation before it happens and to react to it with anxiety. Freud termed this reaction signal anxiety because it was produced by a situation in which the individual anticipated danger. In response to this signal of danger, the ego mobilized defense mechanisms to prevent unacceptable thoughts and feelings from emerging into conscious awareness. Freud used the situation of an infant being left alone by its mother as a way of illustrating a typical danger situation. Infants learn that a relationship exists between the absence of the mother and the experiencing of unpleasurable states of internal turmoil. Based on this experience, the ego learns that separation from the mother is a danger situation and responds accordingly with signal anxiety. If the signal anxiety fails to activate the ego's defensive resources adequately, more persistent or even neurotic symptoms will result. In this regard, Freud conceptualized anxiety as both a symptomatic manifestation of neurotic conflict and an adaptive signal to avoid awareness of neurotic conflict. In this second aspect of Freud's new theory of anxiety, the pleasure principle was intimately related to the function of the anxiety. The signal anxiety that the ego learns to produce in response to the anticipation of danger was viewed as relatively less unpleasurable than the anxiety that would develop if there were no signal and the traumatic situation of abandonment developed fully. Signal anxiety is a way of attenuating a more profound and terrifying anxiety. In this model the phenomenon of anxiety is an ego affect. The signal of danger produced by the ego offers opposition to the emergence of repressed id impulses into conscious awareness. The ego's defense mechanisms are marshaled in response to the signal anxiety. One such defense mechanism is repression, which keeps undesirable id impulses, whether desires, wish-fulfilling fantasies, memories, or affects, from entering the consciousness. The ego serves to censor both the impulse itself and the corresponding intrapsychic representation of that impulse. Nevertheless, the impulse or drive-related wish that has been repressed may still find a way to express itself in the form of a symptom. By the time it manifests itself as a symptom, however, it is likely to be disguised and displaced. For example, the symptom of hysterical paralysis might reflect an underlying wish to strike a parent with murderous intent. The underlying wish related to drive pressures may also be defended against through reaction formation. This defense mechanism involves an overemphasis on one side of an ambivalent attitude. If love and hate are both directed towards a parent, the defense of reaction formation maintains the hate as an unconscious part of the affective state while emphasizing love. The manifestation of this reaction formation might be excessive devotion to the parent and professions of love without any conscious awareness of negative feelings. Hence an exaggeration of a feeling or attitude led Freud to wonder about the other side of the equation buried in the unconscious. This awareness of reaction formation had been observed by writers years before Freud's formulation of anxiety. Ralph Waldo Emerson, for example, once noted, “The louder he spoke of his honor, the faster we counted our spoons.”

KLEIN'S VIEWS OF ANXIETY Melanie Klein expanded on Freud's view by developing a theory of internal object relations linked to drives. She regarded fear of annihilation as the most fundamental anxiety and related it to Freud's death instinct. In her view, the ego engaged in a splitting process to deal with that fear of annihilation. All the derivatives of the death instinct, such as sadism, hatred, aggression, and any form of “badness,” were evacuated from the infant and projected into the mother. The infant then began to suffer persecutory anxiety from the death instinct derivatives projected into the mother. This form of anxiety, which Klein linked to the paranoid-schizoid position, involved a fear that the “bad” mother created by the infant's projections would invade the infant and destroy all the “good” aspects of the infant. As the infant moved from the paranoid-schizoid position to the depressive position, splitting of the ego was overcome by an integrative effort that was designed to link good and bad aspects of the self and of objects. Instead of viewing the mother as “all bad,” the child is now able to see that mother has both good and bad qualities. Similarly, infants also become aware of the presence of good and bad within themselves. When the child becomes aware that the loving and nurturing mother is basically the same person as the hateful, rejecting mother, an important developmental moment has been achieved. Now the infant becomes concerned that it may have harmed or destroyed its mother through its hostile and sadistic fantasies directed toward her. This developmental achievement leads to depressive anxiety. While the infant was mainly concerned about being attacked by the persecutory object during the paranoid-schizoid position, in the depressive position the infant's primary anxiety is that it may hurt love objects, particularly the mother. The child then worries that the good object may be lost through the child's own aggression and sadism. Hence depressive anxiety can be summarized as a concern about the loss of the love object through one's own destructiveness. The child learns to deal with

these guilt feelings through a process of reparation, in which the child attempts to repair the perceived damage through loving behavior toward the ambivalently regarded object.

SELF PSYCHOLOGICAL VIEWS OF ANXIETY Heinz Kohut developed self psychology in the late 1960s and continued his work until his death in 1981. He deemphasized drives and conflicts and emphasized a deficit model in which the self was regarded as immature and lacking in maternal supplies. The emphasis in self psychology is on infantile needs rather than repressed wishes or drives. Kohut felt that the need to maintain self-esteem and well-being was just as powerful as sexuality and aggression in molding the human organism. In his view the child has powerful needs to idealize a parent; to receive affirmation, validation, and empathy from that parent; and to maintain a sense of wholeness of the self. Within this model, disintegration anxiety is the most fundamental concern of the individual. This anxiety is generated by the child's concern that the failure of adequate selfobject responses from persons in the environment will lead to fragmentation of the self. If empathy, affirmation, and validation are not forthcoming from significant individuals, such as parents, the child may then resort to pathological behavior to restore harmony to the self. In adult life these behaviors may include such things as gambling, perverse sexual behavior, disordered eating behaviors, substance abuse, and a myriad of other so-called “acting-out” behaviors. Kohut believed that the anxieties based on the internal drive pressures, such as sexuality and aggression, were breakdown products of preOedipal failures in the provision of selfobject needs.

HIERARCHY OF ANXIETY It is possible to construct a developmental hierarchy of anxiety based on Freud's contributions to the subsequent elaborations by Klein and Kohut ( Table 15.5-1).

Table 15.5-1 A Developmental Hierarchy of Anxiety

The psychodynamic clinician can use this hierarchy to guide the understanding of the unconscious origins of anxiety in a specific patient. These may be regarded as “danger situations” in terms of Freud's 1926 model. The highest level of developmental danger is that of guilt. The presence of superego anxiety reflects that moral standards of conduct have been internalized in the form of parental introjects. The superego provides love and approval or punishment and disapproval based on how closely the individual's behavior (or fantasy life) adheres to these standards of conduct. Moving down the developmental hierarchy, the next typical danger situation is associated with the oedipal phase of development and focuses on the potential damage to or loss of the genitals at the hands of a retaliatory parental figure. This fear is often expressed metaphorically as a loss of a different body part or any other form of physical injury. The next type of anxiety involves the loss of parental love. In this situation, even though the parent (or parent substitute) is present physically, the child may still fear the loss of that object's love. In the adult patient this anxiety may manifest itself as a preoccupation with behaving in a manner that ensures a significant object's ongoing love and attention to fend off the anxiety that the object may become disappointed with the patient. Although the foregoing forms of anxiety are typical of neurotically organized patients, the last three points in the hierarchy are often found as the predominant anxiety in more severely disturbed patients. For example, separation anxiety or the fear of abandonment by the love object is typical of patients with borderline personality disorder. Many of these patients lack object constancy, so they cannot internalize a soothing internal presence in the absence of the parental object. They often develop intense anxiety that a significant other, such as a therapist, a parent, a spouse, or a close friend, will suddenly disappear and no longer be there as a source of support. Margaret Mahler linked this to the rapprochement subphase of separation-individuation. The most primitive forms of anxiety are often found in patients with borderline personality disorder or narcissistic personality disorder and those with psychotic disorders. Those with persecutory anxiety often use projection as a defense and have a paranoid mode of organizing experience, believing that there are outside malevolent forces that will invade and destroy them from within unless vigilance is maintained. Disintegration anxiety can manifest itself either through the fear of fragmentation (the loss of one's sense of a cohesive self) or through merger or fusion with an object. This form of anxiety is particularly prominent in patients who have poorly developed ego boundaries. The hierarchical nature of these developmental anxieties may lead the clinician to assume that the more primitive levels of anxiety are “outgrown” as the child develops. Clinical wisdom, however, has taught us that to some degree the most primitive levels of anxiety persist in everyone. In a well-integrated and high-functioning individual superego anxiety may be the most prominent or leading anxiety, the more fundamental forms of anxiety may be activated in situations of great stress or trauma. Similarly, large group situations are often highly conducive to triggering persecutory anxiety, in which “outsiders” or those with different political views are seen as monstrous attackers. The history of Western civilization is characterized by the development of warring factions based on relatively minor differences in culture, religion, or politics. A corollary of this view that all levels of anxiety persist to some extent in every individual is that symptoms may be multiply determined by anxiety stemming from different developmental levels. Consider the following example: A 26-year-old man came to psychoanalytic treatment because of anxieties triggered by sexual intercourse with his fiancée. Although he professed to love this woman and considered their relationship to be mutually satisfying, he found himself much less interested in sexual intercourse than she was. During the act of intercourse he found himself wishing his fiancée would reach orgasm more quickly so he could retract his penis from her vagina. At the same time he felt reluctant to ejaculate in her, and he often stopped intercourse before reaching orgasm. When his analyst asked him about his fear of ejaculating during intercourse, he said that he wanted to avoid an out-of-wedlock pregnancy. The analyst noted that the patient had previously conveyed that his fiancée was taking oral contraceptives. The patient confirmed that indeed she was, but he recognized that there was still a slight risk of pregnancy associated with birth control pills. The analyst asked the patient if he had any other fears associated with ejaculation. The patient initially said that he did not, but he then associated to a dream in which he was having intercourse with a former high school girlfriend, and after the sexual act was consummated, he noticed that his voice had gone up two octaves and he “talked like a girl.” He looked in the mirror and he had become a woman who looked exactly like his fiancée. As the analyst and the patient worked together to analyze the dream through understanding the patient's associations, it became clear that two separate but related anxieties were operating together to produce the symptom. At one level the patient was worried about losing his penis in his fiancée's vagina. This form of castration anxiety was acting in concert with a more primitive concern—that at the moment of orgasm he would fuse and become one with his fiancée and lose his own identity. The patient stressed that orgasm seemed to be the one moment when he tended to lose a sense of his own boundaries and felt like he was merging with the other person.

This clinical vignette illustrates that a patient often is not aware of the source of anxiety because it is unconscious. Although in this case a vivid dream and its accompanying associations made the meaning of the anxiety much clearer, in many other cases much more psychotherapeutic or psychoanalytic exploration is necessary before the unconscious sources are accessible. The developmental hierarchy provides a set of guidelines for clinicians to think about when they are trying to understand a patient's anxiety. However, there are infinite individual variations on these different themes of loss of the object, persecutory anxiety, loss of the object's love, and so forth. The psychodynamic approach to anxiety is one that acknowledges the uniqueness of each individual's intrapsychic world. In each case the clinician must allow for the possibility that the origins of anxiety may not fit these guidelines precisely and may involve a blend of other concerns that may expand psychodynamic theory.

CONTEMPORARY VIEWS OF ANXIETY The publication of the third edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-III) marked the beginning of an effort to make the official nomenclature of the American Psychiatric Association atheoretical. An unfortunate consequence of this shift has been the decline of interest in the classical neurotic entities along with the psychodynamic model of symptom formation inherent in them. Three separate categories have replaced the neuroses: dissociative disorders, somatoform disorders, and anxiety disorders. The category of anxiety disorders has been further subdivided in the fourth edition of DSM (DSM-IV) into the following entities: panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, and generalized anxiety disorder. This classification reflects growing empirical evidence linking biological mechanisms to the generation of anxiety. Panic attacks, for example, can be experimentally induced by lactate infusion. Moreover, genetic studies suggest a higher concordance rate for certain anxiety disorders in monozygotic twins than in dizygotic twins. Acute panic attacks appear to arise in the brainstem and represent spontaneous hyperactivity of noradrenergic nuclei in conjunction with lowered firing thresholds in medullary respiratory chemoreceptors. By contrast, anticipatory anxiety seems to represent the effect of a kindling in the limbic lobe. Phobic avoidance appears to be cortical in origin. Although these advances in the field of neuroscience are impressive and of considerable heuristic value in understanding anxiety, they by no means preclude a psychodynamic understanding or the use of psychotherapeutic techniques. Of greater concern is that the rise of the atheoretical categorizations in the official nomenclature and the associated research on the biological underpinnings of anxiety may encourage clinicians to think about anxiety as only an illness rather than an overdetermined symptom of unconscious conflict. This view of anxiety may be linked to a specific form of treatment designed to eradicate or at least to reduce the anxiety. This perspective fails to recognize the value of anxiety as a signal of internal distress and conflict that may require some reflection and introspection. In the Menninger Foundation's Psychotherapy Research Project, 18 of 35 patients showed increased anxiety at the termination of psychoanalysis or psychotherapy even though 13 of these 18 cases were judged by independent raters to have undergone substantial improvement. These results were regarded by the investigators as a sign that primary anxiety, which is disorganizing to the patient, must be differentiated from anxiety used as a signal. They stressed that an increase in anxiety tolerance, defined as the capacity to experience anxiety without having to discharge it, may be one positive outcome of dynamic psychotherapy or psychoanalysis and may reflect an expansion of the ego's capacity to deal with anxiety. The presence or absence of anxiety after treatment was insufficient to understand or evaluate the change, because many of the patients with good outcomes showed dramatic improvement in their capacity to use ideational activity more efficiently in the service of understanding the anxiety. Anxiety is likely to surface at various developmental crises throughout one's life. It is a regular accompaniment of existential uncertainty inherent in life. The expansion of ego mastery over anxiety as a result of psychoanalytic therapy appears to facilitate the patient's capacity to use and understand anxiety in a variety of circumstances in which it arises. The anxiety can be normal, adaptive, or maladaptive, and the assumption that all anxiety should be eradicated is certainly unwarranted. Any neurophysiological mechanism involved in the generation of anxiety may produce an adaptive form of signal anxiety as well as the more pathological forms of chronic symptomatic anxiety. It would be erroneous to assume that the biological mechanisms are only associated with highly pathological or symptomatic anxieties, or that psychotherapeutic treatments should deal only with signal aspects of anxiety. Psychoanalytic therapy obviously must work by altering brain functioning. Recent genetic studies have demonstrated that individuals with a somewhat shorter gene involved in serotonin transport may have greater anxiety than those with the longer version. Although the investigators have speculated that many other genes as well as numerous environmental factors may be involved in the generation of anxiety, the findings are encouraging because the shorter gene also is functionally different from the longer gene. It is relatively weaker in terms of its capacity to transport serotonin compared to the longer gene. Of particular interest to this discussion is that nearly 70 percent of people have the shorter and less vigorous version of the gene, which results in greater anxiety. This skewed distribution may well reflect natural selection in that individuals with greater anxiety might be better equipped to survive the dangers in the environment than those who experience less worry or concern. Other problems also have resulted from the differentiation of Axis I anxiety disorders in DSM-IV according to specific symptom profiles and temporal criteria. Many researchers as well as a good many more clinicians have argued that the anxiety syndromes have reified distinctions that are more illusory than real. In actual clinical practice there is a growing recognition of comorbidity among anxiety disorders, largely because many of the disorders are not as separate from one another as the criteria imply. Nevertheless, in this chapter the psychodynamic considerations of each of the major anxiety disorders will retain the DSM-IV classification to promote uniformity across the chapters and to illustrate that a psychodynamic perspective can be applied separately or be integrated with the descriptive and biological approaches to these entities.

PANIC DISORDER Patients with panic disorder generally experience a good deal of distress during the few minutes that the typical panic attack lasts. They may find themselves gasping for breath, shaking uncontrollably, feeling lightheaded, sweating profusely, and feeling certain that death is imminent. The majority of such patients also struggle with agoraphobia, in that they are intensely afraid of being stuck in a situation from which they cannot escape. Many patients with panic disorder develop anticipatory anxiety secondarily because they are worried most of the time about when and where the next panic attack will strike them. In some cases patients with panic disorder accompanied by agoraphobia severely restrict their travel so they will not have to encounter a situation in which a panic attack occurs in a place from which they cannot make a ready escape. Many patients suffering from panic disorder experience the attacks as if they “came out of the blue.” They cannot necessarily identify a precipitating factor linked to the onset. Such patients, and often clinicians as well, may thus regard panic attacks as psychologically “contentless.” Yet careful psychodynamic interviewing of such patients often reveals overlooked factors that may be involved in triggering the onset of panic. Experienced psychoanalysts interviewed nine consecutive patients with panic disorder on videotape. A research psychiatrist with psychoanalytic training then reviewed the videotapes and was able to identify psychologically meaningful stressors preceding the onset of panic in each patient evaluated in this manner. These stressors were connected with an alteration of or decrease in the level of expectations placed on the patient. The expectation changes were often related to job situations in which patients had to take on increased responsibilities. Loss events generally involved emotional or physical separations from key figures in the patients' lives. These events were typically associated with childhood experiences where an attachment to an important person in the patients' lives was threatened. Sexual conflicts did not appear to be prominent in triggering the onset of panic, but seven of the nine patients had considerable difficulty dealing with anger. Another common denominator was the perception of parents as frightening, controlling, demanding, temperamental, and critical. Further analysis of the interviews suggested a pattern of childhood difficulties. Anxiety about socializing with others, parental relationships that were perceived as unsupportive, a sense of frustration or resentment, and a feeling of being trapped were experienced by the patients. Aggression was difficult to handle, and most of the patients described feelings of self-reproach and inadequacy. Some of these observations have been borne out by empirical studies. Compared to normal control subjects, patients with panic disorder report higher rates of dysfunctional parenting and more intense separation anxiety in childhood. In a large study of 1018 female twin pairs, the relationship between parental loss prior to the age of 17 and adult psychopathology was investigated. Panic disorder was strongly and significantly associated with both parental separation and death. Early maternal separation in particular was linked to panic disorder. Other studies have suggested higher rates of stressful life events, especially loss, when compared with controls in the months preceding the onset of panic disorder. There is also preliminary evidence of attachment disturbance in adulthood as well as a pattern of insecurity and dependency in relationships.

There may be a predisposing neurophysiological vulnerability that may interact with certain kinds of environmental stressors to produce the end result of a panic attack. Researchers have identified an inborn temperamental characteristic in a number of children that has been termed behavioral inhibition to the unfamiliar. These children have a tendency to be easily frightened by anything unfamiliar in the environment. To deal with their fear, they tend to rely on their parents to protect them. As they grow they often are afraid that their parents will not be there to protect and comfort them. They may externalize their own inadequacies on their parents, whom they regard as unpredictable and unreliable. These children then become angry at their parents' inconsistent availability, but the anger creates new problems in that they worry that their angry fantasies will be destructive and drive their parents away, leaving them with the loss of a parent who they depend on to provide safety. A vicious cycle results where the child's anger threatens the connection with the parent and thus increases the child's hostile and fearful dependence. The alternative scenario is that an individual without the inborn temperamental predisposition to fear the unfamiliar is sufficiently traumatized by a series of stressors in development such that the same type of cycle results. These individuals may experience rejection or extremely controlling behavior by parents or parental substitutes that contribute to the same pattern of fearful dependence. Some form of attachment difficulty appears to be involved in the pathogenesis of panic disorder. A small preliminary study of attachment style in 18 women suffering from anxiety disorders suggested that all had problematic attachment styles. Fourteen of the 18 were diagnosed with panic disorder. These patients had higher rates of preoccupied attachment. Other studies have shown patients with panic disorder to have greater separation anxiety. Fearful individuals tend to view separation and attachment as mutually exclusive. They have difficulty developing the normal oscillation between separation and attachment because they have a heightened sensitivity to both loss of safety or protection and loss of freedom. Hence they end up operating in an extremely narrow range of behavior that attempts to avoid attachment that is too intense or separation that is too frightening. The end result is an overcontrolling style of interaction. To use Freud's terminology, the signal anxiety function is insufficient to deal with anxiety, leading to an overwhelming and uncontrollable level of panic. Threats to attachment in particular appear to trigger this kind of overwhelming panic. Patients who develop panic disorder are prone to feelings of self-fragmentation and may need a companion (or therapist) to help them feel that they have a firm sense of identity. Some investigators have suggested that the presence of ego defects involving self-other confusion may be related to difficulties in using anxiety as a signal. The intensity of panic attacks may appear to be so biologically driven that medication appears to be the only viable treatment approach. However, when the underlying fear of separation and abandonment is seen to be connected with the panic, psychotherapeutic interventions may be equally effective. A patient with borderline personality disorder and poorly established object constancy could not deal with her psychotherapist's absence over extended weekends. While sitting in her apartment she would be unable to visualize her therapist's face or imagine his voice as a way of soothing herself. She began to hyperventilate, experience tachycardia, feel that her death was imminent, and would become terrified that her therapist would not be there for her next session. When the panic became overwhelming, she would call her therapist on the weekend. The call would generally last less than 30 seconds. The patient would report that she was afraid something terrible had happened to her therapist and that she would never see him again. The therapist would reassuringly state that everything was fine and he would see her at their Tuesday appointment. The patient's panic symptoms including tachycardia and hyperventilation, immediately dissipated on hearing the therapist's voice, and she was able to get off the telephone and return to her weekend activities. In the psychotherapy sessions the patient corroborated that hearing her therapist's voice restored a sense of attachment to him. Such situations confirm the fact that the physiological symptoms such as tachycardia and hyperventilation may be reduced just as dramatically with psychotherapeutic as with pharmacotherapeutic interventions. Another etiological factor in women patients appears to be childhood physical and sexual abuse. Both forms of abuse have been found to be significantly higher in persons with anxiety disorder when compared to a control group. Childhood sexual abuse in particular has been found to occur at a rate of 45.1 percent in women with anxiety disorders compared to a rate of 15.4 percent in a comparison group. The link with panic disorder is even more striking—60 percent of women with panic disorder have a history of childhood sexual abuse compared to 31 percent of women with other anxiety disorders. Since childhood trauma interferes with the child's attachment to the parents, childhood sexual abuse could account for some of the difficulties that panic disorder patients have in feeling safe and secure with significant objects in their lives. These patients may have internal representations of abusive relationships that interfere with the development of trust. The psychodynamics of panic disorder are summarized in Table 15.5-2.

Table 15.5-2 Psychodynamic Themes in Panic Disorder

Psychotherapeutic Techniques In the course of psychodynamic therapy the patient's difficulties in relationships often become centered in the transference to the therapist. Conflicts around separation, independence, and anger are particularly prominent. Active exploration of the patient's fears of becoming overly dependent on the therapist are a crucial part of the psychotherapeutic work. Conversely, anxieties over the loss of the therapist may be equally meaningful to the patient. The patient's difficulty with anger may take the form of avoidance. Patients who feel particularly threatened by anger towards the therapist may simply forget the session or find an excuse not to appear. The fears of anger can often be clarified by an examination of childhood situations in which anger was expressed in the family. Anger may be regarded as uncontrollable because of the patient's experiences with parental anger. When the patient became angry with the parent as a child, the parent may have emotionally abandoned the child. Because patients with panic disorder often avoid expressing anger, the therapist's initial task may be to actively explore the resistances to acknowledging anger. As the transference fantasies about the therapist develop, there is generally a great deal of useful information contained in these fantasies. For example, patients may be convinced that they must operate within a narrow range of behavior or risk losing the therapist's interest or investment. These fantasies can often be traced back to childhood fears of being alone or independent. An integral part of the psychodynamic approach to psychotherapy is the examination of characteristic defense mechanisms. Patients with panic disorder typically use any combination of the following defenses: reaction formation, undoing, somatization, and externalization. Both reaction formation and undoing serve to reassure the patient that negative affects are either absent or completely controllable. The psychotherapist's strategy with such defenses is to make the patient aware of his or her anxiety about the expression of anger and the associated need to disavow it. Hence a patient who repeatedly assures the therapist that he loves his father and that his father can do no wrong may be actively disavowing his anger. The therapist might intervene by noting the defense, as in the following observation: “I often feel that you're very invested in letting me know how much you love your father. It makes me wonder what other feelings you have about him.” The defenses of somatization and externalization are both designed to avoid reflection and introspection. Somatization places the patient's focus on what is happening physiologically. It is an attempt to make the panic attack a phenomenon that is devoid of psychological causes or meaning. Externalization places the origin of the problem in external persons who are viewed as mistreating the patient in some way. In some cases the focus on somatization may unconsciously create a specific form of object relationship in which the patient enlists others as healers who are supposed to fix something in the body. This object relationship may be activated in the transference, and the therapist may clarify how the preoccupation with bodily symptoms establishes a dependent relationship with the therapist. Anger at the therapist may then be explored by examining the patient's disappointment that the therapist is unable to “fix” the patient's problems. A long-range

psychotherapeutic strategy is to help the patient view the panic as an internally generated phenomenon rather than to blame others for it. There is a good deal of outcome data suggesting that cognitive therapy and pharmacotherapy are effective in treating panic disorder. Psychodynamic therapy has not been studied as extensively as the other two modalities, but there are numerous case reports in the literature suggesting that dynamic therapy is useful. Moreover, at least one study used a randomized, controlled design that demonstrates the effectiveness of dynamic therapy at reducing relapse in patients with panic disorder. In this study patients were randomized to treatment with either clomipramine (Anafranil) for 9 months or clomipramine for 9 months combined with 15 weekly sessions of brief dynamic therapy. Whereas all patients in both groups were free of panic attacks within 26 weeks of the start of treatment, the relapse rate was significantly higher in the group that received only clomipramine when the pharmacotherapy was terminated. The investigators concluded that brief dynamic therapy may reduce the psychosocial vulnerability that is associated with panic disorder. Integrations of cognitive techniques with dynamic psychotherapy are also useful. In virtually every case of panic disorder, distortions of thinking need to be addressed as part of the psychotherapeutic strategy. Although both cognitive therapy and pharmacotherapy are effective in the short run, long-term follow-up studies suggest that some patients continue to experience symptoms when the medication is withdrawn or when the brief cognitive therapy has terminated; most patients will require additional treatment. Studies are needed to demonstrate which patients may be particularly suited to extended psychoanalytic therapy either alone or in combination with medication and other techniques.

PHOBIAS Phobias are the most common of all anxiety disorders. In DSM-IV they are subdivided into three categories: (1) agoraphobia without history of panic disorder, (2) specific phobia, and (3) social phobia. Social phobia, which is the most common of all phobias, is further subdivided into two subtypes. The nongeneralized type is characterized by a fear of public situations such as public speaking or performing on stage. As many as 20 percent of the populations surveyed have acknowledged this fear. The second variety is a generalized type in which almost all social interactions are feared. This variant may be difficult to differentiate from avoidant personality disorder. Freud regarded the phobias as neurotic entities and therefore understood the mechanism of symptom formation to be consistent with his 1926 theory of anxiety. When unacceptable aggressive or sexual thoughts that could lead to a fantasy of punishment begin to emerge from the unconscious, signal anxiety is produced, which then leads to the deployment of specific ego defense mechanisms. The first of these is displacement, which involves the redirection of anxiety associated with an unconscious source to a conscious substitute that is often intrinsically harmless. Projection is the second specific defense mechanism used by phobics to get the source outside of themselves and into the external world. The third defense is avoidance, which is simply a systematic process of not coming into contact with the displaced and projected item that the anxiety is associated with. If that item is elevators, the individual always takes the stairs. If the item is dogs, the individual avoids dogs. The end result is that the three combined defenses may eliminate the anxiety because the unacceptable or forbidden thought is re-repressed. However, the anxiety generated by the thought is controlled at the cost of creating a phobic neurosis with all its associated inconvenience. Behavioral therapies using relaxation and in vivo exposure procedures have been highly effective in treating phobias. Cognitive therapies, which usually include an exposure element, have also been effective. There are few controlled studies of psychotherapies other than those of the cognitive or behavioral orientation. Nonetheless, psychodynamic understanding may enhance a broad-based overall treatment plan. Phobias are best understood as reflecting a genetic-constitutional diathesis that is acted upon by environmental stressors. A study of 2163 female twins concluded that the best model for the disorder is the inheritance of a vulnerability to phobias that require environmental factors specific to the individual to produce a diagnosable phobic syndrome. In this study population, parental death before the age of 17 was clearly associated with an increased risk for phobia. Work on the temperamental construct of behavior inhibition to the unfamiliar appears to be applicable to social phobia in much the same way it is relative to panic disorder. The expectation that one will be embarrassed and humiliated by the critical scrutiny of others appears to have some origin in temperamental disposition. Children who are behaviorally inhibited appear to be born with a much lower threshold for limbic-hypothalamic arousal in response to unexpected or novel events in the environment that are difficult to assimilate. To result in shy, withdrawn, and timid behavior at 2 years of age, however, chronic environmental stressors must act on the basic temperamental disposition that was present at birth. It has been suggested that some of these stressors might include criticism and humiliation from an older sibling, parental fighting, and separation from a parent through death or divorce. It was also possible to differentiate children who develop shyness purely in response to environmental factors alone without the underlying temperament. A clinical cohort study examined the families of these children and found that the parents were at greater risk for most anxiety disorders, and particularly social phobia. Compared with parents in control groups, they had higher rates of two or more anxiety disorders. The investigators speculate that such children with behavioral inhibition may go on to develop anxiety disorders in part because of genetic factors and in part because their parents may have greater anxiety and thus convey messages to their children that the world is unsafe. Social phobia is an example of an anxiety disorder that may have been artificially distinguished from other related disorders. The lifetime comorbidity approaches 70 percent with persons with social phobia. This entity is rarely treated by mental health professionals unless it is accompanied by other disorders that bring the person to attention. An underlying genetic constitutional diathesis may actually predispose an individual to several anxiety disorders. Psychotherapeutic Techniques Dynamic psychotherapy with individuals who have social phobia attempts to get to the heart of the patient's fears. Embarrassment and shame are central affects, and the patient's affect states are a good starting point. As the patient begins to feel embarrassed, the therapist encourages exploration of the patient's fantasies of how others will react to him or her. Within these perceptions or fears of other people's reactions, the therapist will find a characteristic pattern of internal object relationships within the patient that is then externalized in any social situation. Patients with social phobia often have internalized representations of others, usually parents, siblings, or caretakers, that involve shaming, ridiculing, humiliating, criticizing, and abandoning the patient. In some cases these representations will be distortions of the way childhood interactions actually occurred; in others they will be closely related to the actual behavior by family members. In either case the therapist's task is to help the patient see that the fantasies of how others react are largely based on adverse childhood experiences rather than on the reality of the interactions in the patient's current environment. Often therapeutic work within the transference is extremely helpful in this regard, as in the following example:

A 27-year-old woman who could not finish her PhD in history came to psychotherapy because a selective serotonin reuptake inhibitor had not significantly helped her with her social phobia. She was too anxious to meet with her dissertation committee so her academic progress had been seriously delayed. After missing one session of her therapy, she came to the next session and apologized for her absence. The therapist asked, “What made you stay away last time?” The patient responded, “I was afraid you were going to criticize me for not going to my meeting with my dissertation committee.” The therapist asked, “Have you experienced me as critical of you in the time we've worked together? The patient replied, “No, not really. You're actually the opposite of critical. You're patient with me, supportive, and always trying to help in any way you can.” The therapist then said, “It may be then that the perception of me being critical arises from within yourself rather than being based on my actual behavior with you.” The patient reflected for a moment and said, “There must be something to that. I'm always imagining that others are going to criticize or embarrass me, even when I don't have any hard evidence that such a response is likely.” The therapist made the following observation, “Your dissertation committee has not actually been critical of you, so it may be that the same concerns you have here with me are applicable with your committee. In other words, your fear of negative responses from them may largely be an internal one rather than a reality-based fear.” Discussion In this case, the therapist is drawing a link between the anxiety in the transference and the anxiety in a present-day situation outside of the therapy. As the therapy progressed, he also made a linkage to the patient's childhood when the patient felt repeatedly humiliated and criticized by her parents. The interpersonal dimensions of phobias are often crucially important in the treatment of phobias. In the case of individuals for example, one often finds that the spouse of such a patient may be instrumental in maintaining the symptomatic behavior. For example, the husband of a woman with agoraphobia may feel much more secure with his wife in the house because he fears that she will find another man if she leaves the home. The husband's jealousy is controlled by keeping his wife indoors. Any treatment effort that tries to change the nature of this system may be doomed because the husband will not cooperate with the treatment plan. The patient herself may also resist the treatment because she fears her husband's jealous rage. Hence in many cases of resistance to behavioral or cognitive-behavioral interventions, a psychodynamic approach may be needed either in a marital or an individual context. An overview of psychodynamic aspects of phobias is summarized in Table 15.5-3.

Table 15.5-3 Psychodynamic Themes in Phobias

OBSESSIVE-COMPULSIVE DISORDER Within the psychoanalytic literature there has been a frequent confusion between obsessive-compulsive personality disorder and obsessive-compulsive disorder. While they were previously thought to reside on the same continuum of symptomatology, the evidence is mounting that the two are somewhat distinct entities. Patients with obsessive-compulsive disorder view their symptoms ego-dystonically, that is, they experience distress connected with their symptoms. By contrast, the traits