Obsessive-compulsive Disorder: Phenomenology, Pathophysiology, and Treatment [1 ed.] 0190228164, 9780190228163

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O BSE SSI V E -​COM P U L SI VE DI SORDER

 

 

OBSESSIVE-​C OMPULSIVE DISORDER Phenomenology, Pathophysiology, and Treatment

EDITED BY

Christopher Pittenger, MD, PhD DIRECTOR, YALE OCD RESEARCH CLINIC ASSOCIATE PROFESSOR OF PSYCHIATRY AND IN THE CHILD STUDY CENTER YALE UNIVERSITY SCHOOL OF MEDICINE

1

 

1 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America. © Oxford University Press 2017 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. CIP data is on file at the Library of Congress ISBN 978–​0–​19–​022816–​3 This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be c­ urrent as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose s­ chedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date p­ ublished product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the m ­ aterial. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. 9 8 7 6 5 4 3 2 1 Printed by Sheridan Books, Inc., United States of America

 

TABLE OF CONTENTS

PREFACE 

ix

CONTRIBUTORS 

xi

1. INTRODUCTION: NARRATIVES OF OCD 

1

Elias Aboujaoude and Christopher Pittenger

11

23

35

14. CLINICAL RATING SCALES FOR OCD 

15. NEUROPSYCHOLOGICAL FUNCTION IN OCD 

47

57

17. INTOLERANCE OF UNCERTAINTY IN OCD 

149

161

171

Ryan J. Jacoby and Jonathan S. Abramowitz 18. PATHOLOGICAL RESPONSIBILITY, THOUGHT-​ACTION FUSION, AND THOUGHT CONTROL IN OCD 

179

Christine Purdon 65

SECTION 3: BIOLOGICAL UNDERPINNINGS  19. GENETICS OF OCD 

189

Paul Arnold

SECTION 2: PHENOMENOLOGY AND COGNITIVE PSYCHOLOGY  

20. NEUROCIRCUITRY UNDERLYING OCD: NEURAL NETWORKS UNDERLYING REWARD AND ACTION SELECTION  75

Maria Conceição do Rosário, Marcelo Camargo Batistuzzo, and Ygor Ferrao 9. INCOMPLETENESS AND HARM AVOIDANCE IN OCD  93 Stefano Pallanti, Jennifer Barnes, Christopher Pittenger, and Jane Eisen

137

Claire M. Gillan

Robert A. King

8. SYMPTOM HETEROGENEITY IN OCD:  A DIMENSIONAL APPROACH 

129

Amitai Abramovitch 16. HABITS AND GOALS IN OCD 

Christina L. Boisseau, Carly M. Schwartzman, and Steven A. Rasmussen 7. PSYCHODYNAMIC PERSPECTIVES ON OCD 

13. VARIABLE INSIGHT IN OCD 

Joseph F. McGuire, Eric A. Storch, and Wayne Goodman

Michael H. Bloch 6. QUALITY OF LIFE AND PSYCHOSOCIAL FUNCTIONING OF OCD 

119

Rebecca J. Hamblin, Jennifer Moonjung Park, Monica S. Wu, and Eric A. Storch

Albina R. Torres, Leonardo F. Fontenelle, Roseli G. Shavitt, Marcelo Q. Hoexter, Christopher Pittenger, & Euripedes C. Miguel 5. NATURAL HISTORY AND LONG-TERM OUTCOME IN OCD 

113

Rachel Ojserkis and Dean McKay

Rachel E. Ginsberg, Samantha Morrison, & Anthony Puliafico 4. EPIDEMIOLOGY, COMORBIDITY, AND BURDEN OF OCD 

11. SENSORY PROCESSING AND INTOLERANCE IN OCD 

12. SCRUPULOSITY AND SLOWNESS IN OCD: PERFECTIONISM AS A CENTRAL MECHANISM 

Fred Penzel 3. PEDIATRIC OCD: CLINICAL COURSE, PHENOMENOLOGY, AND ASSESSMENT 

101

Lauren Mancusi, Dean McKay, and Bunmi Olatunji

Stephanie J. Grimaldi and Emily R. Stern

SECTION 1: CLINICAL PRESENTATION AND DIAGNOSIS  2. CLINICAL PRESENTATION OF OCD 

10. DISGUST AND OCD 

201

Suzanne N. Haber 21. FUNCTIONAL NEUROIMAGING STUDIES IN OBSESSIVE-COMPULSIVE DISORDER: OVERVIEW AND SYNTHESIS 

213

Brian P. Brennan and Scott L. Rauch

v

 

22. TASK-BASED FUNCTIONAL NEUROIMAGING STUDIES OF OBSESSIVE-COMPULSIVE DISORDER: A HYPOTHESIS-DRIVEN REVIEW 

SECTION 5: TREATMENT  231

247

Premika S. W. Boedhoe and Odile A. van den Heuvel 24. BRAIN FUNCTIONAL CONNECTIVITY IN OCD 

259

289

Anahid Kabasakalian and Eric Hollander 27. INFLUENCE OF SEX HORMONES ON OCD 

301

Valeria Guglielmi, Judith Souget, Wouter van Elzelingen, Ingo Willuhn, and Nienke Vulink 28. PANDAS AS A POSTSTREPTOCOCCAL AUTOIMMUNE NEUROPSYCHIATRIC FORM OF OCD  311 Susan E. Swedo and Kyle A. Wiliams

38. COGNITIVE THERAPY FOR OCD 

421

39. MINDFULNESS AND ACCEPTANCE THERAPIES FOR OCD 

431

Kate L. Morrison, Brooke M. Smith, and Michael P. Twohig 40. STANDARD EVIDENCE-​BASED PHARMACOLOGICAL TREATMENT FOR OCD 

41. THE PHARMACOLOGICAL TREATMENT OF REFRACTORY OCD 

323

333

343

353

363

Louis Y. Tee and Guoping Feng

Summer L. Thompson and Stephanie C. Dulawa

vi

495

45. FUNCTIONAL NEUROSURGERY IN SEVERE AND TREATMENT-​REFRACTORY OCD 

507

46. DEEP BRAIN STIMULATION FOR INTRACTABLE OCD 

517

Wayne K. Goodman, Nigel Kennedy, Kyle Lapidus, and Brian H. Kopell 47. INTENSIVE TREATMENT APPROACHES FOR OCD 

533

Joshua M. Nadeau, Bradley C. Riemann, and Eric A. Storch 375

Susanne E. Ahmari 35. PHARMACOLOGICAL AND BEHAVIORAL RODENT MODELS OF OCD 

44. NUTRACEUTICAL AND ALTERNATIVE TREATMENTS FOR OBSESSIVE-​COMPULSIVE AND RELATED DISORDERS 

Erica C. Keen, Alik S. Widge, and Darin D. Dougherty

Nicholas H. Dodman and Louis Shuster

34. TARGETED CIRCUIT MANIPULATIONS IN THE MODELING OF OCD 

487

David A. Camfield and Jerome Sarris

Laura Bradfield, Richard Morris, and Bernard W. Balleine

33. MUTANT MOUSE MODELS OF OCD 

43. FAMILY ACCOMMODATION IN OCD: PREVALENCE, IMPACT, AND CLINICAL IMPLICATIONS  Kristin Koller and Eli R. Lebowitz

Jose Rodriguez-​Romaguera and Gregory J. Quirk

32. SPONTANEOUSLY OCCURRING ANIMAL MODELS OF OCD 

473

S. Evelyn Stewart and Clare Bleakley

Christopher Pittenger, Stephanie Dulawa, and Summer L. Thompson

31. OCD AS A FAILURE TO INTEGRATE GOAL-​DIRECTED AND HABITUAL ACTION CONTROL 

463

Christopher Pittenger

SECTION 4: ANIMAL STUDIES 

30. EXTINCTION OF CONDITIONED FEAR AND AVOIDANCE: RELEVANCE FOR OCD 

443

Jemma E. Reid, Samar Reghunandanan, Ann Roberts, and Naomi A. Fineberg

42. TREATMENT OF PEDIATRIC OCD  29. ANIMAL MODELS OF OCD: A CONCEPTUAL FRAMEWORK 

411

Maureen Whittal 271

Ilse Graat, Martijn Figee, and Damiaan Denys 26. NEUROPEPTIDES IN OCD 

37. EXPOSURE AND RESPONSE PREVENTION IN OCD  Jonathan S. Abramowitz

Carles Soriano-​Mas and Ben J. Harrison 25. NEUROTRANSMITTER DYSREGULATION IN OCD 

403

H. Blair Simpson

M. M. Vaghi and T. W. Robbins 23. THE STRUCTURE OF THE OCD BRAIN 

36. OVERVIEW OF THE TREATMENT OF OCD 

SECTION 6: OCD-​RELATED DISORDERS  385

48. OBSESSIVE-​COMPULSIVE AND RELATED DISORDERS: A NEW CATEGORY IN DSM-​5 

541

Katharine A. Phillips

TABLE OF CONTENTS

 

49. CLINICAL FEATURES, ASSESSMENT, AND TREATMENT OF BODY DYSMORPHIC DISORDER 

547

Lisa Zakhary, Hilary Weingarden, Alexandra Sullivan, and Sabine Wilhelm 50. BODY DYSMORPHIC DISORDER: NEUROBIOLOGY AND GENETICS 

557

51. TRICHOTILLOMANIA AND SKIN PICKING DISORDER  567 Jon E. Grant, Sarah A. Redden, and Eric W. Leppink 579

589

603

62. RESEARCH DOMAIN CRITERIA AND OCD: AN OXYMORON? 

683

689

613

623

Marina Gershkovich, Olivia Pascucci, and Joanna Steinglass

Michael Poyurovsky

715

Allen H. Weg 65. THE INTEGRATION OF NEW TECHNOLOGICAL APPROACHES IN OCD CARE 

723

Seth Feuerstein 66. OCD ADVOCACY AND ADDRESSING STIGMA 

57. OBSESSIVE-​COMPULSIVE SYMPTOMS IN SCHIZOPHRENIA: CLINICAL FEATURES, NEUROBIOLOGICAL CORRELATES, AND TREATMENT  631

703

Monnica T. Williams and Terence Ching 64. OCD IN THE EDUCATIONAL SETTING 

Dean McKay, Rachel Ojserkis, and Jon D. Elhai

58. DIFFERENTIATING AUTISM SPECTRUM DISORDER AND OCD 

61. EVOLUTIONARY PERSPECTIVES ON OCD 

63. OCD IN ETHNORACIAL MINORITIES: SYMPTOMS, BARRIERS TO CARE, AND CULTURAL CONSIDERATIONS FOR TREATMENT 

L. Baer, A. Fang, N. C. Berman, and W. E. Minichiello

56. EATING DISORDER COMORBIDITY WITH OCD 

669

Eyal Kalanthroff, Gideon E. Anholt, and Helen Blair Simpson

SECTION 7: COMORBIDITY 

55. PSYCHOLOGICAL TRAUMA EXPOSURE AND OBSESSIVE-​COMPULSIVE SYMPTOMS 

60. THE DYNAMICS OF OBSESSIVE-COMPULSIVE DISORDER: A HEURISTIC FRAMEWORK 

Gerrit I. van Schalkwyk and James F. Leckman

Michael H. Bloch

54. MOOD AND ANXIETY DISORDER COMORBIDITY IN OCD 

SECTION 8: SPECIAL TOPICS 

Christopher Pittenger, Patricia Gruner, Thomas A. Adams, and Benjamin Kelmendi

Randy O. Frost, Lucy Graves, and Elizabeth Atkins 53. COMORBIDITY IN PEDIATRIC OCD: TOURETTE SYNDROME 

655

Michael G. Wheaton and Anthony Pinto

Jamie D. Feusner and Danyale McCurdy-​McKinnon

52. HOARDING DISORDER: CLINICAL PRESENTATION AND TREATMENT 

59. PERSONALITY PATHOLOGY IN OCD: COMORBIDITY AND CONTRAST WITH OCPD AND OTHER PERSONALITY DISORDERS 

729

Jeff Szymanski and Carly Bourne 67. LIVING WITH OCD 

739

Elizabeth McIngvale Index 

745

643

Robert E. Accordino, W. Philip Bartel, Isobel W. Green, Christen L. Kidd, and Christopher J. McDougle

TABLE OF CONTENTS

vii

 

 

PREFACE

Almost everyone has experienced an unreasonable obsessive thought or a compulsive urge. Distressing obsessions and compulsions occur in approximately 30% of the population, and approximately 2.5% – one person in 40 – experiences sufficient distress or impairment from them to merit a diagnosis of obsessive-compulsive disorder (OCD) at some point in their lives. Our understanding of the clinical features, cognitive psychology, and neurobiological underpinnings of obsessions and compulsions has advanced substantially over the last several decades, as has our ability to treat them. These advances have brought relief to many and have the potential, if evidence-based treatments were universally deployed, to help many more. However, our knowledge remains fundamentally incomplete, and many OCD sufferers respond incompletely or not at all to available interventions. Thus, while we as a field can take some pride in the advances of the last several decades, we must not rest; there is much work still to do. This volume seeks to provide a comprehensive overview of current understanding of OCD, and of its relationship to other common clinical conditions. As the subtitle indicates, the chapter authors and I have attempted to approach the clinical and psychological entity of OCD from a range of complementary perspectives. OCD is remarkably variable in its clinical presentation; we have devoted considerable space to a detailed exploration of different aspects of its phenomenology, in an effort to do justice to this heterogeneity. This includes the perspectives of both clinicians and OCD sufferers, as well as more theoretical considerations. Next, we have considered current understandings of pathogenesis and pathophysiology, from the perspectives of clinical and cognitive psychology, neurobiology, genetics, and relevant studies in animal model systems. Finally, we review multiple forms of treatment, including cognitive-behavioral therapy (CBT), evidence-based pharmacotherapy, less well proven approaches that may have value in refractory cases, and cutting-edge anatomically targeted interventions. In the study and treatment of OCD, there has at times been an unfortunate opposition between advocates of a CBT-based interventions and psychological understanding

of the disorder on the one hand, and pharmacotherapy and a neurobiological perspective on pathophysiology on the other. This is of course an artificial dichotomy; psychological and biological understandings are simply different perspectives on the same underlying construct: the human brain, in all its magnificent complexity, and the corresponding extraordinary richness of human experience and behavior that it subserves. Both sides of this dichotomy are astonishingly intricate when considered in isolation. Our understanding of their interaction, of the relationship of brain to behavior and of psychological symptomatology to neural abnormalities, remains woefully incomplete. The project is made even more difficult when the bidirectional nature of causal relationships between brain and behavior is considered: alterations in the brain can of course produce changes in behavior and cognition; but psychological phenomena, including social interactions and psychotherapy, can also produce measurable neurobiological change. Due to these multiple interacting layers of complexity, psychological and somatic perspectives can be challenging to unify, or even to keep in mind at the same time. It is our hope to facilitate understanding and cross-pollination across different explanatory levels and clinical/scientific perspectives by treating them side by side in the current volume. A project of this scope is possible only through the combined efforts of many, and I wish to acknowledge and thank them here. First and foremost, I  thank the many chapter authors for their contributions. Nobody can be expert in the enormous range of perspectives and material covered in a volume such as this, and the expert knowledge and perspectives of this group of individuals, from all over the world, is what made this project possible. I thank you also for your patience with the time that a volume such as this takes to put together, and with my sometimes-obsessive editing. The publishing team at Oxford University Press has shepherded this project from conception through completion over the past several years, providing needed hand-holding to a first-time editor and expertly striking the difficult balance between micromanaging on the one hand, and leaving me to wander aimlessly in the vales of

 

perfectionism and procrastination on the other. I  particularly thank Andrea Knobloch, Allison Pratt, Devi Vaidyanathan, and Christi Divya Vannarasi Charles, who have helped bring this project through to completion over the past year. Looking back, I am grateful to Craig Panner, who originally approached me about this ambitious project, and to Lani Oshima, who guided it through its middle stages. My scientific and clinical growth and interest in OCD have been fostered by a series of dedicated mentors, and I  take this opportunity to thank them. In particular, my thesis mentor at Columbia University, Eric Kandel, modeled a cross-disciplinary and synthetic perspective on how to approach translational science that has permeated my work ever since. At Yale, Vladimir Coric introduced me to both the clinical care of patients with OCD and to clinical research. John Krystal, Jerry Sanacora, Bob Malison, Jim Leckman, and many others supported my growth as a clinical researcher; and Ron Duman, Jane Taylor, Marina Picciotto, and many others modeled the translational application of more basic and mechanistic studies, supporting me in the development of my own translational research program. I  have been blessed with countless other mentors, collaborators, and colleagues over the years who have

x

helped to guide my development as a clinician and as a translational researcher. I will not attempt a comprehensive list here; but you know who you are. Please know that I do, too, and I am grateful. The community of OCD researchers is remarkably close-knit and welcoming, and I am grateful to a number of more senior members of this community who have welcomed, educated and supported me over the past decade – in particular, Sabine Wilhelm; H. Blair Simpson; Michael Jenike; David Tolin; Randy Frost; Jon Grant; Katherine Phillips; Bob King; Matt State. Any value that this volume has can be ascribed in large part to the extraordinarily collaborative character of this community. Finally, my loving family has been patient and supportive throughout the slow and sometimes painful process of pulling this book together. Jenny, thank you for putting up with me. You are my reality-check, my partner, and frequently my inspiration, without whom nothing else would matter. And to my four kids – this is what Dad’s been up to in the wee hours of the night these past few years. Christopher Pittenger, MD, Ph.D. Bethany, CT July 2017

P R E FAC E

 

CONTRIBUTORS

Amitai Abramovitch, PhD Department of Psychology Texas State University San Marcos, Texas Jonathan S. Abramowitz, PhD Department of Psychology & Neuroscience University of North Carolina at Chapel Hill Chapel Hill, North Carolina Robert E. Accordino, MD, MSc Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Thomas A. Adams, PhD Department of Psychiatry Yale University School of Medicine New Haven, Connecticut Susanne E. Ahmari, MD, PhD Department of Psychiatry Translational Neuroscience Program Center for Neuroscience Center for the Neural Basis of Cognition University of Pittsburgh Pittsburgh, Pennsylvania Gideon E. Anholt, PhD Department of Psychology Ben-​Gurion University of the Negev Ber-​Sheva, Israel Paul Arnold, MD, PhD, FRCPC Departments of Psychiatry and Medical Genetics and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary Alberta, Canada Elizabeth Atkins, BA Smith College Northampton, Massachusetts Bernard W. Balleine, PhD Brain and Mind Center Sydney University Sydney, New South Wales, Australia

Jennifer Barnes, MD McLean Hospital Belmont, Mssachusetts W. Phillip Bartel, BA The Rockefeller University New York, New York Marcelo Camargo Batistuzzo, PhD Institute of Psychiatry University of São Paulo São Paulo, Brazil Noah C. Berman, PhD Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Clare Bleakley, MBBS Department of Psychiatry University of British Columbia Vancouver British Columbia, Canada Michael H. Bloch, MD, MS Child Study Center and Department of Psychiatry Yale University School of Medicine New Haven, Connecticut Premika S.W. Boedhoe, MSc Department of Psychiatry Department of Anatomy & Neurosciences Neuroscience Campus Amsterdam Vrije Universiteit Medical Center Amsterdam, The Netherlands Christina L. Boisseau, PhD Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Butler Hospital Providence, Rhode Island Carly Bourne, MA The International OCD Foundation Boston, Massachusetts xi

 

Laura Bradfield, PhD Brain and Mind Center Sydney University Sydney, New South Wales, Australia

Jane Eisen, MD Department of Psychiatry St. Lukes Hospital and Mt. Sinai School of Medicine New York, NY

Brian P. Brennan, MD McLean Hospital Belmont, Massachusetts Department of Psychiatry Harvard Medical School Boston, Massachusetts

Jon D. Elhai, PhD Department of Psychology University of Toledo Toledo, Ohio

David A. Camfield, PhD School of Psychology and Centre for Health Initiatives University of Wollongong Illawarra Health & Medical Research Institute Wollongong, New South Wales, Australia Centre for Human Psychopharmacology Swinburne University of Technology Hawthorn, Victoria, Australia Terrence Ching, M Soc Sci Center for Mental Health Disparities Department of Psychological & Brain Sciences University of Louisville Louisville, Kentucky Damiaan Denys, MD, PhD Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam Brain and Cognition Netherlands Institute for Neuroscience Amsterdam, The Netherlands Maria Conceição do Rosário, MD, PhD Child and Adolescent Psychiatry Unit (UPIA) Department of Psychiatry Federal University of São Paulo, Brazil Nicholas H. Dodman, BVMS, DACVA, DACVB Cummings Veterinary Medical Center Tufts University N. Grafton, Massachusetts Darin D. Dougherty, MD Department of Psychiatry Massachusetts General Hospital, McLean Hospital, and Harvard University Boston, Massachusetts Stephani Dulawa, PhD Department of Psychiatry University of California San Diego San Diego, California xii

Angela Fang, PhD Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Guoping Feng, PhD McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Cambridge, Massachusetts Ygor Ferrao, MD, PhD Department of Psychiatry Federal University of Health Sciences of Porto Alegre Porto Alegre, Brazil Seth Feurerstein, MD, JD Chief Medical Officer Medical and Digital Magellan Health Care, LLC Department of Psychiatry Yale University School of Medicine New Haven, Connecticut Jamie D. Feusner, MD University of California Los Angeles Martijn Figee, MD, PhD Department of Psychiatry University of Amsterdam Amsterdam, The Netherlands Naomi A. Fineberg, MD Highly Specialized OCD and BDD Services Hertfordshire Partnership University NHS Foundation Trust Department of Postgraduate Medicine University of Hertfordshire Hatfield, United Kingdom Cambridge and Peterborough NHS Foundaiton Trust Cambridge, United Kingdom

C ontributors

 

Leonardo F. Fontenelle, MD, PhD Anxiety and Depression Research Program Institute of Psychiatry Federal University of Rio de Janeiro D’Or Institute for Research and Education Rio de Janeiro, Brazil Randy O. Frost, PhD Department of Psychology Smith College Northampton, Massachusetts Marina Gershkovich, BA Department of Psychiatry Columbia University College of Physicians and Surgeons New York, New York Claire M. Gillan, PhD Department of Psychology New York University New York, New York Department of Psychology Trinity College Dublin, Ireland Rachel E. Ginsberg, PhD Department of Psychiatry Columbia University Medical Center New York, New York Wayne K. Goodman, MD Department of Psychiatry Baylor College of Medicine Houston, Texas Ilse Graat, MD Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Jon E. Grant, JD, MD, MPH Department of Psychiatry & Behavioral Neuroscience University of Chicago Chicago, Illinois Lucy Graves, BA Smith College Northampton, Massachusetts Isobel W. Green Harvard University Boston, Massachusetts

C ontributors

Stephani J. Grimaldi, MA Departments of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai New York, New York Patricia Gruner, PhD Department of Psychiatry Yale University School of Medicine New Haven, Connecticut Valeria Guglielmi, MD Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Suzanne N. Haber, PhD Departments of Pharmacology and Physiology University of Rochester School of Medicine Rochester, New York Rebecca J. Hamblin, PhD Department of Pediatrics University of South Florida Tampa, Florida Rogers Behavioral Health –​Tampa Bay Tampa, Florida Ben J. Harrison, PhD Department of Psychiatry Melbourne Neuropsychiatry Centre The University of Melbourne Melbourne, Victoria, Australia Marcelo Q. Hoexter, MD, PhD Department of Psychiatry University of São Paulo Medical School São Paulo, Brazil Eric Hollander, MD Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York Ryan J. Jacoby, MA Department of Psychology University of North Carolina at Chapel Hill Chapel Hill, North Carolina Anahid Kabaskalian, MD Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York

xiii

 

Eyal Kalanthroff, PhD Department of Psychiatry Columbia University New York, New York Erica C. Keen, MD, PhD Department of Psychiatry Massachusetts General Hospital Boston, Massachusetts Department of Psychiatry Icahn School of Medicine at Mount Sinai New York, New York Benjamin Kelmendi, MD Department of Psychiatry Yale University School of Medicine New Haven, Connecticut Nigel Kennedy, MD Departments of Psychiatry and Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York Christen L. Kidd, MD New York-​Presbyterian Hospital Weill Cornell Medical Center New York, New York

James F. Leckman, MD, PhD Neison Harris Professor of Child Psychiatry, Psychiatry, Psychology, and Pediatrics Yale University Child Study Center New Haven, Connecticut Lee Baer, PhD Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Eric W. Leppink, BA Department of Psychiatry & Behavioral Neuroscience University of Chicago Chicago, Illinois Lauren Mancusi, MA Department of Psychology Fordham University Bronx, New York Danyale McCurdy-​McKinnon, PhD Semel Institute for Neuroscience and Human Behavior University of California, Los Angeles Los Angeles, California

Robert A. King, MD Child Study Center Yale University School of Medicine New Haven, Connecticut

Christopher J. McDougle, MD Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

Kristin Koller, MSc Child Study Center Yale University School of Medicine New Haven, Connecticut

Joseph F. McGuire, PhD Semel Institute of Neuroscience and Human Behavior University of California Los Angeles Los Angeles, California

Brian H. Kopell Departments of Psychiatry and Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York

Elizabeth McIngvale, PhD, LMSW Baylor University Peace of Mind Foundation Houston, Texas

Kyle Lapidus, MD, PhD Department of Psychiatry Hofstra Northwell School of Medicine East Garden City, New York

Dean McKay, PhD Department of Psychology Fordham University Bronx, New York

Eli R. Lebowitz, PhD Child Study Center Yale University School of Medicine New Haven, Connecticut

Euripedes C. Miguel, MD, PhD Department of Psychiatry University of São Paulo Medical School São Paulo, Brazil

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C ontributors

 

William E. Minichiello, EdD Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

Katharine A. Phillips, MD Department of Psychiatry and Human Behavior Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island

Jennifer Moonjung Park, PhD Department of Psychiatry Massachusetts General Hospital Boston, Massachusetts Department of Psychiatry Stanford University Palo Alto, California

Anthony Pinto, PhD Department of Psychiatry Hofstra Northwell School of Medicine Zucker Hillside Hospital Glen Oaks, New York

Richard Morris, PhD Brain and Mind Research Institute Sydney University Sydney, New South Wales, Australia

Christopher Pittenger, MD, PhD Departments of Psychiatry and Psychology and Child Study Center Yale University School of Medicine New Haven, Connecticut

Kate L. Morrison, PhD Department of Psychology Utah State University Logan, Utah

Michael Poyurovsky, MD, PhD Department of Psychiatry Rappaport Faculty of Medicine Institute of Technology Technion, Israel

Samantha Morrison, PhD Department of Psychiatry Columbia University Medical Center New York, New York

Anthony Puliafico, PhD Department of Psychiatry Columbia University Medical Center New York, New York

Joshua M. Nadeau, PhD Department of Pediatrics University of South Florida Tampa, Florida Rogers Behavioral Health –​Tampa Bay Tampa, Florida

Christine Purdon, PhD, C Psych Department of Psychology University of Waterloo Waterloo, Ontario, Canada

Bunmi Olatunji, PhD Departments of Psychology and Psychiatry Vanderbilt University Nashville, Tennessee Stefano Pallanti, MD, PhD Department of Psychiatry University of Florence Florence, Italy Oliver Pascucci, BA Department of Psychiatry Columbia University College of Physicians and Surgeons New York, New York

C ontributors

Gregory J. Quirk, PhD Departments of Psychiatry and Anatomy & Neurobiology University of Puerto Rico School of Medicine San Juan, Puerto Rico Steven A. Rasmussen, MD Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Scott L. Rauch, MD McLean Hospital Belmont, Massachusetts Department of Psychiatry Harvard Medical School Boston, Massachusetts

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Sarah A. Redden, BA Department of Psychiatry & Behavioral Neuroscience University of Chicago Chicago, Illinois

Louis Shuster, MD Department of Integrative Physiology and Pathobiology Tufts University Boston, Massachusetts

Samar Reghunandanan, MD Cambridge and Peterborough NHS Foundation Trust Huntingdon, United Kingdom

Helen Blair Simpson, MD, PhD Department of Psychiatry Columbia University The Center for OCD and Related Disorders New York State Psychiatric Institute New York, New York

Jemma E. Reid, MSc, MBBS, MRCPsych Highly Specialized OCD and BDD Services Hertfordshire Partnership University NHS Foundation Trust Hatfield, United Kingdom Bradley C. Riemann, PhD Rogers Memorial Hospital Oconomowok, Wisconsin T. W. Robbins, PhD Department of Psychology Behavioural and Clinical Neuroscience Institute University of Cambridge Cambridge, United Kingdom Ann Roberts, MA, MBBS, MRCPsych Department of Postgraduate Medicine University of Hertfordshire Thumbswood Mother and Baby Unit Hertfordshire Parthership University NHS Foundation Trust Hatfield, UK Jose Rodriguez-​Romaguera, PhD Departments of Psychiatry and Anatomy & Neurobiology University of Puerto Rico School of Medicine San Juan, Puerto Rico Jerome Sarris, PhD Centre for Human Psychopharmacology Swinburne University of Technology The University of Melbourne Department of Psychiatry The Melbourne Clinic Melbourne, Victoria, Australia Carly M. Schwartzman, BA Butler Hospital Providence, Rhode Island

Brooke M. Smith, MS Department of Psychology Utah State University Logan, Utah Carles Soriano-​Mas, PhD Department of Psychiatry Bellvitge Biomedical Research Institute-​IDIBELL Centro de Investigación Biomédica en Red de Salud Mental Department of Psychobiology and Methodology of Health Sciences Universitat Autònoma de Barcelona Barcelona, Spain Judith Souget, MD Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Jonanna Steinglass, MD Department of Psychiatry Columbia University College of Physicians and Surgeons New York, New York Emily R. Stern, PhD Departments of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai New York, New York S. Evelyn Stewart, MD Department of Psychiatry University of British Columbia Vancouver, British Columbia, Canada

Soseli G. Shavitt, MD, PhD Department of Psychiatry University of São Paulo Medical School São Paulo, Brazil

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Eric A. Storch, PhD Departments of Pediatrics, Psychology, and Psychiatry & Behavioral Neurosciences University of South Florida Tampa, Florida Rogers Behavioral Health –​Tampa Bay Tampa, Florida All Children’s Hospital –​Johns Hopkins Medicine St. Petersburg, Florida Alexandra Sullivan, BA OCD and Related Disorders Program Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Susan E. Swedo, MD Pediatrics and Developmental Neuroscience Branch National Institute of Mental Health National Institutes of Health Bethesda, Maryland Jeff Szymanski, PhD The International OCD Foundation Boston, Massachusetts Louis Y. Tee, PhD New York, New York Summer L. Thompson, MS University of California, San Diego San Diego, California Albina R. Torres, MD, PhD Department of Neurology, Psychology, and Psychiatry Botucatu Medical School Univ Estadual Paulista Botucatu, Brazil

Odile A. van den Heuvel, MD, PhD Department of Psychiatry Department of Anatomy & Neurosciences Neuroscience Campus Amsterdam Vrije Universiteit Medical Center Amsterdam, The Netherlands Wouter van Elzelingen, MD Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Gerrit I. van Schalkwyk, MBChB Yale Child Study Center Yale University School of Medicine New Haven, Connecticut Nienke Vulnick, MD, PhD, MBA Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Allen H. Weg, EdD Stress and Anxiety Services of New Jersey Springfield, New Jersey Hilary Weingarden, MA OCD and Related Disorders Program Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Michael G. Wheaton, PhD Ferkauf Graduate School of Psychology Yeshiva University Bronx, New York

Michael P. Twohig, PhD Depatment of Psychology Utah State University Logan, Utah

Alik S. Widge, MD, PhD Department of Psychiatry Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts

Matilde M. Vaghi, PhD Department of Psychology Behavioural and Clinical Neuroscience Institute University of Cambridge Cambridge, United Kingdom

Sabine Wilhelm, PhD Department of Psychiatry Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts

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Kyle A. Williams, MD, PhD Department of Psychiatry Harvard Medical School Boston, Massachusetts Monica T. Williams, PhD Department of Psychological Sciences University of Connecticut Storrs, Connecticut Ingo Willuhn, PhD Academic Medical Center University of Amsterdam Amsterdam, The Netherlands

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Monica S. Wu, MA Department of Pediatrics Department of Psychology University of South Florida Tampa, Florida Lisa Zakhary, MD, PhD OCD and Related Disorders Program Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

C ontributors

 

1. INTRODUCTION: NARRATIVES OF OCD Elias Aboujaoude, MD, MA and Christopher Pittenger, MD, PhD

I

n one of the earliest descriptions of an individual with likely obsessive-​compulsive disorder, John Moore, an English bishop, refers in a 1691 sermon to individuals consumed by “naughty, and sometimes Blasphemous Thoughts (which) start in their Minds, while they are exercised in the Worship of God (despite) all their endeavors to stifle and suppress them . . . (T)he more they struggle with them, the more they encrease” (Koran, 1999; p. 35). A century ago, such an individual would have been examined under the Freudian lens and conceptualized as regressed to an early psychosexual stage and lacking the mature defenses needed to ward off anxiety stemming from unconscious sexual or aggressive drives (Kay, 1996). Forty years ago, this “obsessive-​compulsive neurosis” might have been successfully treated with the tricyclic antidepressant clomipramine, with or without behavior therapy (Amin et al., 1976; Ananth, 1976). In 2015, a clinician might consider referring the patient to a trial of Virtual Reality Exposure Therapy (Kim et al, 2009), which employs virtual reality technology to gradually desensitize patients to anxiety-​ridden thoughts, images, or urges. For treatment of refractory cases, bilateral subthalamic nucleus electrical stimulation might be considered (Goodman & Alterman, 2012). In many ways, the arc of OCD over time, and of its treatment, has mirrored that of psychiatry itself—​an often frustratingly slow process to uncover the causes of, and treatments for, psychological torment, but one that has been punctuated by clear advances. Indeed, there is no doubt that OCD, the “doubting illness” ( Janet, 1908), is a better understood, more treatable entity today than ever before, with over half of the diagnosed cases quite responsive to extant, reasonably well tolerated therapies. But almost half of our patients continue to suffer, even if they receive the best available evidence-​grounded treatments, and important questions about the etiology, pathogenesis, pathophysiology, and treatment of OCD remain unanswered.

This book seeks to detail established facts regarding the phenomenology, epidemiology, pathophysiology, and treatment of OCD, and to highlight persistent gaps in our knowledge. But it is fitting that this introductory chapter be devoted to a series of clinical cases that introduce the basic features of the disorder. For readers with clinical experience, and those who themselves suffer from OCD, this introduction will contextualize the detailed material that follows. For readers without this personal familiarity with OCD, we hope that this introduction will provide some sense of the core symptomatology, its protean manifestations, and the profound and often existential suffering that it can create. Such a visceral appreciation is the essential foundation of the material that follows. Two patients with OCD that is equally severe, and equally impairing of their ability to lead fulfilling lives, may have not a single specific symptom in common. No OCD case can truly be representative: The variations on the core themes of OCD are endless, and they can interact subtly and pervasively with all aspects of the lives of those who suffer with the disorder. But let us begin at the beginning: with a single patient and her story. NATALIE Natalie* is a 45-​year old accountant who is seeking her first psychiatric consultation for an “embarrassing problem” that she says has impaired her for years. While in college, at age 20, with no particular trigger, she developed a peculiar fear: Natalie started worrying that she may have inadvertently stepped on a baby during her morning jog. Where the baby would have materialized from on the isolated trail where she used to run, or how she might have tripped over it and not noticed, she could not explain, but the need to verify that she did not stomp on a baby was so intense that

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she started to follow her jog with a slow-​paced hike during which she would comb the trail for any evidence of her “crime.” As a result of the time-​consuming pattern, she started missing morning classes, or arriving late. On days where she managed to resist the behavior, her concentration in class was too impacted for her to be productive. Eventually, Natalie graduated with an accounting degree and a B-​average, a clear drop from her mostly A grades during her freshman and sophomore years. After graduating from her suburban college, Natalie moved into the city and lived near the Internet startup where she started working. Her demanding schedule prevented her from any form of exercise, including jogging. Walking everywhere in this urban setting was oddly reassuring: It was harder to inadvertently step on a baby while walking than jogging and, if it were to happen, the constant presence of people in the city environment guaranteed that someone would rescue the baby before it was too late. This relative calm in symptoms was accompanied by good performance at work and personal growth, and, by her mid 20s, Natalie was engaged and house hunting with her fiancé. The newly married couple settled outside the city, close to where Natalie’s husband worked. The move necessitated a change in Natalie’s commute routine to a 20-​minute drive, which she now had to make daily. Driving brought on an unexpected new version of her old problematic behavior:  Natalie started worrying she would run a child over while driving to work and, about three times a week she needed to follow her drive with a repeat performance, during which she would retrace her steps to ascertain that she did not hurt anyone on her first attempt to get to work. The consequent tardiness prompted negative performance reviews and repeated warnings from her boss, and the stress that came with this negative feedback only worsened her OCD. Even though she confided in her husband about her anxiety, Natalie, out of embarrassment, refused his repeated requests that she seek help from a mental health professional. Instead, she relied on him for repetitive reassurances that she could not have, and would not, hurt someone while driving and not notice. On “good days” his encouragement and comforting would suffice, but on “bad days” she would insist that he drive her to work—​she never doubted his ability to drive safely even as she mercilessly doubted hers. Not knowing how else to help, her husband would usually agree. This arrangement, however, was far from satisfactory. Besides the inconvenience, it caused her husband to be frequently late to his work. This led to significant tension within the couple and much guilt feelings in Natalie, who blamed herself for their problems. Eventually, Natalie 2

decided that quitting work would be easier; but the sense of professional failure and financial stress that followed only worsened her mood. Natalie’s fear, fear-​ linked behaviors, and her mood waxed and waned over the years. She has not had other unusual fears or performed other checking behaviors. She has never experienced hallucinations, delusions, manic symptoms, panic attacks, or serious suicidal thoughts, and she has no medical problems. She is a social drinker and has never used other substances. Natalie’s parents and two siblings have no diagnosed mental illness, though her mother may have a tendency toward excessive anxiety. She described a “happy” childhood spent in a loving family and with multiple friends. Her school performance was always superior. Although Natalie has experienced occasional periods of being relatively symptom free, the overall burden of these worries and associated compulsions on her life is clear: Her college grades suffered at the onset of symptoms, which discouraged her from pursuing advanced studies; she has been able to return to work only as a part-​time accountant for a firm that allows telecommuting; and, on the personal level, her marriage remains strained and she has decided not to have children after “reading somewhere” that her condition is heritable. Although she is late in seeking psychiatric care, it is not for lack of clarity as to the abnormal nature of her fears: “I know it’s crazy but I can’t stop myself. I can’t help having this fear or checking to make sure I didn’t hurt anyone.” F R ANC IS Francis* is a 28-​year-​old single white man who lives alone in supportive housing and works part-​time in the mail room of a non-​profit organization. His symptoms were minor prior to college—​he experienced occasional doubts as to whether he had given offense to someone through something he said or failed to say, but this was not disabling, and he sought no psychiatric care. In college, however, he developed a preoccupation with the possibility that he had soiled himself while using the bathroom. This triggered incessant checking of his clothing and frequent washing. Symptoms progressed into a need to spend hours in the bathroom to ensure that he had completely finished urinating and an urge to take long showers after defecating. The hours occupied in these activities let to mockery and social isolation and prevented him from attending class, leading to his withdrawal from school. The need to check whether he had soiled himself expanded into a general need to check his surroundings to make sure that he had not dropped anything. It could take O b sessive - C ompulsive D isorder

 

him hours to extricate himself from a building as he had to keep going back to check. He also washed his hands increasingly, up to 300 times a day, in an effort to keep them clean; this resulted, especially in the winter, in their becoming chapped and cracked. When he felt clean, he would avoid touching things for fear of becoming tainted by fecal matter or other sources of contamination. When he felt dirty, he constrained his actions out of fear that he would contaminate otherwise “clean” aspects of his surroundings. Showers were so time consuming that he would avoid them, washing only once a week. He restricted his eating in an effort to limit how often he had to defecate, and he lost considerable weight. Francis was quite aware that the thoughts that so dominated his mind were irrational; indeed, he described them as feeling different from normal thoughts and imposed on him in some way—​but imposed by his own mind, not any external source. He was also aware how the washing, checking, and other behaviors in which he spent hours every day were excessive and interfered with many other more productive activities. Despite this awareness, the thoughts were so strong, and the distress that he felt when he did not engage in the cleaning and checking rituals was so acute, that he was unable to stop. Over time he came to keep to himself more and more, rarely leaving his apartment if not strongly encouraged to do so by his parents. He was enrolled in a supportive housing program and lived for a time in a group home. With the passage of time he became increasingly passive and accepting of his symptoms and his situation, saying “I guess this is just the way my life is going to be. I can’t imagine anything else.” Francis sought treatment beginning in college—​both medication and psychotherapy. At one point he was treated in an intensive inpatient setting; this led to significant improvement, but it did not last. With intensive outpatient treatment he was gradually able to become more independent, taking a part time job and living increasingly independently, with regular but limited support from a community organization and from his parents. Despite treatment, however, checking and washing symptoms continue to occupy many hours every day. L L OY D Lloyd* is a 45-​year-​old single male painter. He runs his own business and is reasonably financially successful. He often has difficulty completing work, however, because he feels a need to repeat simple actions over and over again. He gives a particular example that happens frequently on the N arratives   of   O C D

job: When he is coming down a ladder, he has to be careful to have a positive thought as he reaches the bottom. If a negative thought crosses his mind—​irritation about the job or about a person; thoughts about sad or distressing events in the world; even a snatch of a song that has negative connotations—​then the act of getting off the ladder feels somehow spoiled and incomplete. This leads not to anxiety, but to an inchoate discomfort that builds with time. To make this feeling go away he has to go back up the ladder and descend again, taking care to have a positive thought as he reaches the bottom. This happens frequently throughout the day. Whenever he finishes something or moves from one place to another, such as when he leaves a room, he reflexively monitors what thought, song, or feeling is in his mind. If it is not a “good thought” he feels a great sense of uneasiness; this leads him to redo the action over and over until he can achieve a “good thought.” Bad thoughts will sometimes contaminate specific things or places: for example, there are places around the city that he avoids due to negative thoughts he had while working there or passing through them in the past; he navigates around these, which can greatly lengthen his driving time. He cannot pinpoint when this pattern started; it seems to extend back into childhood. In childhood he had both vocal and motor tics—​he recalls blinking, sniffing, and coughing. These were a bit socially embarrassing but never impairing, and they waned during adolescence; they are rare and trivial now. He also describes difficulty paying attention in school, which was never diagnosed but caused him academic difficulties; this has improved somewhat with age. His pattern of monitoring his thoughts and repeating actions worsened in adolescence, at about the same time as the tics improved. Lloyd has a long-​term romantic relationship with a woman a few years younger. She is aware of his symptoms, though not of their pervasiveness, and they laugh about them together. He has considered them just to be a benign quirk of personality until recently, when he heard about OCD on a television show and realized that it might describe his experience. Though he has made light of his symptoms, when he thinks through them he recognizes that they complicate many aspects of his life. They add hours to his workday, through repetition of basic tasks and inefficiency of navigation from place to place. This led him to seek treatment. Lloyd is being treated with a combination of an SSRI antidepressant (fluoxetine) and cognitive-​ behavioral therapy. He initially experienced little benefit and some moderate sexual side effects from the medication, and he almost discontinued both modalities of treatment out of 3

 

discouragement; but after about 6 weeks he began to find it easier to resist the urge to repeat things, and by 8 weeks he noted a definite improvement. * The names and certain details of these cases have been changed, to preserve patient confidentiality. DIS C US S ION SYMPTOMS

Although their details are idiosyncratic, the broad outlines of these stories are classic. Natalie’s overwhelming fear of stepping on or running over someone, Francis’ fears of contamination, and Lloyd’s need to achieve “good thoughts” all meet the overarching definition of obsessions found in the Diagnostic and Statistical Manual of Mental Disorders (DSM-​5; American Psychiatric Association, 2013): “recurrent and persistent thoughts, urges, or images that are experienced…as intrusive and unwanted, and that in most individuals cause marked anxiety or distress.” They have made “attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action….” (DSM-​5, p. 237). The actions of Natalie retracing her steps to make sure she did not hurt anyone, Francis washing and checking repeatedly, and Lloyd repeatedly ascending and descending the ladder fulfill the DSM-​5 definition of compulsions, described as “repetitive behaviors… or mental acts…that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly.” Also consistent with the DSM-​5 definition of compulsions, these actions are “aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation” and “are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive” (DSM-​5, p. 237). The obsessions and compulsions encountered in patients with OCD are limitless in their variation. No two are identical, and even the most seasoned OCD experts cannot claim to “have seen it all.” The breadth and variety of the manifestations of OCD are humbling and speak to the complexity and fecundity of the brain itself. However, particular themes emerge again and again. A study of 560 patients with DSM-​III-​or DSM-​III-​R-​defined OCD (Rasmussen and Eisen, 1992a) described the following most common obsessional themes: contamination (50%); pathological doubt (42%); somatic obsessions (33%); aggressive obsessions (31%); sexual obsessions (24%); or multiple obsessions involving two or more of themes (72%). 4

Compulsions in OCD fall under a similarly narrow number of themes: checking (61%); cleaning (50%); counting (36%); need to ask or confess (34%); symmetry or exactness (28%); or multiple compulsions involving two or more themes (58%). Metaanalysis of such factor-​analytic studies has identified several dimensions of symptomatology with impressive consistency (see ­chapter 8; Bloch et al., 2008): •

Fear of potential harm, with checking, counting, or repeating compulsions

•

Aggressive, sexual, or blasphemous obsessions or taboo thoughts, with undoing or counteracting compulsions

•

Contamination obsessions, with washing or decontamination compulsions

•

Symmetry obsessions and ordering compulsions

•

Somatic obsessions, which can be variably associated with the other categories

•

Hoarding, which is now categorized as a separate condition.

Natalie’s obsession, unusual in its somewhat gruesome specifics but classic in its general form, might be classified as an example of pathological doubt or a “what-​if obsession”—​ “What if I hurt someone jogging or driving to work?” It is similar to more common doubt-​related obsessions, such as “What if I didn’t turn off the stove and the house burns down?” or “What if I didn’t lock the door and someone breaks in?” If her obsession were framed primarily as an excessive religious or moral fear, such as the fear of having committed a sinful, deeply immoral act, it might also be considered an example of “scrupulosity” (Nelson et al., 2006; see c­ hapter 12). Her compulsion, on the other hand, involves ritualized, patterned checking of her trajectory, not unlike a patient who may feel compelled to triple-​check the stove while looking for flames and smelling for gas, or someone who has to relock the door then move the knob in preset ways to feel confident that the basic task of door locking, carried out almost unconsciously by most people, has indeed been satisfactorily completed. In addition, Natalie’s repetitive requests for reassurance from her husband that her worst fear has not come true might be classified as a “need to ask” compulsion. All of these compulsions are carried out in response to anxiety stemming from her obsession and are, at least partially and occasionally, efficacious in the short term in containing the anxiety. Although there is no indication that Natalie has suffered from other obsessions, most patients with OCD will experience more than one type, either contemporaneously or O b sessive - C ompulsive D isorder

 

over the course of their illness (Rasmussen & Eisen, 1992b). Francis’ case illustrates this: His initial obsessions were centered around contamination, with attendant showering rituals and hand-​washing, but these grew to encompass equally problematic obsessions that he had lost something, with pervasive checking compulsions. Although Natalie’s checking and reassurance-​seeking and Francis’ hand-​washing can be considered “logically” connected to her obsessions, this is not always the case, in that compulsions may involve rituals that carry no direct bearing on the obsession; Lloyd’s pattern of compulsions illustrates this. Lloyd’s symptoms also illustrate that an obsession need not be a fully formed anxiety or fear but may instead be an inchoate feeling of wrongness or incompleteness, which a compulsion seeks to neutralize (see ­chapter 9). Like the vast majority (91%) of patients with OCD, these three patients manifest both obsessions and compulsions; but this is not a requirement for the diagnosis. A minority of patients will exhibit obsessions without compulsions (“Pure-​O”; 8.5%), or, rarely, compulsions without clear obsessions (0.5%) (Foa & Kozak, 1995).

to collections and the behavior to acts of collecting or accommodating and organizing collections (see ­chapter 52). Autism spectrum disorders are often characterized by narrow, consuming interests and patterned behaviors, but interpersonal and social deficits present differentiate them from OCD (­chapter 58). Tics, defined as “sudden, rapid, recurrent, nonrhythmic” motor movements or vocalizations, are likewise repetitive but are typically less complex and do not aim to neutralize an obsession, whereas OCD compulsions are usually more elaborate behaviors (e.g., getting out of bed to systematically check that each door and window in the house is locked, before returning to bed to try to sleep) and are carried out to calm an anxiety-​producing obsession. Tics are commonly seen in children who go on to develop OCD (sees ­chapter 53). Other conditions are defined by repetitive behaviors that are more “impulsive” than “compulsive,” and include pathological gambling, kleptomania, paraphilias, and problematic Internet use. They differ from OCD in that the impulsive activity is pleasurable, and that they are more defined by pleasure seeking and excitement, rather than by harm avoidance. Finally, obsessive-​compulsive personality disorder (OCPD) is characterized by chronic, relentless RELATED SYMPTOMS rigidity and perfectionism in one’s interactions and viewOther conditions are characterized by obsessions or com- points. Unlike OCD, it is “ego-​syntonic,” not characterized pulsions, loosely defined, and should be distinguished by distressing obsessions or compulsions meant to ease them from OCD; this is covered in detail later in this volume. (see ­chapter 59). For example, several other disorders present with body-​ It is important to distinguish among disorders that share focused preoccupations or behaviors but are distinct from symptoms and aspects of phenomenology because psyOCD in important respects. Patients with body dysmor- chotherapeutic and psychopharmacological interventions phic disorder (see ­chapter 49, 50) are preoccupied by con- often differ, as does prognosis. That said, the DSM diagnoscerns about their physical appearance and perceptions of tic system used by most psychiatrists has many limitations ugliness (those with OCD may have body-​focused obses- (see ­chapter 62), and it is not clear that our current concepsions, such as “will I stop breathing if I stop counting my tion of OCD is truly a “natural kind.” Making diagnostic breaths?” but these are not focused exclusively on appear- distinctions can be challenging—​for example a “complex ance). Likewise, obsessions in OCD may involve food and tic” that involves rocking behavior and that provides some eating (e.g., concerns with salmonella leading to avoid- anxiety relief may be confused with an OCD ritual, and ance of certain foods, decontamination rituals, and weight OCD that involves hair pulling to make eyebrows symmetloss), but this focus differs from that in anorexia nervosa ric may be confused with trichotillomania. These condiand other eating disorders, wherein fear of weight gain pre- tions are frequently comorbid with OCD, and the presence dominates (see c­ hapter 56). Similarly, body-​related repeti- of one clearly does not exclude the other. For example, up tive behaviors, such as hair pulling in trichotillomania to 30% of individuals with OCD have lifetime tic disorder (hair-​pulling disorder) or self-​excoriation in skin-​picking (the DSM-​5 has a specifier, “tic-​related,” to indicate when disorder (­chapter 51), differ from OCD in that there is no the individual has a current or past tic disorder). Similarly, accompanying obsession, beyond the urge to pull or pick, 23% to 32% of individuals with OCD also have obsessive-​ and no ritualistic behavior beyond pulling or picking. compulsive personality disorder (APA, 2013). Other conditions may present obsessional thought patterns or ritualized behaviors but are also considered distinct INSIGHT from OCD. Hoarding disorder, historically subsumed under OCD, has been designated as an independent entity in the For Natalie, the cost of her OCD in wasted time, inferior DSM-​5; the preoccupation is limited to an overattachment school performance, distraction from work, and marital N arratives   of   O C D

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conflict, seems to have been clear to her. Thus, she can be said to possess insight into her condition, a reference to the component of the mental status exam that assesses a patient’s understanding of his or her symptoms, including factors such as underlying causes, consequences, and the need for treatment. Lloyd, on the other hand, had limited insight into the nature of his symptoms for many years, and he only gradually came to appreciate their impact on many aspects of his life. Insight can fall on a continuum, with patients demonstrating lacking, partial, or good insight (see c­ hapter 13). In the case of OCD, the DSM-​5 accompanies the diagnosis with a specifier meant to qualify insight: “With good or fair insight”; “With poor insight”; or “With absent insight/​delusional beliefs” (APA 2013). Fluctuating insight is common, with many patients seeing the irrationality or excessiveness of their thoughts in retrospect but losing sight of this when they are “in the moment”; only 5% of OCD patients have never had insight into the senselessness of their symptoms (Foa & Kozak, 1995). The presence of insight was formerly considered necessary for a thought pattern to be classified as an obsession; but the existence of variable insight, and of this small minority of patients in whom insight is virtually absent, is now clear. Distinguishing between an obsession with no insight and a delusion can be quite difficult, and the dividing line between extreme OCD and psychosis in such patients presents a formidable clinical challenge. DISEASE BURDEN

One reason “obsession” and “compulsion” are overused terms is the high frequency of OCD-​like symptoms in the general healthy population. Almost everyone can describe a fear that can seem obsessional at times, or a preferred way of approaching activities that can appear ritualistic. Think of the student who wears the same shirt on exam days because he performed well on one exam and happened to be wearing it, or the adult who seeks out the number “7” for its supposed luck-​promoting properties, or the person who cannot tolerate “junk” email and has to empty the junk folder as a first step immediately after logging into an email account. If one looks for them, one easily finds patterns, repetitive acts and rituals, as well as the occasional unusual fixation, even in psychologically healthy individuals. We may indeed all be “creatures of habit,” but we do not all have OCD—​only 1% to 2% of us do, a frequency that seems largely consistent across cultures (APA, 2013; see ­chapter 4). That is because for symptoms to meet the definition of “disorder,” the individual has to experience substantial distress or dysfunction related to them. Indeed, “a little OCD” can be a good thing 6

and can be understood as an evolutionary advantage or a prosocial quality:  Anxiety-​driven caution and organization can be self-​preserving, and scrupulous behavior toward others can help with group cohesion. In the cases described here, however, symptoms have crossed the threshold into pathology and are beyond what might be reasonably considered advantageous. TREATMENT

The treatment for most cases of OCD rests on two main pillars:  specialized psychotherapy and psychopharmacology (Koran et  al., 2017; c­ hapter  36). These are described in detail in later chapters. First-​and second-​line treatments can lead to considerable improvement in about two thirds of patients. Unfortunately, as in the case of Francis, some patients show little lasting benefit from even the best evidence-​based treatments; and many who do respond continue to have residual symptoms, or to experience periodic symptom recrudescence. In severe cases and cases of treatment nonresponse, more intensive therapy, polypharmacy, and invasive treatments such as deep brain stimulation are sometimes used (see ­chapters 41, 45, 46, 47). C ONC LU S ION Obsessive-​compulsive disorder is a common potentially debilitating illness. It has been described since ancient times, but it is only relatively recently that effective and generally safe treatments have become available and that a basic understanding of its genetics and neurobiology has started to take form. The symptoms of OCD are endless in their variety, which can create diagnostic challenges, as can the fact that a “symptom” that resembles an obsession or a compulsion is often found in other diseases, not to mention in normal healthy life. Most patients with OCD are well aware of the cost to their lives of their illness and of the strangeness of some of its manifestations, and are desperate to get better. In most cases, the clinician’s job is not to convince patients that they are ill; rather, it is to make them feel at ease to describe their symptoms, and to instill hope, in part through educating them about the full range of effective treatments now available. R E F E R E NC E S American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders, (5th ed.). Washington, DC: Author. Amin, M. M., Ban, T. A., Pecknold, J. C., & Klingner, A. (1976). Clomipramine (Anafranil) and behaviour therapy in O b sessive - C ompulsive D isorder

 

obsessive-​compulsive and phobic disorders. The Journal of International Medical Research, 5, 33–​37. Ananth, J. (1976). Treatment of obsessive-​compulsive neurosis with clomipramine (Anafranil). The Journal of International Medical Research, 5, 38–​41. Bloch, M. H., Landeros-​Weisenberg, A., Rosario, M. C., Pittenger, C., & Leckman, J. F. (2008). Meta-​analysis of the symptom structure of obsessive-​compulsive disorder. American Journal of Psychiatry, 165, 1532–​1542. Foa, E. B., & Kozak, M. J. (1995). DSM-​IV field trial:  Obsessive-​ compulsive disorder. The American Journal of Psychiatry, 152(4), 654. Goodman, W. K., & Alterman, R. L. (2012). Deep brain stimulation for intractable psychiatric disorders. Annual Review of Medicine, 63, 511–​524. Janet, P. (1908). Obsession de la honte du corps. Les obsessions et la psychasthenie. (2nd ed.). Paris: Alcan. Kay, J. (1996). Is psychoanalytic psychotherapy relevant to the treatment of OCD? Journal of Psychotherapy Practice and Research, 5(4), 341–​354.

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Kim, K., Kim, C. H., Kim, S. Y., Roh, D., & Kim, S. I. (2009). Virtual reality for obsessive-​ compulsive disorder:  Past and the future. Psychiatry Investigation, 6(3), 115–​121. Koran, L. M. (1999). Obsessive-​ compulsive and related disorders in adults:  A  comprehensive clinical guide. London:  Cambridge University Press. Koran, L. M., Hanna, G. L., Hollander, E., Nestadt, G., & Simpson, H. B. (2007). Practice guideline for the treatment of patients with obsessive-​compulsive disorder. American Journal of Psychiatry, 64(7 Suppl), 5–​53. Nelson, E. A., Abramowitz, J. S., Whiteside, S. P., & Deacon, B. J. (2006). Scrupulosity in patients with obsessive compulsive disorder:  Relationship to clinical and cognitive phenomena. Journal of Anxiety Disorders, 21(6), 771–​787. Rasmussen, S. A. & Eisen, J. L. (1992a). The epidemiology and clinical features of obsessive-​compulsive disorder. Psychiatric Clinics of North America, 15, 743–​758. Rasmussen, S. A., & Eisen, J. L. (1992b). The epidemiology and differential diagnosis of obsessive-​compulsive disorder. Journal of Clinical Psychiatry, 53(Suppl), 4–​10.

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S ECT I O N 1. CLINICAL PRESENTATION AND DIAGNOSIS

 

 

2. CLINICAL PRESENTATION OF OCD Fred Penzel, PhD 

O

bsessive Compulsive Disorder (OCD) affects approximately 1 person in 40 at some point during their lifetime (Kessler et  al., 2012). Despite being relatively common, it is often less clearly recognized, both by professionals and by the public, than many other major neuropsychiatric conditions. This introductory chapter describes the basic characteristics of the disorder and what a clinician is likely to encounter when meeting a patient who suffers from it. Specific aspects of the heterogeneous phenomenology of the condition, of its underlying causes, and of its treatment are addressed in more detail in subsequent chapters. The focus here is on the clinical presentation:  What do typical patients with OCD look like, and how do they present for clinical care? It is one thing to read the basic description of a disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM; American Psychiatric Association, 2013), but it is quite another to be able to recognize it when you are face-​to-​face with an individual patient, with all of the idiosyncratic details of their presentation, and to understand its nuances. This is particularly the case with OCD, the presentation of which can be astonishingly variable. Despite this heterogeneity, OCD has distinct characteristics that set it apart from other major neuropsychiatric conditions. These make most cases unmistakable to those who are very familiar with the condition and who treat it on a regular basis. But for those who are less familiar with it, or who have never or only rarely encountered it outside of a textbook or lecture, its ability to take on so many different forms can be quite puzzling. HIS TOR Y O F THE D I AG N O SI S OCD has never been particularly well understood by the public, or for that matter by many mental health

professionals. Many people simply dismiss it as “those people who wash their hands a lot,” or whose closets are overorganized. Interestingly, many early descriptions of OCD are remarkably current and precise. In the early 19th century, Esquirol described symptoms that we would today classify as OCD as a reasoning monomania (Esquirol, 1845/​1938). Nearly 40 years later, Legrand du Saulle (1975) referred to similar symptoms as La folie du doute avec delire du toucher [insanity of doubt, with touching delirium]. However, although these early medical observers recognized core features of OCD, they lacked a modern conceptual framework to characterize its complexity. Sigmund Freud described obsessional neurosis, in which symptoms overlapping with what we would now call obsessions and compulsions were explained as deriving from a patient’s unconscious struggle over drives that were unacceptable at a conscious level (Freud, 1913/​1958). Psychoanalytic theory provided a rich conceptual framework to explain symptoms of mental illness; however, this framework fettered the development of alternative understandings of OCD for many years. It was the opinion of many experts that OCD was actually a defense against threatening psychosis, rather than a distinct disease entity in its own right. For many years, OCD was believed to be quite rare (Rudin, 1953); mild to moderate cases may have rarely come to clinical attention (and even more rarely been clearly recognized), and severe cases were probably often misdiagnosed as schizophrenia. The American Psychiatric Association’s DSM-​ III diagnostic manual, in fact, had schizophrenia as one of the exclusion criteria for a diagnosis of OCD (American Psychiatric Association, 1980). OCD was thought to be less than half as prevalent as schizophrenia. In the early 1980s, the Epidemiological Catchment Area Survey was launched, with the aim of determining prevalence 11

 

of psychiatric disorders in five representative communities in the United States, based on the newly operationalized criteria outlined in DSM-​III. The results for OCD were astonishing: It was found to be 40 to 70 times more prevalent than had been previously believed. It was also shown to be twice as prevalent as schizophrenia (Karno et al., 1988). Dr. Michael Jenike, in a 1989 editorial in the New England Journal of Medicine, rightly referred to it as “the hidden epidemic” ( Jenike, 1989). More recent epidemiological studies have confirmed a lifetime prevalence worldwide of 2% to 3%, as reviewed in detail in a later chapter (­chapter 4).

C OR E CL INICAL FEATURES A ND DIAGNOSTI C CRI TERI A OCD is characterized, as the name implies, by obsessions and compulsions. Both can be quite heterogeneous, as described in detail subsequently. Their core features are parsimoniously captured by Foa and Tillmans (1980): •

Obsessions are thoughts, images, or urges that generate anxiety.

•

Compulsions are behaviors—​whether overt or cognitive/​internal—​that are undertaken to manage or mitigate the anxiety associated with obsessions.

In the typical case there is a clear functional relationship between obsessions and compulsions, as implied by these definitions. This functional relationship underlies formulations of both the etiology and maintenance of symptoms and frames how these processes can be interrupted by therapy. This relationship recurs frequently throughout this volume (see ­chapter 60). Obsessions cause anxiety, doubt, or discomfort, which can be extreme. The desire to alleviate these aversive feelings is instinctive and compelling. Behaviors that can provide relief provide negative reinforcement and therefore tend to be repeated; over time, these become compulsions. Because compulsions are often performed under stressful circumstances and because they frequently must be performed in particular or ritualistic ways, the relief the sufferer seeks is often difficult to achieve, and the compulsive behaviors may therefore need to be repeated many times (if this were not the case they would most likely not rise to the level of being a clinical problem and would not be called compulsions). The relief from anxiety provided by compulsions, at least intermittently, is positive in the short term, but in 12

the long term it tends to make obsessions more common and more powerful, in several ways. By permitting sufferers a way to control their anxiety, however imperfectly, engaging in compulsions makes obsessions more salient and therefore more powerful. By proving the possibility of relief, engaging in compulsions makes the desire to seek relief all the more powerful the next time a similar obsession occurs. In particular cases, the obsession may entail fear, specific or inchoate, of a dreadful consequence if the compulsion is not performed (see later for specific examples); in such cases, the fact that the feared consequence did not in fact materialize may be taken as validation of the importance of the compulsion. In any or all of these ways, the mutually reinforcing relationship between obsessions and compulsions generates a self-​perpetuating cycle and can become increasingly rigid. This simple heuristic model is of course not a perfect description of every case. For example, the DSM definition of OCD allows the diagnosis if clinically significant obsessions or compulsions are present; it does not require both. Correspondingly, some patients have troubling obsessions but cannot identify particular compulsions (this scenario is sometimes called pure obsessive, or “pure O”); others engage in problematic compulsive behaviors but cannot clearly identify corresponding obsessions that motivate them. These complexities aside, the model presented in Figure 2.1 is a useful organizing principle in many cases. Much of the remainder of this chapter is devoted to describing common obsessions and compulsions. Readers who have not interacted with many patients with OCD will be struck by their variety. Despite this heterogeneity, the core definitions presented remain constant:  obsessions cause anxiety or discomfort, whereas compulsions are the repetitive behaviors that are engaged to alleviate this discomfort. T YPIC AL C H AR AC T E R IS T IC S OF   OB S E SS I O N S AND C OMPU LS IONS Obsessions and compulsions have a range of common characteristics not captured in the dry definitions found in the DSM. Specific examples of these generalizations are presented subsequently. HALLMARKS OF OBSESSIONS •

Obsessional thoughts are experienced as very real to many sufferers, to the point that they feel a need to act—​even if, O b sessive - C ompulsive D isorder

 

as is often the case, they have a clear understanding that the thoughts are unrealistic or excessive. •

•

Doubt is a significant component, or result, of many of these thoughts. Guilt frequently accompanies obsessional thoughts, especially those that involve imagining harm coming to others. Guilt or a sense of inflated responsibility can be prominent, whether sufferers see themselves as causing harm deliberately or simply failing to prevent it out of negligence.

•

Unrealistic, magical, and superstitious beliefs can often be features of obsessive thoughts. Patients may, and often do, have clear insight into the unrealistic nature of their obsessions; however, this does little to rob them of their power.

•

Obsessions can be limited to a single topic, but they can also change frequently, rotating among several different topics or representing variations on a theme.

•

Obsessions may be either constant or intermittent, and this may change for an individual patient depending upon circumstances.

•

They can be extremely pervasive, seeping into many areas of a sufferer’s life.

•

Obsessions have an uncanny and pernicious knack for picking out things that are most important or sacred to a sufferer.

HALLMARKS OF COMPULSIONS •

The desire to resolve doubt and avoid feelings of guilt is a common (and natural) response to obsessions.

•

The relationship between the specific obsession and the corresponding compulsion sometimes has a rational basis, as when hand washing is used to combat fear of germs or contamination. But in other cases the relationship may seem quite arbitrary or superstitious.

•

As noted, relief is often only intermittently achieved. Compulsions must often therefore be repeated over and over, until the anxiety or discomfort is assuaged. This leads to a pattern of intermittent reinforcement, which produces particularly strong learned associations.

•

Perfectionism is often an important component of people’s attempts to respond to obsessive thoughts (­chapter 12). This may be a reaction to the presence of the serious doubt that accompanies obsessions. Doubt can be so severe that only achieving perfect certainty—​ which is of course often unavailable—​will suffice to relieve it.

•

Compulsions often must be performed according to a specific set of rules if they are to provide relief. These rules can evolve over time and may become increasingly elaborate. Magical or superstitious behaviors are often resorted to when there is no ordinary action that might rationally be turned to in order to prevent a feared

A triggering event occurs (can be a thought, an event, a mental image, a physical sensation, etc.)

An obsessive thought results. It can be doubtful, intrusive, repetitive, or negative (or a combination)

Doubt and/or anxiety

The compulsive behavior is strengthened via negative reinforcement, assuring that it will be performed at the next triggering of the obsession

The doubt and/or anxiety is temporarily reduced or eliminated

A compulsion (mental or physical) is performed to neutralize the thought and/or avoid the negative consequences the thought suggests

Figure 2.1  A typical obsessive-​compulsive cycle.

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negative occurrence (especially in the face of magical or superstitious obsessions). •

Perfectionism often interacts with the need to perform compulsions in a precise way. If the magical ability of the compulsive acts to avert feared consequences is to work properly, it must be performed in an unvarying series of steps. These are commonly referred to as rituals. If errors are made during the performance of a ritual, then the sufferer must often start all over again from the beginning. In more extreme cases, this can lead to compulsive behaviors lasting for hours. It should be noted, however, that although all rituals seen in OCD are compulsions, not all compulsions are ritualistic.

CLINICAL PRESENTATION

A patient with OCD finds him-​or herself thinking thoughts that do not seem to be natural to them, that are intrusive, persistent, negative, doubtful, and unwanted  .  .  .  and yet, here they are, thinking them anyway. They want to know what these mental events could possibly mean, and assume that they must mean something. Sufferers fall along a continuum of objectivity (what is termed “insight” in the DSM-​5) and belief. Those who lie on the low objectivity/​low insight end of the continuum conclude that because they are thinking a particular thought, it must mean something significant and that it must therefore be responded to in some way. They get caught up in a type of reasoning that goes something like: “Why would I be thinking this if it isn’t a reflection of my own mind and desires?” A phrase sufferers use almost universally use is: “It seems so real.” This reasoning is very probably due to the implicit assumption that all of our mental events can only be our own thoughts, and therefore the product of our own minds. These low-​objectivity sufferers, as a group, can be extremely tortured: wracked by doubt and anxiety, and desperately trying to make sense of a thought process that simultaneously appears to be of them and not of them (or as referred to in psychodynamic terms, “ego syntonic” versus “ego alien” or “ego dystonic”). Those who belong to this low objectivity/​low insight group frequently spend a great deal of time analyzing their thoughts, seeking to understand why they are thinking them, what their significance is, how true they may be, and how probable are the negative occurrences the thoughts tell them about. At the other end of the continuum are those who have a greater measure of objectivity or insight about their obsessive thoughts. They say things like, “I know these ideas are totally stupid, crazy, and ridiculous and could never possibly 14

be true, but I just can’t stop thinking them.” Many of these individuals state that given a choice, they would never even consider ideas of the type they are experiencing. They are often bothered less by the content of the thoughts than that they are happening at all and are disturbing their attention and concentration. Their anxiety is consequently often much less than that seen in the former group, and there is also less of a tendency for their lives to be dominated by compulsive behaviors. The frequency of obsessive thoughts can also vary widely among sufferers. There are those who report constant ongoing obsessive activity, those who experience it intermittently throughout the day or week, and those who seem to only have it in episodes that can last for days, weeks, or months, and then remit for long periods of time. OCD was once referred to as “The Doubting Disease” (or la folie du doute, as noted earlier; Legrand du Saulle, 1875). The obsessive doubt experienced by many patients with OCD is unlike the ordinary doubts that cross a healthy person’s mind. It is doubt raised to an extreme level: extremely pervasive, unrelenting, and powerful. Almost nothing seems to be exempt from being subjected to doubt. It can attach to even the most basic and fixed aspects of their lives and behavior: whether or not they are alive; whether they are actually conscious; whether any of their experiences are real or only dreams; whether their sexual orientation has changed; whether they have committed (or will commit) extreme acts of mayhem, blasphemy, or sexual abuse, or have had such things happen to them, and so forth. This is particularly difficult for those unfamiliar with OCD to understand, as such topics are considered beyond question to the rational mind. Among sufferers, this doubt is uncorrelated with intelligence, education, and any knowledge or experience they may possess. It is among the main causes of misdiagnosis when an OCD sufferer presents for treatment, as to those unfamiliar with the disorder it may appear delusional. To further complicate diagnosis, the intrusive thoughts may tell sufferers such things as that they really don’t have OCD, that they are inventing it in a bid to get sympathy, that maybe no one will be able to figure out what is wrong with them, and that they are simply insane in some indefinable way. The most maddening feature of this doubt is that no amount of reassurance or information will relieve it. No matter what strategy a sufferer uses to counter it, is always seems to come back with, “Yes, but…” It is like an itch that cannot be scratched. Reassurance and information may help for a short while, but the doubt soon returns, and always brings the thinker back to their starting point—​as if they simply cannot hold onto the information for more than a O b sessive - C ompulsive D isorder

 

short time (although, again, this is not related to objective deficits in attention or memory). Sometimes, the information the sufferer seeks may paradoxically raise new questions and doubts that hadn’t been thought of in the first place, and only serves to increase the problem. As a result, many sufferers’ lives become centered around achieving certainty that something negative has not happened, is not happening, or will not happen in the future. Achieving this certainty can take on a priority so great that it outweighs every other responsibility and issue in an individual’s life, and in more extreme cases can severely limit their ability to function in even the most basic ways. C OM M ON O BSESSI O N S OCD is protean—​the content of obsessions varies enormously from person to person and seems limited only by the imagination. It can have so many different manifestations that it could be called “The Disorder of 1,000 Faces.” Obsessions can attach to an enormous diversity of topics and seep into every area of a sufferer’s life. They can range from topics that at first appear somewhat plausible, to those that are frankly absurd and even bizarre. Content, unfortunately, is a rocky coast of diagnosis upon which many ships are wrecked. Bizarre obsessions lead many less experienced clinicians to believe they are confronting a delusion and a psychotic process. Despite this heterogeneity, clinical experience and research literature identify common themes; these are addressed further in subsequent chapters. Perhaps the most prominent type of obsessive thoughts relates to (1) harm or an undesirable consequence somehow coming to the sufferer, or (2) harm or an undesirable consequence happening to others, for which the sufferer has some responsibility. The same individual can have thoughts that belong to both of these categories. The harm or undesirable consequence in question can be the result of (1) the sufferer causing it to happen to themselves or others on purpose out of a sense of malice or evil intent, (2) their causing it to happen to themselves or others via negligence or carelessness, or (3)  the consequence coming to themselves or others via unforeseeable happenstance (such as unpreventable accidents, disease, being cursed or possessed, or unrecognized threats that were always somehow present in the individual’s life). Although a majority of patients have a fear of harm as a central aspect of their OCD, there are exceptions. Some, for example, are characterized most prominently by pathological doubt, without much associated fear of harm. An

C linical P resentation   of   O C D

additional group of patients, especially those with preoccupations with symmetry or order, may have less clearly elaborated thoughts of what harm may arise; rather, they may just feel a discomforting and nagging sense of incompleteness when things are not ordered in the way that they would like, and that they cannot stop thinking about them or move forward until things are “just right.” This intriguing subset of patients describes less anxiety and is more likely to have a history of tic disorders. These issues are addressed in detail in subsequent chapters (see ­chapter 9). Over the years, there have been numerous attempts made to categorize obsessions and compulsions. Research on this question is reviewed in detail elsewhere in this volume (­chapter 8); as of yet, there is no definitive system for this categorization, and the extent to which phenomenologically distinct categories map onto different disease processes remains unclear. The categorization presented here, devised by the author a number of years ago, captures much of the diversity of OCD (especially of harm-​related obsessions) and is clinically and descriptively useful (Box 2.1). It is important to recognize that these categories are not mutually exclusive and can overlap substantially in a single patient. A brief note should be made regarding the status of hoarding. Hoarding behaviors have historically been thought of as an aspect of OCD and were so categorized in DSM-​III and DSM-​IV, and in research literature from those eras. However, it has become increasingly clear that hoarding symptoms are distinct from other OCD symptoms, in terms of phenomenology, biology, epidemiology, and response to treatment. Hoarding was therefore removed from OCD and formally established as a separate disorder in DSM-​ 5 (American Psychiatric Association, 2013; see ­chapters 48, 52).

BOX 2.1 

CATEGORIES OF OBSESSIONS

Aggressive Obsessions Sexual Obsessions Contamination Obsessions Religious Obsessions Obsessions of Harm, Danger, Loss, or Embarrassment Superstitious or Magical Obsessions Perfectionistic Obsessions Somatic Obsessions Neutral Obsessions Symmetry/​Ordering Obsessions and “Just-​Right” Feelings

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AGGRESSIVE OBSESSIONS

These obsessions typically involve thoughts that the individual wishes to deliberately cause death or injury to others or act in other antisocial ways (such as smashing or breaking things, shouting obscenities, or undressing) and, given a chance, will do so. The thoughts may be experienced as recurrent mental images, or even urges. Although these are not “thoughts” in a narrow sense, such intrusive distressing images or urges are nevertheless categorized as obsessions (and should not be mistaken for hallucinations). Thoughts of violence can involve such things as pushing people in front of trains or other vehicles or off high places, poisoning them, stabbing or mutilating them with knives or other pointed objects, strangling them, running into them with motor vehicles, shooting them, bludgeoning them, and so forth. Particular targets for these thoughts can be family and friends, pets, or strangers. Many sufferers find themselves particularly anxious in the presence of anyone smaller and weaker that they feel they could easily overpower, such as children, the disabled, or elderly people. They find themselves wondering if they are actually sociopathic murderers or serial killers. A  common thought is that they will one day snap or go berserk and do the things they have been thinking about. Some are even deterred from seeking treatment, as they believe their anxiety over doing such things is the only thing preventing them from acting out their thoughts. SEXUAL OBSESSIONS

These tend to focus on the sufferer committing or having committed sexual acts deemed to be taboo, inappropriate, and/​or criminal. Topics of these thoughts can encompass heterosexual or homosexual relations with one’s own children, parents, strangers, animals, or even inanimate objects. The thoughts often tell them that they want to carry out such acts, or have, in some way, committed them in the past. Sexual obsessions can spill over into blasphemous religious thoughts, involving sexual relations with religious figures (this represents an overlap with the category of religious obsessions, addressed later). Sufferers may involuntarily think about, or somehow be urged to stare repeatedly at, the crotches and breasts of family, coworkers, or strangers. Sufferers with such obsessions often conclude that they must be perverts and deviants. A common sexual obsession is the thought in a sufferer who clearly identifies as heterosexual that they are or will become homosexual, or want to have homosexual relations. Some refer to this as H-​OCD, as just saying the 16

word homosexual causes them great anxiety. The thought, “How do I know I’m not really gay,” constantly permeates their thinking, and no amount of arguing, questioning, or studying will relieve it. It is also not unusual for homosexual individuals with OCD to suddenly have thoughts that they might really be straight. It is worth noting here that such obsessions can raise diagnostic challenges that may cause confusion. It is common for practitioners not familiar with OCD to interpret H-​O CD symptoms as indicative of a repressed conflict about sexual orientation; and of course this possibility must be ruled out. Important diagnostic and even forensic issues also arise in relation to sexual and aggressive obsessions; in particular it is important to distinguish, clinically, between intrusive thoughts of aggressive acts and actual risk of homicide or mayhem, and between intrusive obsessions about inappropriate sexual acts and pedophilia. It is not our purpose here to review such diagnostic complexities in detail. The risk of having obsessions mischaracterized by an anxious clinician as evidence that a sufferer represents a danger to others is real, and fear of this happening sometimes keeps patients from seeking treatment. CONTAMINATION OBSESSIONS

Thoughts and fears of being contaminated probably constitute the best known (and most clichéd) OCD symptoms. There seems to be almost no limit to the list of things that can be viewed as contaminants—​bodily excretions and secretions; blood; semen; garbage; household chemicals; radioactivity; broken glass; greasy or sticky substances; people who appear unwell, shabby, unclean, or otherwise undesirable; spoiled food; lead; asbestos. Tiny amounts of contaminants may be believed to cover very large areas. Associated fears may be very specific (e.g., contracting HIV) or more inchoate. Although fears of contracting a disease or being poisoned often drive this group of obsessions, some sufferers can be seen to be dealing more with feelings of disgust and revulsion rather than fear of harm (see ­chapter 10). Whereas many sufferers may be concerned with something bad happening to themselves, others are more concerned that they will spread contamination or disease to others, harming them (and leading to feelings of guilt and responsibility). Contamination can also have magical components. Such things as names, words, colors, and numbers connected with bad thoughts, evil, negative past occurrences, or the possibility of “bad luck” can be seen as contaminants, and can somehow magically attach themselves to people and objects. O b sessive - C ompulsive D isorder

 

RELIGIOUS OBSESSIONS

Religion and matters of religious practice are of great importance and sensitivity to many people and thus are prime targets for obsessive thinking. OCD can be especially difficult for those whose religion encourages them to follow the strict standards for personal behavior and religious observance. These obsessions typically tell the person that they have sinned or broken a religious law, or displeased their god in some way, either in the past or present, and may therefore go to hell or receive some other type of punishment. Blasphemous thoughts are common, as are thoughts of having lost one’s faith or connection with one’s deity, or of being somehow unworthy. There can be overlap with aggressive obsessions—​for example, thoughts that one will curse or blaspheme aloud during religious services—​ and with sexual obsessions, as mentioned. Perfectionism also can intrude here, as sufferers believe that being insufficiently precise or complete in religious rituals or prayers may lead to divine punishment. A different aspect of this perfectionism can be seen in what is commonly referred to as religious scrupulosity. Here, the obsessions focus on doubts as to whether the sufferer’s level of faith is sufficient or whether they love their deity enough. Many everyday actions and situations become tests of faith, and the sufferer may question how they can tell if their practice is perfect enough, and about how they may achieve perfect practice. OBSESSIONS OF LOSS, DANGER, HARM, OR EMBARRASSMENT

These obsessions are connected by the theme that some type of negative occurrence—​ such as embarrassment, insult, injury, or death—​will either be visited upon the sufferer or on someone else, or the sufferer will cause these things to happen to someone else through negligence. For example, a sufferer may be plagued with frequent thoughts of having run over someone with their vehicle through inattentiveness, or of having accidentally poisoned someone. This particular aspect of carelessness (rather than intent) is what separates the thoughts of harm in this particular category from those in the Aggressive Obsessions group. These thoughts are often accompanied by a sense of exaggerated responsibility, sometimes referred to as hyper-​responsibility, and by serious feelings of guilt. A variation on this can be where the sufferer believes they have somehow cheated others, or taken unfair advantage. The opposite of this is also seen to occur: a sufferer somehow wonders if they have been shortchanged in their careers or relationships, and would be happier in another situation or with someone else. C linical P resentation   of   O C D

Obsessions of the latter type are sometimes called R-​OCD (relationship OCD). SUPERSTITIOUS OR MAGICAL OBSESSIONS

Magic generally connects things that have no causal connection in the real world. Magical thinking of this type is a frequent component of obsessive thought. Many sufferers appear to harbor the belief that the things they think have a magical power to control or influence events and to cause harm to themselves or others. These thoughts can sometimes take the form of common superstitions or religious practices, but are certainly not limited to these. Common obsessive fears can involve “bad luck” words, numbers such as 13 or 666, and even the clichéd fear of stepping on cracks in the sidewalk can be involved. Sometimes the thoughts are simply about being cursed or jinxed in some indefinable way, and in other cases they may involve death, illness, or bad luck magically happening to the sufferer or those close to them. The ubiquitous ideas of negligence and guilt are frequent accompaniments here, as well. In some cases there can be religious components to these obsessions, such as fears of the devil or of being damned or possessed. PERFECTIONISTIC OBSESSIONS

Perfectionism is common in OCD (­chapter 12). Those who experience thoughts in this category have severe doubts about whether they have acted or thought in perfect ways, or have kept things in their environment perfect and pristine, symmetrical, or in precise locations that can never vary. Unlike sufferers in other groups, they do not necessarily see being perfect as a way of preventing bad consequences from happening to themselves or others. Although they do experience anxiety, it seems to be more of a demand for closure and order, and having things be perfect for the sake of perfection itself. The prospect of not achieving these things is the cause of anxiety in this case. Often these sufferers are unable to specify what will happen if perfection is not achieved; just that they will feel incomplete and unable to think about anything else. Some children with this form of OCD can focus on having to get perfect grades, or having to turn in schoolwork that is free of any signs of correction, far beyond ordinary thoughts of wanting to be high-​achieving. The resulting anxiety and upset can, in some cases, paradoxically prevent them from attending school. Perfectionism applied to moral concerns is termed scrupulosity, which is often a particularly challenging domain of symptomatology (­chapter 12). Patients who suffer from significant scrupulosity can be paralyzed by moral doubt or 17

 

ambiguous moral decisions, such as honesty, fairness, or adherence to particular moral codes (religious or otherwise). It is important to distinguish between obsessional perfectionism, which is characterized by anxiety or discomfort, and ego-​syntonic perfectionism as a character trait. The latter, when it becomes clinically problematic, is better captured by the diagnosis of obsessive-​compulsive personality disorder (OCPD) than of OCD. These conditions were thought of as closely related by Freud and his followers, which is why they are similarly named, but are now thought to be importantly distinct (though they can cooccur). OCPD and its relationship to OCD are discussed in ­chapter 59. SOMATIC OBSESSIONS

It is also possible for people to become obsessed with their own bodies. Sufferers can focus upon particular bodily functions (heart rate, breathing), how different parts of their bodies work or feel (e.g., how their heads turn, how they talk or think, how their arms move, or how they walk) and may doubt whether their bodies are working properly. Unlike hypochondriasis/​illness anxiety disorder, there is no presumption of illness or disease, and unlike body dysmorphic disorder, there is no assumption of deformity or ugliness. As with other forms of OCD, the focus here is simply on uncertainty about one’s own workings. NEUTRAL OBSESSIONS

These consist of recurrent thoughts that are essentially meaningless and even nonsensical; they differ from the other categories of obsession in that they cause distress not due to their connection to any sort of harm or negative occurrence, but primarily due to their persistence and intrusiveness and their ability to disrupt the sufferer’s concentration and attention. A variation is excessive noticing or paying attention to what are normally trivial happenings, persons, or objects in their environment—​the way people speak or gesture, the location of furniture in a room, the heights of buildings, or the layout of streets where they live. Another variation would include stubbornly repetitive rhetorical or philosophical (sometimes existential) questions for which there are no real answers. A further type has sufferers constantly focusing on the way specific electrical or mechanical devices work.

accompanied by perfectionist motivations or by fears of consequences (religious or otherwise) if the appropriate ordering is not achieved, but it can also be driven by a feeling of incompleteness, or that something is simply not right (­chapter 9). C OMMON C OMPU LS IONS Compulsions, the other major aspect of the disorder, are essentially maladapative solutions to the problem of having obsessions. As noted earlier, they are performed for the purpose of relieving the anxiety generated by obsessions, and can be either purely mental or physical actions, or combinations of both. Sufferers and practitioners alike frequently mistakenly assume mental compulsions are actually obsessions simply because they are occurring on the thought level. This can lead them to erroneously assume that they have no compulsions and are purely obsessional (“pure-​ O”). Although such purely obsessional patients may exist, it is much more common, on careful assessment, for there to be unrecognized mental or covert compulsions. As a rule of thumb, obsessions are what causes anxiety and distress, whereas compulsions are attempts (usually at least partially or intermittently successful) to alleviate that anxiety and distress. This distinction is of more than semantic importance; as described in detail later in this volume, it is central to cognitive-​behavioral therapy approaches to treatment (­chapter 37). A typology of common compulsions is presented in Box 2.2. As with the listing of common obsessions earlier, this is a categorization derived from clinical experience and is useful but may not be comprehensive. There is a general mapping between categories of obsessions and of compulsions, but this is not strict and may vary from case to case; different categories of compulsion may overlap.

BOX 2.2 

CATEGORIES OF COMPULSIONS

Checking Compulsions Magical/​Undoing Compulsions Decontamination Compulsions Perfectionistic Compulsions Counting Compulsions Touching or Movement Compulsions Somatic Compulsions

S Y M M E T R Y, O R D E R , A N D J U S T- R ​ IGHT FEELINGS

Mental Compulsions

This category of obsessions consists of the feeling that things must be symmetrical, ordered, or organized. This need may be

Protective Compulsions

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Hoarding Compulsions

O b sessive - C ompulsive D isorder

 

CHECKING COMPULSIONS

Checking compulsions are extremely common and often overlap with other categories. Checking can be defined as repetitive, sometimes extreme attempts to obtain certainty that a particular event has or has not actually happened, or that some particular state of affairs does or does not exist. For a sufferer, much can hinge on the outcome of this checking, and great anxiety can result if it is not performed or is performed improperly. Because of the pervasive doubt that accompanies OCD, the relief that results from checking does not tend to last more than a short while, necessitating further checking. The act of checking can range from being a single uncomplicated event, such as asking someone a question, to a drawn out complex process with many steps. If prevented from actual physical checking, some sufferers will do imaginal checking. When magical thinking is involved, the checking can become ritualized, with steps that cannot be altered. Checking may be a physical event utilizing visual, auditory, or tactile means, or else a purely mental event involving repeated reviewing, questioning, or analyzing.

and avoidance behaviors. It is common to see such activities as frequent (and sometimes ritualistic) hand washing, frequent and prolonged showering, the overuse of disinfectants or sterilizing products, excessive house cleaning, discarding possessions, creating clean areas that are off-​limits to others, and frequent clothes changing. Avoidance can involve not touching many objects touched by others in public; avoiding contact with anyone who appears ill, unkempt, or homeless; not using public restrooms; not coming into contact with waste receptacles of any kind; staying away from hospitals; and shunning anything that might possibly have a connection to something said to be a toxic substance. PERFECTIONISTIC COMPULSIONS

A common cliché is that individuals with OCD are all overorganized perfectionists. The perfectionism seen in this disorder, however, is not practiced for the purpose of achieving greater efficiency, nor is it a consistent feature of OCD. Compulsive perfectionism is typically applied to counteract severe doubt, as well as for magical reasons. The inherent paradox is that this perfectionism can cripple or paralyze a sufferer, thus impairing the very behaviors or accomplishments in which perfection is M A G I C A L /​U N D O I N G C O M P U L S I O N S sought. The search for perfection thus often causes more anxiGiven the human predisposition to think in magical ways, ety than it ever relieves. Perfectionism in OCD also generates another well-​ it is natural for sufferers to turn to superstitious rituals recognized hallmark of the disorder—​ procrastination. when faced with magical or superstitious doubts and fears. Magical compulsions must often be performed perfectly Anxiety associated with trying to find ways to perform and in the correct state of mind, and may or may not be tasks perfectly or to make perfect decisions can lead to extensively ritualized. Because of the need for perfection, avoidance of ever initiating the tasks or decisions in the first a great deal of anxiety may accompany the performance place. Sufferers are notoriously bad at making decisions or of these compulsions. This inevitably leads to making accomplishing even some simple tasks. Related to this is mistakes, and then the need to repeat the behaviors until what is mistakenly referred to as obsessive slowness (which they are done correctly. Magical compulsions include pray- should really be known as compulsive slowness), which is ing (using either learned or invented prayers), performing the result of perfectionism. This group of sufferers performs certain actions in reverse, performing particular actions a tasks with extreme slowness as a way of ensuring that they special number of times, using good numbers to cancel bad are doing them perfectly. The need for order and symmetry can be thought of as numbers, performing an action with a special good thought in mind (to undo the same activity that was performed a subset of perfectionism. This is required in some cases by when a bad thought was present), creating special men- magical obsessions, whereas others simply find disorder distal arrangements of thoughts or images, washing off a bad turbing to the point where they are unable to think about thought, and stepping, moving, or touching in special ways. anything else until it is made right. They can be seen to clean, organize, or protect such things as their personal possessions, their room, or the home they live in, not to mention the possessions or dwellings of others. New possessions DECONTAMINATION COMPULSIONS cannot be acquired unless they appear absolutely pristine, These compulsions, which typically accompany obsessions and then must be kept that way. Their personal appearance of contamination, include some of the better known and can also be the object of such treatment. Work must conmost clichéd behaviors associated with OCD. The anxiety-​ stantly be redone, mistakes must be completely erased, and relieving compulsions can include many forms of cleaning even letters must sometimes be perfectly formed. C linical P resentation   of   O C D

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As noted, perfectionism applied to matters of morality or ethics is termed scrupulosity. Individuals with significant scrupulosity tend to go far beyond ordinary religious or social practices. They may feel compelled to always tell the absolute truth as they see it and to confess their supposed wrongs inappropriately to others. Some are motivated by a fear of civil or eternal punishment; others punish or penalize themselves for their perceived transgressions. The characterization of scrupulosity can be complicated in religious groups that reinforce rigid ethical codes, but pathological scrupulosity can still occur in such contexts, and may even be triggered or enhanced by them. COUNTING COMPULSIONS

OCD sufferers often compulsively count, for a variety of reasons. Some may count as way of monitoring whether or not they are performing compulsions for sufficient periods or time or a sufficient number of times. Others count for magical reasons which often have to do with lucky or unlucky numbers (special numbers, odds, evens, etc.). Counting can also be the result of having to keeping track of, or being overfocused on, internal events such as breathing, taking steps, chewing food, and so forth.

may focus upon the workings of their internal organs, such as their heart, gastrointestinal system, or any of their senses. Others may be similarly preoccupied with the functioning of external body parts such as their head, arms, and legs. Where sufferers focus on their internal workings, they may repeatedly check such things as their blood pressure, heart rate, and excretions. Those who are preoccupied with external features will do such things as study the way they walk, the way their head turns, how their mouth moves when they talk, how their eyes blink, and so forth. Somatic compulsions can raise diagnostic questions. Compulsions that are reactions to thoughts of being ugly or deformed in some way are often better categorized as body dysmorphic disorder (American Psychiatric Association, 2013) (see c­ hapter 49). Preoccupation with particular diseases or medical conditions, often accompanied by repeated help-​seeking and an inability to be reassured, is often better categorized as Somatic Symptom Disorder (DSM-​5 300.82) or Illness Anxiety Disorder (DSM-​ 5 300.7) (American Psychiatric Association, 2013). These distinctions can have relevance for treatment decisions, although whether they reflect true underlying differences in etiology or pathophysiology remains a topic of ongoing research. MENTAL COMPULSIONS

TOUCHING OR MOVEMENT COMPULSIONS

Having to move in special ways or touch things in a particular manner or pattern are common types of compulsions. Such compulsions may be performed in the course of magical rituals to control or undo feared events or thoughts. In other cases they are driven less by anxiety or particular thoughts than by a need to achieve a sense of closure or completeness, and to avoid a sense of uneasiness if they are not carried out. These compulsions should not be confused with motor tics, in which touching or movement is being carried out either automatically or to simply satisfy an urge for reasons the sufferer cannot explain (tic disorders and their relationship to OCD are discussed in c­ hapter 53). This distinction can be subtle in individual cases. OCD and tics often cooccur; in Tourettic OCD, tics are incorporated into compulsive routines for the purpose of relieving anxiety caused by obsessions (Mansueto et al., 2005). SOMATIC COMPULSIONS

These compulsions aim to relieve obsessive doubts and the resulting anxiety about the workings or appearance of sufferers’ bodies. Individuals can be seen to double-​check or to attempt to modify their appearance in various ways. They 20

As noted, purely mental compulsions are frequently mistaken for obsessions. Mental compulsions come in a vast assortment of types, and are generally performed to either check if something negative has occurred, is occurring, or will occur in the future, or else are carried out in order to undo harm that has occurred or may occur to the sufferer or others. A common mental compulsion is the repeated review of past events in detail, in order to determine if something bad has occurred or if they, themselves, have behaved badly. Another common type is the internal repetition of magical rituals, such as thinking thoughts in reverse to neutralize them, or thinking good thoughts, words, numbers, or names, for the same purpose. Many sufferers will compulsively analyze their own thoughts and their reactions to them in order to determine what their thoughts may signify, what their motive was in thinking them, and whether these were their own real thoughts or not. Those who are troubled by morbid violent or sexual thoughts often visualize their unpleasant thoughts on purpose to gauge their own reactions to them to try to figure out if they like the thoughts and are comfortable with them. Sufferers may also be seen to carry out such actions as memorizing and mentally hoarding information, creating mental pictures, or making mental maps or lists. O b sessive - C ompulsive D isorder

 

PROTECTIVE COMPULSIONS

This type of compulsion is especially common in those who experience hyperresponsibility and obsessions about harm coming to themselves or others due to their own neglect or incompetence. These individuals tend to focus less on harm in the present than on trying to prevent possible future harm, or on figuring out whether harm may have happened in the past (that they can then somehow remedy). The compulsions often involve sufferers checking their own memory, warning others, or taking action to protect others or themselves from possible future harm. They can be seen trying to prevent themselves from being the cause of the harm, or thinking that it is their responsibility to warn and save others from possible harm. A central concern is often that they would be responsible for the occurrence of harm and would then be forced to live (or not be able to live) with great personal guilt. Some of the more common situations these sufferers seek to prevent are the spreading of poison or disease to others, accidentally hitting others while driving, inadvertently starting fires, or creating unsafe conditions that could lead to accidents. AVOIDANCE

Avoidance of situations that may trigger obsessions and compulsions is common in many or most patients with OCD and can become extreme. It is seen in association with many of the other categories of obsessions and compulsions characterized previously. Avoidance is distinct from other compulsions in that it is not a response to anxiety or discomfort but rather a preemptive strategy to avoid having the anxiety or discomfort arise in the first place. Pervasive avoidance can be a major source of social withdrawal and constricted lives in OCD sufferers. HOARDING COMPULSIONS

Behaviors in this category involve saving and collecting things to great excess. As noted earlier and discussed in detail in later chapters, hoarding is now considered a distinct disorder, rather than part of OCD (American Psychiatric Association, 2013). In many cases hoarding behaviors are ego-​syntonic and not associated with anxiety or distress; this is one of the motivations for considering them distinct from obsessions and compulsions. Nevertheless, hoarding behaviors are frequently seen in individuals with OCD, and they sometimes have the characteristics of compulsions. For example, it may be obsessional to worry that by throwing a particular item away, it will be lost forever, and C linical P resentation   of   O C D

they may one day be in need of it, or they will be unable to remember it, or something connected with it. Guilt and a misplaced sense of environmentalism may also be a factor, as some hoarders worry about wasting or destroying things that could somehow be recycled and may yet have some use to someone. Hoarders often cannot discard anything without prolonged checking, and as a result, they tend to avoid throwing things away in general. C ONC LU S ION OCD is a heterogeneous and protean condition. It is not the purpose of this introductory chapter to exhaustively survey all aspects of its phenomenology Rather, the author has striven to characterize the core symptoms of obsessions and compulsions and the usual relationship between them, and to give examples of the major categories of obsessions and compulsions that are most typically seen by clinicians. Many of the specific issues raised in the discussion above are addressed in much greater detail in subsequent chapters in this volume. Some of them, especially the relationship of different types of obsession and compulsion to one another, and to comorbid conditions, remain active topics of research in the field. It is our hope that this survey provides a foundation for the readers—​ especially those who do not have significant personal or clinical experience with the phenomenology of this fascinating disorder.

R E F E R E NC E S American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author. American Psychiatric Association. (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author. Esquirol, J. E.  D. (1938). Mental maladies:  A  treatise on insanity (E. K. Hunt, Trans). Philadelphia:  Lea & Blanchard. (Original work published 1845) Foa, E. B., & Tillmans, A. (1980). The treatment of obsessive-​compulsive neurosis. In A. Goldstein, & E. B. Foa (Eds.), Handbook of behavioral interventions: A clinical guide. Hoboken, NJ: John Wiley & Sons. Freud, S. (1958). The disposition to obsessional neurosis:  A  contribution to the problem of choice of neurosis ( J. Strachey, Trans.). In J. Strachey (Ed.), The standard edition of the complete works of Sigmund Freud (Vol. 12, pp. 311–​326). London:  Hogarth Press. (Original work published 1913) Jenike, M. A. (1989). Obsessive compulsive and related disorders: A hidden epidemic [Editorial; Comment]. New England Journal of Medicine, 321(8), 539–​541. Karno, M., Golding, J. M., Sorenson, S. B., & Burnam, M. A. (1988). The epidemiolog y of obsessive-​c ompulsive disorder in five US communities. Archives of General Psychiatry, 45(12), 1094–​1 099.

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Kessler, R. C., Petukhova, M., Sampson, M. A., Zaslavsky, J. M, & Wittchen, H. (2012). Twelve-​month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. International Journal of Methods in Psychiatric Research, 21(3), 169–​184. Legrand du Saulle, H. (1875). La folie du doute (avec delire du toucher) [Double Insanity]. Paris: Adrien Delahaye.

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Mansueto, C. M., & Keuler, D. J. (2005). Tic or compulsion? It’s Tourettic OCD. Behavior Modification, 29(5), 784–​799. Rudin, E. (1953). Ein beitrag zur frage der zwangskranheit insebesondere ihrere hereditaren beziehungen. [A contribution to questions about obsessional illness, especially its heredity.] Archiv fur Psychiatrie und Nervenkrankheiten [Archive for Psychiatry and Nervous Diseases], 191, 14–​54.

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3. PEDIATRIC OCD CL I N I CAL COU RSE, P H ENOM ENOLOGY, AND ASSE SSME NT

Rachel E. Ginsberg, PhD, Samantha Morrison, PhD, & Anthony Puliafico, PhD 

O

bsessive-​compulsive disorder (OCD) affects both children and adolescents (henceforth referred to as youth) and can significantly interfere with family, academic, and social functioning. Janet (1903) was the first to record a case of OCD in a child; he referred to obsessions and compulsive behaviors as “forced agitations” ( Janet, 1903, cited in Pitman, 1987, p. 226). Our understanding of the developmental context, phenomenology, dimensionality, and assessment of pediatric OCD has advanced considerably in recent years, and the prognosis for children who receive evidence-​based treatment is largely positive. DIAGNOS IS AN D CLI N I CAL FEATURES In both youth and adults, OCD is characterized by obsessive thoughts, compulsions, or both. Obsessions are defined as repetitive and persistent thoughts, impulses, or images that are experienced as upsetting, unwelcome, and intrusive, and that contribute to significant anxiety or distress. Obsessions are typically associated with feelings of doubt, incompleteness, anxiety, fear, and shame. As in adults, youth with OCD typically make efforts to suppress or neutralize the obsessive thoughts, impulses, or images by engaging in compulsions. Compulsions are defined as any actions or thoughts intended to reduce anxiety and/​or prevent feared consequences from occurring. Compulsions are often not rationally connected to preventing feared consequences, but they provide momentary relief from anxiety. Although only the presence of obsessions or compulsions is required for diagnosis of OCD, most youth present with both (Storch et al., 2004; Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989). Symptoms are considered clinically significant when obsessions and/​ or compulsions

persist for at least 1 hour per day and/​or contribute to significant distress or interference with social, school, or family functioning. Further, to warrant diagnosis, symptoms cannot be specifically related to another diagnosis, such as guilt-​related ruminative thoughts within depression, preoccupation with bodily-​related thoughts better accounted for by body dysmorphic disorder, or delusional thoughts better accounted for by a psychotic disorder (American Psychological Association, 2013). The relationship between obsessions and compulsions is sometimes less clear in youth than in adults, as they may not be able to explain the intended purpose of compulsive behaviors or thoughts (American Psychiatric Association, 2013). Insight into the unrealistic nature of the obsessional thoughts is often more limited than is typical in adults (Geller et al., 2001). CASE EXAMPLE Hallie, 12, suffered from obsessional thoughts that she would take on the negative characteristics of others. While at school and at home, she often worried that she would take on negative characteristics of people whom she touched or with whom she interacted in some way, including family members, teachers, classmates, and even characters on TV. She began avoiding social interactions and watching TV. Her fears brought on related ideas of her losing friends, being “outed” as a fraud, and ruining her future. Driven by her urge to reduce the anxiety and doubts associated with her obsessional fears, Hallie repeatedly asked for reassurance from others. She made efforts to “cancel out” potential negative characteristics by intentionally thinking of people with highly positive characteristics. Further, she mentally rehearsed affirmations that she was a good person, looked in the mirror to ensure that she saw her own

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reflection, and apologized excessively. Hallie also avoided touching the belongings of others with perceived negative traits, and purposely touched the belongings of those with perceived positive traits. Hallie’s compulsive behaviors and avoidance efforts consumed much of her day and began to interfere considerably with her ability to concentrate in class, complete homework, and socialize with friends. Furthermore, her classmates began to comment that her behaviors were “weird” and soon began to avoid her.

This case captures some of the complexities commonly seen in pediatric OCD, highlighting the presentation of “emotional contamination.” Emotional contamination describes a fear that interaction with specific people or places will transmit negative characteristics or personal circumstances. Hallie’s symptoms reflect the complicated interactions of such symptoms with psychosocial and developmental issues, such as the development of sense of self and personal identity, social anxiety and eagerness to “fit in,” and importance of peer relationships, that can particularly complicate the experience and treatment of OCD in youth. Due to the impairment and the disruption of normal psychosocial development that OCD can potentially cause a child or adolescent, it is critical to establish parameters for the careful assessment and effective treatment of OCD in youth to facilitate positive long-​term prognosis and improve global functional outcomes. EP IDEM IOL O G Y OCD appears in 1% to 4% of the pediatric population worldwide (Douglass, Moffitt, Dar, McGee, & Silva, 1995; Flament et al., 1988; Valleni-​Basileet al., 1994); this is similar to prevalence rates reported in adults (Ruscio, Stein, Chiu, & Kessler, 2010; see c­ hapter 4). Fifty to eighty percent of individuals with lifetime OCD experience onset of symptoms in childhood (Millet et al., 2004). Related estimates suggest that 25% to 50% of adults with OCD experienced clinically significant OCD symptoms in childhood (Pauls, Alsobrook, Goodman, Rasmussen, & Leckman, 1995; Rasmussen & Eisen, 1990). OCD is uncommon in early childhood (ages 3–​7), with prevalence significantly increasing in adolescence (Heyman, Fombonne, Simmons, Meltzer, & Goodman, 2001). There appears to be a bimodal distribution of incidence of OCD, with onset peaks in preadolescent children, at a mean age of 10, and a subsequent peak in early young adulthood, at a mean age of 19.5 (Ruscio, Stein, Chiu, Kessler, 2010). Males typically experience earlier onset of symptoms than 24

females, with common onset in males during preadolescence, and in females during adolescence and young adulthood (Tükel et al., 2005). Modal age of onset is 13 to 15 in males, compared with 20 to 24 in females (Rasmussen & Eisen, 1990). However, prevalence rates in late adolescence and adulthood are comparable in males and females (Flament et al., 1998; Parkin, 1997; Zohar, 1999). OCD is more prevalent in Caucasian than African-​ American children in clinical samples (which may reflect limited recruitment of minority families in pediatric treatment studies), but the rates are comparable in adulthood (Rasmussen & Eisen, 1992; see ­chapter 63). Further, although symptom expression may vary based on cultural differences, gender rates, comorbidity, and age of onset of OCD are similar across cultures (American Psychological Association, 2013). C OU R S E , C OMPLIC AT IONS , AND PROGNOS IS Although there is general continuity between youth and adults in the presentation of OCD symptoms, youth typically have heterogeneous symptom profiles that may reflect developmental stages and themes (Geller et  al., 2001). Pediatric-​onset OCD has been associated with higher rates of sensory-​related symptoms (see ­chapters  9, 11). These include mental sensations of incompleteness (Summerfeldt, 2004), which have been termed “not-​just-​right” experiences (Ghisi, Chiri, Marchetti, Sanavio, & Sica, 2010), and body-​focused rituals related to musculoskeletal, tactile, or visual sensations preceding or combined with compulsions (Rosario-​Campos et  al., 2001). Additionally, youth with OCD may exhibit body-​focused rituals, such as breathing and blinking rituals, more than adults with OCD (Rettew, Swedo, Leonard, Lenane, & Rapoport, 1992). Not infrequently, youth exhibit compulsions without distinct or specifically delineated obsessions during the prepubescent years (Geller et  al., 1998; Rettew, Swedo, Leonard, Lenane, & Rapoport, 1992). Despite age of pediatric onset typically ranging from 7.5 to 12.5 years, in a sample of 419 youths with OCD, mean age at first formal assessment of symptoms was found to be 13 years, indicating that there is frequently a delay between onset of symptoms and treatment-​seeking behavior (Karno, Golding, Sorenson, & Burnam 1988). Early intervention is strongly encouraged because obsessive-​compulsive symptoms often persist through adolescence into young adulthood (Stewart et al., 2004). Prompt diagnosis is therefore a priority. O b sessive - C ompulsive D isorder

 

Symptoms tend to fall along identifiable dimensions in pediatric OCD, as in adults (see also ­chapter 8). A metaanalysis of 21 studies with 5000 participants yielded four predominant symptom categories in youth: (1) symmetry obsessions and ordering, repeating, and counting compulsions; (2) obsessions related to forbidden or taboo subjects involving aggressive, sexual, or religious content and checking compulsions; (3) contamination-​related obsessions and cleaning/​washing compulsions; and (4) hoarding obsessions and compulsions (Bloch, Landeros-​Weisenberger, Rosario, Pittenger, Leckman, 2008). (Note that this metaanalysis and the studies that it summarized were performed before hoarding was defined as a distinct disorder.) The content of symptoms in youth tends to change over time (Rettew et al., 1992), as reflected in change in symptom content and profile over 2 to 7 years in a sample of 79 youth with OCD. Intensity and severity of symptoms also fluctuate over time (Stewart et al., 2004), and many youth experience a range of multiple OCD symptoms by late adolescence (Rettew et al., 1992). Multiple obsessions and compulsions are common in youth, with reported mean estimates of 4.0 distinct obsessions and 4.8 distinct compulsions in cases of pediatric OCD (Rettew et al., 1992). Masi et al. (2010) found that in a sample of 257 patients, order and symmetry symptom profiles were more common in male youth, whereas contamination-​ related symptom profiles were more common in females. Further, males had higher rates of “just right” obsessions and compulsions, and females had higher rates of symptoms related to feared consequences (Swedo et al., 1989). Garcia et al. (2009) found that in a younger cohort (ages 4 to 8), catastrophic/​harm and contamination obsessions and checking and washing compulsions were predominant. The prognosis for pediatric OCD is generally positive, given that many youths’ symptoms respond to treatment, remit, or lessen over time (Geller et al., 1998; Stewart et al., 2004). However, earlier onset of symptoms, history of inpatient hospitalization, comorbid psychiatric conditions, and poor early treatment response are risk factors for a poorer prognosis. Symptom subtypes such as scrupulosity (preoccupation with religious piety), sexually themed obsessions, and hoarding obsessions are also associated with greater symptom persistence (Geller et al., 1998). FA M ILY, ACAD EMI C, AN D SO CI AL IM P L IC ATION S Pediatric OCD typically affects family members of the affected youth, with greater than 75% of parents involved in daily accommodation of symptoms (Flessner et al., 2011; P ediatric   O C D

see ­chapter 43). Youth often engage family members in their rituals, by seeking constant reassurance or requiring family members to follow compulsive rules. These demands contribute to family tension, stress, and anger (Geffken et al., 2006; March & Mulle, 1998; Waters & Barrett, 2000). Further, when the child’s demands are compromised or violated, it can often lead to emotional and behavioral dysregulation (Lebowitz, Vitulano, Mataix-​Cols, & Leckman, 2011)  or fits of rage or extreme behaviors (Lebowitz, Vitulano, & Omer, 2011; Storch et  al., 2012). For example, in a study of 86 youth ages 6 to 16 with OCD, “rage attacks” were revealed to be common, and were associated with greater functional impairment and symptom accommodation by family members (Storch et al., 2012). Further, youth with OCD often demonstrate distress when daily structure or routine is interrupted. Because pediatric OCD often involves and affects family members, imparting effective ways for family members to respond to OCD symptoms is essential. Treatment programs have significantly benefited from incorporation of family members into treatment (Comer et al., 2014; Freeman et al., 2003, 2008; March & Mulle, 1998). Children and caregivers typically vary in their ratings of a youth’s functional impairment caused by OCD, with caregivers more commonly endorsing impairments in home and academic functioning (Flament et al., 1990; Piacentini, Bergman, Keller, & McCracken, 2003). Nonetheless, in a sample of 151 youth with OCD, 90% of youth participants expressed at least one area of functional impairment as a result of OCD symptoms, and approximately 50% of participants acknowledged more globalized OCD-​related dysfunction academically, socially, and at home (Piacentini et  al., 2003). Youth with OCD generally demonstrate less insight into symptoms than adults and typically view OCD symptoms as more reasonable (Geller et  al., 2001; see ­chapter  13). Storch and colleagues (2008) found that within a sample of 78 children and adolescents, 45% of the sample met criteria for low insight into symptoms, which was negatively correlated with severity of symptoms. Parents of youth with low insight reported greater family accommodation and symptom impairment. In addition to the adverse effects on family functioning, the presence of OCD in youth can impair social and interpersonal functioning. Further, symptoms can impair socialization and lead to avoidance, as a result of efforts to hide them (Flament et al., 1990). Fifty-​five to one hundred percent of youth with OCD have high levels of social problems (Geller et al., 1998). Peer bullying, often in response to apparent rituals, can lead to exacerbation of emotional, social, and behavioral problems (Storch et al., 2006). 25

 

Within a school context (see ­chapter  64), children with OCD commonly present with behaviors such as checking, ordering, or arranging items in their desk or backpack, becoming fixated on completing assignments perfectly and redoing their work persistently. Obsessive thoughts and mental rituals can interfere with concentration on work at school and at home. Some youth with OCD fail to complete homework or class assignments because this work is associated with anxiety-​provoking obsessions. They may also engage in repeated verbal checking with parents and teachers, leave frequently for the bathroom to wash their hands, and engage in odd or unusual behaviors such as counting, tapping, or avoiding standard interactions (such as using a doorknob). These behaviors make it difficult for children to function at school and complete schoolwork. In a survey of 151 youth with a principal diagnosis of OCD, the two most commonly reported impairments to functioning were difficulty focusing on schoolwork and completing homework (Piacentini et  al., 2003). Youth with OCD demonstrate normal levels of academic achievement, as reflected in college attendance rates of 30% to 70%. However, they tend to later demonstrate high rates of unemployment (Geller et al., 1998; Stewart et al., 2004). NEUROP S Y CHO LO G I CAL IM P L IC ATION S Children with OCD may have impairments in a range of neurocognitive domains, though the literature is limited and mixed (see c­ hapter 15). In one study, youth with OCD demonstrated deficits in visual and verbal memory, as well as weaker performance on attention, short-​term memory, and processing speed tasks, relative to matched controls (Andrés et  al., 2007). However, a recent metaanalysis found that youth with OCD did not demonstrate significant neuropsychological deficits in verbal memory, nonverbal memory, cognitive flexibility/​ set shifting, working memory, attention, processing speed, or visuospatial performance. They slightly underperformed on many subdomains; although these effects did not reach statistical significance, the pattern suggests that subtle deficits might emerge as more studies are reported. The most substantial underperformance was in planning; there was comparable performance on response inhibition tasks. Additional research is essential to examine neurodevelopment and cognitive functioning in youth (Abramovitch et al., 2015).

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E T IOLOGY The onset of pediatric OCD is likely due to a combination of biological, environmental, and individual factors (Rutter & Sroufe, 2000). Data from genetic studies have supported a strong hereditary component to OCD (see ­chapter 19). Nestadt and colleagues (2000) found the lifetime prevalence of OCD to be five times higher among first-​degree relatives of probands with OCD than in a community-​ based sample; familial loading appears to increase with earlier age of onset. Significantly higher concordance rates of OCD have been found in monozygotic compared with dizygotic twins (van Grootheest, Cath, Beekman, & Boomsma, 2005). Neuroimmunological dysregulation has been implicated in pediatric OCD. There may be a particular association between pediatric OCD and group A beta-​hemolytic streptococcal (GABHS) infections. Specifically, GABHS has been associated with an acute and sudden episodic onset or worsening of OCD symptoms in preadolescents, or in the relapse of symptoms in children in remission (Williams & Swedo, 2014). The idea that dysregulated autoimmunity after GABHS infection can trigger OCD symptoms led to the proposed diagnostic entity of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections, or PANDAS (Larson, Storch, & Murphy, 2005; Swedo et al., 1998; see chapter 28). Recently, the broader and more etiologically agnostic diagnosis of Pediatric Acute-​onset Neuropsychiatric Syndrome (PANS; Swedo, Leckman, & Rose, 2012) has been introduced to account for a broader range of potential biological triggers in this population. PANS should be considered diagnostically when OCD symptoms have an acute onset and occur in tandem with other rapid neuropsychiatric changes, such as severe behavioral dysregulation (e.g., oppositional behaviors), developmental regression, motor symptoms, and/​or a notable increase in anxiety. Most pediatric OCD cases are not associated with obvious precipitating psychosocial stressors or triggers. Certain family characteristics, such as higher rates of perfectionism and exactness, are commonly seen in adolescents with OCD (Allsopp & Verduyn, 1990); however, there is no conclusive evidence implicating such factors in symptom onset or expression (Waters & Barrett, 2000). Temperament in youth with OCD is variable, with no evident differences in symptoms among temperament groups (e.g., shy/​inhibited versus uninhibited) (Ivarsson & Winge-​Westholm, 2004).

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Cognitive theories conceptualize OCD as related to faulty thinking, reasoning, and biased attributions, as reflected in interpretations of overresponsibility (Salkovskis, 1999). Cognitive biases in OCD also include the overestimation of the likelihood of negative consequences, as well as “thought-​action fusion,” defined as the notion that thinking of something makes it more likely to occur (Rachman, 1993; see c­ hapter 18). These cognitive biases are also prevalent in youth with other anxiety disorders, when compared with healthy controls (Barrett & Healy, 2003). Behavioral conditioning is believed to play a significant role in the onset and maintenance of OCD, in that compulsive behaviors serve to negatively reinforce the obsessive-​compulsive cycle by providing a momentary decrease in anxiety and thereby increasing the likelihood of repeating compulsive behaviors (Albano, March, & Piacentini, 1999).

PATHOP HY SI O LO G Y O F O CD There are multiple biological factors associated with the development of OCD; these are addressed at length elsewhere in this volume (see Section 3). Here we highlight a few studies that have specifically addressed neurobiological underpinnings in youth. Frontal cortico-​striatal-​thalamic circuits are particularly relevant to OCD pathophysiology. These functional brain systems are involved in filtering information and influencing repetitive and automated behaviors (Rauch & Baxter, 1998; see ­chapters 20, 31). Pediatric imaging studies have revealed structural abnormalities in the basal ganglia, cingulate cortex, and thalamus in youth with OCD (Gilbert et al., 2000; Rosenberg & Keshavan, 1998), and fMRI studies examining performance of youth with OCD on response inhibition and set shifting tasks suggest dysfunction in the orbital frontal cortex, basal ganglia, and thalamus (Britton et al., 2010; Wooley et al., 2008). Specific neurotransmitters that moderate feedback circuits, notably serotonin as well as dopamine and glutamate (Rosenberg & Keshavan, 1998), have been implicated in the onset and maintenance of OCD. Several studies have documented changes in brain function in youth with OCD following SSRI treatment (Diler, Kibar, & Avci, 2004; Lázaro et al., 2008), although one study found no change following treatment with clomipramine (Castillo et al., 2005). Normalized brain activation during planning tasks has also been described after successful cognitive behavioral therapy in youth (Huyser, Veltman, Wolters, de Haan, & Boer, 2010). P ediatric   O C D

Although these overall patterns of structural and functional abnormality are similar in youth to what has been seen in adults, there is some evidence of developmental specificity. Higher frontostriatal metabolism is seen in older children, but decreased activation has been described in preadolescent children (Busatto et al., 2001). Patterns of activation correlate with symptom profile in young children, but with symptom severity in adolescents. However, rapid changes in the brain during development, such as myelination and pruning, make it particularly difficult to study neurobiological markers in the pediatric population (Abramovitch, Mittelaman, Henin, & Geller, 2012). Further investigation into neurobiological and neurocognitive functioning in youth is particularly needed. C OMOR B IDIT Y, DIF F E R E NT IAL DIAGNOS IS , AND AS S E S S ME NT COMORBIDITY AND DIFFERENTIAL DIAGNOSIS

OCD in youth is often comorbid with tic disorders, anxiety disorders, attention and disruptive behaviors disorders, and mood disorders (Geller et al., 2003, Masi et al., 2005; POTS 2004), with comorbid disorders occurring in greater than 50% of youth with OCD in epidemiological samples (Flament et al., 1988). Swedo and colleagues (1989) found that as many as 74% of youth within a clinical sample of 70 children had a cooccurring disorder, and that the majority of these youth will be diagnosed with another psychiatric disorder across the lifespan (Flament et al, 1990). Compared with adults with OCD, those with pediatric-​onset OCD were found to have higher lifetime rates of ADHD and lower rates of mood disorders, eating disorders, and substance use (Mancebo et al., 2008). OCD should be considered as a diagnosis when youth exhibit persistent intrusive or unwanted thoughts and engage in avoidance or ritualized behaviors with the intent to prevent a feared consequence or to achieve a “just right” feeling. However, some such fears, behaviors, and thinking styles occur during normal child development (Geller & March, 2012). These may include magical thinking (inference of causal relationships between personal thoughts/​actions and external events), rituals at bedtime or mealtime that cause distress when interrupted, the need for symmetry and exactness or wanting things in a particular way, collecting/​saving objects, or family-​related worries (such as separation anxiety related to caregivers). Childhood behaviors that resemble OCD symptoms are typically most prominent between the 27

 

ages of 2 and 5 (Evans et al., 1997), and it can be difficult to delineate what resembles normal development and what may represent a precursor to development of OCD in this age range. Ritualized behavior may be considered advantageous and adaptive within development in non-​OCD youth (Carter & Pollock, 2000). When ritualistic behavior is associated with distress and urgency, a diagnosis of OCD should be considered. Distress, rather than insight, is the best indicator of a pathological process; many children do not view their OCD symptoms as foreign and unwelcome to the extent that is typical in adults (Geffken et al., 2005). Repetitive compulsive behaviors associated with pediatric OCD may present similarly to tics (see ­chapter 53). In differentiating OCD from a tic disorder, it is important to consider the function of the repetitive behavior. If the behavior follows a mental action, such as an unwanted thought or image, and is intended to reduce anxiety caused by the thought or image, it is best considered a compulsion. Tics, in contrast, typically follow a sensory urge and are intended to reduce the discomfort associated with that urge. Differentiating tics from compulsions that follow “just right” obsessions can be particularly difficult. In these cases, it is important to consider coexisting symptoms and history to determine the appropriate diagnosis. OCD and tic disorders are frequently comorbid in childhood; in the Pediatric OCD Treatment Study II (POTS II), for example, 22% of the sample of 124 youths with OCD presented with a comorbid tic disorder (Franklin et  al., 2011). Both diagnoses may be appropriate if a child exhibits both compulsions and tics. Compulsions may also resemble stereotypic or perseverative behaviors exhibited in children with autism spectrum disorder (see c­ hapter 58). In OCD, repetitive compulsions are intended to reduce anxiety or prevent a feared outcome from occurring. In autism spectrum disorder, however, repetitive behaviors are typically pleasurable and not meant to reduce anxiety. Finally, due to the irrational nature of many obsessions experienced by youth, certain obsessions may be mistaken for delusional thinking associated with a psychotic disorder. To differentiate obsessions from delusional thinking, it is important to consider copresenting symptoms. Whereas obsessions typically copresent with compulsions, delusional thinking may present with other symptoms of psychosis, such as hallucinatory experiences, withdrawal, cognitive decline, or a looseness of thinking in general. In addition, youth with OCD may demonstrate some insight into the irrational nature of their obsessions, whereas individuals suffering from delusions typically experience them as egosyntonic.

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ASSESSMENT

It is important to conduct a comprehensive, multidiagnostic, and multiinformant evaluation of symptoms to ascertain a diagnosis and inform treatment planning (Masi et  al., 2005). Diagnostic assessment of OCD in youth requires investigation of family history, medical history, developmental history, academic history and performance, past and current symptoms, symptom content, and functional impairment. Obsessions and compulsions are characterized on the basis of content, frequency, duration, severity, and associated distress. Beyond such characterization, evaluation should assess degree, nature, and context of life interference, presence of avoidance behaviors, and insight into symptoms, as well as how the youth responds to symptoms, the nature of efforts to resist or suppress obsessions and compulsions, and the contexts that contribute to an increase or decrease in symptoms and associated rituals (Merlo, Storch, Murphy, Goodman, & Geffken, 2005). For some youth, interviews and evaluation of symptoms can feel anxiety provoking, and it is common for youth to be reluctant to discuss their OCD symptoms. It is important to consider developmental level and to sensitively evaluate symptom-​maintaining factors, such as familial accommodation. Rapport building and “normalization” of symptoms is critical to facilitate effective evaluation and appraisal of symptoms. Prior to evaluation, it is important that the clinician define and provide examples of obsessions and compulsions for the child and/​or parents in order to emphasize that there is nothing alarming or taboo about these obsessions. This phase also lends itself to providing basic psychoeducation about OCD in order to encourage discussion, while emphasizing the framework of OCD symptoms and the range of behavioral responses to symptoms. Providing examples can be a helpful way to engage youth and disarm their anxiety and hesitation about opening up about obsessions that may otherwise feel embarrassing or idiosyncratic. Assessments vary in how they are conducted, in that some entail both the parents and youth present, whereas in other cases parents and youth are interviewed separately. Such decisions are guided by clinical judgment, with an emphasis on obtaining the most comprehensive and accurate information possible. For example, some teenagers may prefer to be interviewed independently due to symptom content (e.g., sexuality-​related obsessions), whereas some children may benefit from parental assistance in describing symptoms and behaviors. It is important to observe behavior

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during the evaluation, to note and inquire about any unusual movements or vocalizations, and to probe to determine the function of observed behaviors (e.g., to reduce anxiety or “cancel out” potential feared consequences).

to focus on symptoms over the previous week. Ratings on the CY-​B OCS use clinical judgment based on both youth and parent report. The first portion of the CY-​B OCS consists of a symptom checklist:  62 common obsessions and compulsions divided into 17 categories that are noted as past or current symptoms. The second portion of the DIAGNOSTIC INTERVIEWS CY-​B OCS consists of the Severity Scale, which combines Evidence-​ based assessment of OCD in youth includes an Obsessions Severity Score and a Compulsions Severity clinician-​ administered diagnostic interviews that com- Score. Symptom frequency, interference, level of distress, prehensively assess for a range of psychiatric disorders and level of resistance, and perceived degree of control are sepaincorporate both youth and parent report. One of the rately assessed on a 0 to 4 scale for obsessions and compulmost common diagnostic interview tools utilized to assess sions. The scale runs from 0 to 40 (0–​20 for the obsessions for OCD is the Anxiety Disorders Interview Schedule subscale and 0–​20 for the compulsions subscale). for DSM-​IV:  Child and Parent Versions (ADIS-​IV-​C/​ The CY-​B OCS has evidence of good validity and reliP; Silverman & Albano, 1996). The ADIS-​IV was devel- ability (Freeman, Flessner, & Garcia, 2011; Scahill et  al., oped with DSM-​IV (American Psychiatric Association, 1997; Storch et al., 2004), with high internal consistency 2000) criteria and is typically administered to the parent(s) and alpha coefficients for total scores ranging from .87 and child independently. It utilizes a 9-​point scale, repre- (Scahill et  al., 1997)  to .90 (Storch et  al., 2006). Internal sented by a “fear thermometer” that parents and children consistency alphas of .80 and .82 have been identified for use to rate symptoms according to the level of severity of Obsessions Severity and Compulsions Severity scores, fear and level of life interference associated with symp- respectively (Storch et al., 2004), with interrater reliability toms. Another common tool in the evaluation of OCD scores for both total scales and subscales in the strong to is the Schedule for Affective Disorders and Schizophrenia excellent range, as reflected in intraclass correlation coeffifor School-​ Age Children-​ Present and Lifetime Version cients (ICC  =  .66 −​.91). Test-​retest reliability was found (K-​SADS-​PL; Kaufman et  al., 1997). The K-​SADS-​PL to be adequate for the Total Score (ICC = .79), Obsessions is a semistructured, clinician-​ administered diagnostic Severity score (ICC = .70), and the Compulsion Severity instrument that measures lifetime and current history of score (ICC  =  .76) (Scahill et  al., 1997, Storch et  al., symptoms, and is typically administered independently to 2004) at a 6-​week interval. The CY-​B OCS has been shown parents and children. It begins with an initial interview, fol- to be sensitive to treatment intervention effects (Benazon, lowed by screening items that determine which diagnostic Ager, & Rosenberg, 2002; Piacentini, Bergman, Jacobs, modules to utilize. McCracken, & Kretchman, 2002). Although CY-​B OCS scores have a central role in assessing and following symptom severity, emphasizing the total C L I N I C I A N -​A D M I N I S T E R E D R A T I N G   S C A L E S score may underestimate severity in patients with predomiClinician-​administered rating scales are particularly effec- nantly obsessional or predominantly compulsive symptive in the assessment and monitoring of OCD symptoms. tomatology. Because about 20% of the pediatric OCD The Children’s Yale-​Brown Obsessive Compulsive Scale population demonstrates a significant difference in clini(CY-​B OCS; Scahill et al., 1997) is adapted from the Yale-​ cal severity between obsessional and compulsive symptom Brown Obsessive Compulsive Scale (Y-​B OCS; Goodman subprofiles, it is important to examine the obsessional and et al., 1989), which is well validated and prominently used compulsive subscales (Storch et al., 2004). with adults with OCD, and is considered to be the “gold standard” in symptom assessment (see ­chapter 14). The CY-​ S E L F -​R E P O R T Q U E S T I O N N A I R E S BOCS is a clinician-​administered, semistructured questionnaire that evaluates the presence, type, and severity of Self-​report questionnaires are valuable in timely screenOCD symptoms; administration requires about 15 to 30 ing and can facilitate report of symptoms that patients minutes. Once a diagnosis of OCD has been made, the CY-​ might otherwise find difficult to discuss. Commonly BOCS is useful in the baseline assessment of symptoms, used questionnaires include the Leyton Obsessional in periodically monitoring OCD severity, and in measur- Inventory-​Child Version (LOI-​CV; Berg, Rapoport, & ing treatment effects and outcomes. It asks respondents Flament, 1986), the Children’s Obsessional Compulsive

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Inventory (CHOCI; Shafran, et  al., 2003), the Child OCD Impact Scale (COIS; Piacentini & Jaffer, 1999), the Multidimensional Anxiety Scale for Children (MASC; March, Parker, Sullivan, Stallings, & Conners, 1997), and the Family Accommodation Scale (Calvocoressi et al., 1995). The more recently developed Obsessive-​Compulsive Inventory-​Child Version (OCI-​CV; Foa et  al., 2010)  is a self-​report scale used to assess the presence of OCD symptoms and dimensions in youth (ages 7–​17) with OCD. The OCI-​CV has good psychometric properties overall, correlates moderately with the CY-​B OCS, and shows good sensitivity to posttreatment changes (Foa et  al., 2010). Another recently developed instrument, the Obsessive Beliefs Questionnaire-​ Child Version (OBQ-​ CV; Coles et al., 2010), is a 44-​item scale with three subscales (importance/​ control of thoughts, perfectionism/​ certainty, and responsibility/​threat estimation). It has good internal validity but requires more investigation of reliability and has weak correlations with the CY-​B OCS (Coles et al., 2010; Wolters et al., 2011). Although there are a number of other self-​report symptom measures, few studies have found them to be sensitive to clinical progress before and after treatment (Keeley, Storch, Dhungana, & Geffken, 2007).

tool that includes symptoms commonly seen in children, with items rated from 0  =  not true, to 2  =  very true or often true. It provides Age-​correlation T-​scores and Total Problems T-​scores, with scores at 70 or greater indicating clinically significant impairment. Information from the BASC and CBCL is particularly useful in highlighting the complexities of clinical presentation and functional impairment, and in informing treatment considerations in youth (Achenbach, 1991). The BASC Teacher Rating Scale and the CBCL-​ Teacher’s Report Form (Achenbach, 1991)  are useful in evaluating symptoms that are observed in the school environment by means of teacher report. Merlo and Storch (2005) developed the Florida Obsessive-​ Compulsive Student Inventory (FOCSI) in order to measure teacher-​ observed OCD symptoms in the school setting (Merlo, Storch, Adkins, Murphy, & Geffken, 2007). Given the extent of functional interference from symptoms in the school environment, it is important to continue to develop and validate teacher-​rated instruments to contribute to comprehensive functional assessment and treatment.

PA R E N T A N D T E A C H E R R E P O R T S

OCD commonly first manifests in childhood and adolescence, though it is often not identified until well after symptoms begin. Early diagnosis and prompt efficacious treatment are essential to prevent symptoms from disrupting normal psychosocial development during these critical years. Although OCD in youth is overall quite similar to what is seen in adults, there are important differences, as highlighted in this chapter, and the manifestation and impact of symptoms can differ depending on developmental stage. Treatment, too, follows the same general outlines as treatment in adults, though with some differences; issues of treatment in the pediatric population are addressed in detail in ­chapters 42, 43, and elsewhere in this volume. Further research examining the onset and progression of symptoms, and maximizing treatment in youth, is needed.

In the evaluation of OCD in youth it is critical to incorporate parent or caregiver reports of their child’s behaviors. When youths’ reports are compared with those of their parents, it appears that youth minimize OCD symptoms (Canavera, Wilkins, Pincus, Ehrenreich-​May, 2009)  and underestimate functional impairment and adverse impact to the family system (Storch et al., 2008). The Behavior Assessment System for Children (BASC; Reynolds & Kamphaus, 1992), which has good psychometric properties, is a parent-​report measure that evaluates common symptoms in childhood and adolescents, with separate versions for preschool, school-​age, and adolescent patients. It provides scores, corrected for age and gender, for categories such as internalizing problems, externalizing problems, school problems, total problems, and total adaptive functioning. Parents complete each of 131 items by utilizing a 4-​point Likert scale from 0 “Never” to 3 “Almost always.” The Child Behavior Checklist (CBCL; Achenbach, 1991)  is one of the most prominently used measures in child and adolescent evaluation of psychological symptoms and adaptive functioning, and has very strong validity and reliability. The CBCL is a 113-​item parent-​report 30

OV E R V IE W AND S U MMAR Y

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4. EPIDEMIOLOGY, COMORBIDITY, AND BURDEN OF OCD Albina R. Torres, MD, PhD, Leonardo F. Fontenelle, MD, PhD, Roseli G. Shavitt, MD, PhD, Marcelo Q. Hoexter, MD, PhD, Christopher Pittenger, MD, PhD, & Euripedes C. Miguel, MD, PhD

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bsessive-​ compulsive disorder (OCD) was once thought to be very rare, but epidemiological surveys beginning in the late 1970s revealed that it affects up to one person in 40 and imposes a heavy burden on society (Hollander et al., 2016). Many sufferers hide their symptoms, due to limited insight, embarrassment regarding symptoms, stigma, avoidant behaviors (e.g., fear of drug side effects, of being contaminated in public places or hospitalized), doubts about treatment effectiveness, limited treatment access (e.g., financial difficulties or lack of adequate public services), and family accommodation to the symptoms (García-​Soriano, Rufer, Delsignore, & Weidt, 2014; Marques et al, 2010; Torres & Prince, 2004; Williams et al., 2008). Many sufferers avoid or delay help-​seeking for many years, worsening the impact of the condition on patients and family members, as well as the costs to society (Hollander et al., 2016).1 Comorbidity with other psychiatric disorders is the rule in OCD (see ­chapters 48–​59) and also plays an important role in how patients seek treatment. It is not uncommon for an OCD sufferer to seek treatment for anxiety or depression, and have their OCD discovered secondarily—​even though it may be their core clinical difficulty (Fullana et al., 2010; Torres et al., 2006, 2007). For all of these reasons, the phenomenological profile of individuals with OCD symptoms may differ substantially between epidemiological and clinical OCD samples. Community-​based studies are essential to improve our understanding of this complex, serious, and still underdiagnosed disorder (Torres et al., 2004). This chapter, therefore, addresses the interrelated topics of OCD epidemiology, comorbidity, and disease burden.

E PIDE MIOLOGY:  OC D PR E VALE NC E , INC IDE NC E , AND R IS K FAC T OR S OCD was considered a rare condition until the 1980s (Rasmussen & Eisen, 1990), but the landmark Epidemiological Catchment Area study identified it as the fourth most common DSM-​III psychiatric disorder (Myers et al., 1984; Robins et al., 1984). These numbers were widely publicized in the following years and helped to increase awareness about the fact that many individuals in the community had disabling and untreated OCD. Subsequent studies reported widely variable estimates of prevalence, ranging from 0.7% (Hwu, Yeh, & Chang, 1989) to 8.0% (Helzer, 1985) according to the Diagnostic Interview Schedule (DIS), 0.5% (Grabe et al., 2000) to 0.9% (Bijl, Ravelli, & van Zessen, 1998) according to the Composite International Diagnostic Instrument (CIDI), and 0.0% (Weissman, Myers, & Harding, 1978) to 1.8% (Mohammadi, 2004) according to the Schedule for Affective Disorders and Schizophrenia. This variability is attributable to a range of methodological factors: the age range of the population under study; the period of time evaluated (e.g., current, 1-​month, 1-​year, or lifetime prevalence); the training of the interviewers (e.g., lay people vs. clinicians); how the assessments were conducted (e.g., face to face interviews vs. interviews by telephone); the assessment instruments employed (e.g., DIS vs. CIDI); and the diagnostic criteria in which the instruments were based (e.g., DSM vs. International Classification of Disease [ICD]), among other factors (Fontenelle, Mendlowicz, & Versiani, 2006). Unfortunately, this methodological heterogeneity may obscure the identification of socioeconomic,

35

 

regional, and cultural factors, and thus complicate the identification of risk factors for OCD. Given these challenges, it is difficult to establish whether there is a uniform OCD prevalence worldwide. However, recent and larger epidemiological studies have found current prevalence rates of approximately 1% and lifetime rates between 2% and 2.5% (Fontenelle et  al., 2006). In the British National Psychiatric Morbidity Survey of 2000 (Torres et al., 2006), for example, the 1-​month prevalence among 8,580 adults was 1.1%; in the Netherlands Mental Health Survey and Incidence Study (de Bruijn, Beun, de Graaf, ten Have, & Denys, 2010), the current prevalence was 0.9% among 7,076 participants; and in the National Comorbidity Survey—​Replication (Ruscio, Stein, Chiu, & Kessler, 2010), the 12-​month and lifetime prevalence rates among 2,073 adult respondents were 1.2% and 2.3%, respectively. There may be some geographic variation to these numbers; in São Paulo city, Brazil, higher prevalence rates were found: the 12-​month prevalence was 3.9% (30% mild, 27.4% moderate, and 42.5% severe cases) (Andrade et  al., 2012), whereas the lifetime prevalence was 6.7%, and the projected risk at age 75 years was 8.9% (Viana & Andrade, 2012). Obsessions and compulsions may occur in the context of other psychiatric disorders, and even in individuals with no diagnosable mental illnesses. Recent epidemiological studies (Adam, Meinlschmidt, Gloster, & Lieb, 2012; Blom, Hagestein-​de Bruijn, de Graaf, ten Have, & Denys, 2011; de Bruijn et al., 2010; Fineberg et al., 2013a; Fullana et al., 2010; Ruscio et al., 2010) have examined subclinical or subthreshold OCD symptoms (SOCD), in addition to full-​blown OCD. SOCD is common in community-​based samples and is associated with substantial interference, disability, suffering, and healthcare utilization (Adam et al., 2012; Blom et al., 2011; de Bruijn et al., 2010; Fullana et al., 2010). The frequency of SOCD in the general population is even more unclear than that of clinical OCD, with estimates ranging from 5.3% for obsessions only (Blom et al., 2011) to 28% for obsessions and/​or compulsions (Ruscio et al., 2010). Some of this variability can be attributed to variable ways that SOCD has been defined and operationalized; different studies have assessed rates of obsessions and/​or compulsions (Blom et al., 2011; Fullana et al., 2010), obsessions and/​or compulsions that do not meet the full DSM criteria for OCD (de Bruijn et al., 2010), and obsessions and/​or compulsions associated with either distress or impairment, but not both (Fineberg et  al., 2013a-​c). In the German National Survey of 4,181 adults, for example, the 1-​year prevalence of OCD was 0.7%, of SOCD 4.5%, and of all obsessive-​compulsive symptoms (OCS), 8.3% (Adam et al., 2012). 36

A consensus definition of SOCD and of OCS is needed. It is useful to use the term SOCD to identify patients with subsyndromal obsessions and compulsions accompanied by distress or some degree of impairment, and the term OCS to indicate the presence of obsessions and/​or compulsions irrespective of distress or impairment. Patients with SOCD and OCS exhibit high comorbidity rates, impaired health and functional status, and increased psychological vulnerability, even after accounting for the influence of other diagnoses (Adam et  al., 2012; Blom et al., 2011; de Bruijn et al., 2010). However, it is unclear how many individuals with SOCD convert to full-​blown OCD in the long term. In a 30-​year population-​ based follow-​up study (Fineberg et al., 2013c), only 4 out of 98 cases with “obsessive-​compulsive syndromes” and 6 out of 107 cases with obsessions and/​or compulsions developed OCD over the course of the study. However, in the Dunedin prospective study in New Zealand, the presence of obsessions or compulsions at age 11 increased by sixfold the risk of OCD in adulthood (Fullana et al., 2010). Obsessions and compulsions usually have an early onset, but this can be difficult to establish, as retrospective identification of symptom onset in adults is likely to be imprecise. Several studies have directly assessed the prevalence of OCD and/​or SOCD among children and adolescents; again, results have been somewhat variable. In the 1999 British Child Mental Health Survey (Heyman et al., 2003), current OCD prevalence among 10,438 youngsters aged 5 to 15 years was 0.25%, with rates increasing exponentially towards puberty. Among 1,883 Italian older adolescents (Maina, Albert, Bogetto, & Ravizza), the point and lifetime prevalence rates were 2.0% and 2.6%, respectively, whereas 12.3% exhibited SOCD. In Israel, 3.6% of 562 16-​to 17-​ year-​old adolescents had current OCD (Zohar et al., 1992). Among 1,035 adolescents aged 12 to 17 years in German schools, OCD occurred in 1.3%, according to the CIDI (Essau, Conradt, & Peterman, 2000), whereas in a sample of 1,514 Spanish children aged 8 to 12 years the prevalence was 1.8% for OCD, 5.5% for SOCD, and 4.7% for OCS (Canals, Hernández-​Martínez, Cosi, & Voltas). In Brazil, among 2,323 adolescents aged 14 to 17 years, the point prevalence of OCD was 3.3% and the 1-​month prevalence of OCS was 18.3%; girls were more likely to be affected (Vivan et al., 2014). In another Brazilian survey (Alvarenga et  al., 2015), 14.7% of 9,937 children aged 6 to 12 years reported OCS; higher prevalence was associated with age and male gender. Interestingly, OCS dimensions (see ­chapter  8) clustered within families; this was particularly true of contamination/​cleaning symptoms (Alvarenga et al., 2015). In a subsequent study, O b sessive - C ompulsive D isorder

 

Alvarenga et al. (2016) categorized 2,512 children from this sample into three diagnostic groups: OCD (n = 77), OCS (n  =  488), and unaffected controls (n  =  1,947). The OCS group resembled the OCD group in overall impairment—​including school problems and delinquent behaviors—​and in mental health services use, an indirect measure of psychopathology. The comorbidity profile was similar in these two groups regarding all anxiety disorders, social phobia, and oppositional defiant, tic, and eating disorders. The OCS group showed intermediate scores in social skills and maladaptive behaviors. These findings suggest a psychopathological continuum between OCS and OCD. Importantly, community-​based studies have confirmed that only the minority of participants presenting with OCD were receiving treatment for their condition, both in adult (Fullana et  al., 2010; Torres et  al., 2006)  and pediatric (Essau et al., 2000; Heyman et al., 2003; Vivan et al., 2014) samples. The literature on OCD incidence is sparser than that on prevalence. One-​year incidence rates of DSM-​III OCD have been reported between 0.12% (Nestadt, Bienvenu, Cai, Samuels, & Eaton, 1998)  and 0.79% (Crum & Anthony, 1993). Incidence estimates have been influenced by changes in the definition of the disorder over the decades. The DSM-​III diagnosis of OCD, formalized in 1980, did not require the presence of time-​consuming, distressing, or interfering symptoms and was relatively unstable on the long run. For instance, Nestadt et al. (1998) reported that many subjects who exhibited symptoms consistent with the DSM-​III diagnosis of OCD did not acknowledge them at assessments conducted up to 13 years later. Revised criteria in DSM-​III-​R , published in 1987, required the presence of at least some degree of distress and interference associated with obsessions and/​or compulsions, which may have improved stability of the diagnosis. Nevertheless, incidence estimates have remained heterogeneous, ranging from 0.05% per year in a US study using the DIS (Nestadt et al., 1998) to 0.2% in a Dutch study using the CIDI (De Graaf, Bijl, Ravelli, Smit, & Vollebergh, 2001). The mean annual incidence of OCD in Taiwan was 27.6 per 100,000 inhabitants; both incidence and prevalence varied with age, peaking at age 18 to 24 years among males and 35 to 44 years among females (Huang et al., 2014). Very few community-​based prospective studies have addressed risk factors for OCD; more work is needed in this area. These studies have identified several potential risk factors, including age (i.e., late adolescence), individual factors (first-​degree family history of OCD; non-​ Caucasian ethnicity), and environmental variables (drugs E pidemiology , C omor b idity , and   Burden

of abuse and stressful/​traumatic life events) (Fontenelle & Hasler, 2008; Veldhuis et  al., 2012). Other potential environmental triggers for OCD include obstetrical complications (Vasconcelos et  al., 2007), group A  streptococcal infections (whether or not associated with rheumatic fever) (Mercadante et al., 2000), traumatic brain injury, and exposure to atypical antipsychotics (Murphy, Timpano, Wheaton, Greenberg, & Miguel, 2010). The Dunedin study from New Zealand, which has followed a birth cohort over decades, has identified several predictors of an OCD diagnosis in adulthood, including social isolation, physical abuse, and negative emotionality (Grisham et  al., 2011). There is some evidence from this study linking specific risk factors to particular OCD symptom dimensions. For instance, perinatal insults were associated with increased risk for symmetry/​ordering and shameful thoughts symptoms, whereas poor childhood motor skills predicted symptoms in the harm/​checking dimension. Difficult temperaments, internalizing symptoms, and conduct problems in childhood were associated with several specific symptom dimensions, and lower IQ nonspecifically predicted increased risk for most symptoms (Grisham et al., 2011). C OMOR B IDIT Y Psychiatric comorbidities in OCD, as in any psychiatric disorder, are very common. Estimated comorbidity rates vary according to methodological approaches, such as sample context (community vs. clinical), period of assessment (current vs. lifetime), age of subjects (adults vs. children/​ adolescents), assessment instruments (screening vs. diagnostic tools), and interviewers (lay vs. mental health professionals). High lifetime rates of comorbidity have been reported in both community and clinical samples. From 60% (De Mathis et al., 2013; Hofmaeijer-​Sevink et al., 2013; Kalra, Trivedi, Dalal, Sinha, & Allet, et  al., 2008; Torres et  al., 2006; Tükel, Polat, Ozdemir, Aksüt, & Türksoy, 2002) to around 90% (LaSalle et al., 2004; Ruscio et al., 2010; Torres et al., 2013) of patients with OCD have been reported to have at least one concurrent neuropsychiatric diagnosis. This appears to be true across the lifespan:  70% of children, 84% of adolescents, and 91% of adults met lifetime criteria for at least one other psychiatric disorder (Pigott, L’Heureux, Dubbert, Bernstein, & Murphy, 1994; Pinto, Mancebo, Eisen, Pagano, & Rasmussen, 2006). Among 955 adult OCD patients in Brazil, 92.3% presented with one or more additional psychiatric disorder (Torres et al., 2013). 37

 

Comorbidity, therefore, is the rule rather than the exception in OCD, across ages, regions, and studies. Depressive disorders (major depression disorder—​ MDD and dysthymia) and anxiety disorders (separation, social and generalized anxiety disorders, panic disorder/​ agoraphobia, and specific phobias) are the most common comorbid syndromes in OCD (see ­chapter 54) (Fineberg et al., 2013; Kalra et al., 2008; LaSalle et al., 2004; Lochner et  al., 2014; Pigott et  al., 1994; Rasmussen et  al., 1990; Ruscio et al., 2010; Torres et al., 2006; Tükel et al., 2002). In a naturalistic study, approximately 74% of patients with OCD had a lifetime history of MDD and 52% had a history of at least one anxiety disorder (Pinto et al., 2006). In the important epidemiological survey by Ruscio et al. (2010), the lifetime rates of comorbid anxiety and mood disorders were 75.8% and 63.3%, respectively. Among the anxiety disorders, social phobia (43.5%), specific phobia (42.7%), and separation anxiety disorder (37.1%) were the most common, followed by panic disorder (20.0%) and posttraumatic stress disorder (PTSD, 19.1%). Major depression occurred in 40.7%, bipolar disorders in 23.4%, and dysthymia in 13.1% of the participants with OCD (Ruscio et al., 2010). A cross-​sectional investigation characterizing more than 800 adult OCD outpatients from the Brazilian OCD Research Consortium (Miguel et al., 2008) showed the following lifetime prevalence rates: MDD, 68% (Quarantini et  al., 2011); social phobia, 35% (Assunção et  al., 2012); separation anxiety disorder, 27% (Franz et al., 2014); panic disorder and/​or agoraphobia, 20% (Torres et  al., 2014); and PTSD, 19% (Fontenelle et  al., 2012). Bipolar disorders have been described in 13% (Timpano, Rubenstein, & Murphy, 2012)  to 16% (Perugi et  al., 1997)  of OCD sufferers. A range of conditions characterized by obsessions, compulsions, or impulsive behaviour have been variably classified over the years as “obsessive-​compulsive (OC) spectrum disorders”; the concept of a group of such related disorders has most recently been formalized in the DSM-​ 5 as the category of “OCD and Related Disorders” (see ­chapter 48). Disorders that have been hypothesized to be similar to OCD in terms of psychopathology, associated features (age of onset, clinical course, and comorbidity), presumed etiology, familial transmission, and/​or response to treatments (Hollander, 1993)  include body dysmorphic disorder (BDD), trichotillomania, skin picking (these three disorders are described in the new DSM-​5 category; see ­chapter 48), tic disorders (Alvarenga et al., 2012; Lochner et al., 2014; Pigott et al., 1994), impulse-​control and substance use disorders (Adam et al., 2012; Alvarenga et  al., 2012; Ruscio et  al., 2010; Torres et  al., 2006), and 38

eating disorders (Pigott et al., 1994; Sallet et al., 2010; see ­chapter 56). Comorbidity with these disorders is also fairly common in OCD patients. Specifically, data from the Brazilian OCD Research Consortium showed that 11% presented with a lifetime history of an eating disorder (Sallet et al., 2010), 12% BDD (Conceição Costa et al., 2012), 16.3% skin picking, 4.9% trichotillomania (Lovato et  al., 2012), and 7.5% alcohol use disorders (Gentil et al., 2009). In another clinical study, BDD and self-​injurious behaviors occurred in 8.7% and 7.4%, respectively, of 457 OCD outpatients from 10 centers of the International College of Obsessive-​Compulsive Spectrum disorders (ICOCS) (Lochner et al., 2014). In the community-​based study by Ruscio et  al. (2010), impulse-​ control disorders were present in 55.9% of the OCD cases, in 92.8% of them preceding OCD onset. Among them, oppositional-​defiant disorder was the most common (27.7%), followed by attention deficit-​hyperactive disorder (ADHD, 18.8%), intermittent explosive disorder (18.6%), and conduct disorder (14.2%). In the same survey (Ruscio et al., 2010), high rates of lifetime alcohol (38.6%) and drug (21.7%) abuse or dependence were reported. The association between OCD and tic disorders or Tourette Syndrome (TS) has been particularly intensively studied (Leonard et al., 1992) (see c­ hapter 53). Based on a family study, Pauls & Leckman (1986) proposed in 1986 that at least some forms of OCD may represent a variant expression of TS. Several subsequent studies have sought to characterize the phenomenology of tic-​related forms of OCD, relative to OCD without tics. OCD patients with comorbid tics have an earlier age of onset of OCS (Diniz et al., 2004; Rosario-​Campos et al., 2001). In one study of adult subjects, 48% of those with early-​onset OCD (before 10 years of age, ascertained retrospectively) presented with tics or TS, compared with only 10% of those with a later onset of OCD symptoms (Rosario-​Campos et  al., 2001). Early-​onset OCD cases with tics exhibit specific clinical features, such as male predominance, more sensory phenomena (subjective experiences preceding repetitive behaviors in the absence of obsessions; see ­chapter 11), higher scores in the “aggression/​ violence” symptom dimension and lower scores in the “contamination-​cleaning” dimension, a higher number of comorbidities (e.g., ADHD), more family history of OCS, and lower rates of treatment response (Alvarenga et al., 2012; de Mathis et al., 2009; Mathis et al., 2006; Miguel et  al., 2005; Rosario-​Campos et  al., 2001). Results from 813 OCD outpatients in the Brazilian OCD Research Consortium showed a lifetime prevalence of tics of 29%, with 9% presenting full-​blown TS (Alvarenga et al., 2012); whereas researchers from ICOCS report 12.5% of O b sessive - C ompulsive D isorder

 

tic disorder comorbidity (Lochner et al., 2014). In studies of children with OCD, rates of tics varied from 20 to 59% (Leonard et al., 1992). It is noteworthy that the prevalence of psychiatric comorbidities varies considerably between community and clinical OCD samples, suggesting a possible influence of comorbidity on help-​seeking behavior. For example, substance use disorders (SUD) are much more common in nonclinical than in clinical populations (Adam et al., 2012; Fontenelle et  al., 2008; Ruscio et  al., 2010; Torres et  al., 2006), suggesting that some sufferers may use alcohol and/​ or drugs to deal with their OCD symptoms, rather than seeking professional help (Gentil et al., 2009). On the other hand, panic disorder and MDD comorbidities tend to favor help-​seeking (Fineberg et al., 2013a; Fullana et al., 2010). In these patients, it is common for the mood or anxiety disorder to be the primary focus of the initial clinical presentation; patients may not reveal their OCD symptoms to the health professional initially, which can delay appropriate treatment (Torres et al., 2007). The profile of comorbidity in OCD patients may also differ between men and women. Men are more likely to present with social anxiety disorder, hypochondriasis, tic disorders, PTSD, and SUD, whereas women more frequently present with comorbid MDD, eating disorders, simple phobias, and impulse control disorders, such as trichotillomania, skin picking and “impulsive-​compulsive” buying (Torresan et al., 2009, 2013). Several investigators have reported that, when present, MDD generally occurs after the onset of OCD (de Mathis et al., 2013; Fontenelle et al., 2008; Karno, Golding, Sorenson, & Burnam, 1988; Kessler et al., 2005a, 2005b; Ruscio et al., 2010), suggesting that depressive symptoms may be a consequence of the negative and usually long-​lasting impact of OCD on the individual’s daily life (Fineberg et al., 2013a). Likewise, 70% of OCD patients with comorbid SUD reported that OCD preceded SUD by at least 1 year, suggesting that substance use may arise at least in part as an attempt at self-​medication for OCD symptoms (Mancebo, Grant, Pinto, Eisen, & Rasmussen, 2009). On the other hand, several studies have shown that the onset of anxiety disorders (panic disorder, specific phobia, separation, social and generalized anxiety disorders) tends to predate OCD onset (Angst et al., 2004; Brückl et al., 2007; Crum et al., 1993; Karno et al., 1988). In the National Comorbidity Survey Replication, almost 80% of all anxiety disorders preceded the onset of OCD. The relationship with other comorbidities was less clear cut in this large cross-​sectional study: The proportion of mood disorders that began before (40.2%) or after (45.6%) OCD was similar (Ruscio et al., E pidemiology , C omor b idity , and   Burden

2010). In 58.9% of the cases SUD began at an earlier age than OCD, and the odds of subsequent OCD were 8.9% in participants with preexisting alcohol dependence. More prospective studies are needed to avoid recall bias regarding age of onset of the disorders. A recent study (de Mathis et al., 2013) examined the trajectory of symptomatology in patients with OCD and tried to establish whether initial symptomatology predicted the development of distinctive lifetime trajectories. OCD patients who first presented with separation anxiety disorder were found to be more likely to develop additional anxiety and somatoform disorders and to present more severe depressive and anxiety symptoms. They were also more prone to develop PTSD when exposed to a traumatic event. Therefore, this group could be regarded as highly vulnerable for multiple anxiety disorders. OCD patients initially presenting with ADHD symptoms had higher frequencies of SUD and a progressively worsening OCD course. Finally, patients with tic disorders as the first presentation were more likely to develop trichotillomania, skin picking, and BDD. This pattern supports the idea that OCD, tic disorders, BDD, trichotillomania, and skin picking are etiologically related conditions (de Mathis et al., 2009, 2013). Overall, these findings suggest that, from a developmental perspective, OCD does not behave as a unitary disorder but rather as a collection of syndromes with distinct longitudinal courses (de Mathis et al., 2013). The mechanisms that mediate these interactions between different symptom domains remain to be explained (Cerdá, Sagdeo, & Galea, 2008). A recent study (Torres et al., 2016) found independent associations between OCD symptom dimensions (see ­chapter 8) and comorbid disorders. The aggressive dimension was associated with PTSD, separation anxiety disorder, and impulse-​control disorders; the sexual-​religious dimension with mood, anxiety, somatoform and tic disorders, and nonparaphilic sexual disorder; the contamination-​cleaning dimension with hypochondriasis; and the hoarding dimension with depressive disorders, specific phobia, PTSD, some impulse control disorders, ADHD, and tic disorders. In an important community-​based study (Fullana et  al., 2010), the association with other psychiatric disorders was particularly marked for the shameful thoughts dimension (major depression, anxiety disorders, and drug dependence) and weakest for the contamination-​cleaning dimension. These patterns of overlap may be due to phenomenological overlap between DSM diagnoses, to common etiological factors, and/​or to overlapping pathophysiology. Comorbidity between OCD and personality disorders (PDs) has also been consistently reported (see ­chapter 59). 39

 

In one study in a clinical population, 38% of patients with OCD also met criteria for at least one DSM personality disorder (Pinto et  al., 2006), especially obsessive-​compulsive (25%) and avoidant PD (16%). Epidemiological studies have shown even higher rates of personality disorders in OCD patients from the community. In the 2000 British National Survey of Psychiatric Morbidity, the prevalence of any personality disorder in the OCD group was 74%, significantly higher than among patients with other “neurotic” disorders (55%) (Torres et  al., 2006). The most frequent comorbid categories were paranoid (35%), obsessive-​ compulsive (29%), avoidant (27%), schizoid (26%), and schizotypal (25%). Notably, despite their historical relationship and similar nomenclature, the rate of comorbid OCPD did not differ between OCD and other “neuroses.” A recent study with treatment-​seeking OCD patients reported that OC, schizotypal, and borderline personality disorders are frequent, tend to be associated with differential expressions of OCD symptoms and higher clinical severity, and influence help-​seeking and response to treatments (Melca et al., 2015). In sum, the presence of comorbidity is the rule in OCD. This increases not only the clinical complexity, but also the level of distress, impairment, and negative consequences on the individual’s daily life (Hofmaeijer-​Sevink et al, 2013). The comorbidity profile is also relevant for OCD prognosis, since some comorbid disorders may increase the likelihood of development of other comorbidities (de Mathis et al., 2013). Moreover, comorbidity may influence the search for, adherence to, and response to treatment. While we await new approaches that will enhance the validity of psychiatric diagnosis, longitudinal studies establishing specific trajectories of psychiatric comorbidities in OCD are warranted (de Mathis et al., 2013). THE BUR DEN O F O CD O N  PATI EN TS, FA M IL IES A ND CARE PROVI D ERS OCD is among the leading causes of disability among psychiatric illnesses, in terms of Disability Adjusted Life Years (DALYs—​the sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability) (Mathers & Loncar, 2006). It has been calculated that in 2015 it resulted in over 5.5 million lost DALYs, worldwide; this number is projected to grow (Mathers et  al., 2006). Correct diagnosis and delivery of appropriate treatment are commonly delayed in OCD (Hollander, Stein, Fineberg, Marteau, & Legault, 2010), and treatment efficacy is limited in many cases (Fineberg et al., 2013). 40

OCD has been associated with high levels of distress, frequent comorbid depression, social isolation, and occupational disability (Hollander et al., 2010; Mancebo et al., 2009). This relates to low self-​esteem, interference with family functioning, difficulty maintaining relationships, academic and career under-​achievement, and suicidality (Hollander et al., 1996). Of great concern is the treatment gap for OCD, expressed as the percentage of individuals who require care but do not receive any treatment, which has been estimated as almost 60% worldwide (Kohn, Saxena, Levav, & Saraceno, 2004). In a British community-​ based study (Torres et al., 2007), most people with OCD, particularly those with no comorbidities, were not in contact with mental health professionals, and very few were receiving appropriate treatments. This scenario is probably even worse in less developed countries. In a recent review addressing treatment delay in OCD, help-​seeking behavior was associated with greater insight, greater severity, aggressive and other “unacceptable” obsessions, and comorbidity, whereas barriers to seeking treatment were shame about the symptoms or about asking for treatment, not knowing where to find help, and perceived inconveniences associated with treatment (García-​Soriano et  al., 2014). The treatment delay observed in a Brazilian multisite, cross-​ sectional study with 630 subjects was 18.1  years (Miguel et  al., 2008). Even when treatment is sought, there is commonly a further delay before the patient receives a correct diagnosis and proper treatment. This further increases the costs and burden of OCD. The World Health Organization (WHO) conceptualizes quality of life (QoL) as a “multidimensional construct describing an individual’s subjective perception of his position in life in the context of the culture and value system in which he lives, and in relation to his goals, expectations, standards and concerns” (The WHOQOL Group, 1996). Patients with OCD can suffer from disability affecting a broad range of health-​related QoL domains, leading to substantial impairments in professional and personal lives. QoL in adults with OCD from community and clinical samples was addressed in a recent review of studies published between 1995 and 2012 (Subramaniam, Soh, Vaingankar, Picco, & Chong, 2013), and is reviewed in ­chapter  6. OCD sufferers experience reduced QoL across all domains. Comorbid depression worsens QoL, as do symptoms in the washing and hoarding dimensions. QoL tends to improve after both pharmacological and cognitive-​ behavioral treatment, with some studies suggesting a correlation between QoL improvement and symptom reduction. Partial hospitalization programs and deep brain stimulation O b sessive - C ompulsive D isorder

 

for those with treatment-​resistant OCD also led to QoL improvement (Subramaniam et  al., 2013). Symptomatic relapse is related to impairment both in QoL and disability. Overall, QoL studies indicate that patients with OCD scored better on QoL domains than patients with MDD, but similarly or even worse than patients with schizophrenia in some domains (Bobes et al., 2001; Bystritsky et al., 2001; Rosa et al., 2012; Subramaniam et al., 2013). Kumar et  al. (2012) described a relationship between cognitive appraisals and specific domains of QoL. For example, importance of thoughts, thought control, and inflated personal responsibility (see ­chapter  18) correlated negatively with the psychological domain of QoL, but only the latter two correlated negatively with total QoL. These authors emphasize that, as QoL measures the impact of OCD on the individual, it should be incorporated as a routine outcome measure for therapeutic interventions. Suicidality represents an extreme and clinically critical manifestation of illness-​associated distress. A  recent metaanalysis of 48 studies (Angelakis, Gooding, Tarrier, & Panagioti, et al., 2015) found suicidality to be elevated in OCD, with higher risk among patients with comorbid psychiatric disorders (especially major depression), more severe obsessive, anxious and depressive symptoms, hopelessness, and previous suicide attempts. One large study of 582 adult outpatients with OCD revealed that 36% of them endorsed lifetime suicidal thoughts, 20% had made suicidal plans, 11% had attempted suicide, and 10% described current suicidal thoughts at the time of assessment (Torres et al., 2011). All of these measures of suicidality were associated with lifetime comorbid MDD and PTSD. Symptoms from the sexual/​religious dimension and comorbid SUD were associated with suicidal thoughts and plans, whereas impulse control disorders were associated with current suicidal thoughts, plans, and attempts. Higher prevalence of suicidal thoughts (59.0% vs 16.3%) and attempts (24.6% vs. 3.8%) were also recently described among adolescents with OCD in India ( Jaisoorya, Janardhan Reddy, Thennarasu, Beena, & Jose, 2015), as compared with controls. Therefore, it is important to carefully investigate suicidal behaviors in OCD patients, especially those with sexual/​religious symptoms and/​or with comorbid MDD, PTSD, SUD, and impulse control disorders. In a recent Swedish population-​ based study of 36,788 individuals (Fernández de la Cruz et al., 2016), those with OCD had an increased risk of both attempting suicide (OR = 5.45) and dying by suicide (OR = 9.83), compared with matched controls. Importantly, these risks remained substantial after adjusting for psychiatric comorbidities, indicating that OCD increases the risk of suicide in its own right. E pidemiology , C omor b idity , and   Burden

Impulsivity can add to the burden of OCD. Kashyap et  al. (2012) studied 869 subjects with OCD and found that patients with poor insight and with low resistance to and reduced control over their compulsions were more likely to follow a deteriorating course, with longer duration of obsessions and greater severity of comorbid hoarding symptoms. The authors suggest that poor insight and poor resistance to and control over compulsions may serve as phenotypic markers of impulsivity in OCD. Identifying these individuals could allow for more targeted treatment and intensive treatment in this high-​risk group. The burden of OCD extends beyond individual patients, often profoundly affecting families and caregivers. In a Chinese study of 77 dyads of OCD adult outpatients and their caregivers (Siu, Lam, & Chan, 2012), 99% of the caregivers reported objective burden associated with the identified patients’ disease. Mothers of patients experienced the greatest subjective burden, and both objective and subjective burden were heavily influenced by level of functional impairment of the patients. A  cross-​sectional study investigating family burden and QoL of caregivers of 50 OCD patients in India described high objective burden in 56% of them; the level of burden and impairment in QoL correlated with patients’ OCD severity (Grover & Dutt, 2011). Older age of the patient and longer duration of illness and of treatment were predictive of poorer QoL in the physical health domain in caregivers. Greater objective burden and disruption of family leisure and interaction due to patients’ OCD symptoms led to overall poorer QoL of caregivers. Higher financial burden, perception of poorer mental health, and higher subjective burden were predictive of poorer physical, general health, and general and psychological QoL, respectively (Grover et al., 2011). A similar Turkish study (Cicek, Cicek, Kayhan, Uguz, & Kaya, 2013) reported greater family burden and reduced QoL in all domains among first-​degree relatives of OCD patients, compared to controls. Longer duration of OCD, comorbid MDD, and poorer insight were associated with greater burden among OCD patients’ relatives. The prevalence of MDD in relatives of OCD patients was significantly higher than among the relatives of controls (Cicek et  al., 2013). Two Brazilian studies have also investigated emotional burden on caregivers of OCD patients. In the first one (Ramos-​Cerqueira, Torres, Torresan, Negreiros, & Vitorino, 2008), 42% of 50 caregivers were themselves diagnosed with a common mental disorder, but only four of these (8%) were receiving treatment. The levels of psychological morbidity, family accommodation, and burden were associated with each other and also with the severity of OCD and depressive symptoms in the patients 41

 

(Ramos-​Cerqueira et al., 2008). Six factors of burden were identified among OCD caregivers (interference in personal life, perception of patient’s dependence, feelings of irritation or intolerance, guilt, insecurity, and embarrassment); all of them were associated with higher OCD severity and with greater accommodation to the patients’ symptoms (Torres, Hoff, Padovani, & Ramos-​ Cerqueira, 2012). Taken together, these findings suggest that, in addition to OCD patient care, attention should be given to the mental health and QoL of family caregivers, as an essential part of a comprehensive OCD treatment plan. OCD creates substantial economic burden on society, due to incapacitation, use of general and specialized health services, and hospitalization (Andlin-​Sobocki & Wittchen, 2005). Hankin et  al. (2011) described similar healthcare costs in a sample of adult patients newly diagnosed with “pure” (non-​comorbid) OCD and “pure” depression, from 1997 to 2006, in terms of the 2-​year median per-​patient healthcare claims and costs for Florida Medicaid. In sum, the burden of OCD is profound. The suffering of patients overflows to affect the well-​being and quality of life of their caregivers. The disorder is responsible for considerable socioeconomic burden for patients and afflicted families, as well as for the healthcare systems worldwide. Diagnosis and treatment are often substantially delayed, resulting in considerable increase in morbidity and burden (Fineberg et al., 2013; Hollander et al., 2016; Torres et al., 2007). C ONCL US ION The WHO’s World Mental Health Surveys indicate that mental disorders are highly prevalent across the globe, with anxiety disorders, including OCD, comprising the single most prevalent group of conditions (Demyttenaere et  al., 2004). OCD affects 1% to 2.5% of the general population, but minor forms, such as subthreshold symptoms—​ which are also associated with distress and functional impairment—​may occur in up to one third of the general population. Comorbidity with other psychiatric disorders is the rule in OCD, increasing not only the severity and negative impact on daily life activities, but also the complexity of management. Comorbid symptomatology may mark disease subtypes with distinct clinical courses. There is a growing awareness of the major contribution of neuropsychiatric disorders to the global burden of disease. In fact, mental, neurological, and substance use disorders are the largest source of global disability worldwide

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OCD Association study. Journal of Affective Disorders, 150(3), 847–​854. Hofmaeijer-​Sevink, M. K., Van Oppen, P., van Megen, H. J., Batelaan, N. M., Cath, D. C., & der Wee, N. J. A. (2013). Clinical relevance of comorbidity in obsessive compulsive disorder:  The Netherlands OCD Association study. Journal of Affective Disorders, 150(3), 847–​854. Hollander, E. (1993). Introduction. In E. Hollander E. (Ed.), Obsessive-​ compulsive related disorders (pp. 1–​16). Washington, DC: American Psychiatric Press. Hollander, E., Doernberg, E., Shavitt, R. G., Soreni, N., Veltman, D. J., Sahakian, B. J., & Fineberg, N. A. (2016). The cost and impact of compulsivity:  A  research perspective. European Neuropsychopharmacology, 26(5), 800–​809. Hollander, E., Kwon, J. H., Stein, D. J., Broatch, J., Rowland, C. T., & Himelein, C. A. (1996). Obsessive-​compulsive and spectrum disorders: Overview and quality of life issues. Journal of Clinical Psychiatry, 57(Suppl 8), 3–​6. Hollander, E., Stein, D. J., Fineberg, N. A., Marteau, F., & Legault, M.(2010). Quality of life outcomes in patients with obsessive-​ compulsive disorder: Relationship to treatment response and symptom relapse. Journal of Clinical Psychiatry, 71(6), 784–​792. Huang, L. C., Tsai, K. J., Wang, H. K., Sung, P. S., Wu, M. H., Hung, K. W., & Lin, S. H. (2014). Prevalence, incidence, and comorbidity of clinically diagnosed obsessive-​ compulsive disorder in Taiwan:  A  national population-​based study. Psychiatry Research, 220(1–​2), 335–​341. Hwu, H. G., Yeh, E. K., & Chang, L. Y. (1989). Prevalence of psychiatric disorders in Taiwan defined by the Chinese Diagnostic Interview Schedule. Acta Psychiatrica Scandinavica, 79, 136–​147. Jaisoorya, T. S., Janardhan Reddy, Y. C., Thennarasu, K. V., Beena, M., & Jose, D. C. (2015). An epidemiological study of OCD in adolescents from India. Comprehensive Psychiatry, 61, 106–​114. Kalra, H., Trivedi, J. K., Dalal, P. K., Sinha, P. K., & Allet, J. L. (2008). Uncomplicated and complicated obsessive-​compulsive disorder: An exploratory study from India. Comprehensive Psychiatry, 49, 51–​54. Karno, M., Golding, J. M., Sorenson, S. B., & Burnam, M. A. (1988). The epidemiology of obsessive-​compulsive disorder in five US communities. Archives of General Psychiatry, 45(12), 1094–​1099. Kashyap, H., Fontenelle, L. F., Miguel, E. C., Ferrão, Y. A., Torres, A. R., Shavitt, R. G., Ferreira-​Garcia, R., do Rosário, M. C., & Yücel, M. (2012). ‘Impulsive compulsivity’ in obsessive-​compulsive disorder:  A  phenotypic marker of patients with poor clinical outcome. Journal of Psychiatric Research, 46(9), 1146–​1152. Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005a). Lifetime prevalence and age-​of-​onset distributions of DSM-​IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6), 593–​602. Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R., & Walters, E. E. (2005b). Prevalence, severity, and comorbidity of 12-​month DSM-​IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6), 617–​627. Kohn, R., Saxena, S., Levav, I., & Saraceno, B. (2004). The treatment gap in mental health care. Bulletin of the World Health Organization, 82(11), 858–​866. Kumar, A., Sharma, M. P., Kandavel, T., & Janardhan Reddy, Y. C. (2012). Cognitive appraisals and quality of life in patients with obsessive compulsive disorder. Journal of Obsessive-​Compulsive and Related Disorders, 1(4), 301–​305. LaSalle, V. H., Cromer, K. R., Nelson, K. N., Kazuba, D., Justement, L., & Murphy, D. L. (2004). Diagnostic interview assessed neuropsychiatric disorder comorbidity in 334 individuals with obsessive-​ compulsive disorder. Depression and Anxiety, 19, 163–​173. Leonard, H. L., Swedo, S. E., Rapoport, J. L., Rickler, K. C., Topol, D., Lee, S., & Rettew, D. (1992). Tourette syndrome and obsessive-​ compulsive disorder. Advances in Neurology, 58, 83–​93.

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Lochner, C., Fineberg, N. A., Zohar, J., van Ameringen, M., Juven-​ Wetzler, A., Altamura, A. C., Cuzen, N. L., Hollander, E., Denys, D., Nicolini, H., Dell'Osso, B., Pallanti, S., & Stein, D. (2014). Comorbidity in obsessive-​compulsive disorder (OCD):  A  report from the International College of Obsessive-​Compulsive Spectrum Disorders (ICOCS). Comprehensive Psychiatry, 55(7), 1513–​1519. Lovato, L., Ferrão, Y. A., Stein, D. J., Shavitt, R. G., Fontenelle, L. F., Vivan, A., Miguel, E. C., & Cordioli, A. V. (2012). Skin picking and trichotillomania in adults with obsessive-​compulsive disorder. Comprehensive Psychiatry, 53(5), 562–​568. Maina, G., Albert, U., Bogetto, F., & Ravizza L. (1999). Obsessive-​ compulsive syndromes in older adolescents. Acta Psychiatrica Scandinavica, 100(6), 447–​450. Mancebo, M. C., Grant, J. E., Pinto, A., Eisen, J. L., & Rasmussen, S. A. (2009). Substance use disorders in an obsessive compulsive disorder clinical sample. Journal of Anxiety Disorders, 23(4), 429–​435. Marques, L., LeBlanc, N. J., Weingarden, H. M., Timpano, K. R., Jenike, M., & Wilhelm, S. (2010). Barriers to treatment and service utilization in an internet sample of individuals with obsessive-​compulsive symptoms. Depression and Anxiety, 27(5), 470–​475. Mathers, C. D., & Loncar, D. (2006). Projections of mortality and burden of disease from 2002 to 2030. PLoS Medicine, 3(11), e442. Mathis, M. A., Rosario, M. C., Diniz, J. B., Torres, A. R., Hasler, G., & Miguel, E. C. (2006). What is the optimal way to subdivide the obsessive compulsive disorder? CNS Spectrums, 11, 762–​768. Melca, I. A., Yücel, M., Mendlowicz, M. V., de Oliveira-​Souza, R., & Fontenelle, L. F. (2015). The correlates of obsessive-​compulsive, schizotypal, and borderline personality disorders in obsessive-​ compulsive disorder. Journal of Anxiety Disorders, 33, 15–​24. Mercadante, M. T., Busatto, G. F., Lombroso, P. J., Prado L, Rosário-​ Campos, M. C., do Valle, R., Marques-​Dias, M. J., Kiss, M. H., Leckman, J. F., & Miguel, E. C. (2000). The psychiatric symptoms of rheumatic fever. American Journal of Psychiatry, 157(12), 2036–​2038. Miguel, E. C., Ferrão, Y. A., Rosário, M. C., et al. (2008). Brazilian Research Consortium on Obsessive-​Compulsive Spectrum Disorders. The Brazilian Research Consortium on Obsessive-​Compulsive Spectrum Disorders:  Recruitment, assessment instruments, methods for the development of multicenter collaborative studies and preliminary results. Revista Brasileira de Psiquiatria, 30(3), 185–​196. Miguel, E. C., Leckman, J. F., Rauch, S., do Rosario-​Campos, M. C., Hounie, A. G., Mercadante, M. T., Chacon, P., & Pauls, D. L. (2005). Obsessive-​compulsive disorder phenotypes: Implications for genetic studies. Molecular Psychiatry, 10(3), 258–​275. Mohammadi, M. R., Ghanizadeh, A., Rahgozar, M., Noorbala, A. A., Davidian, H., Afzali, H. M., Naghavi, H. R., Yazdi, S. A., Saberi, S. M., Mesgarpour, B., Akhondzadeh, S., Alaghebandrad, J., & Tehranidoost, M. (2004). Prevalence of obsessive-​compulsive disorder in Iran. BMC Psychiatry, 4, 2. Murphy, D. L., Timpano, K. R., Wheaton, M. G., Greenberg, B. D., & Miguel, E. C. (2010). Obsessive-​compulsive disorder and its related disorders: A reappraisal of obsessive-​compulsive spectrum concepts. Dialogues in Clinical Neuroscience, 12, 131–​148. Myers, J. K., Weissman, M. M., Tischler, G. L., Holzer, C. E., 3rd, Leaf, P. J., Orvaschel, H., Anthony, J. C., Boyd, J. H., Burke, J. D., Jr, Kramer, M., et  al. (1984). Six-​month prevalence of psychiatric disorders in three communities 1980 to 1982. Archives of General Psychiatry, 41(10), 959–​967. Nestadt, G., Bienvenu, O. J., Cai, G., Samuels, J., & Eaton, W. W. (1998). Incidence of obsessive-​compulsive disorder in adults. Journal of Nervous and Mental Disorders, 186, 401–​406. Pauls, D. L., & Leckman, J. F. (1986). The inheritance of Gilles de la Tourette’s syndrome and associated behaviors: Evidence for autosomal dominant transmission. New England Journal of Medicine, 315, 993–​997. Perugi, G., Akiskal, H. S., Pfanner, C., Presta, S., Gemignani, A., Milanfranchi, A., Lensi, P., Ravagli, S., & Cassano, G. B. (1997).

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The clinical impact of bipolar and unipolar affective comorbidity on obsessive-​compulsive disorder. Journal of Affective Disorders, 46(1), 15–​23. Pigott, T. A., L’Heureux, F., Dubbert, B., Bernstein, S., & Murphy, D. L. (1994). Obsessive compulsive disorder:  comorbid conditions. Journal of Clinical Psychiatry, 55(Suppl), 15–​27. Pinto, A., Mancebo, M. C., Eisen, J. L., Pagano, M. E., & Rasmussen, S. A. (2006). The Brown Longitudinal Obsessive Compulsive Study:  Clinical features and symptoms of the sample at intake. Journal of Clinical Psychiatry, 67(5), 703–​711. Quarantini, L. C., Torres, A. R., Sampaio, A. S., et al. (2011). Comorbid major depression in obsessive-​ compulsive disorder patients. Comprehensive Psychiatry, 52, 386–​393. Ramos-​Cerqueira, A. T. A., Torres, A. R., Torresan, R. C., Negreiros, A. P. M., & Vitorino, C. N. (2008). Emotional burden in caregivers of patients with obsessive-​compulsive disorder. Depression and Anxiety, 25, 1020–​1027. Rasmussen, S. A., & Eisen, J. L. (1990). Epidemiology of obsessive compulsive disorder. Journal of Clinical Psychiatry, 51(Suppl), 10–​13. Robins, L. N., Helzer, J. E., Weissman, M. M., Orvaschel, H., Gruenberg, E., Burke, J. D., Jr, & Regier, D. A. (1984). Lifetime prevalence of specific psychiatric disorders in three sites. Archives of General Psychiatry, 41(10), 949–​958. Rosa, A. C., Diniz, J. B., Fossaluza, V., Torres, A. R., Fontenelle, L. F., De Mathis, A. S., da Conceição Rosário, M., Miguel, E. C., & Shavitt, R. G. (2012). Clinical correlates of social adjustment in patients with obsessive-​compulsive disorder. Journal of Psychiatric Research, 46(10), 1286–​1292. Rosario-​Campos, M. C., Leckman, J. F., Mercadante, M. T., Shavitt, R. G., Prado, H. S., Sada, P., Zamignani, D., & Miguel, E. C. (2001). Adults with early-​onset obsessive compulsive disorder. American Journal of Psychiatry, 158, 1899–​1903. Ruscio, A. M., Stein, D. J., Chiu, W. T., & Kessler, R. C. (2010). The epidemiology of obsessive-​ compulsive disorder in the National Comorbidity Survey Replication. Molecular Psychiatry, 15, 53–​63. Sallet, P. C., Alvarenga, P. G., Ferrão, Y. A., de Mathis, M. A., Torres, A. R., Marques, A., Hounie, A. G., Fossaluza, V., do Rosario, M. C., Fontenelle, L. F., Petribu, K., & Fleitlich-​Bilyk, B. (2010). Eating disorders in patients with obsessive-​compulsive disorder: Prevalence and clinical correlates. The International Journal of Eating Disorders, 43, 315–​325. Siu, B. W., Lam, C. L., & Chan, W. C. (2012). Pattern and determinants of burden in Chinese families of adults with obsessive-​compulsive disorder. Journal of Anxiety Disorders, 26(1), 252–​257. Subramaniam, M., Soh, P., Vaingankar, J. A., Picco, L., & Chong, S. A. (2013). Quality of life in obsessive-​compulsive disorder: Impact of the disorder and of treatment. CNS Drugs, 27, 367–​383. The WHOQOL Group. (1996). What quality of life? The WHOQOL Group. World Health Organization Quality of Life Assessment. World Health Forum, 17, 354–​356. Timpano, K. R., Rubenstein, L. M., & Murphy, D. L. (2012). Phenomenological features and clinical impact of affective disorders in OCD:  A  focus on the bipolar disorder and OCD connection. Depression and Anxiety, 29(3), 226–​233. Torres, A. R., & Prince, M. J. (2004). The importance of epidemiological studies on obsessive-​compulsive disorder. Revista Brasileira de Psiquiatria, 26, 141–​142. Torres, A. R., Ferrão, Y. A., Shavitt, R. G., Diniz, J. B., Costa, D. L., do Rosário, M. C., Miguel, E. C., & Fontenelle, L. F. (2014). Panic disorder and agoraphobia in OCD patients: Clinical profile and possible treatment implications. Comprehensive Psychiatry, 55, 588–​597. Torres, A. R., Fontenelle, R. G., Ferrão, Y. A., Rosário, M. C., Storch, E. A., & Miguel, E. C. (2016). Comorbidity variation in patients with obsessive-​compulsive disorder according to symptom dimensions:  Results from a large multicentre clinical sample. Journal of Affective Disorders, 190, 508–​516. Torres, A. R., Hoff, N. T., Padovani, C. R., & Ramos-​Cerqueira, A. T. A. R. (2012). Dimensional analysis of burden in family caregivers of

E pidemiology , C omor b idity , and   Burden

patients with obsessive-​compulsive disorder. Psychiatry and Clinical Neurosciences, 66, 432–​441. Torres, A. R., Moran, P., Bebbington, P. E., Brugha, T., Bhugra, D., Coid, J. W., Farell, M., Jenkins, R., Lewis, G., Meltzer, H., & Prince, M. (2006). Obsessive-​ compulsive disorder and personality disorder:  Evidence from the British National Survey of Psychiatric Morbidity 2000. Social Psychiatry and Psychiatric Epidemiology, 41(11), 862–​867. Torres, A. R., Prince, M. J., Bebbington, P. E., Bhugra, D. K., Brugha, T. S., Farrell, M., Jenkins, R., Lewis, G., Meltzer, H., & Singleton, N. (2007). Treatment seeking by individuals with obsessive-​compulsive disorder from the British Psychiatric Morbidity Survey of 2000. Psychiatric Service, 58, 977–​982. Torres, A. R., Prince, M. J., Bebbington, P. E., Bhugra, D., Brugha, T. S., Farrell, M., Jenkins, R., Lewis, G., Meltzer, H., & Singleton, N. (2006). Obsessive-​ compulsive disorder:  Prevalence, comorbidity, impact, and help-​seeking in the British National Psychiatric Morbidity Survey of 2000. American Journal of Psychiatry, 163(11), 1978–​1985. Torres, A. R., Ramos-​Cerqueira, A. T., Ferrão, Y. A., Fontenelle, L. F., do Rosário, M. C., & Miguel, E. C. (2011). Suicidality in obsessive-​ compulsive disorder: prevalence and relation to symptom dimensions and comorbid conditions. Journal of Clinical Psychiatry, 72(1), 17–​26. Torres, A. R., Shavitt, R. G., Torresan, R. C., Ferrão, Y. A., Miguel, E. C., & Fontenelle, L. F. (2013). Clinical features of pure obsessive-​ compulsive disorder. Comprehensive Psychiatry, 54, 1042–​1052. Torresan, R. C., Ramos-​Cerqueira, A. T. A., Mathis, M. A., Diniz, J. B., Ferrão, Y. A., Miguel, E. C., & Torres, A. R. (2009). Sex differences in the phenotypic expression of obsessive-​compulsive disorder:  An exploratory study from Brazil. Comprehensive Psychiatry, 50,  63–​69. Torresan, R. C., Ramos-​Cerqueira, A. T.  A., Shavitt, R. G., do Rosário, M. C., de Mathis, M. A., Miguel, E. C., & Torres, A. R. (2013). Symptom dimensions, clinical course and comorbidity in men and women with obsessive-​compulsive disorder. Psychiatry Research, 209, 186–​195. Tükel, R., Polat, A., Ozdemir, O., Aksüt, D., & Türksoy N. (2002). Comorbid conditions in obsessive-​ compulsive disorder. Comprehensive Psychiatry, 43, 204–​209. Vasconcelos, M. S., Sampaio, A. S., Hounie, A. G., Akkerman, F., Curi, M., Lopes, A. C., & Miguel, E. C. (2007). Prenatal, perinatal, and postnatal risk factors in obsessive-​compulsive disorder. Biological Psychiatry, 61(3), 301–​307. Veldhuis, J., Dieleman, J. P., Wohlfarth, T., et al. (2012). Incidence and prevalence of “diagnosed OCD” in a primary care, treatment seeking, population. International Journal of Psychiatry in Clinical Practice, 16, 85–​92. Viana, M. C., & Andrade, L. H. (2012). Lifetime prevalence, age and gender distribution and age-​of-​onset of psychiatric disorders in the São Paulo metropolitan area, Brazil:  Results from the São Paulo Megacity Mental Health Survey. Revista Brasileira de Psiquiatria, 34(3), 249–​260. Vivan, A. S., Rodrigues, L., Wendt, G., Bicca, M. G., Braga, D. T., & Cordioli, A. V. (2014). Obsessive-​compulsive symptoms and obsessive-​compulsive disorder in adolescents:  A  population-​based study. Revista Brasileira de Psiquiatria, 36(2), 111–​118. Weissman, M. M., Myers, J. K., & Harding, P. S. (1978). Psychiatric disorders in a U.S. urban community: 1975-​1976. American Journal of Psychiatry, 135, 459–​462. Williams, D. R., Herman, A., Stein, D. J., Heeringa, S. G., Jackson, P. B., Moomal, H., & Kessler, R. C. (2008). Twelve-​month mental disorders in South Africa: prevalence, service use and demographic correlates in the population-​based South African Stress and Health Study. Psychological Mediocine, 38(2), 211–​220. Zohar, A. H., Ratzoni, G., Pauls, D. L., et al. (1992). An epidemiological study of obsessive-​compulsive disorder and related disorders in Israeli adolescents. J Am Acad Child Adolesc Psychiatry, 31(6), 1057–​1061.

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5. NATURAL HISTORY AND LONG-​T ERM OUTCOME OF OCD Michael H. Bloch, MD, MS

A

s of the year 2000, the World Health Organization estimated that Obsessive-​ Compulsive Disorder (OCD) accounted for 2.5% of the total Global Years Lost to Disability worldwide and was the 10th leading cause of disability in the developed world, and among the top 20 leading causes of disability worldwide in individuals 18 to 44 years old (Ayuso-​Mateos, 2002). By contrast, more recent estimates regarding the global burden in 2014 do not have OCD placed nearly as prominently (Eaton et al., 2008). Although OCD is still estimated to have a lifetime prevalence of 1% to 3%, the development and dissemination of effective treatments for OCD has decreased the morbidity substantially for many patients. The introduction of effective medications to treat OCD—​initially clomipramine, (DeVeaugh-​Geiss, Landau, & Katz, 1989; Insel et al., 1983), followed by serotonin reuptake inhibitors (SSRIs) such as fluvoxamine (Goodman et al., 1989) and fluoxetine (Tollefson, Birkett, Koran, & Genduso, 1994; Tollefson, Rampey, et al., 1994) (see ­chapter 40)—​has dramatically improved the lives of many adults and children with OCD. Additionally, the demonstrated efficacy, dissemination, and widespread use of effective cognitive behavioral therapy (CBT) for OCD has led to similar treatment gains (see c­ hapters 37, 38). Although the placebo response rates in pharmacological trials of OCD have consistently been observed at less than 10% (Soomro, 2012), more than half of OCD patients prescribed an SSRI or given a full course of evidence-​based psycho­ therapy for OCD will experience a significant improvement of their OCD symptoms (Foa, 2010; Soomro, 2012). This chapter reviews the clinical course and long-​term outcome of both children and adults diagnosed with OCD. It consider studies conducted before and after the introduction of evidenced-​based treatment for OCD separately. Although naturalistic follow-​ up studies examining the course of OCD before the introduction of SSRI/​CBT shed

light on the underlying natural history of the disorder, more recent studies examining the clinical course of OCD during treatment with SRIs and/​or CBT provide data about the current prognosis of individuals who do receive effective, evidence-​based treatments. AGE OF   ONS E T   IN  OC D Metaanalytic latent class analysis of nine studies examining age of onset in OCD has suggested a bimodal age of onset (Taylor, 2011). Eight of the nine studies were best described by a two-​class solution, corresponding to early-​onset and late-​onset OCD. The early-​onset OCD group had an average age of onset of 11  years (range:  9–​14  years), whereas the late-​onset group had an average age of onset around 23 years, with a greater spread. Early-​onset and late-​onset OCD frequency distributions have substantial overlap; there is, not surprisingly, little agreement in the literature regarding an exact delineation between “early-​onset” and “late-​onset” OCD in individual cases. Early-​onset OCD was associated with: (1) a greater prevalence of comorbid tic disorders (odds ratio [OR] = 2.4, 99% confidence interval [CI] 1.6–​3.7); (2) a greater proportion of males (OR = 1.7, 99% CI 1.2–​2.3); (3) greater overall OCD symptom severity; and (4) a greater prevalence of OCD among first-​degree relatives (OR = 1.7, 99% CI 1.1–​2.7) (Taylor, 2011). Indeed, a recent heritability analysis suggested a much greater heritability (43%) in early-​ onset cases of OCD (defined as onset ≤16 years) compared with late-​onset OCD cases (27%, defined as onset >16 years) (Davis et al., 2013). Table 5.1 provides a comparison between the characteristics of early-​onset and late-​onset OCD. Early-​onset and late-​onset OCD appear to have differences in the frequency of various types of obsessions and compulsions (see ­chapter  8). Early-​onset illness has a 47

 

These studies primarily date to between the 1930s and 1960s, before the formalization of the modern definition of OCD in DSM-​III in 1980, and describe patients with Early-​Onset OCD Late-​Onset OCD “obsessional neurosis” (Goodwin, 1969; Reddy & Math, Average age of onset 11 years 23 years 2007). They generally report that a substantial proportion of patients experience a chronic course of illness (roughly Range of Onset 6–​16 years 18–​50 years 30%–​60% in most studies) and a minority experience Gender distribution Slight male Even gender remission (10%–​30%). They also report a substantial propredominance distribution portion that spontaneously improved (roughly 30%–​50%), Common comorbid Tic disorders and ADHD Anxiety and even if they did not achieve remission. conditions depression* However, there are several reasons to believe that these Overrepresented 1. Fear of harm Sexual obsessions data present an overly optimistic estimate of the likelihood OCD symptoms obsessions of OCD improving if untreated. First, although “obses2. Symmetry, ordering and sional neurosis” is considered the antecedent to the modern arranging symptoms conception of obsessive-​compulsive disorder, many of these 3. Just right or sensory-​ patients likely suffered from conditions that we would now based compulsions recognize as separate disorders, with comparatively better Heritability Modest (43% estimate) Slight (27% estimate) prognosis for spontaneous recovery. Obsessional neuroEffective treatments SSRI pharmacotherapy and sis was defined in the DSM-​II as a disorder characterized Cognitive Behavioral Therapy by the persistent and repetitive intrusion of unwanted * Actual rates of anxiety and depressive disorders between early-​onset and late-​onset thoughts, urges, or actions that the sufferer is unable to preOCD cases may not differ in adulthood. However, anxiety and depressive disorders are overrepresented in adults with OCD compared with children. vent. These thoughts may consist of single words, ideas, or ruminations often perceived by the sufferer as nonsensical. The repetitive urges or actions vary from simple movements greater proportion of: (1) symmetry, ordering and arranging to complex rituals; anxiety or distress is the underlying emoobsessions and compulsions; (2)  aggressive (fear of harm) tion or drive state; and the ritualistic behavior is a learned obsessions; and (3) OCD symptoms related to sensory phe- method of reducing the anxiety. Many individuals who nomenon and compulsions related to a need to get things would now be diagnosed with generalized anxiety disorder “just right” (Leckman et al., 2010; Pinto, Mancebo, Eisen, or ruminative depression may have been included in these Pagano, & Rasmussen, 2006) (see c­ hapter 11). Much of this initial “OCD” cohorts. Second, these studies predated the difference may be attributable to the higher prevalence of tic-​ availability of systematic and quantitative assessments of related OCD in the early-​onset group (see ­chapter 53). The OCD symptomatology, so assessment of “improvement” ideal way to divide prognostic studies might be to use DSM-​ was less precise than in more modern studies. Comorbid 5 subtypes of OCD, and newly recognized disorders, rather symptomatology, such as depression or anxiety, may have than age of onset—​specifically (1) the presence or absence significantly improved, while the actual OCD symptoms of comorbid tics, (2) presence of hoarding symptoms, and were still present. Last, these studies generally involved (3) degree of insight. Unfortunately, studies dividing cases highly selected clinical samples rather than epidemiologic on the basis of these DSM-​5 subtypes are sparse, compared samples, limiting generalizability. Caution should be taken with analyses comparing pediatric and adult samples. in extrapolating these results to contemporary patients who reject available treatments for OCD, as these individuals are not likely to be representative of OCD patients as a A DULTS W ITH O CD whole in terms of illness severity, acceptance of treatment, and other variables. One landmark 1999 study stands as the gold standard N A T U R A L I S T I C F O L L O W -​U P regarding the likely prognosis of OCD prior to the availS T U D I E S B E F O R E E V I D E N C E - ​B A S E D ability of evidence-​based treatments. Skoog and Skoog INTERVENTIONS FOR OCD (1999) published data on 40-​year outcomes in 144 out of Table 5.2 describes the results of several long-​term out- 176 eligible, nondeceased patients admitted with OCD to come studies conducted in adults with OCD, prior to the the Sahlgrenska University Hospital in Goteberg, Sweden widespread use of cognitive-​behavioral therapy and SSRIs. from the late 1940s to early 1950s. Eighty-​six percent of CO M PAR I S O N B E T W E E N E A R LY - O ​ N S E T A N D LATE-​ ON SET OBSESSI V E - ​C O M P UL S I V E D I S O R D E R TA B L E   5 . 1  

48

O b sessive - C ompulsive D isorder

 

LO N G I TUD I N A L O UT C O ME S T UD I E S E XA M I N I N G O B S ES S I V E- C ​ O M P ULS I V E S YM P TO M S P R I O R TO  THE INTRO D U CTI ON O F   E VI D E N C E -​B A S E D T R E AT M E N TS TA B L E   5 . 2  

Study

N

Follow-​up Interval (in years)

Luff & Garrod, 1935

49

3

England

39

34

Unspecified “Obsessional States”

Lewis, 1936

50

>5

England

32

34

Obsessions defined as contents of consciousness which . . . (1) are accompanied by the experience of subjective compulsion, and which (2) cannot be got rid of . . . and (3) are recognized as senseless.

Langfeldt, 1938

27

1–​11

Norway

26

33

Not specified

Rudin, 1953

130

2–​26

Germany

12

61

Not specified

Muller, 1953

57

15–​35

Switzerland

28

22

Not specified

Pollitt, 1957

67

1–​15

England

24

28

Obsessions defined as recurrent or persistent idea, thought, image, feeling, impulse, or movement, which is accompanied by a sense of subjective compulsion and a desire to resist it; the event being recognized by the individual as foreign to the personality and . . . has insight.

Hastings, 1958

23

6–​12

USA

13

47

Not specified

Balslev-​Olesen & Geert-​ Jørgensen, 1959

52

0–​8

Denmark

6

37

Not specified

Ingram, 1961

46

1–​11

England

9

61

Same definition of obsessions as Lewis, 1936

Grimshaw, 1965

97

1–​14

England

40

35

Obsessions are abnormal mental compulsions. They are experiences with a compelling quality which persistently intrude into consciousness. Though recognized by the patient as an irrational product of his own mind and resisted by him, they are incapable of being expelled. They may be thoughts, images, fears, urges, or acts. An obsessional disorder is one where such symptoms dominate the clinical picture and are not associated with any underlying psychosis.

Kringlen, 1965

85

13–​20

Norway

4

45

Same as Politt, 1957

Lo, 1967

87

1–​14

Hong Kong

20

44

Defined by criteria in Schneider, 1958; they are regarded as contents of consciousness which, when they occur are accompanied by the experience of subjective compulsion, and which cannot be got rid of, though on quiet reflection they are recognized as senseless.

Skoog & Skoog, 1999

144

40

Sweden

20

17

Based on Schneider, 1958 criteria that are quite similar to Pollitt, 1957

Location

Remitted (%) Unimproved (%)

Diagnostic Criteria

These studies are summarized in further detail in previous reviews (Goodwin, 1969; Reddy & Math, 2007).

 

the sample was retrospectively judged to meet DSM-​IV criteria for OCD based on case review. Over 80% of the patients had improved to some degree since the period of their inpatient hospitalization. One fifth of patients made a complete recovery, defined as the absence of clinically significant symptoms for 5 years. Among those who had recovered, 38% did so in the first decade following treatment. However, roughly half the sample had clinically significant OCD that lasted at least 30 years. Early age of onset, lower initial social functioning, and “magical obsessions” were associated with poor outcome (Skoog & Skoog, 1999). FOLLOW-U ​ P S T U D I E S E X A M I N I N G L O N G -​ T E R M O U T C O M E A F T E R   E V I D E N C E - ​B A S E D INTERVENTIONS FOR OCD

Long-​term outcome in adults with OCD has improved since the introduction of SSRIs and effective CBT. Sharma, Thennarasu, and Reddy conducted a metaanalysis examining outcomes at ≥1 year in adults diagnosed with OCD by DSM-​III-​R , DSM-​IV-​T R, or ICD-​9/​10 criteria who received treatment with SRIs and/​or CBT in studies that used a clinical rating scale to measure OCD severity (Sharma, Thennarasu, & Reddy, 2014). Metaanalysis of 17 studies involving 1,265 patients suggested a pooled long-​term remission rate of 53% (95% CI:  42%–​65%) after an average follow-​up duration of slightly under 5 years. There was a large degree of heterogeneity in likelihood of remission between studies. Prospective studies and studies conducted in India were associated with increased likelihood of remission. In metaregression, greater OCD severity and greater proportion of males in the sample were associated with lower likelihood of remission. Sources of heterogeneity that were not examined in this analysis included:  (1)  evidence-​based treatment received prior to inclusion in longitudinal cohorts (prior SRI trials, proportion of samples that previously received CBT, etc.); (2) comorbidity; and (3) quality and number of treatments received during the follow-​up period. Several additional studies have suggested that poor initial medication response is associated with poor long-​ term prognosis (Bloch et al., 2013). Table 5.3 depicts the characteristics of the 17 studies included in the previous metaanalysis as well as the predictors of outcome generated in each study. Among the studies examining long-​term outcome after the introduction of evidence-​based treatments for OCD, the Brown Longitudinal Obsessive-​ Compulsive Study (BLOCS) stands out as particularly germane to Western populations. BLOCS was a large NIH-​funded naturalistic 50

study that prospectively examined long-​term outcome in over 200 adults presenting to Brown (a tertiary academic referral center) for treatment of OCD. The BLOCS study is exceptional in its regular assessment of symptoms throughout the follow-​up interval and the wealth of assessments collected at each time point. At 2-​year follow-​up, only 6% of individuals were in full remission from OCD, whereas 24% experienced partial remission. Earlier age at onset of OCD, greater severity of OCD symptoms, older age at intake, and male gender were associated with a decreased likelihood of remission. Surprisingly, degree of insight, diagnostic comorbidity, and treatment were not associated with likelihood of achieving full or partial remission at two-​ year follow-​up (Eisen et al., 2010). At 5-​year follow-​up, a slightly greater percentage of OCD participants (17%) experienced full remission; the rate of partial remission was not significantly different from at 2 years (22%). Hoarding symptoms were associated with a poor prognosis, whereas aggressive symptoms were associated with an improved prognosis. Increased OCD severity and greater duration of illness prior to enrollment were also associated with poor response (Eisen et  al., 2013). Relapse once symptom remission had been achieved was rare. Importantly, the fact that the BLOCS study cohort was seen at a tertiary referral center limits its generalizability; many of these patients may have sought out such a specialty center because they had not achieved improvement in the community. These results underline the poor prognosis of many patients seeking treatment at academic referral centers, at least over 2 to 4 years. PE DIAT R IC OB S E S S IV E -​C OMPU LS IV E DIS OR DE R As discussed earlier in this chapter and summarized in Table 5.1, pediatric-​onset OCD (or early-​onset OCD) differs in several important ways from adult-​onset (or late-​onset) OCD. It has a male predominance, is more likely to be associated with comorbid tic disorders and ADHD (see c­ hapter 53), has greater heritability, and has an increased likelihood of being associated with particular obsessions and compulsions, compared to adult-​onset OCD. Limited data exist regarding long-​ term outcome of early-​ onset OCD prior to the introduction of evidence-​based treatments. A  limited number of case series focus largely on adolescents initially receiving inpatient treatment. These reports describe severe continuing impairment among these patients, with few O b sessive - C ompulsive D isorder

 

LO N G I TUD I N A L O UT C O ME S T UD I E S O F O B S ES S I V E- C ​ O M P ULS I V E D I S O R D ER A FTER THE I N TRO D UC TION O F  EV I DEN C E-​BA S E D T R E AT M E N T S TA B L E   5 . 3  

Study

N

Follow-​up interval (in years)

Design

Interim Treatment

Remission (%)

Predictors of Long-​Term Outcome

Eisen et al., 1999

66

2

Prospective

SRIs (77%), CBT (18%), or both depending on need

52

Not examined

Zitterl et al, 2000

70

1.5

Prospective

SRIs and CBT for 6 months

31

No significant predictors of outcome identified. Comorbid depression was not associated with prognosis.

Alonso et al., 2001

60

2.5

Prospective

SRIs (100%) and CBT (62% completed)

58

Poor outcome associated with sexual and religious OCD symptoms

van Oppen, van Balkom, de Haan, & van Dyck, 2005

102

5.5

Retrospective

CBT(100%) or SRI (38% received fluvoxamine initially and most CBT only subjects received SRI in follow-​up period)

43

CBT dropout was associated with poor outcome

Rufer et al., 2004

30

7.2

Retrospective

CBT (10)%), SRIs (50% randomized to fluvoxamine and most CBT only subjects received SRI in follow-​up period)

43

Longer duration of illness associated with poor outcome

Biondi and Picardi, 2005

32

3.13

Prospective

SRIs (100%) and CBT (50% of subjects)

34

Initial CBT treatment predicted decreased likelihood of relapse.

Reddy et al.,_​ 2005

75

12

Retrospective

SRIs (75%), CBT (15%), or both

76

Presence of additional Axis I comorbidity associated with poor outcome

Catapano et al_​ 2006

55

3

Prospective

SRIs only

56

Significant predictors of poor outcome included a longer duration of illness, a greater severity of OCD symptoms, and the presence of comorbid schizotypal personality disorder.

Math et al., 2007

44

5

Retrospective

SRIs (100%), CBT, (20; moderate to high levels of OCD severity) (Eisen et al., 2006). However, symptom severity explains only a small fraction of the variance in QoL (Rapaport et  al., 2005). Thus, other, more specific factors likely affect patients’ perception of well-​being. For example, Kugler et  al. (2013) examined how perceived interference of OC symptoms in daily life and amount of effort exerted in resisting obsessions and compulsions may explain the relationship between overall OC severity and QoL. They found that the more patients perceived their symptoms as hindering their work and social functioning, and the more they yielded to engaging with the disordered thoughts and rituals instead 59

 

of attempting to fight or control them, the more diminished QoL they experienced. Treatments focused on ritual prevention often result in QoL improvement, a point to which we return later in this chapter. Nevertheless, this research highlights that QoL impairment occurs across the range of OCD severity, making it incumbent for clinicians to assess these domains with all patients, and not just the ones severely ill. Research has also examined the relative impact of obsession severity versus compulsion severity on QoL. Several studies have found QoL impairment to be more strongly associated with obsession severity than with compulsion severity (Eisen et al., 2006; Hou et al., 2010; Masellis et al., 2003; Rodriguez-​Salgado et al., 2006). For example, Eisen and colleagues (2006) found that obsession and compulsion symptom severity were each significantly correlated with QoL, but there were stronger associations with regard to obsessions, across multiple domains of functioning. Such findings have led some researchers to hypothesize that the intrusive, overpowering, and distressing nature of obsessions have a greater perceived impact on emotional well-​being, ability to enjoy leisure activities, and other QoL domains than do the compulsions, which aim to reduce anxiety or discomfort triggered by obsessions. In contrast, other studies have reported a stronger association between compulsion severity and QoL compared with obsession severity (Stengler-​Wenzke, Kroll, Riedel-​Heller, Matschinger, & Angermeyer, 2007). These authors suggest that certain aspects of QoL such as physical, environmental, and psychological well-​being may be impacted more by compulsions because they are often time-​consuming, physically and emotionally exhausting, and result in less time spent with family and friends. Yet another study found that obsessions and compulsions impacted QoL impairment equally (Moritz et al., 2005). The differences in findings between studies may in part be due to methodological differences, including the measures employed to assess QoL. Further research is needed in this area.

OCD SYMPTOM DIMENSIONS

Albert et al. (2010) reported that symmetry-​related obsessions, along with repeating, counting, and ordering and arranging compulsions, were inversely related to vitality, social functioning, role emotional health, and mental health QoL. Individuals with symmetry and exactness may become so hyperfocused on these concerns that they isolate themselves from social interaction and support, and 60

therefore exhibit decreased social functioning and emotional health. Additionally, multiple studies have found that contamination obsessions and washing and cleaning compulsions are associated with increased impairment in work and daily activities due to physical health concerns as well as decreased perceived physical health (Albert et al., 2010; Fontenelle et al., 2010; Huppert et al., 2009). Individuals with contamination obsessions and excessive washing and cleaning behaviors may inadvertently bring about negative health consequences, such as dermatologic problems like chapped hands or eczema, dental or hygienic complications, and other irritations or infections (Albert et al., 2010). Research from the BLOCS further highlights the differential influence that particular OCD symptoms have on QoL (Schwartzman, Boisseau, Mancebo, Eisen, & Rasmussen, 2015). OCD-​related hoarding was the only symptom subtype that predicted impairment in household functioning. Indeed, Saxena and colleagues (2011) found that OCD patients with hoarding symptoms demonstrated significantly lower satisfaction with their living arrangements than the nonhoarding OCD patients. Such findings are not surprising, given the profound impact clutter can have on the ability to engage in routine household activities. Excessive clutter often leads to unsanitary, disorganized rooms and living spaces that can no longer be used for their intended purpose, preventing one from completing basic daily tasks like cooking, cleaning, sleeping, or moving around the home (Kim, Steketee, & Frost, 2001; Saxena et al., 2011). In accordance with prior studies (Albert et  al., 2010; Huppert et  al., 2009), BLOCS also found that symmetry and contamination-​related symptoms significantly predicted deficits in satisfaction with social relationships, whereas hoarding, overresponsibility for harm, and contamination predicted poor QoL related to physical health (Schwartzman et  al., 2015). As mentioned previously, those with symmetry and contamination obsessions may become so consumed with these thoughts and related behaviors that they forgo or even fear social interaction. Likewise, individuals with hoarding, overresponsibility, and contamination symptoms may engage in compulsions that reduce anxiety triggered by those thoughts, such as cluttering the house or excessively hand-​ washing and showering, but consequently cause harm to their physical health. Importantly, these relationships held regardless of OCD or depression severity, suggesting that it is truly the content of the specific symptoms, not illness severity, that predicts which QoL domains are most impaired. Outside of symptom dimensions, our BLOCS research suggests that incompleteness or the need to have O b sessive - C ompulsive D isorder

 

things “just right or perfectly so” is also a marker of overall poor quality of life and functional impairment (Sibrava, Eisen, Mancebo, & Rasmussen, 2010), as these individuals often use excessive time and energy to complete daily tasks, or simply avoid the tasks altogether to evade the inevitable discomfort and rituals. Taken together, this research highlights the differential impact of specific OC symptoms or symptom dimensions on QoL in OCD. COMORBIDITY

Obsessive-​compulsive disorder does not typically occur in isolation; the majority of patients with OCD present with at least one other diagnosis (see ­chapter 4) (Barlow, 2004). Consistent with research in other psychiatric disorders, the presence of comorbidity almost inevitability has a negative impact on QoL and functioning, compared to patients with OCD alone. For example, Rodriguez-​Salgado et al. (2006). demonstrated that OCD patients with psychiatric comorbidities had lower QoL regarding pain, general health, vitality, social functioning, and mental health than those without concurrent disorders. Individuals with OCD and comorbid diagnoses such as substance use disorders, anxiety disorders, impulse control disorders, and BDD exhibit greater functional impairment than those without such comorbidity (Didie et  al., 2007; Fontenelle et  al., 2010; Grant, Mancebo, Pinto, Eisen, Rasmussen, 2006; Huppert et al., 2009). Much of the research on comorbidity has focused on MDD, which cooccurs in 25% to 50% of patients with OCD (Crino & Andrews, 1996; Hong et al., 2004; Nestadt et al., 2001). Numerous studies have found that comorbid MDD is associated with decreased QoL and functioning in OCD (Abramowitz, Storch, Keeley, & Cordell, 2007; Tükel, Meteris, Koyuncu, & Tecer, 2006; Tükel, Polat, Özdemir, Aksüt, Türksoy, 2002). This is true across a variety of domains, including social relationships, occupational functioning, sense of well-​being, and global functioning (Albert et al., 2010; Cassin, Richter, Zhang, & Rector, 2009; Hou et al., 2010). More broadly, depressive symptoms and impaired ability to regulate mood are associated with decreased psychological and physical well-​being (Moritz et al., 2005; Quilty, Van Ameringen, Mancini, Oakman, & Farvolden, 2003; Stengler-​Wenzke, 2007). A few researchers have investigated the relative contribution of depression and OC symptoms to QoL. Masellis and colleagues (2003) and Huppert et al. (2009) found that depression severity accounted for the relationship between OCD symptom severity and QoL, indicating that depression may be even more important than OCD severity in Q uality of L ife and P sychosocial F unctioning

contributing to decreased QoL in OCD populations. Thus, comorbid MDD or depressive symptoms may impart additional challenges that limit an individual’s QoL beyond OCD symptoms, such as a lack of motivation to engage in pleasurable activities, interact with others, or complete daily tasks in the home or workplace. IMPAC T OF   T R E AT ME NT ON  QU ALIT Y OF   LIF E IN  OB S E S S IV E -​C OMPU LS IV E DIS OR DE R Although assessment of treatment outcome has traditionally focused on symptom remission or reduction, there is growing consensus supporting the need to look beyond symptom improvement toward patients’ subjective sense of well-​being. Studies assessing QoL as an outcome have generally found an improvement in QoL following gold-​standard treatment. Some studies suggest that this improvement is correlated with improvement in symptoms (Moritz, 2005; Norberg, 2008), whereas others report QoL improvement as independent of symptom improvement (Bystritsky et al., 1999; Tenney, Denys, van Megen, Glas, & Westenberg, 2003). One study found larger QoL improvement in responders to cognitive behavioral therapy (CBT; see ­chapters 37–​38) than in nonresponders, suggesting that symptom improvement alleviated some of patients’ difficulties with daily functioning (Moritz et al., 2005). Similarly, Norberg and colleagues (2008) found an association between symptom improvement and QoL following CBT treatment for OCD. In classifying participants as treatment responders, partial treatment responders, or treatment nonresponders based on OC symptom improvement, they found that responders showed significant improvement on each QoL domain they assessed, including self-​ worth, self-​ enhancement, community, and social life, whereas the partial responders improved on three of those four domains. However, the treatment nonresponders showed no improvement on any of these domains, with some participants even worsening from pre-​ to post-treatment. Thus, OC symptom severity increase or decrease was directly related to improvement or worsening of QoL (Norberg et al., 2008). Hollander and colleagues (2010) examined adults with OCD participating in two randomized controlled trials consisting of treatment with a serotonin reuptake inhibitor (SRI). They also found that improvement in psychosocial functioning and QoL related to improvement in symptoms, and that deterioration or relapse of OC symptoms led to worsening of functioning and QoL. 61

 

In contrast, in a 12-​week SRI treatment study, both responders (reductions of 35% on the Y-​B OCS) and nonresponders experienced an improvement of QoL (Tenney et al., 2003), suggesting that change in QoL may be related to factors other than symptom improvement. The authors hypothesize that patients in treatment, irrespective of the effectiveness of treatment, may rate their QoL higher because of their hope for change or efforts already undertaken to improve their current situation. Another treatment study conducted in a 6-​week partial hospitalization program, in which medications, CBT, and other services were provided, found significant changes in several dimensions of subjective QoL following the program, but these changes were not associated with changes in OC symptom severity (Bystritsky et al., 1999). Thus, although it is clear that treatment with SRIs and CBT generally improves QoL in OCD patients, more research is needed to clarify the relationship between symptom improvement and QoL. Moreover, as mentioned previously, MDD and other comorbid disorders may contribute to poor QoL above and beyond OC symptom severity; improvement in comorbid symptomatology may be a source of improved QoL independent of improvement in OC symptoms (Huppert et al., 2009; Hong et al., 2004; Nestadt et al., 2001; Vikas et al., 2011). In addition, specific OC symptoms or symptom dimensions can lead to poorer QoL in certain domains (Albert et al., 2010; Schwartzman et al., 2015; Sibrava et al., 2010). Hence, a myriad of factors apart from improvement in overall OCD symptoms may influence the impact of treatment on QoL. C ONCL US ION Obsessive-​compulsive disorder is associated with significant morbidity, high rates of functional impairment, and markedly decreased quality of life (Eisen et al., 2006; Koran, 2000). Research findings are mixed regarding the specific factors that may distinctly impact QoL deficits, though obsession severity, comorbid MDD, and specific symptom dimensions seem to have the strongest support. Both CBT and pharmacotherapy for OCD can help improve QoL, psychosocial functioning, and overall life satisfaction. Therefore, in treatment and research settings alike, QoL deficits and changes over time should be tracked in addition to symptom severity to ensure patient stability and improvement. Finally, although there is a growing consensus on the importance of measuring QoL, greater standardization surrounding its assessment will be critical to clarify

62

discrepancies in the literature and advance research going forward. R E F E R E NC E S Abramowitz, J. S., Storch, E. A., Keeley, M., & Cordell, E. (2007). Obsessive-​ compulsive disorder with comorbid major depression: What is the role of cognitive factors? Behaviour Research and Therapy, 45(10), 2257–​2267. Albert, U., Maina, G., Bogetto, F., Chiarle, A., & Mataix-​Cols, D. (2010). Clinical predictors of health-​related quality of life in obsessive-​ compulsive disorder. Comprehensive Psychiatry, 51(2), 193–​200. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (revised 4th edition). Washington, DC: Author. Barlow, D. H. (2004). Anxiety and its related disorders: The nature and treatment of anxiety and panic. New York: Guilford Press. Bengtsson-​Tops, A., & Hansson, L. (2001). Quantitative and qualitative aspects of the social network in schizophrenic patients living in the community. Relationship to sociodemographic characteristics and clinical factors and subjective quality of life. International Journal of Social Psychiatry, 47(3), 67–​77. Bobes, J., Gonzalez, M., Bascaran, M., Arango, C., Saiz, P., & Bousono, M. (2001). Quality of life and disability in patients with obsessive-​ compulsive disorder. European Psychiatry, 16(4), 239–​245. Bystritsky, A., Liberman, R., Hwang, S., Wallace, C. J., Vapnik, T., Maindment, K., & Saxena, S. (2001). Social functioning and quality of life comparisons between obsessive–​compulsive and schizophrenic disorders. Depression and Anxiety, 14(4), 214–​218. Bystritsky, A., Saxena, S., Maidment, K., Vapnik, T., Tarlow, G., & Rosen, R. (1999). Quality-​of-​life changes among patients with obsessive-​ compulsive disorder in a partial hospitalization program. Psychiatric Services, 50(3), 412–​414. Cassin, S., Richter, M., Zhang, K., & Rector, N. (2009). Quality of life in treatment-​seeking patients with obsessive-​compulsive disorder with and without major depressive disorder. Canadian Journal of Psychiatry, 54(7), 460–​467. Crino, R., & Andrews, G. (1996). Obsessive-​compulsive disorder and axis I comorbidity. Journal of Anxiety Disorders, 10(1), 37–​46. Didie, E. R., Loerke, E. H., Howes, S. E., & Phillips, K. A. (2012). Severity of interpersonal problems in individuals with body dysmorphic disorder. Journal of Personality Disorders, 26(3), 345–​356. Didie, E., Walters, M. M., Pinto, A., Menard, W., Eisen, J. L., Mancebo, M., Rasmussen, S. A., & Phillips, K. A. (2007). A comparison of quality of life and psychosocial functioning in obsessive-​compulsive disorder and body dysmorphic disorder. Annals of Clinical Psychiatry, 19(3), 181–​186. DuPont, R. L., Rice, D., Shiraki, S., & Rowland, C. (1995). Economic costs of obsessive-​ compulsive disorder. Medical interface, 8(4), 102–​109. Eaton, W., & Kessler, L. (1985). Epidemiological field methods in psychiatry:  The NIMH epidemiologic catchment area study. NewYork: Academic Press. Eisen, J. L., Pinto, A., Mancebo, M. C., Dyck, I. R., Orlando, M. E., & Rasmussen, S. A. (2010). A  2-​year prospective follow-​up study of the course of obsessive-​compulsive disorder. The Journal of Clinical Psychiatry, 71(8), 1033. Eisen, J. L., Sibrava, N. J., Boisseau, C. L., Mancebo, M. C., Stout, R. L., Pinto, A., & Rasmussen, S. A. (2013). Five-​year course of obsessive-​ compulsive disorder: Predictors of remission and relapse. The Journal of Clinical Psychiatry, 74(3), 233. Eisenm, J., Mancebo, M., Pinto, A., Coles, M. E., Pagano, M. E., Stout, R., & Rasmussen, S. A. (2006). Impact of obsessive-​compulsive disorder on quality of life. Comprehensive Psychiatry, 47(4), 270–​275.

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Endicott, J., Nee, J., Harrison, W., & Blumenthal, R. (1993). Quality of life enjoyment and satisfaction questionnaire. Psychopharmacol Bulletin, 29(2), 321–​326. Fontenelle, I., Fontenelle, L., Borges, M., Prazeres, A. M., Rangé, B. P., Mendlowicz, M. V., & Versiani, M. (2010). Quality of life and symptom dimensions of patients with obsessive–​compulsive disorder. Psychiatry Research, 179(2), 198–​203. Gielen, A., McDonnell, K., Wu, A., O’campo, P., & Faden, R. (2001). Quality of life among women living with HIV:  The importance violence, social support, and self care behaviors. Social Science & Medicine, 52(2), 315–​322. Grabe, H., Meyer, C., Hapke, U., Rumpf, H. J., Freyberger, H. J., Dilling, H., & John, U. (2000). Prevalence, quality of life and psychosocial function in obsessive-​compulsive disorder and subclinical obsessive-​ compulsive disorder in northern Germany. European Archives of Psychiatry and Clinical Neuroscience, 250(5), 262–​268. Grant, J. E., Mancebo, M. C., Pinto, A., Eisen, J. L., & Rasmussen, S. A. (2006). Impulse control disorders in adults with obsessive compulsive disorder. Journal of Psychiatric Research, 40(6), 494–​501. Hollander, E., Stein, D., Fineberg, N., Marteau, F., & Legault, M. (2010). Quality of life outcomes in patients with obsessive-​compulsive disorder: relationship to treatment response and symptom relapse. Journal of Clinical Psychiatry, 71(6), 784. Hong, J. P., Samuels, J., Bienvenu, O. J., 3rd, Cannistraro, P., Grados, M., Riddle, M. A., Liang, K. Y., Cullen, B., Hoehn-​Saric, R., & Nestadt, G. (2004). Clinical correlates of recurrent major depression in obsessive–​compulsive disorder. Depression and Aanxiety, 20(2), 86–​91. Hou, S., Yen, C., Huang, M., Wang, P., & Yeh, Y. (2010). Quality of life and its correlates in patients with obsessive-​compulsive disorder. The Kaohsiung Journal of Medical Sciences, 26(8), 397–​407. Huppert, J., Simpson, H., Nissenson, K., Liebowitz, M., & Foa, E. (2009). Quality of life and functional impairment in obsessive–​compulsive disorder:  a comparison of patients with and without comorbidity, patients in remission, and healthy controls. Depression and Anxiety, 26(1), 39–​45. Jenike, M. A. (1989). Obsessive–​compulsive and related disorders: A hidden epidemic. New England Journal of Medicine, 321(8), 539–​541. Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005). Lifetime prevalence and age-​of-​onset distributions of DSM-​IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6), 593–​602. Kim, H-​J., Steketee, G., & Frost, R. O. (2001). Hoarding by elderly people. Health and Social Work, 26(3), 176–​184. Koivumaa-​Honkanen, H., Honkanen, R., Antikainen, R., Hintikka, J., & Viinamäki, H. (1999). Self-​reported life satisfaction and treatment factors in patients with schizophrenia, major depression and anxiety disorder. Acta Psychiatrica Scandinavica, 99(5), 377–​384. Koran, L. M. (2000). Quality of life in obsessive-​compulsive disorder. Psychiatric Clinics of North America, 23(3), 509–​517. Koran, L. M., Thienemann, M. L., & Davenport, R. (1996). Quality of life for patients with obsessive-​compulsive disorder. The American Journal of Psychiatry, 153(6), 783. Kugler, B., Lewin, A., Phares, V., Geffken, G., Murphy, T., & Storch, E. (2013). Quality of life in obsessive-​compulsive disorder: The role of mediating variables. Psychiatry Research, 206(1), 43–​49. Leon, A. C., Portera, L., & Weissman, M. M. (1995). The social costs of anxiety disorders. The British Journal of Psychiatry Supplement, April(27), 19–​22. Mancebo, M. C., Greenberg, B., Grant, J. E., Pinto, A., Eisen, J. L., Dyck, I., & Rasmussen, S. A. (2008). Correlates of occupational disability in a clinical sample of obsessive-​compulsive disorder. Comprehensive Psychiatry, 49(1), 43-​50. Masellis, M., Rector, N., & Richter, M. (2003). Quality of life in OCD:  Differential impact of obsessions, compulsions, and depression comorbidity. Canadian Journal of Psychiatry, 48(2), 72–​77.

Q uality of L ife and P sychosocial F unctioning

McHorney, C., Ware, J., Jr, & Raczek, A. (1993). The MOS 36-​Item Short-​Form Health Survey (SF-​36):  II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical Care, 31(3), 247–​263. Moritz, S., Rufer, M., Fricke, S., Karow, A., Morfeld, M., Jelinek, L., & Jacobsen, D. (2005). Quality of life in obsessive-​compulsive disorder before and after treatment. Comprehensive Psychiatry, 46(6), 453–​459. Mundt, J. C., Marks, I. M., Shear, M. K., & Greist, J. M. (2002). The Work and Social Adjustment Scale: A simple measure of impairment in functioning. The British Journal of Psychiatry, 180(5), 461–​464. Murray, C. J. L., & Lopez, A. D. (eds.). The Global Burden of Disease. A comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. (GBD Series Vol. I. Harvard School of Public Health on behalf of the World Health Organization and the World Bank, Cambridge, Massachusetts, 1996). Nestadt, G., Samuels, J., Riddle, M. A., Liang, K. Y., Bienvenu, O. J., Hoehn-​Saric, R., Grados, M., & Cullen, B. (2001). The relationship between obsessive–​compulsive disorder and anxiety and affective disorders: Results from the Johns Hopkins OCD Family Study. Psychological Medicine, 31(03), 481–​487. Norberg, M., Calamari, J., Cohen, R., & Riemann, B. (2008). Quality of life in obsessive-​compulsive disorder: An evaluation of impairment and a preliminary analysis of the ameliorating effects of treatment. Depression and Anxiety, 25(3), 248–​259. Parker, P. A., Baile, W. F., de Moor, Cd, & Cohen, L. (2003). Psychosocial and demographic predictors of quality of life in a large sample of cancer patients. Psycho-​Oncology, 12(2), 183–​193. Pinto, A., Mancebo, M. C., Eisen, J. L., Pagano, M. E., & Rasmussen, S. A. (2006). The Brown Longitudinal Obsessive Compulsive Study: Clinical features and symptoms of the sample at intake. The Journal of Clinical Psychiatry, 67(5), 703–​711. Quilty, L., Van Ameringen, M., Mancini, C., Oakman, J., & Farvolden, P. (2003). Quality of life and the anxiety disorders. Journal of Anxiety Disorders, 17(4), 405–​426. Rapaport, M., Clary, C., Fayyad, R., & Endicott, J. (2005). Quality-​ of-​Life impairment in depressive and anxiety disorders. American Journal of Psychiatry, 162(6), 1171–​1178. Rodriguez-​ Salgado, B., Dolengevich-​ Segal, H., Arrojo-​ Romero, M., Castelli-​Candia, P., Navio-​Acosta, M., Perez-​Rodriguez, M. M., Saiz-​ Ruiz, J., & Baca-​Garcia, E. (2006). Perceived quality of life in obsessive-​ compulsive disorder: related factors. BMC Psychiatry, 6(1), 20. Saxena, S., Ayers, C., Maidment, K., Vapnik, T., Wetherell, J., & Bystritsky A. (2011). Quality of life and functional impairment in compulsive hoarding. Journal of Psychiatric Research, 45(4), 475–​480. Schwartzman, C., Boisseau, C., Mancebo, M., Eisen, J., & Rasmussen, S. (2015, November). The relationship between symptom subtype and quality of life in OCD. Paper presented at the Association for Behavioral and Cognitive Therapies, Chicago, IL. Sheehan, D. (1986). The anxiety disease. New York: Bantam. Sibrava, N. J., Eisen, J. L., Mancebo, M., & Rasmussen, S. (2010). Harm avoidance and incompleteness in a clinical sample of OCD. Paper presented at 44th Annual Meeting of the American Psychiatric Association, New Orleans, LA. Sørensen, C., Kirkeby, L., & Thomsen, P. (2004). Quality of life with OCD. A self-​reported survey among members of the Danish OCD Association. Nordic Journal of Psychiatry, 58(3), 231–​236. Stengler-​ Wenzke, K., Kroll, M., Matschinger, H., & Angermeyer, M. (2006). Subjective quality of life of patients with obsessive-​ compulsive disorder. Social Psychiatry and Psychiatric Epidemiology, 41(8), 662–​668. Stengler-​Wenzke, K., Kroll, M., Riedel-​Heller, S., Matschinger, H., & Angermeyer, M. (2007). Quality of life in obsessive-​compulsive disorder:  The different impact of obsessions and compulsions. Psychopathology, 40(5), 282–​289. Tenney, N. H., Denys, D. A., van Megen, H. J., Glas, G., & Westenberg, H. G. (2003). Effect of a pharmacological intervention on quality

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of life in patients with obsessive–​compulsive disorder. International Clinical Psychopharmacology, 18(1), 29–​33. Tükel, R., Meteris, H., Koyuncu, A., Tecer, A. (2006). The clinical impact of mood disorder comorbidity on obsessive–​compulsive disorder. European Archives of Psychiatry and Clinical Neuroscience, 256(4), 240–​245. Tükel, R., Polat, A., Özdemir, Ö., Aksüt, D., & Türksoy, N. (2002). Comorbid conditions in obsessive-​ compulsive disorder. Comprehensive Psychiatry, 43(3), 204–​209. Vikas, A., Avasthi, A., & Sharan, P. (2011). Psychosocial impact of obsessive-​ compulsive disorder on patients and their caregivers:  A  comparative study with depressive disorder. International Journal of Social Psychiatry, 57(1), 45–​56.

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Weissman, M., Bland, R., Canino, G., Greenwald, S., Hwu, H. G., Lee, C. K., Newman, S. C., Oakley-​Browne, M. A., Rubio-​Stipec, M., Wickramaratne, P. J., et al. (1994). The Cross National Collaborative Group. The cross national epidemiology of obsessive compulsive disorder. The Journal of Clinical Psychiatry, 55(suppl 3), 5–​10. WHO. (1948). World health organization constitution. Basic Documents. 1. WHO. (1998a). Development of the World Health Organization WHOQOL-​BREF quality of life assessment. Psychological Medicine, 28(3), 551–​558. WHO. (1998b). The World Health Organization quality of life assessment (WHOQOL): Development and general psychometric properties. Social Science & Medicine, 46(12), 1569–​1585.

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7. PSYCHODYNAMIC PERSPECTIVES ON OCD Robert A. King, MD

T

he psychodynamic perspective on obsessive-​compulsive disorder (OCD) seeks to understand OC phenomena in terms of conflicting intrapsychic motives or personal imperatives, with an emphasis on characteristic coping or defensive styles and the developmental vicissitudes of conscience and culture. Aside from its clinical claims on our attention, which are extensively treated elsewhere in this volume, OCD is a philosophically intriguing condition, in that it illustrates how slippery and often unsatisfactory our common-​sense notions of a unitary “self ” and “will” are. The patient “thinks his obsessional thought, and yet experiences it as not his own; he wants urgently to perform his compulsive act, and yet at the same times strives desperately to resist the urge” (King & Noshpitz, 1991). This quality of a self divided over the ownership or repudiation of various urges, intentions, or thoughts is the most striking feature of OCD, one alluded to by the description of obsessional thoughts or compulsive urges as “ego-​dystonic” or “ego-​alien.” Psychoanalysis had its origins in the investigations of 19th century neurologists (such as Charcot, Janet, Breuer, and Freud) into dissociative symptoms and states, which hinted at the notion of patients having sometimes conflicting motives, feelings, or attitudes of which they were not always fully aware. It was a natural extension of these same themes that led Freud and his early psychoanalytic colleagues to study OCD. OBS ES S IVE-​C O MPULSI VE P HENOM ENA AS A PARAD I G M OF INTRA P SYCHI C CO N FLI CT: OCD A ND O CPD As early as the 12th century, theologians struggled with the question of religious over-​scrupulosity and compulsive

doubt as a spiritual malady—​one that afflicted both Loyola and Luther (Cefalu, 2010; van Megen, 2010). By the 18th century psychiatrists and neurologists (not yet distinguished as different disciplines) had taken note of the condition, which Esquirol termed folie de doubte (Esquirol, 1838/​1845). As Freud elaborated his theory of the role of unconscious conflict in the genesis of neurotic symptoms, he took OCD as a cardinal example. Freud hypothesized that many psychopathological symptoms were the result of intrapsychic conflict, that is, conflict “between wishes, impulses, feeling, and thoughts [on the one hand] and, on the other hand, the prohibitions, inhibitions, and ideals that comprise the human psyche” (Beres, 1995). Although Freud saw such conflicts as inevitable aspects of human existence, their intensity and how they were handled determined what adaptive or maladaptive character traits and psychopathological symptoms the individual might develop. Because these conflicts, usually largely unconscious, threaten to cause anxiety or distress, the individual “unconsciously resorts to certain mental processes that oppose these [problematic] ideas or feelings and render them less disturbing. These mental processes, which take place outside of the person’s awareness, he called ‘defenses’ ” (Willick, 1995), or, as we might put it in more contemporary, theory-​free parlance “coping mechanisms” (Vaillant, 2012). Such mechanisms included such processes as intellectualization, projection, rationalization, reaction formation, regression, repression, reversal, sublimation, splitting, undoing, and turning against the self (Vaillant, 1992). Depending on the particular array of defenses to which a person habitually resorted (a matter that Freud believed was partially constitutionally determined), different neurotic symptom clusters might emerge—​hysteria (conversion disorder), depression, dissociation, or obsessive-​compulsive phenomena.

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The term “psychodynamic” denotes “regarding the forces that comprise the psyche.” Hence it was natural that psychoanalytic investigators turned readily to the notion of intrapsychic conflict as providing an explanation of the particular force of obsessive-​compulsive phenomena, with the very terms implying forces in opposition—​“obsession” derived from the Latin obsidere, to besiege, and “compulsion” from “that which is compelled.” In this view, then, individuals struggle with anxiety-​provoking internal conflicts caused by troublesome aggressive or sexual impulses that are unacceptable to their conscience. If, in this struggle to ward off anxiety stirred by seemingly dangerous or transgressive impulses, the individual resorts heavily to specific characteristic coping or defense mechanisms—​such as undoing, reaction formation, isolation of affect/​intellectualization, doubting, or magical thinking—​ obsessive-​ compulsive character traits or symptoms may result. Numerous defense mechanisms have been enumerated by different theorists. A few are of particular relevance to understanding the phenomenology of OCD: • Undoing represents a subject’s attempt to take back or undo some problematic thought, urge, or action. • Reaction formation represents a similar maneuver in the character realm, wherein the subject attempts to reverse an attitude by taking a psychological stance diametrically opposed to an unacceptable impulse (for example, replacing rebellious or angry urges with compliant meekness, angry urges to soil or mess with compulsive neatness, or sexual or voluptuous urges with asceticism or puritanism). • Isolation of affect or intellectualization consists of separating thoughts or behaviors from their affective associations or connections, so that the idea alone remains conscious, but as a thought stripped of feeling. • Magical thinking is a stance that equates thought with action, resulting in guilty anxiety that a bad thought is the same as a bad action (e.g., Matthew 5:28, “whosoever looketh on a woman to lust after her hath committed adultery with her already in his heart”); alternatively, magical thinking may manifest itself in mental compulsions triggered by the effort to have the “correct” thought (“I love X”) or mental ritual in order to neutralize the moral onus or feared hurtful consequences of an unacceptable thought (“I hate X”; “I wish X were dead.”) 66

If these defensive measures suffice, a stalemate may prevail, with the anxiety contained, but at the cost of personality constriction and the rigid character traits of the obsessive-​compulsive personality:  ruminative perfectionism, overconscientiousness, and a rigid need for control (Millon, 2011). If even these strenuous efforts are insufficient, Freud believed, frank symptoms of clinical obsessive-​compulsive disorder could emerge—​such as the troubling intrusive obsessional thoughts or the debilitating compulsive cleaning, checking, or counting that characterize OCD proper. The psychoanalytic literature is often confusing to a modern reader because it conflates (or at any rate assumes continuity between) conditions that current descriptive nosologies, such as the DSM-​5, regard as distinct. Freud’s formulation suggests a continuity between obsessive-​compulsive personality disorder (OCPD) and OCD. Such a continuity was indeed assumed for many years, with the distinction between the two that is enshrined in the DSM-​ 5 becoming clear only in recent decades (see c­ hapter 59) (Esman, 1989). OCD is defined by impairing or distressing obsessions and compulsions; OCPD, on the other hand, is characterized by a personality style of rigid preoccupation with orderliness, control, and perfectionism regarding details and rules. Contrary to Freud’s proposal, it has become clear that most patients with OCD, especially child patients, do not have obsessive-​compulsive personalities. Thus, in community or clinical samples of children with OCD, only about 15% meet criteria for OCPD (Flament et al., 1988; Rapoport, 1986). Very few children with OCD are meticulous, orderly, or overly compliant outside the ambit of their specific obsessions and compulsions. As Anna Freud (1966) observed, “Even well-​defined obsessional symptoms, such as bedtime ceremonials or counting compulsions, are found in children with otherwise uncontrolled, restless, impulsive personalities…” (p. 151). Similarly, only a minority of adults with OCD meet criteria for OCPD (see Stein et al., 1994, and ­chapter 59). Conversely, although individuals with OCPD may be discouraged or distressed because of the ineffectuality of their attempts to complete tasks or maintain order to the degree of perfection they require, they usually do not struggle against their overscrupulousness or preoccupations per se, and do not experience them as ego-​alien in the way of obsessions. Rather, individuals with OCPD usually strive ever harder in an often futile attempt to be a “better” or more efficiently productive obsessive-​compulsive (Millon 2011; Salzman, 1975). That said, the dangers that the obsessive-​compulsive personality works so hard to keep under control and out O b sessive - C ompulsive D isorder

 

of awareness—​mess, sexual desire, anger, defiance—​are indeed the same dangers that form the core of what so consciously perturbs patients with OCD. For this reason, the psychodynamic perspective on both conditions continues to be concerned with both the struggle against obsessive-​compulsive urges and thoughts and the obsessive-​compulsive “mode of thinking which is characteri[z]‌e d in particular by rumination, doubt and scruples, and which leads to inhibitions of thought and action” (Laplanche & Pontalis, 1973). In Anna Freud’s words, “No other mental phenomena display . . . with equal clarity the human quandary of relentless and unceasing battles between innate impulses and acquired moral demand” (Nagera, 1976, p. 9). Different authors have emphasized different aspects of the conflict(s) and maladaptive response(s) hypothesized to underlie OC phenomena; hence there is no single, unified psychodynamic theory of OCD, or even consensus about what the obsessional patient fears and must guard against most: guilt over aggression or sexual impulses; fear of loss of control; or the threat of the loss of love or approval of significant others (Millon, 2011). Freud (1908) emphasized difficulties in the “anal-​sadistic” stage of development (speculated to relate to struggles over toilet training), with attendant conflicts over aggression, angry messing, autonomy, and stubborn opposition on one hand, pitted against a reactive overemphasis on submissiveness, compliance, and orderliness on the other. In contrast, Adler (1964) suggested that OCD resulted from the patient’s unconscious attempts to compensate for a perceived lack of control in important aspects of his life by exerting mastery over more mundane matters, what Rachman and Hodgson (1980) described as a “compensatory rebound” from experienced helplessness (quoted in Jakes, 1995. p.  86). In Salzman’s words, “the obsessive compulsive dynamism is a device for preventing any feeling or thought that might produce shame, loss of pride or status or a feeling of weakness or deficiency whether such feelings are aggressive, sexual, or otherwise” (quoted in Esman, 1989). In this view, these symptoms arise from a need to control both. In a similar spirit, Fromm (1947) saw the obsessive-​compulsive as feeling beleaguered by the outside world: “orderliness signifies mastering the world outside by . . . keeping it in its proper place in order to avoid the danger of intrusion.” For these theorists, the excessive need for control “may be the consequence of the child’s effort to cope with both ‘interpersonal dangers,’ such as parental inconsistency and reliability, and ‘miscellaneous’ external dangers… .” (Esman, 1989). More eclectic analytic theorists have emphasized cognitive styles and distortions, such as David Shapiro’s P sychodynamic P erspectives

description of a “rigid” cognitive style that is overly focused on detail, or Horowitz’s emphasis on distorted information processing. Similarly, Beck and Freeman (1990) observe: “There are certain cognitive distortions (i.e., systematic errors in information processing) that are characteristic of OCPD. Among these is a dichotomous thinking, the tendency to see things as all-​or-​nothing and in strictly black-​and-​white terms. It is this tendency that underlies the obsessive’s rigidity, procrastination, and perfectionism. Another cognitive distortion . . . is magnification or catastrophizing . . . by which] the importance or consequences of an imperfection or error become greatly exaggerated.” Other distortions include a “primitive absolutistic and moralistic style of thinking” that emphasizes “shoulds” and “musts” “rather than what they desire to do or what is preferable to do.” From the point of view of empirical personality theory, Costa and Widiger (1993) emphasize the role of “clearly maladaptive extreme variants of conscientiousness,” whereas from the perspective of his tridimensional theory of personality and temperament, Cloninger (1987) saw the salient features as “basic response characteristics of low novelty seeking, high harm avoidance, and low reward dependency.” And finally, as the field has moved away from broad unified theories of personality, cognitive-​behavioral conceptual models have emphasized maladaptive or distorted beliefs concerning responsibility/​ threat estimation, perfectionism/​certainty, and importance/​control of thought as underlying the various OCD symptom dimensions (Wheaton et al., 2010). T H E OB S E S S IONAL-​C OMPU LS IV IT Y OF   E V E R YDAY  LIF E Transient obsessions and compulsions, with content similar to that of OCD patients, are common in nonclinical subjects; however, compared with OCD patients, nonclinical subjects experience their obsessions as rarer, briefer, less vivid, and more easily dismissed without efforts to neutralize them through compulsive acts (Rachman & de Silva, 1978). Whether a compulsive trait, such as frugality, attention to detail, cleanliness, or orderliness is seen as a pathologic symptom or as an adaptive virtue is not merely a matter of degree, but is often in the eye of the beholder and dependent on the cultural, family, or interpersonal setting. OCD symptoms (and obsessive-​compulsive personality traits) thus exist on a continuum in both children and adults, and where to draw the line between the “normal” or expectable and the pathological is not always clear in practice. The DSM severity criteria of being “time consuming 67

 

(e.g., take more than 1 hour per day)” or “causing clinically significant distress or impairment” are not always easy to apply or to operationalize in epidemiological studies (e.g., Zohar et  al., 1993)  or in family studies of non-​clinically identified relatives of OCD or tic disorder probands. Repetition, rituals, and a certain degree of compulsiveness are expectable, adaptive aspects of normal development and everyday adult functioning, in certain contexts. Rituals, rules, and repetition provide reassuring routine for young children. Although parents may play a role in initiating or attempting to shape these routines, preschoolers often come to insist passionately on them on their own initiative. Some of these rituals, such as bedtime or goodbye rituals, attempt magically to ward off uncertainties about separation or other dangers. Through such rituals, as Adams (1973) puts it, the child tries “to force object constancy, to make his significant people more static, more reliable through enmeshing them in a transitory obsessional web.” For example, many children develop bedtime rituals that must be scrupulously observed before they can safely yield themselves up to the uncertainties of sleep. “Going to bed is also . . . complicated, for the two year old bedtime demands have often grown into an elaborated and rigid structure. There is a coming upstairs ritual, brushing the teeth ritual, getting into bed, pulling down the shades, kissing, and even a specially worded good-​ night ritual” (Gesell & Ilg, 1943, p. 182). Other transient normative preschool rituals may concern food or dress or toys. “The ritualism so characteristic of 30  months may weigh heavily on the entire household. The child  .  .  .  is likely to know where everything belongs and to insist that everything remain in its place…. Chairs must be placed at specific angles and certain pictures must remain on certain tables” (Gesell & Ilg, 1943, p.  188). Routines and compulsive behaviors are common in community samples of preschoolers (Zohar & Felz, 2001), with over 75% of the parents of children 2 to 4 years old in one sample reporting compulsive-​like behaviors, including bedtime routines, perfectionism, and other “just-​right” phenomena (Evans et al., 1997). Psychodynamic theorists see these common obsessive-​compulsive concerns coinciding with a greater awareness of the unpredictability of the world and heightened conflicts over compliance and being “good” on one hand and impulses towards autonomy, willfulness, or self-​ assertion on the other. Whether there is any relationship between the intensity of these early childhood forms of compulsivity and other vulnerabilities is an understudied question. Even in samples of normally developing young children, higher levels of ritualistic compulsive-​like behaviors, especially if they persist 68

beyond age 4  years, may be associated with greater fearfulness, relatively poorer set shifting on neuropsychological tasks, poorer response inhibition, and greater evoked potential sensitivity to asymmetrical target visual stimuli, suggesting an association with neurocognitive features that are also found in OCD proper (Evans & Maliken, 2011; Pietrefesa & Evans 2007; Zohar & Dahlan, 2016; Zohar & Felz, 2001). Throughout childhood, repetitious play provides a gratifying mixture of orderliness, mastery, and intrinsic excitement, what Buhler and Piaget referred to as Funktionlust or “activity pleasure” (Csikszentmihalyi et  al., 2005). The child’s emphasis on order and repetition parallels and supports involvement in school and educational activities. In the school-​age child, group play may be very rule oriented, with debating and negotiating the rules an important part of the pleasure. Youngsters immerse themselves in practicing emerging cognitive skills in amassing, comparing, classifying, and ordering extensive, elaborate collections of real and virtual objects, such as stuffed animals, Pokemon cards, dolls, stickers, etc. Part of the appeal of organizational activities, such as Cub Scouts or Brownies, involves uniforms, paraphernalia, and rituals, which also include exhortations to various forms of conscientiousness. Many of these school-​age activities, with their elaborate rules, organization, and variations, provide the opportunity for the pleasurable exercise of preformal operational cognitive skills such as seriation, classification, and comparison. Some childhood games and superstitions hint, however, that more than cognitive pleasure may be at stake, such as dealing with more serious impulses and dangers. For example, some school yard games involve boys excitedly fleeing the dangerous “cooties” that girls threaten to inflict on the boys by touching them, but then foraying back into girls’ territory to harass them before fleeing again. Part of the thrill of the game is simultaneously toying with and warding off strong currents of implicit sexual excitement. Other superstitious “games” play at preventing the dangers of hostile intentions or of the unknown. One common game is to avoid stepping on sidewalk cracks, with the admonition “step on a sidewalk crack, break your mother’s back.” Another is to hold one’s breath while passing by a church or grave yard, repeating some hopefully efficacious preventive phrase. Certain moments, such as 11:11 (in our era of digital clocks), may be especially hazardous. As with adults, sports may be the object of various superstitious, with lucky charms or rituals, such as properly rolled socks, or unwashed jerseys from a winning streak, especially propitious for the team’s or one’s personal success. O b sessive - C ompulsive D isorder

 

In their struggles against the inner and outer uncertainties of life, developing children thus display many of the same defense mechanisms apparent in clinical OC syndromes. These normal developmental forms of compulsivity and ritualization appear to differ from pathological OC in crucial respects. Children usually find such rituals pleasant and enjoyable, and these normative compulsive behaviors usually do not interfere with adaptive functioning and can be abandoned with little or no anxiety under external pressure (Leonard et al., 1990). Obsessive-​compulsive features also color many aspects of adult interpersonal life, especially those that have to do with pair-​bonding. The early phases of romantic love are often colored by intense ruminative preoccupations (usually pleasurable, but sometimes anxiety ridden or fearful (e.g., Proust, 1914/​1928). Similarly, during later stages of pregnancy and the early postpartum phase, parents are deeply preoccupied with the new baby, what Winnicott described as primary maternal preoccupation (see ­chapter 61). Again, these reveries are usually pleasurable, but they may also include frequent checking and other rituals to keep the infant safe and intrusive anxieties that the baby might be harmed or defective; in postpartum depression, fears that the baby is damaged or even evil can reach delusional intensity (Leckman et al., 1999).

countervailing or protective compulsions involving washing, purification, checking, undoing, confession, or other form of reassuring atonement. Such symptoms certainly provide fertile ground for psychodynamic theorizing, suggesting internal conflicts between aggressive, sexual, or other transgressive impulses and developed acquired scruples prohibiting them, resulting from either an excessive endowment or hypertrophy of these drives on one hand, or overdeveloped, overly harsh strictures against them. For example, Freud hypothesized that although obsessional anxieties are conscious, they are distorted, disguised substitutes for warded-​off impulses that remain unconscious (Esman, 1989). Although the inappropriate intensity, the apparently out-​of-​context triggering, and the difficulty of suppressing or extinguishing OCD anxieties is remarkable, their content has parallels in everyday life. Much of life in our own and other cultures is deeply concerned with ordered relationships between individuals and the sexes in the context of an overall social structure. Just as topographic representations of important body parts (face, hand, etc.) loom large in the somatosensory and motor cortex, we might analogously imagine that as intensely social beings shaped by and immersed in evolved cultures, the various norms, prohibitions, boundaries that structure and guide our social behavior might have similarly broad representation in our neurological makeup. In Purity and Danger, the anthropologist Mary Douglas’ (1970) far-​reaching analysis THE C ONTE N T O F O C of different cultures’ approaches to cleanliness and polluS Y M P TOM ATO LO G Y tion, she emphasizes “the cultural relativity of dirt.” If dirt is matter out of place, “it implies two conditions: a set of Factor analytic studies of OCD clinical subjects find cerordered relations and a contravention of that order. Dirt, tain recurring themes and symptom contents (e.g., Mataix-​ then, is never a unique isolated event. Where there is dirt Cols et al., 2005; see ­chapter 8). These include: there is system” (p.  48). A  deeper understanding of cultural notions of contamination and disorder undoubtedly 1. Contamination-​related obsessions and cleaning involves an analysis of social structure and conventions and compulsions. how these are represented in the individual psyche. Post 2. Obsessional worries about being responsible for harm Pasteur, many OCD patients in the developed world couch and compulsions related to checking the need for their extensive contamination worries/​cleaning compulreassurance. sions in terms of “germs” or fear of specific illnesses (formerly often syphilis, now perhaps more often HIV or other 3. Intrusive violent, sexual, or blasphemous obsessional emerging infections). But considering the recency of the thoughts and compulsive mental rituals intended to germ theory, it seems likely that such specific formulations neutralize them. merely garb more fundamental concerns in contemporary 4. Obsessions about the need for symmetry, exactness, or terms and that it is a mistake to reduce the propensity to completeness and arranging or counting compulsions. pollution concerns to supposedly ill-​informed ideas about hygiene (an explanatory perspective that Douglas (1970), The first three of these factors involve avoidance of harm, echoing William James, terms “medical materialism”). guilt, or shame linked to obsessional concerns over contamA fourth commonly found symptom factor in OCD ination, aggression, sexual or religions transgression, with is comprised of “just-​right” phenomena:  concerns over P sychodynamic P erspectives

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symmetry, “evening up,” odds vs. evens, or various forms of “incompleteness” itself (see c­ hapter 9). Although some cultures assign moral virtues to balance or completeness, such OC symptoms are harder to formulate from a dynamic perspective. Why incompleteness or asymmetry should be perceived as troubling or problematic is unclear. Zeigarnik first described the eponymous phenomenon that we are more likely to experience intrusive thoughts about interrupted tasks (or tasks otherwise left incomplete) compared with completed tasks (Baumeister & Bushman, 2008). It is an interesting, but unanswered, question whether subjects whose OC symptoms concern symmetry, balance, or completeness are more susceptible to the Zeigarnik effect than other OCD patients or normal controls. Humans, as well as many other species, recognize and have a preference for symmetry. Infants manifest this as early as the first year of life (Bornstein et  al., 1981). The possible adaptive functions of this preference have been the basis of much debate (Rhodes, 2006). However, empirical studies of cognitive biases and the study of neural responses to symmetrical/​asymmetrical stimuli do find a propensity to link disgust with asymmetry. There is also some evidence that greater evoked potential reactivity to asymmetric or “odd-​ball” stimuli may be associated with compulsive traits (Evans & Maliken, 2011). Such studies suggest experimental means of studying interpersonal differences in these cognitive biases/​preferences and how perceptions of asymmetry may be affectively and subjectively elaborated. P S Y C HODY N AMI CALLY I N FO RMED TR EATM ENT There are few, if any, well-​controlled or systematic studies of the efficacy of psychodynamic psychotherapy for the treatment of OCD, and there seems to be a consensus, even among proponents of a psychodynamic approach, that the technique is not helpful for obsessions and compulsions per se (Esman, 1989; Gabbard, 2001; Kay et al., 1996). Writing in 1984, John Nemiah remarked: “It is one of the ironies of clinical psychiatry that, although the obsessive-​compulsive disorder illuminates the psychoanalytic concept of psychodynamic conflict perhaps better than any other psychoneurosis, its symptoms generally remain impervious to psychoanalytic treatment.” Despite this pessimism, there may be a role for psychodynamic approaches to obsessive-​compulsive personality traits (Millon, 2011). For a variety of reasons, the “gold

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standard” of randomized clinical trials (RCTs) is notoriously difficult to adapt to the study of psychodynamic psychotherapy (Leichsenring, 2005). Nonetheless, an RCT comparing moderate-​length psychodynamic psychotherapy to CBT in patients with Cluster C personality disorders (i.e., avoidant, compulsive or dependent personality disorders) found comparable efficacy and durability with respect to core personality pathology, symptoms, and interpersonal problems (Svartberg et al., 2004). Furthermore, psychodynamic insight into the conflicts and character defenses of individual patients is often invaluable in developing a therapeutic alliance and helping to deal with the comorbidities, resistances, and extensive family accommodations that may complicate their ability to collaborate or engage with CBT and/​or pharmacotherapy (Kay et al., 1996; Lebowitz & Omer, 2013; Millon, 2011). In summary, the psychodynamic perspective on obsessive-​ compulsive symptoms and personality traits is best understood as a vivid description of the subjective world of the OC patient, rather than as a fully coherent explanatory theory or road map to therapeutic intervention. In addition to helping the clinician empathize with the peculiar distress of the OC patient—​a distress that can neither be argued nor reassured away—​the psychodynamic perspective also helps to locate the disorder against the backdrop of normal child development and conscience formation and against the context of cultural notions of cleanliness and proper order vs. the dangers of pollution and disorder.

R E F E R E NC E S Adams, P. L. (1973). Obsessive children. New York: Brunner/​Mazel. Adler, A. (1964). Problems of neurosis. New York: Harper. Albert, S., Amgott, T., Krakow, M., & Howard, M. (1979). Children’s bedtime rituals as a prototype rite of safe passage. Journal of Psychological Anthropology, 2(1), 85–105. Baumeister, R. F., & Bushman, B. J. (2008). Social psychology and human nature. Belmont, CA: Wadsworth. Beck, A. T., & Freeman, A. (Eds.). (1990). Cognitive therapy of personality disorders. New York: Guilford. Beres, D. (1995). Conflict. In B. E. Moore, B. D. Fine (Eds.), Psychoanalysis: The major concepts (pp. 477–​484). New Haven, CT: Yale University Press. Bornstein, M. H., Ferdinandsen, K., & Gross, C. G. (1981). Perception of symmetry in infancy. Developmental Psychology, 17,  82–​86. Cefalu, P. (2010). The doubting disease:  religious scrupulosity and obsessive-​compulsive disorder in historical context. The Journal of Medical Humanities, 31(2), 111–​125. Cloninger, C. R. (1987) A systematic method for clinical description and classification of personality variants. Archives of General Psychiatry, 44, 573–​588.

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Costa, P. T., & Widiger, T. (Eds.). (1993). Personality disorders and the five-​ factor model of personality. Washington, DC:  American Psychological Association. Csikszentmihalyi, M., Abuhamdeh, A., & Nakamura, J. (2005). Flow. In A. J. Elliot, & C. S. Dweck (Eds.), Handbook of motivation and competence (pp. 598–​608). New York: Guilford Press. Douglas, M. (19700. Purity and danger: An analysis of concepts of pollution and taboo. Hammondsworth, UK: Penguin. Esman, A. H. (1989). Psychoanalysis and general psychiatry: Obsessive-​ compulsive disorder as paradigm. Journal of the American Psychoanalytic Association, 37(2), 319–​336. Esquirol, É. (1845). Mental maladies: A treatise on insanity (E. K. Hunt, Trans.). Philadelphia: Lea and Blanchard. (Original French edition published 1838). Evans, D. W. & Maliken, A. (2011). Cortical activity and children’s rituals, habits and other repetitive behavior:  A  visual P300 study. Behavioural Brain Research, 224(1), 174–​179. Evans, D. W., Leckman, J. F., Carter, A., Reznick, J. S., Henshaw, D., King, R. A., & Pauls, D. (1997). Ritual, habit, and perfectionism: The prevalence and development of compulsive-​like behavior in normal young children. Child Development, 68(1), 58–​68. Flament, M. F., Whitaker, A., Rapoport, J. L., Davies, M., Berg, C. Z., Kalikow, K., Sceery, W., & Shaffer, D. (1988). Obsessive compulsive disorder in adolescence: An epidemiological study. Journal of the American Academy of Child and Adolescent Psychiatry, 27(6), 764–​771. Freud, A. (1966). Obsessional neurosis: a summary of psycho-​analytic views as presented at the Congress. The International Journal of Psycho-​analysis, 47(2), 116–​122. Freud, S. (1958). The disposition to obsessional neurosis. In J. Strachey (Ed. and Trans.), The standard edition of the complete psychological works of Sigmund Freud (Vol. 12, pp. 317–​326). London: Hogarth Press. (Original work published 1913) Freud, S. (1925). Character and anal eroticism. In Collected papers (Vol. 2). London: Hogarth. (Original work published 1908) Fromm, E. (1947). Man for himself. New  York:  Hold, Rinehart& Winston. Gesell, A., & Ilg, F. L. (1943). Infant and child in the culture of today: The guidance of development in home and nursery school. New York: Harper and Brothers Publishers. Gabbard, G. O. (2001). Psychoanalytically informed approaches to the treatment of obsessive-​compulsive disorder. Psychoanalytic Inquiry, 21(2), 208–​221. Jakes, I. (1996). Theoretical approaches to obsessive-​compulsive disorder. Cambridge, UK: Cambridge University Press. Kay, J., Gabbard, G. O., & Greist J. (1996). Is psychoanalytic psychotherapy relevant to the treatment of OCD? The Journal of Psychotherapy Practice and Research, 5(4), 341–​354. King, R. A., & Noshpitz, J. D. (1991). Pathways of growth: Essentials of child psychiatry (Vol. 2 -​Psychopathology). New York: John Wiley & Sons. Laplanche, J., & Pontalis, J-​B. (1973). The language of psychoanalysis. (D. Nicholson-​Smith, Trans.). New York: W.W. Norton. Lebowitz, E., & Omer, H. (2013). Treating childhood and adolescent anxiety: A guide for caregivers. New York: John Wiley & Sons. Leckman, J. F., Mayes, L. C., Feldman, R., Evans, D. W., King, R. A., & Cohen, D. J. (1999). Early parental preoccupations and behaviors and their possible relationship to the symptoms of obsessive-​compulsive disorder. Acta Psychiatrica Scandinavica. Supplementum, 396, 1–​26. Leonard, H. L., Goldberger, E. L., Rapoport, J. L., Cheslow, D. L., & Swedo, S. E. (1990). Childhood rituals:  Normal development or obsessive compulsive symptoms. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 17–​23. Leichsenring, F. (2005). Are psychodynamic and psychoanalytic therapies effective?:  A  review of empirical data. (2005). International Journal of Psycho-​Analysis, 86, 841–​868.

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Mataix-​Cols, D., Rosario-​Campos, M. C., & Leckman, J. F. (2005). A  multidimensional model of obsessive-​ compulsive disorder. American Journal of Psychiatry, 162(2), 228–​238. Millon, T. (2011). Disorders of personality: Introducing a DSM/​ICD spectrum from normal to abnormal (3rd ed.). Hoboken, NJ: John Wiley and Sons. Nagera, U. (1976). Obsessional neurosis: Developmental psychopathology. New York: Jason Aronson. Nemiah, J. C. (1984). Forward. In T. R. Insel (Ed.), Obsessive-​compulsive disorder (pp. ix-​xi). Washington DC: American Psychiatric Press. Pietrefesa, A. S., & Evans, D. W. (2007). Affective and neuropsychological correlates of children’s rituals and compulsive-​like behaviors:  Continuities and discontinuities with obsessive–​compulsive disorder. Brain and Cognition, 65(1), 36–​46. Proust, M. (1928). Swann’s way (C. K. Scott Moncrieff, Trans.). New York: The Modern Library. (Originally published as Du cote de chez Swann, 1913) Rachman, S. J., & de Silva, P. (1978). Abnormal and normal obsessions. Behaviour Research and Therapy, 16, 233–​248. Rachman, S. J., & Hodgson, R. J. (1980). Obsessions and compulsions. Englewood Cliffs, NJ: Prentice Hall. Rapoport, J. L. (1986). Childhood obsessive compulsive disorder. Journal of Child Psychology and Psychiatry, 27(3), 289–​295. Rhodes, G. (2006). The evolutionary psychology of facial beauty. Annual Review of Psychology, 57, 199–​226. Salzman, L. (1975). Treatment of the obsessive personality. New York: Jason Aronson. Shaprio, D. (1965). Neurotic styles. New York: Basic Books. Stein, D. J., Hollander, E., & DeCaria, C.M. (1994). Personality disorders and obsessive compulsive disorder. In E. Hollander, J. Zohar, D. Marazziti, & B. Olivier (Eds.), Current insights in obsessive compulsive disorder (pp 41–​51). Chichester, UK: John Wiley and Sons. Svartberg, M., Stiles, T., & Seltzer, M. H. (2004). Randomized, controlled trial of the effectiveness of short-​term dynamic psychotherapy and cognitive therapy for Cluster C personality disorders. American Journal of Psychiatry, 161, 810–​817. Vaillant, G. E. (1992). Ego. Mechanisms of defense: A guide for clinicians and researchers. Washington, DC: American Psychiatric Press. Vaillant, G. E. (2011). Involuntary coping mechanisms:  A  psychodynamic perspective. Dialogues in Clinical Neuroscience, 13(3), 366–​370. van Megen, H. J. G. M., den Boer-​Wolters, D., & Verhagen, P. J. (2010). Obsessive compulsive disorder and religion: A reconnaissance. In P. Verhagen, H. M. Van Praag, J. J. López-​Ibor, Jr, J. Cox, & D. Moussaoui (Eds.), Religion and psychiatry: Beyond boundaries (pp. 271–​282). New York: Wiley. Wheaton, M. G., Abramowitz, J. S., Berman, N. C., Riemann, B. C., & Hale, L. R. (2010). The relationship between obsessive beliefs and symptom dimensions in obsessive-​compulsive disorder. Behaviour Research and Therapy, 48(10), 949–​954. Willick, M. S., (1995). Defense. In B. E. Moore, & B. D. Fine (Eds.), Psychoanalysis:  The major concepts (pp. 485-​ 493). New Haven, CT: Yale University Press. Zohar, A. H., & Dahan, D. (2016). Young children’s ritualistic compulsive-​like behavior and executive function:  A  cross sectional study. Child Psychiatry and Human Development, 47(1), 13–​22. Zohar, A. H., & Felz, L. (2001). Ritualistic behavior in young children. Journal of Abnormal Child Psychology, 29, 121–​128. Zohar, A. H., Ratzoni, G., Binder, M., Pauls, D. L., Apter, A., Kron, S., Dycian, A., King, R., & Cohen, D. J. (1993). An epidemiological study of obsessive-​compulsive disorder and anxiety disorders in Israeli adolescents. Psychiatric Genetics, 3, 184.

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S ECT I O N 2. PHENOMENOLOGY AND COGNITIVE PSYCHOLOGY

 

 

8. SYMPTOM HETEROGENEITY IN OCD A D I M E NSI ONAL A P P ROACH

Maria Conceição do Rosário, MD, PhD, Marcelo Camargo Batistuzzo, PhD, and Ygor Ferrao, MD 

S

tandard classification manuals, such as the DSM-​5 (American Psychiatric Association, APA, 2013) and the International Classification of Diseases and Related Health Problems—​10th revision (ICD-​10) (World Health Organization, 1992), define obsessive-​compulsive disorder (OCD) as a unitary entity. However, both clinical experience and empirical research demonstrate that OCD is a clinically and etiologically heterogeneous disorder. Clinical presentations can vary enormously, both between patients and in the same patient over time, and the possible variety in Obsessive Compulsive Symptoms (OCS) is almost without limit (Rosario-​Campos et  al., 2006; see ­chapters  1, 2). This heterogeneity is problematic because it can make it difficult to interpret the results of clinical, genetic and neuroimaging studies and limit the development of more effective treatment strategies. Therefore, since the earliest descriptions of OCD, investigators have tried to define more homogeneous subtypes of patients. A classic distinction is between “washers” from “checkers” (Matsunaga et al., 2001; Rachman & Hodgson, 1980). Many of these categorical subtyping attempts had limited success because patients with “pure” symptoms of just one category are rare, and the recruitment of sufficient sample sizes of each subtype is extremely difficult (Mataix-​ Cols et al., 2002). Furthermore, with very few exceptions, these studies have not been able to identify specific neurobiological substrates or treatment response profiles for these subtypes. The two most robust categorical subtypes have been tic-​related and early-​onset OCD. A “tic-​related” specifier was included in the DSM-​5 as a specifier (APA, 2013). More recently, a dimensional approach to dealing with the OCD heterogeneity has proven to be more fruitful. The dimensional approach is based on two assumptions: (1) that OCD is most likely the result of a multitude of factors, all with

small but important contributions to OCD risk and to its expression in an individual patient; and (2) that OCD represents a continuum of symptom severity, with persons without any obsessive-​compulsive (OC) behavior on one side of the continuum and very severe OCD patients on the other side of the same continuum (Leckman et al., 2005; Taylor, 2005). This dimensional approach started with a series of factor analyses of the most frequently used scales to assess OCD patients. Based on these results, it was proposed that a small number of symptom dimensions could summarize the complex clinical and etiological OCD presentations of individual patients (Mataix-​Cols et al., 2005). These symptom dimensions (or factors) represent groups of obsessions and compulsions that tend to cooccur:  for instance, contamination worries tend to cooccur with cleaning compulsions, and the need for symmetry tends to cooccur with ordering/​ arranging rituals. This approach proposes that these symptom dimensions represent a spectrum of potentially overlapping vulnerabilities that are likely to be continuous with “normal” worries and extend across traditional nosological boundaries (Leckman et al., 2005; Mataix-​Cols et al., 2005). Such factor analytic studies have found from three to six OCS dimensions and have reported that these are similar in children, adolescents and adults and are temporally stable (Bloch, 2008; Mataix-​Cols et al., 2002, 2005). Furthermore, the usefulness and validity of this dimensional approach has been proven by studies reporting the association between the OCS dimensions and various genetic, neuroimaging, and treatment response variables (Mataix-​Cols et al., 2005). This chapter reviews the most relevant studies using the dimensional approach to describe the heterogeneity of OCD symptomatology. Throughout the chapter the words “dimensions” and “factors” are used interchangeably. 75

 

HIS TOR IC A L PERSPECTI VE

checking” and the “sexual/​religious” dimensions need further study, as it is unclear whether they form a single facBaer (1994) was the first to factor-​analyze the Yale Brown tor (Cavallini et  al., 2002; Leckman et  al., 1997, 2003; Obsessive Compulsive Scale symptom checklist (Y-​B OCS-​ Summerfeldt et  al., 1999), or can be broken down into SC). He identified three factors (or dimensions) in a sample two separate dimensions (Baer, 1994; Foa et  al., 2002; of 107 OCD patients, accounting for 48% of the variance: Hantouche & Lancrenon, 1996; Mataix-​Cols et al., 1999, “symmetry/​hoarding”; “contamination/​cleaning”; and 2002; Summerfeldt et  al., 1999; Tek & Ulug, 2001). Similarly, it is unclear how to regard the “somatic” obses“pure obsessions” (Baer, 1994). Leckman and colleagues (1997) performed principal sions and the “miscellaneous” obsessions and compulsions component analysis of the thirteen Y-​B OCS-​SC catego- described in the Y-​B OCS. For instance, the “somatic” obsesries in two previously described samples of OCD patients sions have loaded on the contamination/​washing factor in (Leckman et  al., 1994; Pauls et  al., 1995), totaling over some studies (Baer, 1994; Hantouche & Lancrenon, 1996), 300 cases, including both current and lifetime symptoms. but on the obsessions/​checking or with sexual obsessions in This study identified four factors accounting for more than other studies (Cavallini et al., 2002; Feinstein et al., 2003; 60% of the variance in each data set (Leckman et al., 1997). Leckman et al., 1997, 2003; Mataix-​Cols et al., 2002). Factor analyses conducted with children and adolesThe first factor included obsessions related to aggression, cents have yielded similar factor solutions, even though sex, religion or moral rightness, as well as checking comsome of the symptoms loaded differently than in adult pulsions (accounting for 30.1% of the variance). A second factor accounted for 13.8% of the variance and included samples. For instance, Stewart et  al. (2007) reported that obsessions concerning a need for symmetry or exactness, the “symmetry/​ordering” dimension was the first to emerge repeating rituals, counting, and ordering/​arranging com- and that somatic and aggressive symptoms loaded with the pulsions. The third factor accounted for 10.2% of the “contamination/​cleaning” dimension. Figure 8.1 summarizes the findings from the Bloch et al. variance and was composed of contamination obsessions and cleaning and washing compulsions. The fourth factor (2008) metaanalysis, and the differences between factor included hoarding and collecting obsessions and compul- analyses performed on childhood and adult samples. It is sions and accounted for 8.5% of the variance. Hoarding important to mention that this metaanalysis included eight was considered a manifestation of OCD at the time of studies from non-​English-​speaking countries, indicating these early studies, though most hoarding symptoms are that these symptom dimensions have cross-​cultural validity now conceptualized as representing a distinct disorder (see (Bloch et al., 2008). A major limitation of this literature is that many stud­chapter 52). ies have used categorical instruments (i.e., the Y-​B OCS) Subsequently, Summerfeldt and colleagues used confirmatory factor analyses to evaluate four OCD symptom to identify whether specific OCS dimensions are present structure models:  a single-​factor (i.e., OCD as a single or absent. A true dimensional approach should ideally rate dimension); a two-​factor (i.e., obsessions and compulsions); symptoms along a continuum, with symptom severity rangthe three-​factor model of Baer (1994); and the four-​factor ing from a “no symptom at all” to a “most severe symptom” model found in the Leckman et al. (1997) study. Adequate presentation. Reasons for using a categorical approach to analyzfit was found only for the four-​factor model (Summerfeldt ing OCS dimensions include the fact that the dimenet al., 1999). Many other factor analyses followed, both in adult and sional approach is a relatively recent development and childhood samples, conducted in many different countries. that instruments capable of assessing severity of the OCS To date, there have been around 26 factor analytic stud- dimensions independently have become available only ies involving more than 5,000 subjects. These studies have recently. In 2006, Rosario-​Campos and colleagues developed reported fairly consistent results, yielded three to six OCS and validated the Dimensional Yale-​ Brown Obsessive-​ dimensions, and have been well described by two reviews Compulsive Scale (DY-​ B OCS), which assesses the (Bloch, 2008; Mataix-​Cols et al., 2005). A metaanalysis (Bloch et al., 2008) demonstrated that presence and severity of OCS along six dimensions some of the OCS dimensions have been consistently repli- (Rosario-​Campos et al., 2006). The DY-​B OCS consists of cated across studies, such as the “contamination/​washing,” an OCS checklist and semistructured scales for assessing the “symmetry/​ ordering,” and the “hoarding” dimen- the presence and severity of OCS dimensions. The 88-​item sions. However, the results suggested that the “aggressive/​ checklist was designed to provide a detailed description of 76

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Obsessions

Factors

Compulsions

obtained by combining the sum of the total severity scores for frequency, distress, and interference (ranging from 0 to 15) Ordering and the Impairment score (ranging from 0-​15), yielding Repeating Symmetry Symmetry a maximum total global severity score of 30 (Rosario-​ Counting Campos et al., 2006). Aggressive The DY-​B OCS was initially developed and validated in Checking Sexual Forbidden English and Portuguese (Rosario-​Campos et al., 2006). It Thoughts Religious has already been validated in Spanish (Pertusa et al., 2010), Somatic Japanese (Okada et  al., 2015), and Hungarian (Harsányi et al., 2012); it has been translated to Dutch and German Cleaning Contamination Cleaning ( Jakubovski et al., 2011) and Chinese (Li et al., 2009); and is being used in many countries. The DYBOCS is free of Figure 8.1  Factor structure of the Yale-​Brown Obsessive-​Compulsive Scale symptom checklist charge and available upon request. across the lifespan.  Symptom categories shaded in white are associated with Abramowitz et  al. (2010) developed the Dimensional the same factor across the lifespan. Symptom categories shaded in gray are associated with different factors in adults and children. Solid lines Obsessive-​Compulsive Scale (DOCS), a 20-​item measure indicate that a symptom category is associated with a particular factor in that assesses four OC symptom dimensions: (1) concerns adults. Dashed lines indicate that the symptom category is associated about germs/​ contamination; (2)  concerns about being with a particular factor in children only. The hoarding and symmetry factors that are surrounded by a dashed box were collapsed into the responsible for harm, injury, or bad luck; (3) unacceptable same factor in some subgroup analyses, including when studies included thoughts; and (4)  concerns about symmetry, completenon-​English-​speaking subjects or when ratings of symptom severity were ness, and the need for things to be just-​right. The DOCS used. The forbidden thoughts factor split into two separate factors in subgroup analyses involving non-​English-​speaking subjects and when only has demonstrated excellent psychometric properties (see studies using item-​level data were considered. ­chapter 14). (Bloch et al., 2008) In sum, available data support a dimensional approach obsessions and compulsions that are divided into six dif- to address OCD heterogeneity. There have been many studferent OCS dimensions: (1) obsessions about harm due to ies investigating the clinical and neurobiological validity injury/​violence/​aggression/​natural disasters, and related of these OCS dimensions. Indeed, clinical and neurobiocompulsions; (2)  obsessions concerning sexual/​ moral/​ logical investigations of the hoarding dimension in OCD religious themes, and related compulsions; (3)  obsessions contributed to the delineation of hoarding disorder as a disabout symmetry/​“just-​right” perceptions, and compulsions tinct condition in the DSM-​5 (see ­chapter 52). to count or order/​arrange; (4)  contamination obsessions Below we present some of the studies that have supand cleaning compulsions; (5) obsessions and compulsions ported the utility of a focus on OCS dimensions, using both related to hoarding; and (6) miscellaneous obsessions and categorical and dimensional approaches. Although differcompulsions that relate to somatic concerns and supersti- ent authors have defined the dimensions of OCS in slightly tions, among other symptoms. By dividing OCS according different ways and using different instruments, most studies to these dimensions, the DY-​B OCS is capable of inquiring have focused on the same four or five core dimensions: fear-​ about symptoms that frequently appear in more than one of-​harm/​checking, intrusive sexual/​religious/​violent or dimension (such as checking, mental rituals, repetitive and taboo thoughts (which are sometimes combined with the avoidance behaviors). checking dimension), contamination/​cleaning, symmetry/​ The second part of the DY-​B OCS includes severity ordering, and hoarding. scales for each dimension and an overall estimate of total Because this is a young area of investigation, the literaOC symptom severity. These scales are composed of three ture has yet to converge on clear clinical, neuropsychologordinal scales with six anchor points that focus on symp- ical, and biological correlates of these different dimensions tom frequency (ranging from 0 to 5), the amount of dis- (beyond the unique characteristics of hoarding). The state tress they cause (ranging from 0 to 5), and the degree to of the literature is such that it would be premature to conwhich they interfere with the patient’s functioning (ranging struct overarching models of the underlying differences from 0 to 5). In addition, the patients are also asked about between OCS dimensions and their relationship to one the impairment caused by having OCS in their general another. It is to be hoped that, with ongoing investigation activities and self-​esteem, ranging from “none” (zero) to along the lines of the studies summarized here, the etiolog“severe” (15 points). The Total Global DY-​B OCS Score is ical significance and clinical correlates of these symptom Hoarding

Hoarding

Hoarding

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dimensions will become increasingly clear and will prove useful to guide treatment decisions.

obsessions; and having had treatment prior to entering the study (Chase et al., 2015). Other studies also reported that severity in this dimension was predicted by greater levels of hostility, and by a past history of nonalcohol substance VA L IDATION FRO M CLI N I CAL AN D dependence (Brakoulias et al., 2013). EP IDEM IOL O G I CAL STUD I ES When evaluating early maladaptive schemas of OCD patients using the Young Schema Questionnaire, Kim and Since the initial descriptions, many studies have inves- colleagues (2014) found that the “sexual/​religious/​moral” tigated the validity of OCS dimensions. Clinical and dimension severity was significantly correlated with two epidemiological studies have investigated whether these schemas:  vulnerability to harm or illness, and undeveldimensions are present in all age ranges, whether they are oped self (Kim et  al., 2014). This “forbidden/​unaccepttemporally stable, and whether they have distinct patterns able thoughts” dimension was associated with increased of comorbidity. importance/​control of thoughts (Brakoulias et  al., 2013, 2014) according to the three OC cognitive domains identified by the Obsessive Beliefs Questionnaire (Brakoulias et al., P S Y C H O PAT H O L O G Y A N D C O M O R B I D I T Y 2014; see Chapter 18). STUDIES Fontenelle and colleagues (2013) evaluated insight Aggression/​Injury/​Violence/​Natural for each of the OCS dimensions, using the Brown Disasters Dimension Assessment of Beliefs Scale (BABS). They found that onset OCD was associated with lower insight Higher severity scores in the aggressive/​checking dimen- early-​ about the “sexual/​religious/​moral” symptom dimension sion have been found to be associated with tic disorders (Fontenelle et al., 2013). (Nikolajsen et al., 2011). Higher frequencies of the “sexual/​ religious/​ moral” Using categorical analyses, a higher frequency on the “aggressive/​checking” dimension has been associated with dimension have been described as more frequent in OCD female gender (Torresan et al., 2013), higher risk for comor- patients with comorbid BDD (Costa et al., 2012) and major bidity with body dysmorphic disorder (BDD) (Costa et al., depression (Torresan et al., 2013). Torresan and colleagues 2012), and good insight (Cherian et  al., 2012). A  recent (2013) found that among men, symptoms of the “sexstudy reported that the aggressive dimension was independ- ual/​religious/​moral” dimension were more frequent and ently associated with posttraumatic stress disorder (PTSD), more severe (Torresan et al., 2013), confirming the results separation anxiety disorder, any impulse-​control disorder, found in children and adolescents with OCD (Mataix-​ Cols et  al., 2008). Counterintuitively, however, higher and skin picking (Torres et al., 2016). scores on this dimension in childhood have been associated with improved quality of life in adulthood (Palermo et al., Sexual/​Religious/​Morality Dimension 2011); and “Sexual/​religious” scores were associated with For some authors, the “aggression/​injury/​violence/​natu- higher levels of the brain derived neurotrophic factor (dos ral disasters” dimension is merged with the “sexual/​reli- Santos et al., 2011). gious/​moral” dimension (Brakoulias et al., 2013; Palermo It is important to note that high scores on the “sexual/​ et  al., 2011), but, for others there is potential utility in religious” dimension have been associated with suicidal assessing these symptoms separately (Wetterneck et  al., thoughts and plans in large samples, and that this relation2015). Some studies describe this dimension as the “for- ship persisted after logistic regression analyses (Torres et al., bidden, unacceptable, or taboo thoughts” dimension 2011; Velloso et al., 2016). These patients thus require par(Pinto et al., 2008). ticularly careful clinical evaluation for suicidality. The severity of this factor remained significantly higher De Mathis et  al. (2012) investigated the trajectory than other symptom dimensions at both admission and of OCD and comorbid disorders and found that OCD discharge of OCD patients, leading some to infer that it patients who exhibited separation anxiety symptoms before may exhibit uniquely impairing features, when compared the onset of OCD had significantly higher scores in the to the other dimensions (Chase et al., 2015). These authors “sexual/​religious” dimension, higher scores on the Beck reported that higher scores on this dimension were pre- Depression and Anxiety Inventories, and higher frequendicted by male gender; higher Y-​B OCS obsession sub-​ cies of comorbid PTSD. These results suggest that from scores; amount of time, distress, and attempt to control the a developmental perspective OCD does not behave as a 78

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unitary disorder but rather as a group of symptoms that interact with other domains of psychopathology, increasing the vulnerability for the development of subsequent specific disorders (de Mathis et al., 2013).

Contamination/​Washing/​Cleaning

Fontenelle et al. (2010) investigated quality of life (QoL) of OCD patients (see c­hapter  6) using the Short-​Form Health Survey-​36 (SF-​36), and found that washing symptoms explained 31% of the limitation due to physical health problems. This level of physical disability is comparable to Symmetry/​Ordering/​Arranging Dimension that associated with many chronic diseases. Sustained washSymptoms in the “symmetry/​ ordering” dimension ing symptoms may lead to physical exhaustion and to severe have been associated with decreased global functioning dermatological problems (Moritz et al., 2005). (Matsunaga et al., 2010a), higher OCD severity (Matsunaga Albert et  al. (2010) reported that higher scores on et al., 2010a), and an earlier age of onset (Matsunaga et al., the “contamination/​washing” symptom dimension and a 2008; Zhang et  al., 2013). As with the “sexual/​religious/​ positive family history for an anxiety disorder other than moral” dimension, Fontenelle and colleagues (2013) found OCD predicted higher scores on several domains of family lower insight about “symmetry/​ ordering” symptoms in accommodation (see ­chapter 43). early-​onset OCD patients. Patients with “contamination/​ cleaning” symptoms Kichuk et  al. (2013) assessed age of onset and clinwere more likely to report OCD onset during pregnancy or ical course of the OCS dimensions in 955 adult OCD postpartum (OR = 9.3; see c­ hapters 27, 61) (Labad et al., patients and found that, compared with the other symp2010). Other studies have reported that females presented tom dimensions, patients with high scores on the “symhigher frequencies of this dimension (Torresan et al., 2013; metry/​ordering” dimension had an earlier age of onset, Zhang et  al., 2013)  and that washing compulsions were were less likely to have a waxing and waning course, and associated with poor insight (Cherian et al., 2012). had a higher frequency of tics. Other studies have similarly Interestingly, a study comparing clinical characteristics reported that higher scores in the “symmetry/​ordering” of early onset OCD patients with and without tics reported dimension were associated with higher comorbidity with higher severity scores of the “contamination/​ cleaning” tic disorders (Baer, 1994; Leckman et  al., 1997; Mataix-​ dimension in early onset OCD patients without comorbid Cols et al., 1999a), as well as with eating disorders (Halmi tics, compared with those with a comorbid tic disorder (de et al., 2003). Mathis et al., 2009). Rosso et al. (2012) examined the relationship between stressful life events and all of the OCS dimensions. Only the “symmetry/​ordering” dimension was significantly assoHoarding Obsessions and Compulsions ciated with stressful life events, including “hospitalization of a family member,” “major personal physical illness,” and Prior to DSM-​5, hoarding symptoms were considered an “loss of a personally valuable object.” The authors hypoth- aspect of OCD (see c­ hapter 48). The hoarding dimension esized that this OCS dimension is more associated with has been extensively investigated and found to be associated with specific clinical characteristics; these investigations environmental factors than others. “Symmetry/​ ordering” symptoms have been found provided the basis for the decision to separate out these to be associated with perfectionism and intolerance of symptoms into the a new diagnosis of hoarding disorder in uncertainty, as measured using the Obsessive-​ Beliefs the DSM-​5 (see c­ hapter 52). Because these symptoms have Questionnaire (Brakoulias et  al., 2014). Martinelli et  al. been included in most studies of the dimensional structure (2014) investigated subdomains of perfectionism—​ of OCD, we discuss them here. Mataix-​Cols et al. (2008) examined 238 children and concern over mistakes, doubts about actions, personal standards, parental criticism, parental expectations, and adolescents referred to a specialty pediatric OCD clinic organization—​ and found, intuitively, that the “organ- and found that girls were more likely to endorse hoardization” domain was a significant predictor of ordering ing compulsions. In children and adolescents, higher symptoms. Doubts about action were associated with over- scores on the hoarding dimension have been associated all OCD severity and with checking symptoms. Another with increased levels of pervasive slowness, responsibility, study reported that ordering, counting, and cleaning com- indecisiveness, pathological doubt, depression, and a varipulsions in children were associated with perfectionism and ety of emotional difficulties, both self-​rated and parent-​ with parental rigidity, when compared with control fami- rated (Mataix-​Cols et  al., 2008). Hoarding symptoms in childhood appear to predict both the persistence of OCD lies (Calvo et al., 2009). S ymptom H eterogeneity in O C D :   A   D imensional A pproach

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symptoms and poorer QoL in early adulthood (Palermo et al., 2011). This association of hoarding symptoms with reduced QoL appears robust. Fontenelle et  al. (2010) reported that the best model in a series of stepwise linear regression analyses of QoL included a dimensional measure of hoarding, depressive symptoms, and employment status. These variables predicted 62% of the variance of the social functioning subscale of the SF-​36 QoL scale. Matsunaga et al. (2010b) also reported an association between the hoarding dimension and lower QoL, lower rates of marriage, longer duration of illness, decreased global functioning, and greater OCD severity. Many studies have reported an association between hoarding and poor insight (Ardizzone et al., 2010; Fontenelle et al., 2013; Matsunaga et al., 2010b; Torres et al., 2012), using the BABS or other instruments. Torres et  al. (2012) also found hoarding to be independently associated with being older, living alone, an earlier age of symptom onset, an insidious onset of obsessions, and higher anxiety scores, in a logistic regression. Another study reported that patients with hoarding symptoms were more likely to report OCD onset at menarche (OR = 4.1) (Labad et al., 2010). Regarding comorbidity patterns, “hoarding” has been positively associated with dysphoria, lifetime history of bipolar I, and BDD (LaSalle-​Ricci et al., 2006). Other studies have reported associations with: major depression, attention deficit/​hyperactivity disorder, compulsive buying, tic disorders (Torres et al., 2012), PTSD (La Salle-​Ricci et al., 2006; Torres et  al., 2012), and schizotypal and obsessive-​ compulsive personality disorders (Matsunaga et al., 2010b). Gender may moderate the comorbidity patterns:  among men, hoarding has been associated with generalized anxiety and tic disorders, whereas among women hoarding has been associated with social phobia, PTSD, BDD, nail biting, and skin picking (Wheaton et al., 2008). Hoarding symptoms have been strongly associated to the presence and number of personality disorders, especially from the anxious-​fearful cluster (Mataix-​Cols et al, 2000; Wheaton et  al., 2008). Hoarding was negatively correlated with the NEO-​Personality Inventory-​Revised (NEO-​PI-​R) factor of conscientiousness and positively associated with the NEO-​PI-​R factor of neuroticism (La Salle-​Ricci et  al., 2006). Even though sensitivity to punishment is a common personality feature to many OCD patients, it is more pronounced in patients with higher scores on the Hoarding dimension. More severe hoarding symptoms have also been associated with lower impulsivity and lower novelty seeking (Fullana et  al., 2004). According to the Temperament and Character Inventory, 80

the hoarding dimension was associated with lower self-​ directedness scores and higher persistence scores, after adjusting for age, OC symptom severity, and depression severity (Kim et al., 2009). Hoarding is the only OCS dimension that is partially predicted by parental traits, specifically, low parental emotional warmth (Alonso et al., 2004). Hoarding, perfectionism, and preoccupation with details are significantly more frequent in parents of children with OCD (Calvo et  al., 2009). Together with the “contamination/​cleaning” dimension, the “hoarding” dimension also seems to be related to family accommodation, especially if the family member is the patient’s spouse (Gomes et al., 2014). TEMPORAL STABILITY

Clinical and epidemiological studies have demonstrated that these OCS dimensions are fairly stable over time, that symptom evolution is more frequently within the same dimension than across dimensions, and that the best predictor of having a particular dimension is having had that symptom dimension in the past (Leckman et al., 2007; Mataix-​Cols et al., 2002). Such observations encourage the view that these symptom dimensions are meaningful disease subcomponents, rather than artificial constructs. For instance, Rettew et al. (1992) assessed the longitudinal course of OCS in 76 OCD children and adolescents. They found that the type of symptom changed from baseline to follow-​up, but that these changes occurred within (rather than between) symptom dimensions. Mataix-​Cols et al. (2002) similarly found the pattern of OC symptoms to be stable over a 2-​year period. Stability may differ across OCS dimensions. Rufer et al. (2005) investigated the OCS stability in 54 adult OCD patients over a 6-​year period and found that the severity of “aggressive/​checking,” “symmetry/​ordering,” and “contamination/​cleaning” symptoms significantly changed over time, whereas the severity of “sexual/​religious” and “hoarding” symptoms did not. In contrast, another study reported that subjects with primary OCD symptoms in the “sexual/​ religious” dimension were more likely to report a waxing-​ and-​waning course (Kichuk et  al., 2013). Symptoms on the “hoarding” dimension did not significantly reduce its severity over time, according to Rufer et al. (2005) and to Mataix-​Cols et al. (2002). In nonclinical samples, Fullana et al. (2007) investigated the temporal stability of OCS dimensions in 132 undergraduate students during a 2-​year period. They reported that the scores of each dimension at follow-​up were strongly O b sessive - C ompulsive D isorder

 

and uniquely predicted from the scores on the same dimension at baseline. EPIDEMIOLOGICAL STUDIES

There are very few epidemiological studies investigating the OCS dimensions. One recent study evaluated 9,937 Brazilian school-​age children (6–​12  years old) and their biological relatives using the Family History Screen. OCS were present in 14.7% of the index children, 15.6% of their siblings, 34.6% of their mothers, and 12.1% of their fathers. The prevalence of overall OCS and of each of the OCS dimensions gradually increased from ages 6 to 12  years. OCS in children were associated with the presence of other psychiatric symptoms and with behavioral/​school impairment. Interestingly, the four OCS dimensions significantly aggregated within families (Alvarenga et al., 2015). Fullana et al. (2009) analyzed data from the Dunedin Multidisciplinary Health and Development Study. They assessed presence of obsessions, compulsions, and mental disorders with the Diagnostic Interview Schedule (DIS) at ages 11, 26, and 32. The 1-​year prevalence of any obsession or compulsion was 21% at age 26 and 25% at age 32. Among individuals with mental disorders other than OCD these rates increased to 31% and 49%, respectively. These percentages were much higher than the prevalence of categorically defined OCD according to DSM-​IV criteria, which was 2.3% at age 26 and 1.8% at age 32. The authors generated four OCS dimensions from the DIS and reported that shameful thoughts and obsessions about a relative being hurt were the most frequent obsessions (5%–​6% of the total sample). Checking to prevent harm was the most common compulsion (10%). The authors found these symptom dimensions to be temporally stable and associated with increased comorbidity. Having OCS at age 11 predicted a high risk of an adult OCD diagnosis in adulthood (Fullana et al., 2009).

VA L IDATION FRO M G EN ETI C STUD I ES Genetic studies have emphasized the etiologic heterogeneity of OCD, and that this heterogeneity may be reflected in phenotypic variability (see ­chapter  19). Heterogeneity reduces the power of gene localization methods, such as linkage analysis. The use of OCS dimensions as quantitative covariates in genetic analysis has been described by many authors as a potentially powerful tool for the identification of genetic factors in the OCD etiology.

Alsobrook et  al. (1999) were the first to use OCS dimensions in a family genetic study. They found that higher proband scores on the “aggressive/​sexual/​religious/​ checking” and the “symmetry/​ordering” dimensions almost doubled the risk for OCD among relatives, when compared with the relatives of probands who had low scores on these dimensions. Similarly, a Danish retrospective study found that high scores in the “symmetry/​ordering” dimension were related to a higher risk of OCD in first-​degree relatives (Nikolajsen et al., 2011). A sibling-​ pair study conducted by the OCD Collaborative Genetics Study Group (n  =  418 sib pairs) reported significant and robust sib-​sib correlations for the “hoarding” and the “aggressive/​sexual/​religious/​checking” dimensions. Smaller, but still significant, sib–​sib correlations were also found for the “contamination/​cleaning” and the “symmetry/​ordering” dimensions (Hasler et  al., 2007). Another study from the same group included 485 adult OCD patients and a subsample of 145 sib-​pairs. Even though the authors found sib–​sib associations for four of the five factors, the “hoarding” and the “taboo thoughts” dimensions were the most robustly familial (Pinto et  al., 2008). Another sib-​pair study found an effect of gender on the sib–​sib correlation (Chacon et  al., 2007):  when both sibs were male, there was a significant sib–​sib correlation in the “contamination/​cleaning” dimension severity. When both sibs were female, they had significant correlations for the “hoarding” dimension. Two sib-​pair studies using the data collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG) Affected Sibling Pair Study provided additional support for the validity of these OCS dimensions (Leckman et al., 2003; Zhang et al., 2002). The first reported that over 50% of the siblings of probands with TS, 30% of the mothers and 10% of the fathers had an OCD diagnosis. Among these, the factor scores for the “aggressive/​sexual/​religious/​checking” and the “symmetry/​ ordering” dimensions were significantly correlated in the TS sib-​pairs. Mother–​child correlations, but not father–​ child correlations, were also significant for these two factors. Segregation analyses demonstrated significant evidence for genetic transmission of all four factors (Leckman et al., 2003). Using the same TSAICG data set, Zhang et al. (2002) performed a linkage analysis of the “hoarding” dimension on 77 TS sib-​pairs, using both standard and recursive partitioning techniques among the siblings concordant for the “hoarding” dimension, including “hoarding” as both a dichotomous and a quantitative trait. Significant allele sharing was observed for both the dichotomous and the

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quantitative hoarding phenotypes for markers at the 4q34-​ 35, 5q35.2-​35.3 and the 17q25 chromosomal sites. Family-​g enetic and sib-​pair studies have difficulty distinguishing environmental and genetic factors. Unfortunately, twin studies investigating the OCS dimensions are still rare. One exception is the twin study analyzing the data from a population sample of 1,383 female twins from the Virginia Twin Registry. They found that all OCS dimensions shared variation with a latent common factor, that is, OCD behavior in general. Variation in this common factor was explained by both genes (36%) and environmental factors (64%). Only the “contamination/​ washing” dimension appeared to be influenced by specific genes, above and beyond this common factor (van Grootheest et  al., 2008). It is important to note that this study used the Padua Inventory, a 20-​item self-​report questionnaire that does not contain “symmetry/​ordering” or “hoarding” items, what may have limited the findings in these symptom domains. Another twin study investigated the overlap between genetic and environmental risk factors for the OCS dimensions, and their association with symptoms of other anxiety disorders (AD) or obsessive-​compulsive related disorders (OCRD). The authors analyzed the data from 2,495 twins aged 18 to 45 in the Australian Twin Registry. They found the “symmetry/​ ordering” dimension to have the highest genetic correlation with OCRD (more specifically Hoarding and BDD symptoms), but shared environmental influences with AD symptoms. On the other hand, the “obsessing” (aggressive, sexual, religious, and moral) and the “contamination/​cleaning” dimensions had the highest genetic correlations with the AD symptoms (López-​Solà et al., 2016) Katerberg et  al. (2010) performed item and category-​ level factor analyses of the YBOCS from 1,224 OCD subjects and performed heritability analyses in 52 OCD-​ affected multigenerational families. The “taboo” and “doubts” dimensions, as well as the “contamination/​cleaning” and the “symmetry/​hoarding” dimensions showed shared genetic influences. The “contamination/​cleaning” and the “symmetry/​hoarding” dimensions showed shared genetic variance with symptom severity. NEUROP S Y CHO LO G I CAL STUD I ES Few studies have used a dimensional approach to investigate the neuropsychological correlates of OCS dimensions (see Chapter 15). More have used a categorical approach to assess patients with checking compulsions, motivated by 82

the hypothesis that there might be a connection between checking rituals and memory deficits. These studies have demonstrated that OCD patients do not have difficulties with memory or memory consolidation, such as are present in patients with dementia (Kuelz et  al., 2004; Olley et  al., 2007). OCD patients with checking symptomatology do, however, appear to have lower confidence in their memory (Cha et  al., 2008; 1984; Hoenig et al., 2002; Sher et al., 1983; Weber et  al., 2014). Interestingly, similarly reduced confidence in memory was induced in healthy university students when they were asked to repeatedly check a virtual gas stove (van den Hout & Kindt, 2003). Memory accuracy was not affected by repeated checking, but memory confidence, vividness, and level of detail were greatly reduced in the experimental group. The authors concluded that repetitive checking may, perversely, cause and/​or worsen memory distrust. Other studies have reported that individuals with subclinical checking symptoms have memory deficits related to everyday activities and reduced ability to distinguish between memories of real and imagined events (Rubenstein et al., 1993; Sher et al., 1983; 1984). Subclinical checkers have also shown deficits similar to those of OCD patients in some classical neuropsychological memory tests, such as the Wechsler Memory Scale (Sher et al., 1984) and the Wisconsin card sort test (Goodwin & Sher, 1992). Following this line of research, a series of studies comparing OCD checkers, OCD patients without checking symptoms, and controls indicated that the checkers presented deficits both in memory and in various aspects of executive function, including inhibitory control and cognitive flexibility (Hoenig et al., 2002; Omori et al., 2007; Weber et  al., 2014). Corroborating these findings, Cha et al. reported that nonverbal memory was impaired in 24 checking OCD patients versus 23 cleaning OCD patients (Cha et al., 2008). Mataix-​Cols and colleagues characterized 35 subjects with subclinical OCS and 36 non-​compulsive controls in a battery of neuropsychological tests (Mataix-​Cols et  al., 1999c). Performance was correlated with scores on the checking items of the Padua Inventory, a measure of subclinical OCS across multiple dimensions (r = 0.32). Another study used the Iowa Gambling and the Wisconsin Card Sorting Tests to compare 39 OCD patients with 40 controls, and found that OCD patients had poorer set-​shifting abilities than controls and that the “symmetry/​ ordering” symptoms were negatively associated with performance (Lawrence et  al., 2006). A negative correlation between the “symmetry/​ordering” O b sessive - C ompulsive D isorder

 

dimension severity and attentional control was also found while investigating executive function in OCD patients (Pedron et al., 2015). The “symmetry/​ ordering” and “obsessions/​ checking” dimensions were also associated with deficits of nonverbal memory and organizational strategies in a large dimensional neuropsychological study (n  =  144 OCD subjects) ( Jang et al., 2010a). These authors performed their own factor analysis, yielding a five-​factor solution, reinforcing the hypothesis that these dimensions are stable across cultures. In a sample of 63 OCD patients in Japan, Hashimoto and colleagues (2011) found a negative association between the “symmetry/​ordering” dimension and the Logical Memory subset of the Wechsler Memory Scale-​Revised (assessing verbal memory), the Trail Making test, and the Stroop test (assessing inhibition control). They found a negative correlation between the “aggression/​checking” dimension and various aspects of executive function, such as organizational strategies. Interestingly, the authors found a positive association between the “contamination/​cleaning” dimension and attention, verbal memory, and executive functioning. None of these correlations survived correction for multiple comparisons. But the association between the “contamination/​cleaning” dimension and better cognitive performance was corroborated by another recent study, which showed that both the “contamination/​washing” and the “symmetry/​ordering” dimensions were positively associated with better performances in the Iowa Gambling Task (Martoni et al., 2015). Numerous neuropsychological studies have highlighted the specific characteristics associated with the “hoarding” dimension. These include impaired verbal and nonverbal memory; slower and more variable reaction time; increased impulsivity; greater difficulty distinguishing targets and nontargets; and poorer spatial attention and decision-​ making abilities in the Iowa Gambling test (Grisham et al., 2007; Hartl et al., 2004; Lawrence et al., 2006). These deficits may explain the difficulty patients with hoarding symptoms have in making daily decisions as to what to keep and what to discard. This literature is small, and most studies have small sample sizes; the findings summarized should be considered preliminary and in need of replication. The most consistent finding is that the presence of checking OCS (both subclinically and in clinical populations) is associated with lower memory confidence in recognition tasks; this confidence appears to be more compromised than memory per se (Boschen & Vuksanovic, 2007; Cougle et al., 2007; Cuttler & Graf, 2009; Radomsky et al., 2006; 2014).

NE U ROIMAGING S T U DIE S The hypothesis that OCD patients have deficits in the cortico-​striatal-​thalamic-​cortical circuits is widely accepted (see ­chapter 21). However, many authors believe that this represents an overly simplistic model (Mataix-​Cols & van den Heuvel, 2006; Menzies et al., 2008), and that a dimensional approach could contribute to a better understanding of the abnormalities in brain circuitry that underlie OCD symptomatology (Harrison et al., 2013).

FUNCTIONAL NEUROIMAGING

In a seminal early study, Rauch and colleagues (1998) found that “symmetry/​ordering” symptoms were associated with a trend toward reduced regional cerebral blood flow in the right caudate nucleus during a continuous performance task. A  number of subsequent functional neuroimaging studies have used a categorical approach to investigate brain activation differences in OCD patients with predominantly “contamination/​washing,” “checking,” or “hoarding” symptoms. Several studies have examined brain activity/​perfusion during symptom provocation. Murayama and colleagues (2012) found that the caudate and the anterior cingulate cortex (ACC) were hyperactive upon symptom provocation in checkers, whereas broad regions of cortex, and cerebellum, were more active in washers. Another small symptom provocation study reported that washers had predominantly insular and visual cortical activation, whereas healthy volunteers and patients with checking-​ related symptoms presented a pattern of activation predominantly within dorsal prefrontal, visual, and temporal cortices and the caudate nucleus (Phillips et al., 2000). Several studies have reported greater activation in limbic areas, such as the insula and the parahippocampal gyrus, and in the ventral part of the prefrontal cortex during symptom provocation in OCD patients with “washing” symptoms (Mataix-​Cols et al., 2003b, 2004; Phillips et al., 2000; Shapira et  al., 2003). A  provocation study that examined several different symptom domains, with stimuli provocative of “washing,” “checking,” and “hoarding” symptoms, found that:  (a)  provocation of contamination/​ washing symptoms produced significantly greater activation in OCD patients than in controls in bilateral ventromedial prefrontal regions and right caudate nucleus; (b)  checking symptoms were associated with activation in putamen, globus pallidus, thalamus, and dorsal cortical areas; and (c)  hoarding symptoms were associated with activation of left precentral gyrus and right orbito-​frontal cortex

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(Mataix-​Cols et  al., 2004). Overall, symptom-​provocative stimuli appear to produce qualitatively similar patterns of activation in OCD patients and controls, although the activation is much more pronounced in patients (Mataix-​Cols et al., 2003b, 2004). This leads to the suggestion that OCD patients would present quantitative differences rather than qualitative differences in neural circuits when compared to controls (Mataix-​Cols & van den Heuvel, 2006). These observations have led to a model suggesting that the “contamination/​washing” and “hoarding” symptom dimensions are associated with limbic/​affective dysregulation, whereas “symmetry/​ordering” and “checking” symptoms are associated with fronto-​striatal dysfunction (Phillips & Mataix-​Cols, 2004). This idea can be extended to describe phenomenology in other, related psychiatric disorders (Figure 8.2). This model suggests that contamination and hoarding symptoms involve the amygdala, insula, and ventromedial prefrontal cortex, and are associated with phenomenological characteristics such as anticipatory anxiety, arousal, and avoidance behavior. The symmetry/​ordering and checking dimensions, in contrast, may be more closely related to areas of the sensorimotor cortico-​striato-​ thalamic loops and may have a closer relationship to tics, Tourette Syndrome, and trichotillomania. More studies are needed to investigate and refine this hypothesis. Recently, studies of resting state functional connectivity have begun to shed light on alterations of brain functional organization in OCD and other neuropsychiatric conditions (see c­ hapter  24). These studies have corroborated the well-​known notion of alterations in the ventral

eating disorders

BDD

hypochondriasis panic disorder specific phobia

obsessions checking contamination washing

PTSD social phobia

hoarding

GAD

‘limbic’

Tourette’s syndrome

Symmetry ordering

tic disorders

pathological grooming

‘frontal-striatal’

Figure 8.2  A limbic-​frontal-​striatal spectrum model for the relationship between OCS dimensions and other Axis I disorders.  BDD, body dysmorphic disorder; GAD, generalized

anxiety disorder; pathological grooming, pathologic grooming behaviors such as trichotillomania, nail biting, skin picking; PTSD, posttraumatic stress disorder. (Mataix-​Cols & van den Heuvel, 2006)

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striatum–​OFC circuitry (Anticevic et al., 2014; Harrison et  al., 2009; Hou et  al., 2013; Jhung et  al., 2014; Sakai et al., 2011), in the circuitry related to the Default Mode Network (Hou et al., 2013; Jang et al., 2010b; Stern et al., 2012), and in other brain circuits of OCD patients (del Casale et al., 2011). Only a few studies have investigated resting-​state connectivity correlates of OCS dimensions. In 2013, Harrison et  al. reported that “aggression” symptoms were associated with alterations in connectivity between the ventral striatum, amygdala, and ventromedial prefrontal cortex; that “sexual/​ religious” symptoms were associated with alterations in ventral striatal-​insular connectivity; and that “hoarding” symptoms were associated with alterations in ventral and dorsal striatal functional connectivity with frontal regions (Harrison et al., 2013). Jhung et al. (2014) compared 13 OCD patients with predominant “contamination” and 13 OCD patients without these symptoms, and found that contamination patients had altered functional connectivity between the ventral striatum and the insula. This is consistent with the idea developed earlier, that pathology in limbic cortices may be associated with symptoms in the “washing/​ contamination” dimension (Mataix-​Cols et al., 2004). STRUCTURAL NEUROIMAGING

In one of the first studies to examine the structural correlates of OCD symptom dimensions, Pujol et al. (2004) reported that 30 patients with “aggressive/​checking” symptoms had decreased gray matter (GM) volume in the right amygdala. Corroborating this, van den Huevel et al. (2009) analyzed 55 OCD patients and found that bilateral temporal lobe GM and white matter (WM) were negatively correlated with the “harm/​checking” dimension. Using the DY-​B OCS, Alvarenga et  al. (2012), found a negative correlation between the scores in the “aggression” dimension and GM volumes of the bilateral insula, left putamen, and left inferior OFC. On the other hand, they found a positive correlation between the scores from this dimension and GM volumes in the lateral parietal cortex, bilaterally. This study also found scores on the “sexual/​ religious” dimension to be positively correlated with GM volumes within the right middle lateral OFC and right dorsal lateral prefrontal cortex, and negatively correlated with bilateral ACC. No significant correlations were found between GM volumes and the “contamination” or “symmetry” dimensions in the 37 treatment naïve OCD patients (Alvarenga et al., 2012). More recently, another study using the DY-​B OCS reported negative correlations between the O b sessive - C ompulsive D isorder

 

“aggression/​checking” dimension scores and regional right cerebellum decreased volumes (Okada et al., 2015). A much larger study, conducted by the International OCD Brain Imaging Consortium, found that “aggression/​ checking” symptoms were associated with greater lingual gyrus volume and smaller superior parietal GM and WM volumes in 331 OCD patients (de Wit et al., 2014). This study also reported that “sexual/​religious” symptoms had greater associations with GM volume of middle temporal gyrus, and that “symmetry/​ordering” dimension scores correlated with smaller fusiform cortex GM volume. They did not find any association with scores in the “contamination/​ washing” dimension. In contrast, van den Heuvel et al (2009) found a negative correlation between symptoms in the “contamination/​ washing” dimension and GM volume of the bilateral dorsal caudate nucleus, as well as WM volume in the right parietal region (van den Heuvel et al., 2009). Higher “contamination/​washing” symptom severity was also associated with smaller GM volume in the right premotor and supplementary motor area (Gilbert et  al., 2008)  and negatively correlated with the right insula (Okada et al., 2015). Van den Heuvel et al. (2009) also found scores on the “symmetry/​ ordering” dimension to negatively correlate with GM volumes in the bilateral parietal cortex and positively correlate with bilateral medial temporal GM and WM volumes. The “hoarding” dimension has been more intensively investigated. Hoarding symptoms have been variably reported to positively correlate with GM volume in the left superior lateral OFC and negatively correlate with GM volume in the right parahippocampal gyrus (Alvarenga et al., 2012), right cerebellum (de Wit et al., 2014), left premotor and supplementary motor area (Gilbert et al., 2008), and the left caudate (Valente et al., 2005). Structural brain abnormalities associated with OCD overall, including changes in the orbitofrontal cortex and the cortico-​striatal circuitry, are increasingly well characterized (see ­chapter 23) (Radua & Mataix-​Cols, 2009; Rotge et al., 2009). Interestingly, in most studies, the correlates of dimensional measures of symptomatology are in areas distinct from this core cortico-​striatal circuitry. One exception to this generalization is the association in a recent systematic review of volumetric abnormalities in the lateral OFC and the presence of “symmetry/​ordering” symptoms (Piras et al., 2015). Generally, “contamination/​washing” and “hoarding” dimensions have been linked with brain abnormalities in regions associated with emotional processing (i.e., limbic system), whereas checking, symmetry, and ordering dimensions have been associated with more cognitive regions, such as the DLFC and dorsal striatum.

This pattern is consistent with the spectrum hypothesis described above (Mataix-​Cols & van den Heuvel, 2006). However, results from brain morphometric studies have been highly variable and inconclusive regarding the structural neural correlates of specific symptom dimensions in OCD. More work is needed.

T R E AT ME NT R E S PONS E Treatment outcome in OCD is highly variable (see ­chapters 36, 37, 40). The dimensional approach may be useful in the identification of predictors of treatment response and the development of more tailored treatment strategies. Many authors have tried to identify associations between treatment response and OCS dimensions, using both categorical (presence vs. absence of specific symptom dimensions) and dimensional (severity for each OCS dimension) approaches. Table 8.1 summarizes some of these studies. The “hoarding” dimension has been extensively studied and has consistently been associated with worse treatment response to both SSRI pharmacotherapy and CBT. A recent metaanalysis reviewed 21 studies involving 3,039 OCD patients, including 304 with hoarding symptoms. Patients with hoarding symptoms were significantly less likely to respond to traditional OCD treatments than OCD patients without hoarding symptoms (OR = 0.5, p OCD

A

Z = 62 OCD Patients > Comparison Subjects

L

Siblings > Comparison Subjects P

(D)

x = –12

8 6 4 2 0 –2 –4 –6

Size of Effect

Size of Effect

(C)

1 2 3 4 Co PD OCD HC L Amygdala x, y, z = –14, –8, –20

4 3 2 1 0 –1 –2 –3

1 2 3 4 Co PD OCD HC R Amygdala x, y, z = 22, –8, –16

Figure 21.4  BRAIN REGIONS OUTSIDE THE TRADITIONAL CORTI CO-​S TRIATAL-​T HALAMO-​C ORTICAL CIRCUIT IMPLICATED IN OBSESSIVE-​C OMPULSIVE

DISORDER (OCD).  A. Increased left presupplementary motor area activity in participants with OCD and siblings relative to comparison participants during a stop-​signal task. B. Reduced activity in right inferior frontal cortex, right supplementary motor cortex, right superior temporal gyrus, and right fusiform gyrus in participants with OCD compared with healthy comparison participants during a go/​no-​go task. C. Greater interference-​related activation in dorsal anterior cingulate cortex in particiapants with OCD compared with healthy comparison participants during a multisource interference task. D. Increased activity in left (L) and right (R) amygdala in response to OCD-​related emotional interference during an emotional Stroop task in participants with OCD compared to healthy comparison participants (Co) and plot of size of effect in this region. HC, hypochondriasis; PD, panic disorder.  (A reproduced with permission from de Wit et al., 2012: B reproduced with permission from Roth et al., 2007; C reproduced with permission from Fitzgerald et al., 2010; D reproduced with permission from van den Heuvel et al., 2005b) (see color plate)

mechanisms of treatment response in OCD. The singular discovery from this work, the identification of CSTC circuit dysfunction, has paved the way for groundbreaking OCD interventions, such as DBS, that target brain regions within the CSTC circuit. However, the realization that brain regions outside the CSTC also contribute to OCD pathophysiology provides the opportunity

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to look for other candidate targets. More superficial therapeutic targets may be more amenable to less invasive neuromodulatory techniques, such as repetitive transcranial magnetic stimulation (rTMS). Such approaches could be used as stand-​alone therapies or as a means to augment behavioral treatments. Indeed, low-​frequency inhibitory rTMS over the SMA has been one of the more

O b sessive - C ompulsive D isorder

 

Central executive network

X = 42

X = –58

Z = 36

X = –2

Y = 10

Z = –6

X = –4

Y = –12

Z = 28

Salience network

Defaultmode network

Figure 21.5  Three core intrinsic brain networks—​central executive network, salience network, and default mode network—​as identified by resting state

functional connectivity analysis.  (Reproduced with permission from Menon, 2011.) (see color plate)

efficacious target sites in TMS trials of OCD patients thus far (Berlim et al., 2013), and trials using a pre-​SMA site are ongoing. Given the heterogeneity of OCD and the likelihood that neurobiological abnormalities may vary in relationship to dissociable symptom dimensions, it will be critical going forward for the field to further examine similarities and differences amongst patient subgroups at a neural systems level, in order to develop more individualized treatment approaches. Functional neuroimaging is likely to continue to play a central role in the ongoing elucidation of OCD pathophysiology and the development of increasingly targeted and personalized therapies.

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F unctional neuroimaging studies in O C D

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22. TASK-BASED FUNCTIONAL NEUROIMAGING STUDIES OF OBSESSIVE-COMPULSIVE DISORDER: A HYPOTHESIS-DRIVEN REVIEW M. M. Vaghi, PhD and T. W. Robbins, PhD

T

 he ultimate goal of cognitive neuropsychiatry is to establish meaningful correlations between psychiatric symptoms, related cognitive processes, and associated brain circuits (Halligan & David, 2001). Adopting this approach has been critical to furthering our understanding of the neurobiological substrates of obsessive-​compulsive disorder (OCD). Early imaging studies examining cerebral glucose metabolic rate at rest in OCD patients by means of positron emission tomography (PET) have shown elevated metabolic rate in the orbitofrontal cortex (OFC) and the caudate nucleus (Baxter et  al., 1987; Saxena et  al., 1999), as further validated by meta-​analysis (Whiteside, Port, & Abramowitz, 2004) (see also ­chapter 21). These early observations have been corroborated by structural studies showing volumetric abnormalities (Radua & Mataix-​Cols, 2009; Rotge et al., 2009, 2010) and, more recently, morphometric alterations (Shaw et al., 2015) in similar brain regions (see ­chapter 23). In addition, a recent metaanalysis revealed the biological independence of OCD from other anxiety disorders by showing that OCD patients have increased bilateral gray matter volumes in the putamen extending to the caudate nucleus, not only when compared with healthy volunteers, but also when compared with other anxiety disorder groups (Radua, van den Heuvel, Surguladze, & Mataix-​ Cols, 2010). These observations have led to the formulation of a “modal model” of the neural changes in OCD, whereby abnormalities within fronto-​striatal “loops” projecting from cortical regions, including the prefrontal cortex (PFC), to the striatum, via direct and indirect pathways to the pallidum/​substantia nigra, and thence back to the frontal lobes via the thalamus, might underlie the disorder (Graybiel & Rauch, 2000; Haber & Heilbronner, 2013).

Extending this model via cognitive tasks might deepen our understanding of the contribution of abnormalities in this circuitry to OCD symptomatology. Accordingly, functional neuroimaging has been used in tandem with behavioral tasks, in order to examine the neural substrates of OCD with greater nuance. In this effort, different strategies can be devised. First, it is possible to relate task-​ independent findings, such as the ones originating from resting-​state connectivity analyses or structural MRI, to off-​line behavioral performance in relevant cognitive tests. Alternatively, event-​related functional MRI (fMRI) analysis can be employed to map spatially distinct brain areas germane for OCD. Functional connectivity can be incorporated into event-​related designs via psychophysiological interaction analysis. In neurocognitive settings, brain activation might be coupled with a demonstrable behavioral correlate. Alternatively, a behavioral task can “challenge” relevant brain areas, even in the absence of an observable difference in performance (Wilkinson & Halligan, 2004). In the case of patient populations, the lack of major behavioral impairment can represent an advantage, as it allows performance to be matched between groups. Between-​group differences cannot then simply be attributed to the behavioral performance differences and their concomitants, such as differences in receipt of positive and negative feedback or in motor performance. On the other hand, if there are no behavioral differences at all, there is the difficulty of interpreting what either hypoactivation or hyperactivation means in functional terms; for example, hypoactivation in combination with normal levels of performance could be construed as representing greater efficiency of performance.

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For these reasons, it is often a sound principle to parametrically vary the load (e.g., the difficulty) in a behavioral task, which can help to resolve these uncertainties. Sound interpretation of functional neuroimaging requires careful consideration of the underlying neuroanatomy. Evidence from the existing behavioral and cognitive neuroscience literature in rodents (Dalley, Cardinal, & Robbins, 2004; Mailly, Aliane, Groenewegen, Haber, & Deniau, 2013; Yin & Knowlton, 2006), primates (Haber, 2003), and humans (Draganski et al., 2008; Martino et al., 2008)  has begun to elucidate the functional neuroanatomy of reciprocal cortical-​basal ganglia interactions (see ­chapter  20). Based on the connections between specific sectors of the basal ganglia and confined territories of the frontal cortex, it has been suggested that each of the identified fronto-​striatal “loops” plays a specific functional role influencing a broad range of behaviors concerned not only with motor control but also with higher cognitive functions (Alexander, DeLong, & Strick, 1986). Abnormalities in the cortico-​basal ganglia network in OCD are thought to be linked to sub-​optimal performance on a range of executive functions and to the acquisition and maintenance of habitual behavior (Graybiel & Rauch, 2000). Establishing a neural signature of OCD has been hampered by several factors, theoretical, pragmatic, or methodological in nature. At the pathophysiological level, OCD is not associated with a known overt locus of neuronal degeneration, as, for example, in the case of Parkinson’s disease. For this reason, it is difficult to formulate and test specific a priori hypotheses regarding causative factors and associated neurobiological mechanisms. An important issue pertains to patterns of hypo-​ or hyper-​activation, which may be observed even within the same region, depending perhaps on the particular experimental paradigm used—​implying that group differences might be context dependent, as further elaborated later on. More straight-​forward, yet still fundamental, sources of variability in findings may include demographic differences, symptom severity, comorbidities, and medication status (Kuelz, Hohagen, & Voderholzer, 2004). In addition, a further complexity is the prominent clinical heterogeneity of the disorder represented by symptoms focusing on different dimensions (e.g., doubt and checking, contamination and cleaning, symmetry and ordering, taboo thoughts; see ­chapter 8) (Mataix-​Cols, Rosario-​Campos, & Leckman, 2005). Importantly, despite this heterogeneity, pathophysiological changes among orbitofrontal-​ striatal regions have been observed for all symptoms dimension, suggesting a core deficit (Harrison et  al., 2013). Finally, technical and methodological constraints can limit results. For example, the OFC lies at the interface between tissues 232

and air-​filled sinuses and is susceptible to drop-​out artefacts in fMRI (Ojemann et al., 1997). Coronal slicing direction and shimming can be employed in order to recover OFC signal. Comparison across studies can sometimes be further impeded by differences in anatomical labelling conventions used by different authors, especially when considering the boundaries of the different sectors of the PFC. The aim of this chapter is not to provide an exhaustive review of the literature, which would require an extensive, quantitative metaanalysis (see, e.g., Eng, Sim, & Chen, 2015; Menzies et al., 2008). Rather, we offer a summary of current knowledge of the neurobiological underpinnings of OCD, as revealed specifically by functional neuroimaging, and we elucidate critical points that should be addressed in future studies to develop a more detailed neurobiological model of the disorder. NE U ROC OGNIT IV E MAR K E R S OF   OC D:  A  H YPOT H E S IS DR IV E N ANALY S I S EXECUTIVE FUNCTIONS

OCD is associated with executive function impairments with medium to large effect sizes (Abramovitch, Abramowitz, & Mittelman, 2013; Shin, Lee, Kim, & Kwon, 2014; Snyder, Kaiser, Warren, & Heller, 2015) (­chapter 15). A metaanalysis collapsing case-​control comparisons in a variety of cognitive tasks, mostly related to executive functions, revealed disturbances in a widespread network, including the anterior cingulate cortex, the lateral PFC, and the OFC as well as the caudate and the putamen in OCD patients (Menzies et al., 2008). Although the PFC is generally believed to be the anatomical seat of executive function, equivalence between PFC activity and executive function cannot be assumed. Anatomically, the PFC is not homogenous, and several regions can be identified on the basis of their cytoarchitectonic characteristics (Figure 22.1) and the neural interactions with other regions, such as the parietal and temporal lobes (Middleton & Strick, 1996), the amygdala (Kelley, Domesick, & Nauta, 1982), and the hippocampus (Goldman-​Rakic, 1987), as well as the striatum (Alexander, DeLong, & Strick, 1986). At the behavioral level, executive function can be decomposed into separate, independent (albeit intertwined) constructs, such as inhibition, shifting, and updating working memory (Friedman et  al., 2006; Miyake et al., 2000). Dissociable aspects of executive function appear to be mediated by distinct neural systems that engage different regions of the PFC (Dias, Robbins, & O bsessive - C ompulsive D isorder

 

SMA (BA 6)

Caudate

DL-PFC (BA 9) DL-PFC (BA 46) IFG (BA 44/45) Frontal Pole (BA 10) Lateral OFC (BA 12/47)

Putamen

Medial OFC/VM-PFC

Figure 22.1  Schematic illustration of the cortical and subcortical areas relevant for OCD.

Cytoarchitectonic characteristics and neural interactions with different neural regions mark the boundaries of the different regions of the prefrontal cortex (PFC) for which specific functions have been identified (see also Table 22.1). Topographically organized projections enable cross-​talk between different areas of the PFC to functionally interrelated regions of the striatum. The precise interaction between the PFC and both caudate and putamen during cognitive tasks and their contribution to OCD remains to be elucidated. SMA, supplementary motor area; DL-​PFC, dorsolateral prefrontal cortex; IFG, inferior frontal gyrus; OFC, orbitofrontal cortex; VM-​PFC, ventromedial prefrontal cortex; BA, Brodmann Area. (see color plate)

Roberts, 1996; Shallice & Burgess, 1996; Stuss & Knight, 2013). This theoretical framework can be used to navigate the OCD fMRI literature, in order to link psychological and neurobiological findings (Table 22.1). Inhibition is a useful construct in the context of OCD, as the emergence of goal-​directed, purposeful behaviors is dependent in part upon the inhibition of competing behaviors. “Inhibition” is a multifaceted construct covering a broad range of behaviors (Bari & Robbins, 2013). “Response inhibition,” indexed as the ability to control prepotent motor responses in the Go/​No-​Go and the theoretically more sophisticated Stop Signal Task (Logan, Cowan, & Davis, 1984), is a particularly useful paradigm in laboratory settings (Box 22.1). In neuroimaging studies, response inhibition tasks usually recruit the right inferior frontal gyrus (IFG) (Aron, Robbins, & Poldrack, 2014; Garavan, Hester, Murphy, Fassbender, & Kelly, 2006; Garavan, Ross, & Stein, 1999; Kelly et al., 2004; Konishi, Nakajima, Uchida, Sekihara, & Miyashita, 1998). The IFG probably acts in concert with the pre-​supplementary motor area (pre-​SMA) (Duann, Ide, Luo, & Li, 2009) and subcortical structures, such as the subthalamic nucleus and the caudate T ask - B ased F unctional N euroimaging studies   I N   O C D

nucleus (Aron & Poldrack, 2006; Boehler et al., 2011), to enable successful inhibition of motor responses. Studies of neural activation during response inhibition tasks have quite consistently revealed decreased activation of the right IFG in OCD patients (Page et al., 2009; Roth et al., 2007). A recent study including healthy volunteers, OCD patients, and their first-​degree relatives replicated this reduced IFG activation in OCD patients during response inhibition, albeit at sub-​threshold statistical significance (de Wit et al., 2012). In addition, both patients and their siblings showed increased recruitment of the SMA, the degree of activation of which correlated with behavioral performance (de Wit et al., 2012). Importantly, right IFG hypoactivation was unique to patients and not shared with first-​degree unaffected relatives. This suggests that IFG hypoactivation is a contributor to OCD symptomatology, whereas increased SMA recruitment may be a biomarker of disease risk. A  deficit in IFG-​mediated response inhibition might contribute to the observed behavioral phenotype of OCD, as characterized by the inability to stop intrusive thoughts—​it having been shown that response inhibition is impaired in OCD patients in response to 233

 

BRAIN ABNORMALITIES AND THEORETICAL CONSTRUCTS REVEALED DURING FMRI OF COGNITIVE TASKS IN OCD PATIENTS Theoretical constructs, behavioral tasks and brain regions putatively implicated are shown. We selected tasks that (1) are theoretically grounded according to specific neurobiological hypothesis; (2) have been used in conjunction with functional MRI in OCD patients; and (3) have the greatest potential in terms of translational power. At the theoretical level, dissociation between the different executive functions was inspired by psychometric analysis showing that separate, independent, constructs can be identified (Friedman et al., 2006; Miyake et al., 2000). Goal-​directed behavior/​habit learning and fear extinction have been hypothesized to have theoretical relevance according to the neural substrates implicated in OCD (Gillan et al., 2015) and according to the clinical manifestation of the disorder (Milad & Rauch, 2012). TABLE 22.1 

Putative Brain Regions

Results in OCD

Theoretical Constructs

Methodological Probes

Inhibition

Go/​No-​Go, Stop Signal task Measures stopping ability as an indicator of impulsivity and motor inhibitory control. Staircase functions are used in the Stop Signal Task to estimate the time that a subject needs to withhold a response.

IFG SMA

−​ +

Roth et al., 2007; Page et al., 2009; de Wit et al., 2012 de Wit et al., 2012

Cognitive Flexibility*

Reversal learning Measures the ability to flexibly alter behavior based on negative feedback and respond to a previously incorrect stimulus.

Lateral OFC

−​

Remijnse et al., 2006; 2009; Chamberlain et al., 2008

Updating and manipulation of information

Working memory, Tower of London Measures of subject's ability to retain spatial information and to manipulate items in the working memory. The Tower of London task taps more specifically onto spatial planning.

DL-​PFC

No differences + −​

van der Wee et al., 2003; de Vries et al., 2014; van den Heuvel et al., 2005

Goal-​directed behavior and habit learning

Devaluation Measures to what extent actions are mediated by the knowledge of the causal relationship between the action and its consequences.

Caudate

+

Gillan et al., 2015†

Fear Extinction

Pavlovian fear conditioning Measures fear learning by coupling a neutral sensory stimuli (conditioned stimulus; e.g., a tone) to an aversive stimulus (unconditioned stimulus; e.g., a shock). Extinction and reversal fear conditioning are employed to measure the ability to modify learned fear responses.

VM-​PFC

−​

Milad et al., 2013 (extinction recall)

Another form of cognitive flexibility is attentional set-​shifting for which consistent evidence of impairment in OCD patients has been provided (Chamberlain et al., 2007; Chamberlain, Fineberg, Blackwell, Robbins, & Sahakian, 2006) but little evidence of its precise neural substrates. *

Greater activation was shown for OCD patients showing a bias toward habits vs. OCD patients without habits. IFG, inferior frontal gyrus; SMA, supplementary motor area; OFC, orbitofrontal cortex; DL-​PFC, dorsolateral prefrontal cortex; VM-​PFC, ventromedial prefrontal cortex; + increased functional activation was found in OCD patients; -​decreased functional activation was found in OCD patients. †

OCD-​ meaningful stimuli (Morein-​ Zamir, Fineberg, Robbins, & Sahakian, 2010). Other findings are more difficult to reconcile with this picture. Activity in the premotor cortex, anterior cingulate cortex, and subcortical brain areas, including the thalamus and the caudate, has been found to be both increased and decreased in OCD patients relative to comparison subjects (de Wit et al., 2012; Page et al., 2009; Roth et al., 2007). Perseverative and repetitive behaviors observed in OCD may map onto deficits in cognitive flexibility, which are frequently reported in patients with OCD (Bannon, Gonsalvez, Croft, & Boyce, 2006; Chamberlain, Fineberg, Blackwell, Robbins, & Sahakian, 2006; Gruner & Pittenger, 2016; Veale, Sahakian, Owen, & Marks, 1996; Watkins et al., 234

2005) and have been proposed as a cognitive endophenotype of the disorder (Chamberlain, Blackwell, Fineberg, Robbins, & Sahakian, 2005). The umbrella term “cognitive flexibility” subsumes task-​set switching, attentional set-​shifting, and reversal learning (see Box 22.1); these may engage distinct processes (Robbins, 2007). Task-​set switching entails the switching from one set of well-​trained responses to another, based on an explicit instruction. Task-​set switching tasks do not depend on learning over the course of task performance, which might conflate task demands. Gu and colleagues (Gu et al., 2008) demonstrated a behavioral impairment on task-​ switch trials in OCD patients that was related to significantly lower levels of activation, compared with the control group, in distributed areas including the dorsolateral-​PFC, O bsessive - C ompulsive D isorder

 

BOX 22.1 

DESCRIPTION OF THE MAIN BEHAVIORAL TASKS AND COGNITIVE CONSTRUCTS

Go/​No-​Go paradigm and Stop Signal Task are used to study response inhibition and motor inhibitory control. In both paradigms, subjects are instructed to withhold a motor response when a No-​Go or a Stop signal is presented. In the Stop Signal Task (SST), subjects are asked to press a left or right hand button when a corresponding arrow pointing to the left or right is presented. On a random selection of the trials, a Stop signal is presented after a variable delay and participants should withhold their response to the stimulus on those trials. Staircase functions are used in the SST to estimate the time that a subject needs to withhold a response (i.e., Stop signal reaction time), providing an estimate of the time needed to a participant to withhold an ongoing response. The SST represents a possibly superior index of response inhibition as compared with Go/​No-​Go paradigms, in which subjects are told to press the response key for a given stimulus and not to press the response key for another given stimulus. The index of inhibitory control in that procedure is represented by the probability of executing a response on a no-​go trial. Reversal learning tasks measure the ability to flexibly alter behavior based on negative feedback. For example, visual discrimination tasks can be employed where subjects learn to respond according to the opposite stimulus-​reward pairing. In these situations, subjects have to adapt their behavior and respond to a previously incorrect stimulus. Attentional set-​shifting tasks measure the ability to switch attention from one aspect of a stimulus to another in an ongoing task. Extradimensional set (EDs)-​shifting specifically refers to the ability of shifting to another, previously irrelevant dimension. Task-​switching tasks measure the capacity to flexibly alter behavior on a continuous basis between well-​learned stimulus-​response mappings. Unlike reversal and attentional-​set shifting tasks where subjects learn over the course of the performance, in task-​set switching tasks, participants are explicitly cued as to which task should be performed. Wisconsin Card Sorting Task (WCST) is mainly used in clinical contexts. The participant is presented with stimulus cards with shapes on them. The cards differ in color, number, and form of the shapes. The subject is asked to sort the cards into piles according to one of these rules. The participant is not told which stimulus dimension to use in order to sort the cards but the administrator provides a trial-​by-​trial feedback. Unbeknown to the participant, the sorting rule changes during the test and the participant must discover the new sorting rule on a trial-​and-​error feedback basis. Attentional set-​shifting paradigm is equivalent to a category shift on the WCST. N-​back task is an executive working memory task measuring subjects’ ability to retain spatial information and to manipulate items in the working memory. Participants are presented with a series of stimuli in sequence and have to decide whether each stimulus matches the one that appeared n-​items ago. Load on the working memory can be parametrically varied (e.g., n = 2, 3, 4). Tower of London task is used to assess high-​level visuospatial planning. It requires participants to rearrange a set of colored balls to match a target configuration according to specific rules. The aim is to solve each problem in the minimum number of moves. Planning abilities are indexed by the number of correct responses and by latencies to give the answer to a specific problem. Difficulty can be varied parametrically, depending on the number of moves necessary to arrange the balls according to the target or goal display. Outcome devaluation is used to assess the relative contribution of goal-​directed vs. habitual control over action control. It measures to what extent actions are mediated by the knowledge of the causal relationship between the action and its consequences. A shock-​avoidance paradigm has been devised whereby subjects were instructed to avoid mild electric shock to their wrists by pressing a corresponding pedal. Following overtraining, an instructed outcome devaluation procedure was used and subjects were explicitly told that one wrist was disconnected from the shocker (devalued), while the other one was still connected. Habits were measured as the number of unnecessary responses performed (i.e., number of times the foot-​pedal was pressed to avoid shock on the disconnected wrist). Pavlovian fear conditioning is a behavioral paradigm measuring fear learning by coupling a neutral sensory stimuli (conditioned stimulus; e.g. a tone) to an aversive stimulus (unconditioned stimulus; e.g. a shock). Extinction and reversal fear conditioning are employed to measure the ability to modify learned fear responses.

the anterior cingulate cortex, caudate nucleus, ventromedial (vm)-​PFC, and the OFC. With respect to attentional set-​shifting (also defined as extradimensional set-​shifting, EDS) and reversal learning T ask - B ased F unctional N euroimaging studies   I N   O C D

(Box 22.1), fiber-​sparing, excitotoxic lesions of the ventrolateral (VL-​) PFC and the OFC were found to disrupt attentional set-​shifting and reversal learning, respectively, in marmoset monkeys (Dias et  al., 1996). This double 235

 

dissociation was replicated in an event-​related functional MRI study in humans (Hampshire & Owen, 2006), with EDS-​shifting being related to the VL-​PFC and reversal learning to a network including the lateral OFC and the posterior parietal cortex. The same paradigm was employed in a study of OCD patients and their first-​degree relatives (Chamberlain et al., 2008). In OCD, impairments in EDS shifting have been reported multiple times (Chamberlain et  al., 2007; Chamberlain, Fineberg, Blackwell, Robbins, & Sahakian, 2006; Watkins et al., 2005) at the behavioral level (although with a failure of replication in some laboratories [Simpson et  al.,  2006]). When investigated with fMRI, brain activation during EDs-​shifting was not significant across the whole study, and so did not permit between-​ group comparisons. By contrast, reversal learning elicited less activation in OCD patients and their relatives in the lateral OFC-​PPC network, although the patients showed no behavioral impairment (Chamberlain et  al., 2008). In a separate study, decreased resting-​state functional connectivity between the caudate and the left superior frontal gyrus (BA 10/​11/​47) was selectively associated with more severe impairment in off-​line measured (i.e., outside the scanner) attentional set-​shifting in OCD patients (Vaghi et  al., 2016). Strikingly, an independent analysis revealed that connectivity between the caudate and BA 10/​11/​47 was significantly reduced in OCD patients compared with healthy volunteers, suggesting that this pattern of decreased connectivity might constitute a valuable biomarker with a cognitive relevance (Vaghi et al., 2016). An earlier single-​photon emission computed tomography study using the related Wisconsin Card Sorting Test (see Box 22.1), found a positive significant association between the number of errors required to recognize changes in the sorting rule and the cerebral blood flow in the left “inferior frontal cortex” and the left caudate nucleus in OCD patients (Lucey et al., 1997). Together (Chamberlain et  al., 2008), these studies suggest abnormalities in both attentional set-​shifting and reversal learning. These studies need to be extended, perhaps using functional connectivity measures to determine possible relationships to specific fronto-​striatal pathways. The causal relationship between these measures of cognitive inflexibility and the development of OCD symptoms remains to be elucidated. Working memory describes the ability to hold information in mind over short periods of time for immediate use and is routinely assessed with n-​back tasks (see Box 22.1). Working memory has been relatively under-​investigated in OCD patients; there is evidence for an impairment in spatial working memory at high levels of task difficulty (Chamberlain et  al., 2007; Purcell, Maruff, Kyrios, 236

& Pantelis, 1998). In one fMRI study (van der Wee et al., 2003), using a spatial n-​back working memory task (Gevins & Cutillo, 1993), patients showed poor performance at the highest level of task difficulty, but brain activation in an a priori identified region of interest was comparable to that exhibited by healthy control participants, suggesting that the neural system for working memory was not compromised, despite altered performance. In contrast, elevated activity in the anterior cingulate cortex was observed at all difficulty levels, which was interpreted as mirroring the difficulty of maintaining an efficient performance strategy, or representing increased error monitoring (van der Wee et al., 2003). In another study, hyperactivity of a fronto-​parietal network subserving spatial working memory, including the DL-​PFC, pre-​SMA, and left precuneus, was found in OCD patients and their unaffected relatives (de Vries et al., 2014). The authors suggested that increased activation in patients and their siblings might represent compensatory activity for preserving performance at low task loads, which was insufficient to maintain performance at high task loads in patients. The cognitive operations related to the manipulation of information maintained in working memory may be supported by additional neuroanatomical substrates. The Tower of London (ToL) (see Box 22.1) task has been classically employed to evaluate high-​level planning (Shallice, 1982). Participants are required either to perform or, in some alternative versions of the task (Owen, Evans, & Petrides, 1996), to simply indicate the number of moves necessary to rearrange a configuration of stimuli in the bottom half of the screen to match a target or goal configuration in the top half. The more difficult trials of the task maximize the look-​ahead requirements by requiring solutions as long as five moves. Thus, in order to reach the correct solution, it is necessary to select the appropriate sequence of subgoals by anticipating the consequences of one course of action on another (“if–​ then” conditional performance). Premotor regions, DL-​ PFC (BA 9/​46), as well as the frontopolar cortex (Baker et al., 1996) and striatum (Owen, Doyon, Petrides, & Evans, 1996), are pivotal brain regions implicated in planning. In OCD, there is evidence for impaired performance in some studies (Nielen & Den Boer, 2003; Purcell et  al., 1998; Veale et al., 1996; Watkins et al., 2005), mainly in terms of lengthened response times. Inconsistent findings are likely to have arisen due to various factors, including the difficulty level of the task, as there is evidence that patients are particularly impaired on more difficult task versions (Chamberlain et al., 2007) where they achieve a significantly lower number of correct responses. When investigating the associated neural underpinnings, compared with controls, OCD patients had worse performance (i.e., increased errors), coupled O bsessive - C ompulsive D isorder

 

with reduced activation in the DL-​PFC and the striatum, including the caudate nucleus and the putamen (van den Heuvel et al., 2005). Reduced resting state functional connectivity between the right putamen and the right DL-​PFC was selectively associated with impaired performance at the most difficult levels of planning in OCD patients (Vaghi et  al., 2016). In addition, hypoactivation in the DL-​PFC and reduced functional connectivity with the putamen during planning represent a candidate endophenotype, as it was found not only in OCD patients but also in their first-​ degree unaffected relatives (Vaghi et al., 2014). It should be noted that planning can also be considered as a set of instrumental learning tasks that measure single-​contingency goal-​ directed behavior.

Since the caudate nucleus is associated with goal-​directed control over action (Tanaka, Balleine, & O’Doherty, 2008; Yin & Knowlton, 2006), these results have been interpreted as being consistent with a bias toward habit formation in OCD resulting from a deficit in the goal-​directed system. The development of ego-​dystonic thoughts and actions that patients feel driven to perform seems to be supported by deficits in the goal-​directed system, resulting in an imbalance in behavioral control toward compulsive habits. The functional connectivity of the caudate nucleus to the rest of the brain depending on the psychological context during the avoidance training was also assessed. Patients developing habitual responses exhibited reduced coupling between the caudate nucleus and the right IFG. This preliminary observation might represent an interesting starting point for addressing the relationship between impulsivity and G O A L -​D I R E C T E D B E H A V I O R compulsivity in OCD patients and identifying experimenAND HABIT LEARNING tal approaches for clarifying to what extent the incapacity Considerable evidence links PFC functions to the represen- to inhibit prepotent responses might result in compulsive tation of goals and plans for attaining those goals (Balleine behavior. & O’Doherty, 2009). In both rodents and humans, goal-​ To capture the neural imbalance between habitual and directed learning recruits medial PFC and caudate nucleus. goal-​directed systems in the context of OCD symptoms, a In some circumstances, this system competes for behavioral novel symptom provocation task was designed whereby it was control over action with a habit-​based system that includes possible to dissociate the neural correlates underlying phases of the putamen (or dorsolateral striatum, in rodents) (Tricomi, exposure and decision to perform a compulsive action (Banca Balleine, & O’Doherty, 2009; Yin, Knowlton, & Balleine, et al., 2015). Symptoms were provoked by, for example, plac2004). Some data suggest that in OCD and in other dis- ing provocative stimuli in patients’ hands or by having real-​ orders characterized by compulsive behavior, there is an time video exposure of the experimenter littering their home “imbalance” between these systems in favour of the habit while patients were in the scanner. As patients could decide system. This is consistent with the observation that patients to terminate the provocation, it was possible to analyze, on a with OCD have larger putamens (Radua et al., 2010), an trial-​by-​trial basis, the neural correlates of the symptom provoeffect related to age, which might be related to the pro- cation, the urge to avoid, the rejection and, finally, the relief. longed performance of compulsions (de Wit et al., 2014). In this study, hypoactivation of the neural structures associRecent evidence collected by means of new behavioral ated with the goal-​directed system, namely the VM-​PFC and tasks and fMRI lends neurobiological support to this so-​ the caudate, was followed by compulsive avoidance behavior, called habit hypothesis of OCD (see also ­chapter  16) with associated hyperactivity of the putamen bilaterally (Banca (Gillan & Robbins, 2014). A  shock avoidance paradigm et al., 2015). There is an apparent discrepancy between caudate (Gillan et al., 2015) was used in combination with fMRI hyperactivity in patients showing premature development of and an outcome devaluation procedure to assess habit for- habits (Balleine & O’Doherty, 2009) and the caudate hypomation in healthy volunteers and OCD participants (see activity observed during symptom provocation (Banca et al., Box 22.1). A  significantly higher proportion of OCD 2015); this may be due to differences in experimental context. patients was biased toward the development of habits Alternatively, it might be that the two studies tapped into dif(defined as actions persisting despite changes in the value of ferent anatomical subdivision of the caudate (i.e., peak coordithe associated outcome (Adams & Dickinson, 1981)), rep- nates were found in the caudate head and in the caudate body licating previous results obtained in an independent sample for hyperactivity coupled with habits and hypoactivity durof patients (Gillan et al., 2014). Those patients (about 50%) ing symptom provocation, respectively), for which different showing clear evidence of habitual responses were char- behavioral and functional connectivity specificities have been acterized by hyperactivation of the right caudate nucleus demonstrated (Robinson et al., 2012). (Gillan et al., 2015). Moreover, hyperactivation of the right Other results support the view that obsessions and comcaudate correlated with the self-​reported “urge” to respond. pulsions are related to impairments in goal-​directed behavior. T ask - B ased F unctional N euroimaging studies   I N   O C D

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OCD patients were found to have blunted activation of the ventral striatum/​nucleus accumbens (NAc) during a reward anticipation task that requires goal-​directed behavior (Figee et al., 2011). In addition, it has been demonstrated that deep brain stimulation (see ­chapter 46) restored NAc activity and normalized excessive cortico-​(BA 45; BA 32/​10)-​striatal connectivity, with greater changes in connectivity between the left NAc and the lateral PFC (BA 45)  being correlated with greater symptom reduction (Figee et  al., 2013). Similarly, in a task in which participants were required to navigate a maze and find rewards, mesolimbic and ventral striatal regions showed increased activation in healthy controls and decreased activation in OCD patients when receiving unexpected rewards, further suggesting abnormal functioning of the reward system (Marsh et al., 2015). Specifically, it would appear that patients with OCD have impaired prediction errors during learning. A parallel may exist with drug addiction, in which the drug “hijacks” the reward system, making it unresponsive to conventional rewards (Volkow, Fowler, Wang, & Goldstein, 2002); the same might happen in the case of OCD, with respect to obsessions and compulsions. At a neurobiological level this might be mirrored by a shift of control from the ventral striatum to the dorsal striatum (Everitt & Robbins, 2005; Volkow et al., 2006), possibly sustained by ascending spiralling connections between corticostriatal loops (Haber, Fudge, & McFarland, 2000). This model, in which impaired goal-​directed control leads to overreliance on habits and hence to compulsions, implies that obsessions may be developed secondarily, as post-​hoc rationalization for these behaviors. This idea departs from the traditional account, in which compulsions are performed in response to intrusive thoughts and worries; rather, it is suggested that obsessions might arise from compulsive behaviors because of a need to reduce cognitive dissonance (Gillan & Robbins, 2014; Gillan & Sahakian, 2015). Validation of this model would require longitudinal studies to track the first manifestations of OCD during development, in order to evaluate whether compulsions or obsessions, and their associated neural correlates, occur first. Ritualistic behaviors are common in children (Evans et al., 1997) and may represent an initial manifestation of compulsions, which might be elaborated into disease in some individuals, due to genetic factors and environmental events. OCD A ND OFC:  N O T A SI MPLE R EL ATIONS HI P It is increasingly clear that the OFC, which has been repeatedly implicated in OCD (see c­ hapter 21), is functionally and anatomically heterogeneous (Zald & Rauch, 238

2006)  (­chapters  20, 31). Evidence from the analysis of resting-​ state functional connectivity (Kahnt, Chang, Park, Heinzle, & Haynes, 2012), task-​based functional connectivity (Zald et al., 2014), and gray matter covariance patterns (Liu, Qin, Qi, Jiang, & Yu, 2015) supports a functional dichotomy between the lateral (BA 47/​ 12) and medial (BA 13, 14, 11) portions of the human OFC. This may mirror the orbital and medial networks identified in monkey’s OFC (Carmichael & Price, 1996; Öngür & Price, 2000). As revealed by resting state and task-​based functional connectivity, the lateral and medial OFC apparently work in parallel with the head of the caudate and the ventromedial striatum, respectively (Kahnt et  al., 2012; Martino et  al., 2008; Zald et  al., 2014). Thus, rather than considering the OFC as unitary brain region, we will analyze results implicating the OFC in the pathogenesis of OCD in light of this dichotomy, which may help to clarify the literature. LATERAL OFC AND REVERSAL LEARNING

As described, reversal learning is a type of cognitive flexibility entailing the ability to reverse stimulus-​ reward associations after negative feedback. The integrity of the OFC is required to achieve successful reversal learning, as shown in monkeys (Butter, 1969; Dias et  al., 1996; Iversen & Mishkin, 1970)  (though recent evidence has challenged this view [Rudebeck, Saunders, Prescott, Chau, & Murray, 2013]). Evidence in humans further supports the hypothesis that the lateral OFC in particular is required for reversal learning (Hampshire, Chaudhry, Owen, & Roberts, 2012; Hampshire & Owen, 2006). Converging evidence in the monkey (Clarke, Robbins, & Roberts, 2008; Divac, Rosvold, & Szwarcbart, 1967) and rat (Dunnett & Iversen, 1980) implicates the ventrolateral sector of the caudate nucleus, as well. Cognitive inflexibility and the inability to make appropriate shifts of behavioral set is one of the prominent symptoms of OCD and it is thought to contribute specifically to compulsivity (Chamberlain, Blackwell, Fineberg, Robbins, & Sahakian, 2005; Chamberlain, Fineberg, Blackwell, Robbins, & Sahakian, 2006). Functional imaging of reversal learning in OCD patients reveals hypoactivation of the lateral sectors of the OFC (Remijnse, Nielen, van Balkom, & et al, 2006), a neurobiological pattern distinct from that seen in major depressive disorder (Remijnse et al., 2009). Dampened activation of the lateral OFC, lateral PFC, and parietal areas was found not only in OCD patients but also in their first-​ degree relatives, thus teasing apart the possible confounding effects of depression and medication (Chamberlain et  al., O bsessive - C ompulsive D isorder

 

2008). This evidence suggests that abnormalities in the lateral OFC, its projections to the caudate nucleus, and possibly the anterior cingulate cortex may result in impaired cognitive flexibility and, thereby, to OCD symptomatology (Chamberlain, Blackwell, Fineberg, Robbins, & Sahakian, 2005). The possible contribution of the anterior cingulate to altered cognitive flexibility in OCD patients is highlighted by a metaanalysis, which identified focal abnormalities in the anterior cingulate cortex of OCD patients (Menzies et al., 2008). Selective serotonin reuptake inhibitors (SSRIs) are the first-​line pharmacological treatment for OCD (see ­chapter 40). This therapeutic efficacy resonates with studies in marmoset monkeys: prefrontal serotonin depletion induced by the neurotoxin 5,7-​ dihydroxytryptamine causes perseverative responding on a reversal learning task (Clarke, Dalley, Crofts, Robbins, & Roberts, 2004). This effect is specific to reversal learning, and not attentional set-​shifting (Clarke et al., 2005). In rats, a 5-​HT-​2A receptor antagonist has also been shown to impair spatial reversal learning (Boulougouris, Glennon, & Robbins, 2008). Reversal learning deficits in rats are linked to OFC 5-​HT depletion and can be reversed by treatment with the SSRI citalopram (Barlow et al., 2015; Lapiz-​Bluhm, Soto-​Piña, Hensler, & Morilak, 2009). These results across species suggest that PFC serotonin is of crucial importance for behavioral flexibility in the context of changing stimulus-​reward contingencies, which is likely to be highly relevant to OCD. In humans, an in vivo PET study in drug-​naïve OCD patients directly investigated the serotoninergic system by showing significant reduction of 5-​HT-​2A receptor availability in several frontal regions (dorsolateral frontal cortex, the superior frontal gyrus, the medial frontal cortex including anterior and middle cingulate cortex), the parietal cortex, and the associative structures in the temporal gyrus (Perani et al., 2008). Moreover, in the same study, a significant inverse correlation between 5-​HT-​2A binding potential in fronto-​parietal areas (including the OFC) and symptom severity was found in OCD patients. However, caution is warranted, as an independent study with a larger sample size failed to replicate the results. No differences were found in 5-​HT-​2A availability between OCD patients and controls; nor was there a significant correlation between 5-​HT-​2A availability and clinical scores in the patient population (Simpson et al., 2011). Interestingly, despite the absence of group differences, early onset OCD patients showed higher 5-​HT-​2A availability compared to later-​onset OCD, suggesting a role of 5-​HT-​2A receptor in the pathogenesis of the disorder. T ask - B ased F unctional N euroimaging studies   I N   O C D

M E D I A L O F C / V​ E N T R O M E D I A L P R E F R O N T A L CORTEX AND FEAR EXTINCTION

Multiple tiers of evidence—​neuroanatomical, neuropsychological, and neuroimaging—​encourage the view that the medial orbital cortex (BA 11, 13, 14), the vm-​PFC (BA 24, 25, 32), and the frontal pole (BA 10)  represent an anatomical complex with fundamentally different functions from other portions of the frontal lobe, including the lateral OFC (BA 12/​47) and DL-​PFC (BA 9,46). Neuroimaging studies have linked activation of the VM-​ PFC to seemingly disparate functions across social, cognitive and affective domains (see review [Roy, Shohamy, & Wager,  2012]). Of particular relevance here, the VM-​ PFC, in concert with the amygdala and the dorsal anterior cingulate cortex, makes specific contributions to Pavlovian fear conditioning (Fullana et al., 2016; Schiller & Delgado, 2010). As overgeneralization of fear is characteristic of posttraumatic stress disorder (PTSD) and other anxiety conditions (Lissek, 2012; Pitman et al., 2012), fear conditioning has been extensively considered as a model for anxiety disorders in which conditioned fear acts as a drive that motivates and reinforces avoidance (Eysenck, 1976). The neural mechanisms underlying the ability to flexibly respond in the context of learned fear may be relevant to understanding the symptoms of OCD (Milad & Rauch, 2012). In one recent study, OCD patients were tested using a protocol entailing fear conditioning (see Box 22.1), extinction, and recall of the “safety memory” formed during extinction training (Milad et al., 2013). Analysis of the skin conductance response (SCR) revealed normal acquisition of the conditioned fear and its associated extinction in OCD patients. However, patients did not activate the VM-​PFC in response to the extinguished fear during the recall test. This was interpreted as reflecting an incapacity to appropriately react when faced with stimuli that trigger fears (Milad & Rauch, 2012). However, interpretation of these findings is not entirely straightforward. There were also paradoxical correlations whereby higher symptom severity was associated with higher extinction retention, as measured by SCR (i.e., as symptoms worsened, extinction memory improved). The finding of impaired extinction recall in OCD patients relative to controls has been replicated (McLaughlin et al., 2015), but the correlation of OCD symptom severity with the magnitude of extinction recall has not. Importantly, the same paradigm was also used in patients suffering from PTSD, who also showed lesser activation in the VM-​PFC during extinction recall (Milad et al., 2009). Crucially, patients with PTSD showed greater amygdala activation during extinction learning; patients 239

 

with OCD did not. Extinction is one of the therapeutic strategies that can be employed to modify conditioned fear and is central to the cognitive behavioral therapy of OCD (see ­chapter 37); it taps into the ability to flexibly and rapidly update changing contingencies in the environment (Schiller & Delgado, 2010). Abnormal neural activity during extinction recall may reflect more general deficits in updating the values of outcomes in OCD. THE ROL E O F EX PERI MEN TAL CO N TEX T As outlined by Milad and Rauch (2012), hypoactivation of the lateral OFC in OCD does not generalize across all imaging contexts. In fact, early imaging studies using symptom provocation paradigm consistently revealed hyperactivation in the OFC (Saxena & Rauch, 2000) (see c­ hapter 21). Early studies did not explicitly address the distinction between medial and lateral OFC; but a more recent quantitative metaanalysis localized hyperactivity during symptom provocation to the pars triangularis and pars opercularis of the PFC (i.e., IFG) and lateral OFC (Rotge et al., 2008), precisely where activation is blunted in OCD during reversal learning (Chamberlain et al., 2008). These apparently contradictory patterns of activation are difficult to reconcile. Methodological differences, (i.e., PET measuring glucose metabolism for most of the symptom provocation studies vs. fMRI measuring the BOLD signal in the cognitive studies) may contribute; but a recent fMRI study using symptom provocation clearly localized a pattern of hyperactivation in OCD patients in the lateral OFC (Morgiève et al., 2014), so this is not a sufficient explanation for the discrepancy. Future studies should directly interrogate if and how different experimental contexts interact with abnormalities in the fronto-​striatal system in OCD. One obvious distinction is between affectively arousing paradigms such as symptom provocation (“hot” or emotionally-​ laden situations) and most executive function tasks, which are affectively neutral (“cold” situations). Most studies in OCD have examined single tasks; comparisons between tasks are therefore also comparisons between different cohorts of patients, tested at different times and in different contexts. Even within the spectrum of “cold” executive function tests, there are clear advantages to simultaneously testing contrasting tasks that rely on partly overlapping fronto-​striatal circuitry in the same group of patients. First, they will allow us to rule out potential confounding effects of demographic and diagnostic differences, which might confound comparisons of separate

240

studies examining different samples. Second, and more theoretically relevant, comparison of different tasks in the same subjects may shed new light on the mechanisms underlying the implementation of complex behavioral computations within fronto-​striatal brain networks. This experimental approach has already provided direct empirical support for the hypothesis that the specific experimental context might differentially affect fronto-​striatal system in OCD. More specifically, Morein-​Zamir and colleagues (Morein-​Zamir et al., 2016) used a combined attentional shifting and Go/​ No-​Go (response inhibition) task to demonstrate divergent patterns of activation in fronto-​parietal and associated subcortical regions in the caudate and thalamus, with underactivation during shifting and overactivation during stopping in OCD patients, as compared with control participants. DR AW ING T H E   B OU NDAR IE S B E T W E E N OC D AND ANX IE T Y DIS OR DE R S The new Diagnostic and Statistical Manual of Mental Disorders, 5th Ed. has shifted OCD out of the category of anxiety disorders into the new category of “Obsessive-​Compulsive and Related Disorders” (see ­chapter 49), emphasizing ways in which it is clinically distinct. The relationship of OCD and anxiety disorders has been a topic of considerable debate (Mataix-​ Cols, Pertusa, & Leckman, 2007; Stein et al., 2010). Studies of Pavlovian fear conditioning in nonhumans have identified the amygdala as the central hub of a neural system underlying fear responses by detecting and coordinating responses to natural dangers (LeDoux, 2000). This has led to the natural prediction that amygdala hyperactivity may underlie anxiety states. However, although some neuroimaging studies observed elevated amygdala activation in OCD (Breiter et al., 1996; van den Heuvel et al., 2004; Van Laere et al., 2006) during symptom provocation, the majority have not (see ­chapter 21). In sharp contrast, quantitative metaanalysis providing a comparison of neural reactivity to emotional stimulation across patients suffering from PTSD, social anxiety, or a specific phobia revealed consistent hyperactivity of the amygdala in all three disorders (Etkin & Wager, 2007; Shin & Liberzon, 2009), suggesting that abnormally elevated fear responses may represent a commonality across them. Direct comparisons between OCD and other anxiety disorders of brain activity during cognitive tasks have been scarce. One of the few direct comparisons to be described adopted the standardized ToL task, and showed that failure of recruitment of the caudate was especially pronounced in OCD patients when compared with controls.

O bsessive - C ompulsive D isorder

 

However, there were no differences across patients suffering from OCD, panic disorder, and hypochondriasis; all groups exhibited decreased recruitment of the precuneus, caudate nucleus, globus pallidus and thalamus (O. A. van den Heuvel et al., 2011). A clearer dissociation emerged in a study of an emotional Stroop task traditionally used in affective syndromes to investigate attentional bias to words with positive or negative connotations. Relative to individuals with panic disorder or hypochondriasis, OCD patients showed impaired performance during incongruent vs. congruent nonvalenced words, possibly due to OCD-​specific difficulties in executive function. Increased recruitment of the anterior cingulate cortex and other limbic regions (including the amygdala) was seen in OCD patients, selectively in response to OCD-​related words. Patients with panic disorder and hypochondriasis showed a more generalized bias toward threat-​related cues and increased cognitive elaboration, with widespread activity in prefrontal, striatal, and temporal regions in response to both OCD-​ related words and panic-​related words. Most patients with OCD experience high anxiety states, especially linked to specific worries and compulsions. However, details of the underlying mechanisms remain to be elucidated—​in particular, why the neural structures typically implicated to other anxiety disorders do not seem to contribute similarly to OCD. It remains to be clarified whether anxiety represents in part an epiphenomenon of the disorder or if it is rather fundamental to it. Stress and anxiety contribute to habit formation (Schwabe & Wolf, 2010); executive functions such as working memory have a protective role against the deleterious effects of acute stress (Otto, Raio, Chiang, Phelps, & Daw, 2013). The effects of anxiety on executive functions and habit formation in OCD are not well characterized and may represent a useful focus for further functional neuroimaging investigations. C ONCL US IO N S AN D FUTURE PRO SPE C T S The data summarized lead to a conceptualization of OCD as characterized by a lack of sufficient top-​down control epitomized by weak response inhibition, reduced cognitive flexibility and impaired goal-​directed control over abnormally functioning striatal circuitry (see Figure 22.1 and Table 22.1). The importance of functional integration across the cortico-​striatal loops is now recognized (Haber, 2003). It remains to be elucidated to what extent abnormalities along the topographically organized projections from the PFC to the striatum contribute to the cognitive

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deficits and symptomatology seen in OCD. There are many paradoxes still to resolve with respect to patterns of hyperactivity and hypoactivity in these circuits, and the precise role of anxiety in modulating the functioning of fronto-​ striatal systems. Although different symptom dimensions (e.g., washing, checking) have specific neurobiological features during symptom provocation (Mataix-​Cols et al., 2004)  and at rest (Harrison et  al., 2013)  (see c­ hapter  8), there are no functional data addressing possible differences in cognitive functions across these symptom domains. We suggest that refinement and testing of proposed neuroanatomical models for OCD will depend on a more detailed characterization of frontal-​ subcortical interactions by means of tailored functional connectivity analyzes. Such models may provide new insight into pathophysiology and may be important for refining diagnostics schemes, such as that provided by the National Institute of Mental Health’s initiative on Research Domain Criteria (see c­hapter  62) (Insel et al., 2010).

AC K NOW LE DGE ME NT S Our research is supported by a grant from the Wellcome Trust (104631/​ Z/​ 14/​ Z). We would like to thank Annemieke Apergis-​ Schoute, Annette B.  Brühl, Claire M.  Gillan, Sharon Morein-​Zamir, and Professor Barbara J. Sahakian for their contributions to this work.

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23. THE STRUCTURE OF THE OCD BRAIN Premika S. W. Boedhoe, MSc and Odile A. van den Heuvel, MD, PhD

A

convergence of animal studies and human neuroimaging research points to the involvement of parallel, partly segregated, cortico-​striato-​thalamo-​cortical (CSTC) circuits in behavioral control functions involving motor, cognitive, affective and motivational processes (Alexander, 1986; Cummings, 1993; Groenewegen & Uylings, 2000). These CSTC circuits involve direct and indirect pathways projecting from the specific cortical areas to the specific subregions of the striatum and thalamus with recurrent projections to the cortex (see ­chapters  20, 31). Disease models of obsessive-​compulsive disorder (OCD) propose that abnormalities in these regions and their connections play an important role in its pathophysiology, and specific CSTC circuits are hypothesised to mediate the specific symptoms of OCD, related to the various functional domains (Mataix-​Cols & van den Heuvel, 2006; Milad & Rauch, 2012; van den Heuvel et  al., 2015)  (see ­chapters 8, 21). Milad and Rauch (2012) proposed three important CSTC circuits for OCD: the “affective circuit,” the “dorsal cognitive circuit,” and the “ventral cognitive circuit” (see ­chapter 21, Figure 21.3). The affective circuit connects the ventromedial prefrontal cortex and the anterior cingulate cortex with the nucleus accumbens and the thalamus and is relevant for affective and reward processing. The dorsal cognitive circuit connects the dorsolateral prefrontal cortex, the caudate nucleus, and the thalamus and is crucial for executive functions such as working memory and planning. The ventral cognitive circuit connects the anterolateral orbitofrontal cortex, anterior part of the putamen, and the thalamus and is involved in motor preparation and response inhibition (Milad & Rauch, 2012). In a recent review of the brain circuits implicated in compulsivity, van den Heuvel et al. (2015) extended the model by including the sensori-​motor CSTC related to habitual

behavior (van den Heuvel et al., 2015). Based on three decades of brain imaging research in OCD, it is evident that the pathophysiology cannot be explained by alterations in function and structure of the classical CSTC areas exclusively, but that fronto-​limbic and fronto-​parietal connections are important as well, and that the role of the cerebellum needs more attention in future research (van den Heuvel et al., 2015). Findings from functional neuroimaging studies of OCD have validated the involvement of the fronto-​striatal, the fronto-​limbic, fronto-​parietal, and cerebellar regions in the pathophysiology. Data on structural abnormalities are less conclusive but seem to underlie, at least partially, these functional abnormalities. This chapter focuses on the most consistent findings for specific anatomical regions of interest, and discusses their relationship within the implicated networks. It ends with a discussion regarding future directions in OCD research. H IS T OR IC AL V IE W ON  ADVANC E S IN  B R AIN IMAGING T E C H NIQU E S Since the late 1980s, rapid growth in the number of imaging studies in OCD and improvements in imaging technology and analysis methods have led to considerable advances in our understanding of the neural substrates of OCD pathophysiology. The first studies suggesting brain abnormalities were based on qualitative evaluation, whole brain measurements, and ventricle-​to-​brain ratios of computed tomography scans (Behar et al., 1984; Insel et al., 1983). Subsequent volumetric studies in OCD were mainly based on magnetic resonance (MRI) data, using manual tracing techniques. Given the major emphasis on the orbitofrontal cortex (OFC), striatum, and thalamus in the pathophysiology of OCD, several studies have primarily focused on anatomical

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differences in these brain regions. Further work, using both positron emission tomography and functional MRI (fMRI), investigated dysfunction in the orbitofronto-​ striatal circuit and connected limbic structures, such as the anterior cingulate cortex (ACC) and temporolimbic areas, during symptom provocation studies (see c­hapter  21). More recent studies, mostly using fMRI, suggested that the cognitive deficits in patients might not be underpinned exclusively by OFC pathology, and broadened the focus to other frontal areas such as dorsolateral and ventrolateral prefrontal cortices, and the fronto-​parietal connections, using a variety of cognitive paradigms (see ­chapters 21, 22). The techniques used in structural imaging studies of OCD are diverse, and include manual tracing of specific regions of interest (ROIs) and whole-​brain voxel-​based morphometry (VBM) for both gray matter (GM) and white matter (WM) volume comparisons. The ROI-​based approach requires manual delineation of cerebral regions in sequential MRI slices; the areas obtained in each slice are summed up to provide a measure of the volume of the brain structure of interest. In order to minimize observer bias, landmarks and rules for manual tracing must be clearly defined a priori. The ROI procedure is laborious, limiting the number of brain regions analyzed and the sample size. In addition, ROI-​based studies are limited in the investigation of neocortical morphology, because of the inherent difficulties in defining structurally complex and variable regions of the human cortex. The development of automated techniques in the last decade, such as VBM, has facilitated systematic morphometric evaluation of the brain as a whole and increased reliability. VBM is an operator-​independent, whole-​brain voxel-​based technique to analyze structural

MRI data, which enables the detection of regional structural differences (Ashburner & Friston, 2000). A key feature of this automated method of analysis is that it examines differences in GM and WM throughout the brain, without the need to prespecify ROIs for investigation. More recent studies have used newer approaches, investigating fractional anisotropy with tract-​based spatial statistics (TBSS) and in diffusion tensor imaging (DTI), cortical thickness and subcortical volumes demarcated using FreeSurfer, and structural covariance. GR AY  MAT T E R BASAL GANGLIA AND THALAMUS

The basal ganglia (BG) are central to the CSTC circuits (see ­chapters 20, 31). The main input nucleus of the BG is the striatum, which consists (in primates) of the caudate nucleus and putamen. The main output nuclei of the BG are the internal part of the globus pallidus and the substantia nigra pars reticulata (Hoover & Strick, 1993; Tepper et al., 2007). Several studies have shown increased volume in different components of these deep GM structures in OCD patients compared with healthy controls (Pujol et al., 2004; Gilbert et al., 2008; Szeszko et al., 2008; Yoo et al., 2008; Zarei et al., 2011). VBM studies, including VBM metaanalyses, have repeatedly, although not completely consistently, reported increased bilateral regional GM volumes in the lenticular nucleus (putamen and globus pallidus), extending to the caudate nucleus (Peng et  al., 2012; Radua & Mataix-​Cols, 2009; Radua et al., 2010; Rotge et al. 2010) (Figure 23.1.).

inhibition dorsal system

lack of control decreased emotion regulation decreased executive functioning

compulsivity

Increased volume in the ventral circuit ‘emotion’/’motivation’

Decreased volume in the dorsal circuit ‘cognition’

decreased ‘top-down control’ Figure 23.1  A Schematic representation of interacting circuits in the pathophysiology of OCD. (see color plate)

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The largest study to date on subcortical brain volumes, by the Enhancing NeuroImaging through Genetics (ENIGMA) OCD consortium, including 622 pediatric subjects and 2,967 adult subjects, reported increased pallidum volume in adult OCD patients (Boedhoe et al., 2016), supporting these earlier results. A cross-​disorder metaanalysis by Radua et  al. (2010) suggested common as well as distinct neural substrates in OCD, compared with other anxiety disorders. The BG are implicated in both OCD and other anxiety disorders. The direction of the findings, however, is diametrically opposite, with OCD showing increased BG volume, whereas other anxiety disorders are characterized by decreased BG volume (Radua et  al., 2010). Because the volume of the BG correlates with the severity of OCD (Radua & Mataix-​ Cols, 2009)  and habitual behavior differentiates OCD from other anxiety disorders (see ­chapter 16, 22, 31), the increased BG volume in OCD may reflect the unique repetitive phenomenology (Radua et al., 2010). OCD is not a unitary disorder; it consists of multiple, potentially overlapping symptom dimensions (Leckman et al., 2007; Mataix-​Cols et al., 2005; see ­chapter 8), which are temporally (Mataix-​Cols et al., 2002; Rufer et al., 2005) and transculturally (Matsunaga et al., 2008) stable. Several functional imaging studies have suggested that these symptom dimensions may be mediated by partially distinct neural systems (An et al., 2009; Lawrence et al., 2007; Mataix-​Cols et al., 2004; Saxena et al., 2004). In support of this idea, Pujol and colleagues (2004) found that high scores on the “contamination/​washing” dimension correlated negatively with the volume of the dorsal parts of the bilateral dorsal caudate nucleus; this was replicated by van den Heuvel et al. (2009). Pujol et  al. (2004) showed that the relative enlargement of striatal areas in OCD patients was driven by age and disease duration, whereas the volumes of cortical areas were independent of these clinical characteristics. These findings suggest that BG alterations progress over the course of illness. Additional support for this idea came from a recent megaanalysis by the OCD Brain Imaging Consortium (OBIC) using VBM (de Wit et  al., 2014). Whereas a metaanalysis combines the results of independent studies, a megaanalysis refers to summarizing the results of independent studies using data from individual subjects. The latter approach provides greater power to study subtle alterations in regional GM and WM volume and to examine the effects of demographic and clinical factors. Results from the VBM OBIC megaanalysis showed a group-​by-​age interaction effect in the putamen, suggesting a relative preservation of putamen volume in patients, compared with the T he S tructure of the O C D   B rain

reduced volume that naturally occurs in healthy subjects with increasing age. These findings were based on cross-​ sectional data; long-​term longitudinal studies are needed to make definite conclusions about neuroplastic changes over the lifespan, under influence of both chronic symptomatology and treatment interventions. Because such changes accrue over the course of illness, investigation of OCD pathophysiology may benefit from studying the illness in childhood, just after onset of the disorder. By minimizing the potentially confounding effects of plastic changes as a result of chronic symptomatology and long-​term treatment, this approach enables disentangling the neural correlates of vulnerability, chronicity, and treatment effects. However, pediatric studies are scarce and small, and therefore the results are not yet conclusive. Using VBM, Gilbert et  al. (2008) compared pediatric OCD patients with a high-​risk group of unaffected siblings. The OCD patients compared with their unaffected sibling, but not compared with controls, showed greater volume in the right putamen. Szeszko et al. (2008) found increased putamen volumes, bilaterally, in pediatric OCD patients compared with healthy controls. Symptom severity significantly correlated with putamen volume in pediatric medication-​ naïve OCD children (Szeszko et al., 2008) as well as adolescents (Zarei et  al., 2011), suggesting that alterations in this region relate to the clinical expression of OCD. In contrast, other pediatric studies reported decreased volumes in the putamen (Rosenberg et al., 1997) and globus pallidus (Szeszko et al., 2004), and some studies reported no striatal volume alterations in pediatric OCD (Carmona et al., 2007). The volume of the thalamus, a key relay station in the CSTC circuits, is increased in both adult (Atmaca et  al., 2006, 2007)  and pediatric OCD patients (Gilbert et  al., 2000). Additional support for this finding came from two metaanalyses by Rotge et al., (2009, 2010) showing thalamus enlargement in OCD patients while combining pediatric and adult data. Notably, Gilbert et al. (2000) found a reduction of thalamic volume in pediatric OCD patients after 12-​week treatment with the SSRI paroxetine (Gilbert et al., 2000), but not following cognitive behavioral therapy (CBT) (Rosenberg et  al., 2000). These findings suggest a differential effect of cognitive behavioral and pharmacological treatments on brain structure. In contrast to the studies mentioned, other recent metaanalyses show no differences of thalamus volume in adult OCD patients and controls (Peng et al. 2012; Radua & Mataix-​Cols, 2009; Radua ,et al. 2010), and the recent OBIC megaanalysis (de Wit et  al., 2014)  even showed decreased thalamic volume in adult OCD. Notably, the ENIGMA-​OCD consortium reported 249

 

an enlarged thalamus only in pediatric, not in adult, OCD patients (Boedhoe et al., 2016). These contradictions suggest an interaction of thalamic volume effects with other clinical variables. In conclusion, these results indicate that an increased caudate/​putamen volume seems to be present in adult OCD (probably related to disease severity, disease chronicity and/​or treatment), whereas increased thalamus volume seems more likely to be found in children (probably related to altered neurodevelopment; Boedhoe et al., 2016).

study populations. The observed increased regional GM volume of the OFC was more pronounced in patient populations without comorbid depression (Christian et  al., 2008; Kim, 2001; Valente et al., 2005). Rotge et al. (2009) argued that disease duration, more specifically the duration of untreated symptoms, and medication may influence OFC volume in OCD. Although the recent megaanalysis by De Wit et al. (2014) did not report significant group differences in the OFC, group-​by-​age interaction analyses showed age-​ related preservation of orbitofrontal WM volumes in OCD samples compared with controls. Huyser et al. (2013), ORBITOFRONTAL CORTEX studying pediatric OCD, reported increased orbitofrontal The OFC has been consistently implicated in functional volume after 6 months of CBT. After a 2-​year follow-​up neuroimaging studies of OCD and constitutes the basis in these patients, a group-​by-​time effect for OFC volume of a widely accepted neurobiological model of OCD (see was observed (Huyser et al., 2014). The effect was driven ­chapter 21, 31). However, structural neuroimaging of the not only by patients, who showed an increase of OFC OFC in both adult and pediatric samples has been inconsis- volume over time, but also by the pair-​wise age-​matched tent. Metaanalyses have reported normal (Radua & Mataix-​ healthy controls, who showed a decrease of volume over Cols, 2009; Radua et al., 2010), bigger (Rotge et al., 2010), time. The sustained OFC volume increase during follow-​ or smaller (Peng et al., 2012; Rotge et al., 2009) OFC vol- up in patients suggests a differential maturation of OFC umes in OCD patients. in pediatric OCD compared with controls. Findings were These metaanalyses have used different methods to most pronounced at younger age, indicating aberrant brain aggregate data across studies, which may partially explain development in pediatric OCD patients in early life. the discrepant results. These include traditional ROI-​based These results, both in adults and in children, highlight metaanalysis (Rotge et al., 2009) and voxel-​based metaana- the importance of age as a factor in understanding the varilytic approaches such as anatomical likelihood estimation ability of brain structure alterations in OCD. These age-​ (ALE; Rotge et al., 2010) and effect size-​signed differential related neural differences in orbitofrontal volume in OCD mapping (ES-​SDM; Peng et  al., 2012; Radua & Mataix-​ seem to be related to altered neurodevelopment (most Cols, 2009; Radua et  al., 2010). The ALE algorithm has relevant for child-​onset OCD) and/​or secondary to neubeen particularly widely used in coordinate-​based meta- roplastic changes during disease course due to symptom analyses of neuroimaging data. An advantage of the ALE persistence or compensatory processes related to cognitive algorithm is the option to apply cluster-​inference correc- dysfunction (most pronounced in adult OCD). tions based on the regions of volumetric differences. One of the drawbacks, however, is that analyses are not weighted DORSAL PREFRONTAL REGIONS AND by sample size. The ES-​SDM method adopted the positive ANTERIOR CINGULATE CORTEX features of ALE and introduced a series of improvement and novel features. The ES-​SDM method, thus, optimizes Findings of structural abnormalities in the more dorsal the sensitivity of existing peak-​probability methods while parts of the prefrontal cortex (PFC), mainly the ACC but protecting against the false positives. extending into the dorsomedial PFC (dmPFC), appear to A second possible explanation for the inconsistency in be more consistent, irrespective of the methods utilized. OFC findings is that the precise location of abnormalities Several metaanalyses, including both pediatric and adult in this region varies across studies. Studies have reported data, have reported decreased bilateral regional volume different directions of change in different subcomponents in ACC and dmPFC in OCD patients, compared with (e.g., lateral/​medial) of the OFC. The OFC is heteroge- healthy controls (Peng et al. ,2012; Radua & Mataix-​Cols, neous both in structure and function, and the precise role 2009; Radua et al., 2010) (see Figure 23.1.). Only one metaof its subterritories in OCD phenomenology is still left to analysis did not report this finding (Rotge et al., 2010). be unravelled (see ­chapters 20, 31). The smaller ACC/​dmPFC volume could be a critiThird, the heterogeneity between studies may be cal factor in the pathophysiology of OCD. The ACC can explained, at least in part, by the clinical features of the be subdivided into a ventral “affective” part and a dorsal 250

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“cognitive” part (Bush et  al., 2000). The affective part of the ACC, through its strong connections with the limbic system, is involved in the assessment of emotionally relevant information and the initiation of emotional responses, implicated in the expression of anxiety and distress observed in OCD (Aouizerate et al., 2004). The cognitive part, which has strong connections to the dorsolateral prefrontal cortex (dlPFC), the ventrolateral PFC, and the inferior frontal gyrus (IFG), is implicated in error detection and conflict monitoring (Bush et al., 2000), and in emotion regulation by cognitive reappraisal (Ochsner & Gross, 2005). In agreement, the megaanalyses by OBIC, using both VBM (de Wit et al., 2014) and cortical thickness (Fouche et  al., 2017), also showed smaller volumes of dmPFC (including the ACC) in OCD patients compared with healthy subjects. The VBM OBIC megaanalysis showed that the smaller volume of the dmPFC was most pronounced in patients with additional comorbid anxiety and/​ or depression (de Wit et al., 2014); this suggests a common pathophysiological mechanism across disorders related to a shared deficit in emotion regulation (van Tol et al., 2010). Indeed, Radua et al. (2010) showed that OCD and other anxiety disorders are characterized by overlapping decreased dmPFC/​ ACC volume. Goodkind et  al. (2015) even showed that patients across six diagnostic groups (including schizophrenia, bipolar disorder, depression, addiction, OCD, and anxiety disorders) all show, in comparison with controls, decreased volume of the dmPFC. This suggests that smaller volume of the dmPFC is a more general characteristic of mental disorders, probably related to impaired emotion regulation and other aspects of cognitive control. The metaanalyses by Peng et al. (2012) and Rotge et al. (2009) also reported smaller dlPFC volume. This converges with functional imaging results showing altered activation patterns (both a failure of task-​related recruitment as well as compensatory task-​related hyperactivation) during both symptom provocation paradigms (e.g., Adler et  al., 2000; van den Heuvel et  al., 2004)  and cognitive control paradigms (e.g., van den Heuvel et al., 2005, 2011; de Vries et al., 2013). INFERIOR FRONTAL GYRUS AND ANTERIOR INSULA

Other frontal regions, such as the IFG and the anterior insula—​a combined area often called operculum—​seem to be affected as well in OCD. The IFG is known to be critical in both response inhibition (Aron et al., 2003) and attentional set-​shifting (Hampshire & Owen, 2006) (see c­ hapter 22). Pujol et al. (2004), Yoo et al. (2008), and van den T he S tructure of the O C D   B rain

Heuvel et al. (2009) reported decreased GM volume in this region in adult OCD; this has been replicated in a pediatric sample by Carmona et al. (2007). The OCD Brain Imaging Consortium megaanalyses also reported smaller regional GM volume in the IFG extending to the anterior insula in OCD patients compared with healthy subjects, both using VBM (de Wit et al., 2014) and cortical thickness analyses in FreeSurfer (Fouche et al., 2017). Although the IFG/​insula findings were very robust in these megaanalyses, metaanalyses have not found a difference between patients and controls (Peng et al., 2012; Radua & Mataix-​Cols, 2009), or even increased volume in patients compared with controls (Rotge et al., 2010). The OCD Brain Imaging Consortium showed a group-​ by-​age effect for insular volume, suggesting a relative preservation of insular volume during aging in patients compared with controls (de Wit et al., 2014), who normally show a volume decrease with healthy aging (Ziegler et al., 2012). Besides having a role in cognitive control (Tops & Boksem, 2011)  and attention (Corbetta & Shulman, 2002), the inferior frontal cortex/​ anterior insula is implicated in interoceptive awareness (Critchley et  al., 2004)  and disgust perception (Calder et  al., 2001). Given that these functions are thought to be abnormal in OCD (Menzies et al., 2008; Paulus & Stein, 2010) (see ­chapter 10), it may be that the observed aging effect in the anterior insula is related to (compensatory) activation-​induced neuroplastic changes. Although the direct relationship between the volume and the function of the IFG/​anterior insula has not been studied so far, altered activation patterns in this brain area have been published, using various emotional and cognitive fMRI paradigms (e.g., de Wit et al., 2012; Tops & Boksem, 2011). As is the case for the dmPFC, Goodkind et al. (2015) showed that decreased IFG/​insula volume is not specific for OCD, but also present in many other mental disorders. HIPPOCAMPUS AND AMYGDALA

The ENIGMA-​OCD consortium showed a reduction of hippocampal volume in adult OCD patients. The effect was notably more pronounced in the medicated patients. The smaller hippocampal volume seemed to be driven, at least partly, by the OCD patients with comorbid depression and late disease onset (Boedhoe et  al., 2016). The OBIC FreeSurfer megaanalysis also reported decreased hippocampal volume in patients (Fouche et  al., 2017). However, most previous metaanalyses (Peng et  al., 2012; Radua et al., 2010; Rotge et al., 2009, 2010) and the OBIC VBM megaanalysis did not report volumetric differences 251

 

in the amygdala-​hippocampal complex in OCD. They did show, though, that the (para)limbic part of the medial and lateral temporal cortex, regions that are relatively preserved in healthy aging (Grieve et al., 2005), show greater aging-​ related volume loss in OCD (de Wit et al., 2014). The parahippocampal and inferior temporal cortices are involved in emotional perception (Sabatinelli et  al., 2011)  and emotional memory formation (Phelps, 2004). These brain regions are specifically vulnerable to stress-​related toxic changes (Kassem et al., 2012). Greater volume loss in these regions may thus be related to chronic stress and the exaggerated emotional responsiveness seen in OCD (Menzies et al., 2008). Limbic involvement seems to vary across the various subtypes of OCD. Pujol and colleagues (2004) found a relative decrease in right amygdala volume in patients with elevated scores on the “aggressive/​checking” dimension, and Van den Heuvel et al. (2009) reported that the “harm/​ checking” symptom dimension associated with smaller bilateral anterior temporal volumes. The specific association between the checking dimension with amygdala/​anterior temporal volume is consistent with some fMRI studies (e.g., Harrison et  al., 2009). Volume reduction in similar regions has been described in panic disorder (Massana et al., 2003a, 2003b), which, like the OCD subtype with harm/​ checking symptoms, is characterized by the overestimation of threat. CEREBELLUM

Several metaanalyses have shown no volumetric differences in the cerebellum (Peng et al., 2012; Radua & Mataix-​Cols, 2009; Radua et  al., 2010; Rotge et  al., 2009, 2010). This might be explained by the tendency, until recently, not to list cerebellar findings even in case of significant group differences, due to the old but incorrect presumption that the cerebellum is not involved in emotion and cognition. Some studies do not even include the whole cerebellum during acquisition of the data. There is accumulating evidence that the cerebellum, besides its role in motor control, is also involved in cognitive and emotional regulatory processes (Tobe et al., 2010; Middleton & Strick, 2000; Schutter & van Honk, 2005). The megaanalysis by De Wit et al. (2014) showed greater cerebellar GM volume bilaterally in OCD patients compared with healthy subjects. The cerebellum is structurally and functionally connected to the CSTC circuitry and is thought to integrate cortico-​striatal information flow (Middleton & Strick, 2000). Aberrant cerebellar activity

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has been shown in OCD patients during rest and task performance (Menzies et  al., 2008), and alterations in functional connectivity in the cerebellum in OCD have recently been reported (Anticevic et al., 2014). Cerebellar volume changes may thus be directly related to cognitive dysfunction and OCD symptomatology.

W H IT E   MAT T E R In contrast to the extensive literature on GM alterations in OCD, the WM tracts that connect the GM regions implicated in OCD have received considerably less attention (Fontenelle et  al., 2009). There is growing evidence that OCD symptoms may be at least partly underpinned by WM abnormalities (Douzenis et  al., 2009; Fontenelle et al., 2009). Although some of the published VBM studies described included information on WM volumes, DTI is more suited to study the integrity of WM tracts in OCD. DTI is a widely used neuroimaging technique to study brain tissue microstructure by quantification of the diffusion characteristics of water molecules (le Bihan et  al., 2001). Anisotropy, generally expressed as fractional anisotropy (FA), is a directionally dependent property of water diffusivity. In healthy WM, the anisotropy is high, reflecting relatively rapid water diffusion along the fibers and slow diffusion perpendicular to them. In GM and cerebral spinal fluid the anisotropy approaches zero, as the diffusivity is similar in all directions (Pierpaoli et al., 1996). In WM, an increased FA is putatively related to increased myelination and neuronal remodelling. In diseased WM, abnormally increased FA probably leads to functional hyperconnectivity. In contrast, decreased FA could be a marker of decreased or disrupted myelination, or reduced coherence of fibers, functionally leading to hypoconnectivity. Available evidence for WM abnormalities in OCD is quite inconsistent. Several reasons for the discrepancies exist. First in OCD, WM alterations might be subtle, thus difficult to detect. Second, medication effects seem to confound findings (Benedetti et  al., 2013; Fan et  al., 2012; Radua et al., 2014; Yoo et al., 2007). Third, because myelination continues into the third decade of life, ongoing brain maturation complicates studies with pediatric and adolescent OCD and in young adults (Peters et al., 2012). Last, small samples and inconsistent methodologies have been used (Radua et  al., 2014). Therefore, conclusions can be made only with caution. Here the most consistently reported results on WM abnormalities in OCD are discussed.

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Yoo et  al. (2007) investigated the potential effects of medication on WM integrity. At baseline (i.e., unmediThe corpus callosum constitutes the main pathway for inter-​ hemispheric communication. Its anterior parts connect the cated state), adult OCD patients exhibited increased FA in right and left prefrontal areas, which play a critical role in the corpus callosum. After 12 weeks of pharmacotherapy the context of internal monitoring, performance control, with citalopram, this FA increase had mostly disappeared. and inhibitory processes (Schmahmann et al., 2007). One This suggests that these alterations in WM microstructure of the most consistent findings in the OCD literature is the may be amenable to treatment and/​or reversible after clinifinding of microstructural abnormalities in the corpus cal- cal improvement. Koch et  al. (2012) investigated the symptom losum (Koch et al., 2014; Piras et al., 2013a). dimension-​ specific correlates of WM integrity. Severity Radua et  al. (2014) performed a multimodal metaanalysis of studies of WM volume and FA, including of the “obsessing” dimension correlated negatively with both adult and pediatric samples. Findings were particu- WM integrity in the corpus callosum. These results indilarly robust in the anterior midline structures, such as the cate that obsessions, or the patients’ inability to control corpus callosum, which showed increased WM volume their thoughts, may be related to impaired integrity of and decreased FA. WM volume and FA are expected to the corpus callosum. The WM abnormalities reported are spatially close to increase or decrease in parallel where fiber tracts are orgathe dmPFC region that has been consistently found to nized in parallel. However, when fibers cross, WM volume show decreased volume in metaanalyses (Radua & Mataix-​ increase can be accompanied by decreased FA. Decreased FA and increased WM volume in the corpus callosum Cols, 2009; Radua et al., 2010) and megaanalysis (de Wit therefore may suggest increased fiber crossing in OCD. et al., 2014). Altered WM diffusivity in callosal fibers may Crossed fibers generally include a thicker (dominant) and influence information transmission to the affected cortices, a thinner (non-​dominant) tract. OCD patients may have and by this, interfere with task-​relevant circuit function. increased thickness of nondominant tracts, which would The dmPFC has also been reported abnormally activated result in increased volume and in water flowing in two in imaging studies including resting state (Swedo et  al., directions rather than one (i.e., those of the two crossing 1989), symptom provocation (de Wit et al., 2015; Rauch tracts) and thus lower FA. However, other interpretations et al., 1994), and tasks requiring cognitive control (van den are possible. For example, changes in WM volume and Heuvel et al., 2005). FA could be due to changes in membrane permeability or to the presence of nonaxonal components such as other CINGULUM BUNDLE cells, vessels, or interstitial fluid. Due to insufficient number of pediatric studies, Radua et al. (2014) were unable The cingulum bundle interconnects the cingulate cortex, to draw specific conclusions regarding WM alterations in thalamus, amygdala, and hippocampus, which are major pediatric OCD. components of the fronto-​striatal and fronto-​limbic cirKoch et al. (2014) reviewed DTI studies in both adult cuits (Catani et al., 2002; Wakana et al., 2004). The cinguand pediatric OCD patients. They concluded that in adult lum bundle is structurally and functionally complex and patients WM integrity is decreased in the corpus callosum. heterogeneous. It is mainly involved in emotion processing, In contrast, in pediatric and adolescent patients, the cor- nociception, and motor function, but also in higher-​level pus callosum and cingulate bundle points may be charac- cognitive processes such as attention, conflict or error monterized by increased WM connectivity. Pediatric studies by itoring, and visuospatial and memory function (Devinsky Gruner et al. (2012) and Zarei et al. (2011) showed a pos- et al., 1995). itive correlation between CY-​B OCS scores and FA in the Several DTI metaanalyses showed a lower FA in the cincorpus callosum and other regions such as the cingulum, gulum bundle (Peng et al., 2012; Piras et al., 2013a; Radua SLF, and ILF/​IFOF. These results suggest that myelination et  al., 2014), and Radua et  al. (2014) found significantly may occur prematurely in patients with early-​onset OCD increased WM volume in this region. Additionally, Koch and be most pronounced in severe cases. This fits with the et  al. (2012) reported a negative correlation between FA neurodevelopmental hypothesis of OCD, or at least sug- in the cingulum bundle and the severity of obsessions. In gests that early-​onset OCD may represent a neurobiologi- contrast, studies in pediatric and adolescent patients point cally different, neurodevelopmental subtype of the disorder toward increased FA of the cingulum bundle (Gruner et al., (Fontenelle et al., 2003). 2012; Koch et al., 2014). Because this was also the case for CORPUS CALLOSUM

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the corpus callosum, the findings suggest that increased WM connectivity, perhaps due to a premature myelination, may characterize this specific subgroup of young patients. Metaregression analysis by Radua et al. (2014) showed that the decrease in FA of the anterior midline structures, including the cingulum bundle, was most prominent in samples that had higher percentages of medicated patients. Although the effects of selective serotonin reuptake inhibitors on WM parameters are not well understood, these results converge with previous work indicating that compared with drug-​naïve OCD patients and healthy controls, drug-​treated OCD patients exhibit significant WM integrity differences (Benedetti et al., 2013). The findings of Radua et al. (2014) provide additional support to the concept of a structural and functional abnormality in the anterior cingulate bundle and adjacent cortex in OCD. These abnormalities may be shared with other anxiety and mood disorders (Goodkind et al., 2015; Radua et al., 2010; van Tol et al., 2010) rather than being specific to OCD. Although the biological implications of these WM alterations are still unclear, they are likely to be associated with neural changes within limbic-​cortical networks. For example, the dorsal cingulate and its efferent pathways toward frontal cortex areas are known to be highly important for processes such as performance monitoring and cognitive control (Bush et al., 2000) and seem to be altered in connectivity in patients with OCD (Schlösser et al., 2010).

et  al., 2005). The involvement of the fronto-​parietal connections in the pathophysiology of OCD and other mental disorders seems to be relevant mainly for the understanding of cognitive dysfunctions related to the disease (Bernal & Altman, 2010; Hoeft et al., 2007; Karlsgodt et al., 2008; Madhavan et al., 2014). I N F E R I O R F R O N T A L -​O C C I P I T A L FA S C I C U L U S A N D L O N G I T U D I N A L FA S C I C U L U S

The inferior longitudinal fasciculus (ILF) connects the anterior part of the temporal lobe to the occipital lobe and plays a role in emotional processing, probably through a wide network also involving the uncinate fasciculus (UF). Metaanalyses show that OCD patients have lower FA in the ILF (Peng et al., 2012; Radua et al., 2014) and higher FA in the left UF (Peng et al., 2012). The involvement of both the UF and ILF could to be related to the emotional processing deficits seen in OCD patients. The inferior frontal-​occipital fasciculus (IFOF) is a major cortical association pathway connecting the frontal and occipital lobes, and with superficial and dorsal branches connecting the frontal lobe with the parietal lobe and the superior and middle occipital lobe (Catani et  al., 2002; Matsumoto et  al., 2010). Metaanalyses by Radua et al. (2014) and Peng et al. (2012) also reported reduced FA in the IFOF in OCD patients. Koch et al. (2012) found the severity of ordering symptoms to be associated with reduced WM integrity in the IFOF. Microstructural abnormalities in the IFOF are parS U P E R I O R L O N G I T U D I N A L FA S C I C U L U S ticularly relevant for the study of OCD, because this The superior longitudinal fasciculus (SLF) is a major asso- bundle represents the main long intra-​hemispheric conciation pathway, connecting the middle frontal gyrus/​ nection to and from the orbitofrontal cortex, which has dorsolateral prefrontal cortex with the superior parietal long been implicated in OCD pathogenesis (­chapter 20). lobule. Its connectivity with other cortical regions facili- Atrophy in the frontal branch of the IFOF is generally tates higher cognitive functions such as speech processing, associated with the presence of executive problems, apaattention, working memory, somatosensory monitoring, thy, and personality change (Piras et al., 2013a). Scores and visuospatial perception (Bernal & Altman, 2010; Hoeft on anxiety-​related personality traits, in healthy subjects, et al., 2007; Karlsgodt et al., 2008; Madhavan et al., 2014). are related to WM integrity of the large association fibers Metaanalyses by Radua et al. (2014), Piras et al. (2013a) and such as the IFOF and the SLF (Westlye et  al., 2011). Peng et al. (2012) reported reduced FA in the SLF in OCD Alterations in WM microstructure in these regions may patients. In addition, Radua et  al. (2014) observed that be a marker of a biological susceptibility to anxiety dissamples with higher mean Y-​B OCS scores most strongly orders, including OCD. Because the parietal lobe is interconnected with the contributed to this increased FA in the bilateral SLF. Because patients with depression also show decreased IFOF and SLF, these findings provide additional support FA in the left SLF (Murphy & Frodl, 2011), this abnor- to a growing body of evidence that other regions outside mality in WM integrity may be a nonspecific finding. the traditional CSTC loops, such as the parietal cortex, Disturbances in connectivity of this bundle may result in may be involved in OCD (Menzies et al., 2008; Piras et al., impaired attention and spatial working memory (Makris 2013b). 254

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connectivity along ventral cortico-​striatal axis, implicatThe OBIC megaanalysis (de Wit et  al., 2014)  reported ing the OFC and surrounding areas. In contrast, they decreased WM volumes in frontal regions in the patient found reduced functional connectivity between the dorgroup, suggesting abnormalities of WM connections sal striatum and lateral PFC. Future studies should focus between the prefrontal and subcortical regions of the on exploring a multimodel integration of abnormalities in frontal-​striatal circuits. These results were consistent with structural and functional connectivity, including its specific some previous studies on WM volume by Togao et  al relationship to specific emotional, cognitive, and behavioral (2010) and van den Heuvel et al (2009) and converge with deficits. One of the most recent advances in the field is the a metaanalysis (Peng et al., 2012) showing altered frontal-​ Human Connectome Project (van Essen et al., 2013). This striatal WM microstructure in OCD (Togao et al., 2010; Peng et  al., 2012; van den Heuvel et  al., 2009). Ha et  al. project uses different imaging modalities, such as resting (2009) showed that patients with predominant contamina- state fMRI and DTI, to acquire information about brain tion/​cleaning symptoms exhibited higher FA in the bilat- connectivity (both at structural and functional level), task-​ eral prefrontal WM, which probably leads to functional based fMRI to reveal brain activation patterns during spehyper-​connectivity in this region in this specific subgroup cific emotional and cognitive processes, and structural MRI of patients. Altered structural connectivity in frontal to capture the shape, volume, and thickness of the cortex regions may be related to functional connectivity altera- and subcortical regions. Results from such multimodal data tions, related to the impairments in cognitive control and analyses might help to integrate various findings from previous studies. emotion regulation. Other modalities such as genetics should be considered, to facilitate a more holistic view on the neural basis and course of OCD (Pauls et al., 2014). Menzies et al. (2008) C ONCL US IO N S AN D FUTURE D I RECTIONS were the first to report that abnormal WM integrity in parietal and frontal regions of OCD patients were also evident The literature reviewed supports the position that the brain in unaffected first-​degree relatives of OCD patients. This abnormalities found in OCD patients are best understood suggests that there are WM endophenotypes representing at a system or network level, rather than as discrete brain markers of increased genetic risk for OCD. More recent regions (Menzies et al., 2008). The widespread abnormali- neuroimaging studies of twin pairs with and without OCD ties across several different regions and circuits seem to be have begun to disentangle the environmental and genetic related to the complex phenomenology of OCD, which contributions to the observed structural and functional includes different emotional, cognitive, and behavioral brain alterations in OCD (den Braber et  al., 2010, 2011, 2012). Den Braber et al. (2010) found that during the perdomains. Using the multicenter database of the OCD Brain formance of a planning task, task-​related activation patterns Imaging Consortium, Subira et  al. (2015) investigated are strongly influenced by genetic risk factors of OCD. structural covariance or volumetric correlations across dis- Although these studies confirm that OCD genetic risk contant brain regions in OCD. Structural covariance examines tributes to brain characteristics of the disease, they are as yet how networks of brain regions vary in concert across sub- unable to identify specific genetic variants that contribute jects, with or without disease. Patients showed increased to those changes. To overcome the limitations of studies on OCD so far, structural covariance between bilateral ventral-​rostral putasampled, separate for men and the left inferior frontal gyrus. Patients also showed which were predominantly small-​ increased structural covariance between right centromedial-​ pediatric and adult OCD cases, unimodal, and “monodiagsuperficial amygdala and the ventromedial-​prefrontal cor- nostic” (i.e., comparing OCD patients with well-​matched tex (Subira et  al., 2015). These results provide evidence but super-​healthy controls), new opportunities now exist for structural network-​level alterations in OCD, involving within the international platform ENIGMA (Enhancing Neuro-​Imaging Genetics by Meta-​Analyses). ENIGMA is both the frontal-​striatal and fronto-​limbic circuits. Harrison et al. (2009) studied cortico-​striatal networks an unprecedented initiative to pool MRI and genetic data genetics metaanalyses (Thompson using resting-​state fMRI (see also ­chapter  24). Resting-​ to perform imaging-​ state fMRI provides a sensitive measurement of functional et al., 2014). The overall goal is to unite the imaging and connectivity in large-​scale brain networks. They found that genomics communities to solve biomedical problems that patients with OCD had significantly increased functional no one group could address alone. Metaanalyses within FRONTAL REGIONS

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ENIGMA are conducted in an individual participant data-​ based fashion. Standardized and harmonized data processing and quality check methods ensure low methodological heterogeneity. This will eventually allow us to study disease specificity and neural correlates of the disease across related disorders. Hibar et  al. (2015) recently found significant concordance between OCD risk variants and genetic variants related to increased striatal and thalamus volume (Hibar et al., 2015). These findings fit nicely with the very recent findings from the first ENIGMA-​OCD working group metaanalysis, showing that OCD patients have increased volume of the pallidum (in adults) and thalamus (in children) (Boedhoe et al., 2016). These results are largely consistent with current models of OCD. As illustrated by van den Heuvel et al. (2015), the brain circuits associated with compulsivity are plastic. Findings of neuroimaging studies therefore often vary depending on the developmental stage of the subjects included, the stage and chronicity of disease, and the effects of past and current treatments. Therefore, the study of the neural correlates of disease across the lifespan needs to be prioritized. Only with longitudinal studies following subjects from before disease onset until death, will we be able to fully understand the neurodevelopment aspect of the disease.

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24. BRAIN FUNCTIONAL CONNECTIVITY IN OCD Carles Soriano-​Mas, PhD and Ben J. Harrison, PhD

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 he emergence of functional neuroimaging in the late 1970s revolutionized clinical neuroscience research and the study of neuropsychiatric disorders, including obsessive-​compulsive disorder (Baxter et  al., 1987). Early studies used nuclear imaging approaches, such as positron emission tomography (PET). Subsequently, functional magnetic resonance imaging (fMRI) has dominated the study of these disorders. The majority of fMRI studies, including all of the studies that are reviewed here, measure blood-​oxygenation-​level-​dependent (BOLD) contrast, which is an endogenous hemodynamic signal that reflects changes in blood oxygenation linked to neuronal activity. BOLD fMRI is thus an indirect or surrogate measure of neuronal function (Raichle & Mintun, 2006). Because BOLD fMRI is sensitive to differences between brain states, it has been primarily used in the study of regional changes in brain activity (termed “activation”) when people are required to perform different experimental tasks (for an excellent introductory text, see Huettel et al., 2004). However, in the early 2000s, it became more widely recognized that BOLD fMRI was also capable of detecting spontaneous fluctuations of neuronal activity, and that these consistently reflected the coordinated activity of large-​scale brain systems (Fox & Raichle, 2007). This phenomenon was revealed through the combination of “resting-​state” experiments (participants lying awake and still in the scanner) and analysis methods designed to capture changes in brain functional connectivity, which is defined as the spatiotemporal dependency or correlation among distributed brain regions. Resting-​state fMRI is particularly well suited for measurements of functional connectivity, but functional connectivity can also be reliably studied in the context of experimental tasks (Friston et  al., 1997). At a neuronal level, resting-​state functional connectivity is broadly interpreted as representing slow fluctuations of neuronal excitability among regions with

strong direct or indirect axonal-​anatomical connections (Raichle, 2015). Because the results of resting-​state fMRI studies have well recapitulated the functional anatomy of well-​studied large-​scale human brain systems, the analysis of functional connectivity in resting-​state data has become a method of choice in the study of brain network dysfunction in neuropsychiatric disorders (Fornito & Bullmore, 2010; Griecius, 2008). After a brief introduction of the statistical methods most commonly used to assess brain functional connectivity in fMRI studies, this chapter reviews the existing literature in OCD. ANALYZ ING B R AIN F U NC T IONAL C ONNE C T IV IT Y For an in-​depth overview of the methods available to assess brain functional connectivity in fMRI studies, the reader is referred to the excellent reviews by Fornito & Bullmore (2010), Margulies et al. (2010), van den Heuvel & Hulshoff Pol (2010), Lee et al. (2013), or Smith et al. (2013). The history of resting-​state fMRI and functional connectivity from the personal perspective of the initiators of this field of neuroimaging research can be found in Snyder & Raichle (2012) and Biswal (2012). S E E D - ​B A S E D F U N C T I O N A L C O N N E C T I V I T Y

Region-​ of-​ interest or “seed”-​ based approaches provide a fairly straightforward method for the assessment of the functional connectivity of a specified region or node. In practice, this involves selecting a particular region of interest (or multiple regions), sometimes termed the seed, and then extracting its BOLD fMRI time series. The extracted time series can then be correlated with the time series of 259

 

other brain regions (or, more typically, of all other voxels in the brain), with the aim of quantifying the degree of temporal correlation or coherence between them. This approach has been widely implemented (Vincent et al., 2007). With this approach, a critical factor is the selection of the seed region(s) of interest, which ideally needs to be strongly hypothesis-​driven and sensible on anatomical grounds. A common criticism of this approach, and of all other approaches that will be described in this section, is that it does not support inferences about the directionality of observed functional connectivity relationships (i.e., whether the activity in one region leads to changes in another). In other words, functional connectivity results are purely correlational in nature. Drawing conclusions about causality would involve making use of other approaches assessing effective connectivity, but this is beyond the scope of this chapter. Examples of the application of such methods to OCD research can be found in Schlösser et al. (2010), Abe et al. (2015), Han et al. (2015), or van Velzen et al. (2015).

increasingly used to characterize brain network alterations in neuropsychiatric disorders in terms of the functional organization of networks via functional connectivity measurements, but also the functional properties of networks in terms of how specific regions interact and shape network organization. Most generally, a graph is made up of vertices and edges; paths through a graph consist of succeeding vertices connected by edges, of different lengths. When applied to fMRI data, vertices correspond to voxels, collections of adjacent voxels, or anatomically defined regions of interest, and edges to the estimates of functional connectivity between them. Whole-​brain data-​driven graph theoretical analyses are extremely computationally intensive. In practice, many studies therefore limit analysis to a smaller number of regions selected a priori. Graphs may be characterized by their local and global properties. Local properties refer to the characteristics of individual vertices, whereas global properties refer to the overall characteristics of the graphs. The “degree” of a vertex, a local property, refers to the number of edges it is connected with—​that is, in fMRI data, the number of other I N D E P E N D E N T C O M P O N E N T A N A LY S I S vertices with which it is significantly correlated. Calculation Independent component analysis (ICA) is a data-​driven of degree allows estimates of the functional connectivity technique that allows the separation of complex multivari- strength of each vertex and identification of “hubs,” which ate signals into different statistically independent compo- are regions of high degree (or centrality) within graphs (i.e., nents. ICA methods have been successfully developed and vertices or regions that are densely connected). applied to the analysis of fMRI studies, particularly in the Measures of clustering and modularity are global characseparation of common spatiotemporal noise components teristics of a graph. These refer to the existence within a graph of the fMRI time series data from the genuine activity of of modules that are highly internal connected but only sparsely large-​scale brain networks. In comparison with seed-​based connected to one another. Alterations affecting a hub or a region approaches, ICA approaches are more exploratory in nature with high centrality may alter functional connectivity throughand do not require strong a priori hypotheses about specific out the graph; in contrast, in highly modular systems, local disregions or networks of interest. A general challenge for ICA ruptions will more rarely cause global alterations. Average path studies relates to the identification and separation of com- length is another global metric that is commonly used in graph ponents (i.e., networks) of interest from common large-​ analyses. It refers to the mean distance between any pair of verscale noise components. In practice, this typically involves tices, and can be used as proxy for integration within a network. using anatomical templates or results from prior studies to The combination of all these measurements can be used to charinform the selection of the components, which introduces acterize networks as having “small-​world” properties, which a degree of arbitrariness into the application of this method. denotes a combination of modularity and efficient long-​range Nevertheless, ICA based approaches have been successfully connections that maximizes parallel processing, minimizes wirapplied to the study of functional connectivity alterations ing costs, and increases resilience to local disruptions. in a range of neuropsychiatric disorders. GRAPH THEORY

Graph theory is a field of mathematics that has a long history of applications to the study of complex networks. More recently, graph theoretical approaches have been specifically developed for the assessment of brain networks as derived from fMRI studies. These methods have also been 260

S E E D-​B AS E D APPROAC H E S Most studies to date assessing functional connectivity alterations in OCD patients have used seed-​based approaches. Among these, seeds have been principally located in corticostriatal or frontostriatal circuits, although other networks of interest, such as the “default mode network,” have been O bsessive - C ompulsive D isorder

 

also investigated. This section starts by reviewing studies employing seed-​based approaches, organized according to the placement of the seeds of interest. Studies that have assessed interactions between brain functional connectivity and task performance are not reviewed here. Such studies in OCD include Cardoner et al. (2011), Beucke et al. (2012), de Vries et al. (2014), de Wit et al. (2015), or van Velzen et al. (2015).

densely connected with the ventromedial and ventrolateral prefrontal cortices. The putamen nucleus, and more specifically its dorsal-​caudal division, is linked with the premotor and primary motor cortices. Information processed by these circuits is conveyed to the thalamus via synaptic relays in the globus pallidus and the pars reticulata of the substantia nigra; the thalamus then conveys information back to the cortex. At a broad functional level, these circuits appear to support different domains of processing, which has led CORTICOSTRIATAL CIRCUITS to the description of distinct “cognitive” (dorsal striatal-​ The basal ganglia have long been implicated in the patho- prefrontal cortex), “limbic” (ventral striatal-​prefrontal corphysiology of OCD and remain central to contempo- tex), and “sensorimotor” (putamen-​motor cortices) loops. rary neurobiological models (Menzies et  al., 2008, Milad The characterization of these circuits, and how they are & Rauch, 2012)  (see ­ chapters  20–​ 23). Basal ganglia–​ dysregulated in neuropsychiatric conditions such as OCD, thalamocortical circuits (“corticostriatal” or “frontostriatal” has been greatly advanced by the application of resting-​state loops), which are partially segregated into sensorimotor, fMRI analyses. In 2008, Di Martino et al. (2008) reported associative, and limbic territories of the basal ganglia, are the first functional connectivity study clearly showing a clear implicated in motor, cognitive, and emotional aspects of distinction in the pattern of cortical connectivity of dorsal behavior, respectively. Dysregulation of these circuits and ventral striatal regions, consistent with the notion of segis implicated in a range of neuropsychiatric disorders regated cognitive, limbic, and motor corticostriatal networks. (Shepherd, 2013). Our group subsequently applied this approach in a study A detailed overview of the functional anatomy of these of 21 patients with OCD compared with 21 healthy concircuits is beyond the scope of this chapter (see c­ hapter 20). trols. In this study, we demonstrated for the first time alteraAlthough modern descriptions have added nuance, an early tions in frontalstriatal circuits, involving both increases and suggestion that parallel corticostriatal circuits are orga- decreases in functional connectivity. Patients with OCD nized along a dorsal-​ventral axis remains heuristically use- had increased functional connectivity between ventral ful (Alexander et al., 1986; Cummings, 1993; Haber, 2003; striatal seeds and the orbitofrontal cortex and surrounding Lawrence et al., 1998; Nakano et al., 2000). For instance, ventromedial areas, but reduced functional connectivity the dorsal subregion of the caudate nucleus is densely con- between dorsal caudate seeds and the lateral prefrontal cornected with the dorsolateral prefrontal cortex, whereas tex and between dorsal putamen seeds and the supplementhe ventral caudate and nucleus accumbens subregions are tary motor area (Figure 24.1). Outside the frontal cortex, (a)

(b)

Increased FC in OCD patients

Overlap

Increased FC in controls

Figure 24.1  ALTERED SEED-​B ASED FUNCTIONAL CONNECTIVITY IN ADULTS WITH OCD.  A. Resting-​state functional connectivity of cortical regions to a

seed in the dorsal caudate (blue circles on the anatomical image on the left) is generally reduced in individual with OCD relative to healthy controls, with marked reductions in posterior parietal cortex and lateral prefrontal cortex. B. In contrast, resting-​state functional connectivity of cortical regions to a seed in the ventral striatum/​accumbens (red circles in the anatomical image) is increased in OCD, especially in the medial prefrontal cortex.  (Adapted with permission from Harrison et al., 2009.)

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we observed decreased functional connectivity between the ventral striatum and the midbrain ventral tegmental area, where most of the dopaminergic input to the limbic part of the striatum originates. Connectivity between the ventral caudate/​nucleus accumbens region and the anterior orbitofrontal cortex correlated with overall symptom severity. This pattern of results was replicated in a more recent study (Harrison et al., 2013), in which we assessed 74 OCD patients and 74 healthy controls and observed again that functional connectivity increases between the ventral striatum and the ventromedial/​orbitofrontal cortex were correlated with patients’ overall symptom severity. This alteration may be a common neurobiological marker of the disorder, consistent across highly variable clinical presentations. Similar seed-​based approaches focused on the functional connectivity of segregated striatal regions have been reported in other studies. For instance, Sakai et al. (2011) replicated the original findings of Harrison et  al. (2009), reporting hyperconnectivity between ventral striatal and ventromedial prefrontal regions in 20 unmedicated OCD patients (after a wash-​out period of 8 weeks). In this study, increases in functional connectivity of the ventral striatum extended to dorsolateral prefrontal regions, which was not observed in the Harrison et  al. studies. In another study with unmedicated patients, Jung et  al. (2013) reported increased functional connectivity between ventral striatal regions and the lateral orbitofrontal cortex. The issue of medication effects was further discussed in the report of Posner et al. (2014). Contrary to the initial findings with medicated patients (Harrison et al. 2009) and the results of Sakai et al. (2011), they reported decreased functional connectivity between the ventral striatum and the ventromedial prefrontal cortex in unmedicated patients with OCD. Also contrary to previous reports (Harrison et al., 2009, 2013), these authors reported a negative correlation between functional connectivity of the ventral striatum and the ventromedial prefrontal cortex and symptom severity. These results were interpreted as evidence that previous reports of increased functional connectivity in the ventral corticostriatal circuitry were due to lasting effects of antidepressant treatments. In Posner et  al. (2014) almost half of the patients (11/​23) were medication naïve, and the rest were off medication for an average of 94 weeks. However, this remains a speculative interpretation of the discrepancy; studies specifically assessing the effect of selective serotonin reuptake inhibitors (SSRIs) on ventral striatum-​ventromedial prefrontal cortex connectivity have not shown significant effects (McCabe & Mishor, 2011). Other aspects of the results reported in Posner et  al. (2014) were partially coincident with previous findings. 262

In agreement with Harrison et  al. (2009), they showed decreased functional connectivity within the sensorimotor corticostriatal loop in OCD. However, contrary to Harrison et  al. (2009), they reported functional connectivity increases between the dorsal caudate and the anterior prefrontal cortex and the inferior parietal lobe. Interestingly, such increased functional connectivity between the dorsal caudate and the anterior prefrontal cortex was in agreement with the findings reported in Fitzgerald et al. (2011), who, in addition, assessed changes in functional connectivity within the corticostriatal loops across development. These authors reported functional connectivity decreases specific to children with OCD (8–​12  years). Such alterations affected the connectivity between the dorsal caudate and the rostral anterior cingulate cortex (ACC) as well as between the medial thalamus and the dorsal ACC. More recently, Bernstein et al. (2015) have also found functional connectivity decreases in adolescent patients with OCD, in this case involving the putamen and the left frontal operculum/​ anterior insula, a finding that is in agreement with the results reported in Harrison et al. (2009) in adult patients. These results suggest that the developmental trajectory of corticostriatal circuits must be taken into account to provide a complete account of their dysregulation in patients with OCD, although more work is needed in this area. D E FA U LT M O D E N E T WO R K

The default mode network (DMN) is arguably the most investigated resting-​state brain network, in studies of both healthy and neuropsychiatric populations. Physiologically, the notion of a brain “default mode” refers to the tendency of this system to increase in activity during passive imaging conditions, such as wakeful resting states, as compared to when subjects perform specific cognitive tasks or pay attention to external world. Psychologically, this default activity has been linked to self-​referential cognition (i.e., thinking about oneself ), which is characteristic of conscious resting states in general, and of popular notions of “mind wandering” and “daydreaming.” In anatomical terms, the DMN comprises a large-​scale network of brain regions, including the medial prefrontal cortex, the anterior and posterior cingulate cortices, the inferior parietal cortex, and the lateral temporal cortex. In the first study assessing this network in OCD patients, Jang et al. (2010) placed a seed region of interest in the posterior cingulate cortex (PCC) and observed attenuated functional connectivity within the DMN in OCD, compared with controls. Specifically, the authors observed O bsessive - C ompulsive D isorder

 

reduced functional connectivity between the PCC and the anterior cingulate cortex, the middle frontal gyrus, and the putamen. Functional connectivity between the PCC and the putamen correlated inversely with anxiety levels. In partial agreement with these results, Peng et al. (2014) found that short-​distance functional connectivity from a PCC seed (that is, involving brain areas surrounding the seed) was decreased in OCD patients, whereas connectivity with regions from outside the DMN (anterior insula, inferior frontal and superior temporal and parietal cortices) was increased. Importantly, short-​distance functional connectivity decreases from the PCC were also observed in nonaffected relatives of the OCD patients, and this result predicted greater symptom severity. Taken as a whole, the results from these studies suggest that in OCD functional connectivity is decreased within the DMN, whereas connectivity between DMN regions (i.e., PCC) and regions from other functional networks may be increased. This idea is supported by another study (Stern et al., 2012), which reported reduced negative correlations (i.e., increased connectivity) between different regions of the DMN (i.e., PCC, medial frontal cortex or inferior parietal lobe) and regions of the frontal parietal network (typically engaged in tasks depending on external stimuli). These results suggested that OCD patients might experience difficulties in disengaging from internally generated thoughts when performing tasks requiring attention to external stimuli. The same group also demonstrated reduced functional connectivity within the DMN in pediatric patients, specifically involving the PCC and the ventral part of the medial frontal cortex (Fitzgerald et al., 2010). In a more recent study, Beucke et  al. (2014) assessed the functional connectivity of 11 different seed-​regions of interest within the DMN, with the intent of discriminating alterations within midline core regions of the network (i.e., PCC and anterior medial prefrontal cortex) and in self-​ referential (i.e., dorsal medial prefrontal cortex) and episodic memory (i.e., medial temporal lobe) subsystems (this classification scheme was based on Andrews-​Hanna et al., 2010). Overall, the pattern of results of this study concurred with previous research, showing reduced functional connectivity in OCD within the midline core regions of the DMN, and within the dorsal medial prefrontal cortex self subsystem. Likewise, in agreement with previous reports, the authors found greater connectivity between the self subsystem and salience and attention networks. Interestingly, in this study a positive correlation of symptom severity with functional connectivity between the dorsal medial prefrontal cortex and the ventral striatum was observed.

B rain F unctional C onnectivity

OTHER SEED-B ​ ASED FUNCTIONAL CONNECTIVITY STUDIES

Several studies have used task-​ based fMRI analysis or structural neuroimaging, rather than a priori theoretical considerations, to generate seeds for connectivity analyses. Stern et al. (2011), for instance, used an error-​eliciting interference task with a varying motivational context and identified hyperactivations in OCD patients in the ventromedial prefrontal cortex and the anterior insula/​frontal operculum. Subsequently, they placed a seed in the ventromedial prefrontal cortex an assessed its intrinsic functional connectivity (i.e., independent of event-​related activity) with the rest of the brain, finding an increased coupling between this region and bilateral anterior insula/​frontal operculum and right thalamus in OCD patients. These results were interpreted as suggesting that, in OCD, greater activations during error commission in regions associated with emotion and stimulus valuation are partially dependent on the existence of enhanced functional connectivity between the brain networks underpinning such processes. Using a similar approach, Marsh et al. (2014) observed that OCD patients hyperactivated the putamen and surrounding regions in response to the alternation of congruent and incongruent trials in a conflict Simon task. Irrespective of task condition, OCD patients showed increased functional connectivity of this putamen region with frontostriatal and parietal regions. In another study, Hou et al. (2013) derived their seed regions-​ of-​ interest from a voxel-​ based morphometry analysis of structural MRI data. They found that OCD patients had gray matter volume increases in the left caudate, left thalamus, and posterior cingulate cortex, as well as volume decreases in the bilateral medial orbitofrontal cortex, left anterior cingulate cortex, and left inferior frontal gyrus (see ­chapter  23). In seed-​based functional connectivity analyses, they observed increased connectivity in OCD between regions of the corticostriatal loops (e.g., caudate nucleus and thalamus with ventrolateral and ventromedial prefrontal cortices), as well as decreased functional connectivity between regions of the DMN (e.g., ACC and medial orbitofrontal cortex with PCC and left angular gyrus). They also found increased functional connectivity between the PCC and regions of the corticostriatal circuits. Interestingly, increased functional connectivity within corticostriatal circuits positively correlated with overall symptom severity. Likewise, Ping et  al. (2013) assessed short-​ range synchronized activity in 20 patients with obsessive-​compulsive disorder and 20 healthy controls using an analysis approach

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know as regional homogeneity (ReHo), which evaluates, voxel-​wise, the similarity between the time series of brain voxels and their nearest neighbors. With this method, they observed significantly increased ReHo in the orbitofrontal cortex, cerebellum, and insula, and decreased ReHo in the ventral anterior cingulate cortex, caudate, and inferior occipital cortex. Moreover, the authors also observed increased long-​range functional connectivity between the orbitofrontal cortex and the ventral anterior cingulate cortex. Other studies have combined resting-​state with task acquisitions. Jung et  al. (2013) observed that functional connectivity between the nucleus accubmens and the ventromedial prefrontal cortex was decreased in OCD patients at rest, but increased during loss anticipation in a monetary incentive delay task. In this same study, patients showed decreased functional connectivity between the nucleus accumbens and the amygdala specifically during incentive processing. Similarly, in a study mentioned earlier, Fitzgerald et al. (2010) showed that pediatric patients hyperactivated the dorsal anterior cingulate cortex during a performance monitoring task. Functional connectivity of this region with the ventromedial frontal cortex was only increased during task performance, but not at rest; at rest, this same seed region showed a specific connectivity decrease with right frontal operculum. Finally, Kang et al. (2013) combined a resting-​state acquisition with a response inhibition task (stop-​signal). They found that, during task performance, OCD patients hypoactivated the dorsal caudate nucleus and hyperactivated the parahippocampal cortex. Subsequently, analyzing functional connectivity from these two seed regions throughout the resting-​state sequence, they found increased functional connectivity of both of them with the middle cingulate cortex, which predicted poorer task performance. Overall, these results may be interpreted as reflecting alterations of reciprocal interactions between different brain networks, which are likely to manifest as intrusive/​modulatory inputs from the DMN and affective/​motivation networks during task performance. Following a different methodological approach, the putative modulatory role of affect on OCD symptoms was also described in Fontenelle et  al. (2012). They assessed functional connectivity of a seed-​region located in the subgenual ACC during two different scanning conditions: neutral and sad mood induction. During sad mood induction, patients with OCD showed heightened connectivity between the subgenual ACC and the ventral caudate and hypothalamus, whereas controls showed increases in functional connectivity between the seed-​region of interest 264

and other frontal regions. These results were interpreted as suggesting that in patients with OCD, contrary to controls, induced sadness activates the corticostiatal OCD circuit, which may partially explain why OCD symptoms tend to develop and worsen with negative emotions. Jhung et  al. (2014) also combined resting state with a sequence acquired under symptom induction. They evaluated OCD patients with contamination/​ washing symptoms and found that the decreased functional connectivity between the ventral striatum and the insula at rest was increased during provocation of washing symptoms, in comparison with both healthy controls and OCD patients without contamination/​washing symptoms. Also, functional connectivity between the ventral striatum and the insula correlated with contamination/​washing symptom severity. Finally, in a recent study combining resting-​state functional connectivity with prediction of treatment response, Dunlop et al. (2015) showed that OCD patients responding to a repetitive transcranial magnetic stimulation aimed at the dorsomedial prefrontal cortex had higher connectivity between this region and the ventral striatum at baseline; reduction of such connectivity between pre-​ and post-​ treatment assessments predicted symptomatic improvement. S T U DIE S U S ING INDE PE NDE NT C OMPONE NT ANALYS IS ICA has been applied less frequently to the assessment of functional connectivity alterations in OCD than seed-​ based analyses. However, this approach has the ability to investigate more diffuse patterns of brain alteration across large-​scale brain functional networks. There are some interesting results derived from these studies that are well worth reviewing here. In the first ICA study in OCD, Cocchi et al. (2012) used a cognitive control task (the Multisource Interference Task) in combination with an ICA analysis focused on four different networks:  the paralimbic, sensorimotor, dorsal attention, and default mode networks. The authors observed that, during transitions between task and resting blocks, OCD patients showed increased functional connectivity within the paralimbic network, involving dorsal anterior cingulate and anterior insular cortices. Interestingly, the strength of the functional connectivity of this last region during task performance correlated with anxiety symptoms, which led the authors to interpret the results of their study as suggestive of an increased arousal state in OCD patients during task performance. O bsessive - C ompulsive D isorder

 

Cheng et al. (2013) used ICA to analyze resting-​state data in a series of 23 medication-​naïve patients and 23 matched healthy controls. They observed decreased functional connectivity strength in OCD patients within the DMN, mainly affecting the precuneus and the PCC, and increased functional connectivity within a network involving the ventromedial prefrontal cortex, the medial orbital frontal cortex, and the pregenual ACC. Significantly, symptom severity showed a negative correlation with functional connectivity within the DMN, but a positive correlation with functional connectivity within the ventromedial prefrontal/​ACC network. More recently, Grützmann et  al. (2014) used ICA to decompose fMRI data acquired during a flanker task, which evaluated hyperactive performance monitoring in OCD. The authors performed a simultaneous electroencephalographic acquisition during task performance, and found that the amplitude of the error related negativity potential, which occurs 50 msec after the execution of an incorrect response, was correlated with fMRI activity within two independent components, the posterior midcingulate cortex and the presupplementary motor area, implicating hyperactivity of these regions in performance monitoring in OCD. ICA has been also used to analyze fMRI data in samples of pediatric patients with OCD. Weber et al. (2014) assessed a small sample of 11 medication-​naïve children and adolescents with OCD and 9 healthy controls and reported increased functional connectivity within the auditory network and decreased functional connectivity in regions associated with the DMN. Gruner et  al. (2014) assessed 23 pediatric OCD patients and 23 healthy volunteers. The authors used logistic regression to identify the components that maximally discriminated OCD patients from healthy controls, finding three networks (the middle frontal/​dorsal anterior cingulate, the anterior/​posterior cingulate, and the visual networks) that separated groups, with an overall classification accuracy of 76.1%. Specifically, patients showed higher connectivity in the middle frontal/​dorsal anterior cingulate and the anterior/​posterior cingulate networks, but lower in the visual network. These findings were interpreted as indicative of the relevance of abnormalities within the cingulate cortex and other cognitive control regions in the pathogenesis of OCD. GRA P H THEO RY AN D RELATED APPROAC H E S As described, graph theory-​based analyses provide information about the strength of functional connectivity of different brain regions and the intrinsic properties of brain B rain F unctional C onnectivity

networks. In contrast to seed-​based approaches, functional connectivity is estimated for all brain regions. Graph theory-​based approaches are sometimes supplemented with seed-​based analyses to ascertain the specific functional connectivity pattern of regions with altered functional connectivity strength. Regarding the intrinsic properties of brain networks, studies have typically reported information about clustering and modularity, as well as about the efficiency of information processing within the networks, which is normally inferred from small-​word architecture estimates. In the first study that applied a graph theory approach to the analysis of resting-​state neuroimaging data from OCD patients, Zhang et  al. (2011) reported that OCD patients showed significantly higher local clustering within a network involved in top-​ down control of behavior. These results implied that functional connectivity within this network (including the cingulate gyrus, the thalamus, the precuneus and the cerebellum) was increased in OCD, although connectivity with other networks was reduced. Such imbalance between modularized and distributed information processing led the authors to suggest that—​contrary to healthy controls—​the top-​down control network of OCD patients did not show an optimal small-​ world architecture. In line with these findings, Göttlich et al. (2014) have shown that unmedicated OCD patients display stronger connectivity within the regions of the executive/​attention network, but decreased connectivity within the limbic network and between limbic, basal ganglia, default mode, and executive/​attention networks. This may explain why intrusive thoughts are considered threatening and difficult to reappraise in OCD subjects. Meunier et al. (2012) assessed a group of OCD patients and a group of stimulant-​dependent individuals in comparison with healthy controls. Both clinical groups showed decreased functional connectivity degree in the medial and lateral right orbitofrontal cortices, which was correlated with compulsivity scores. This decrease was more evident in the OCD group, especially for the medial orbitofrontal cortex. In post hoc analyses, the authors also observed that, in both patient groups, regions showing reduced functional connectivity with the orbitofrontal cortex included the premotor, sensorimotor, dorsal cingulate, and left temporal cortices. OCD patients also showed a significant reduction of the functional connectivity degree in the area of the posterior cingulate cortex. Using a similar approach, Beucke et al. (2013) reported contrasting findings. These authors differentiated between local (i.e., inside a 12-​mm sphere around a given voxel) and distant functional connectivity, and found that medial 265

 

and lateral orbitofrontal cortices of unmedicated patients showed greater functional connectivity both at the distant and local range. Moreover, distant connectivity estimates were associated with greater symptom severity. In follow-​ up seed-​based analyses, the authors showed that the pattern of regions displaying altered functional connectivity with the orbitofrontal cortex was quite similar to the pattern reported in Meunier et  al. (2012), including precentral and superior temporal cortices, although, in this case, these regions were hyperconnected in OCD. Beucke et al. (2013) found that the subthalamic nucleus of OCD patients showed increased distant connectivity, whereas the putamen displayed greater connectivity exclusively at the local level. Comparing medicated and unmedicated patients, medication effects were only evident as a reduction of local connectivity at the level of the ventral striatum, and, therefore, the differences with the results of Meunier et al. (2012) were not explained by the treatment status of the participants. Results of Beucke et  al. (2013) could be interpreted as supportive of the data obtained with seed-​based approaches demonstrating an increased functional connectivity of basal ganglia regions in OCD, which might be modulated by antidepressant medication. Nevertheless, results involving the orbitofrontal cortex, although concurred with the findings of the seed-​based study of Ping et al. (2013) reported, were in clear contradiction with those of Meunier et al. (2012). Anticevic et al. (2014) used a similar analysis approach to assess functional connectivity strength of the orbitofrontal cortex. In agreement with Meunier et  al. (2012), these authors reported decreased functional connectivity degree in the left lateral prefrontal cortex in OCD patients, both at whole-​brain and local (i.e., within the prefrontal cortex) level. Conversely, in agreement with Beucke et al. (2013), they reported enhanced functional connectivity degree in the right putamen and within the basal ganglia circuitry (mainly located in dorsal striatum and anterior thalamus), which was reduced in patients on medication, as in Beucke et al. (2013). Interestingly, degree connectivity was increased throughout the dorsal caudate and putamen and the thalamus, but decreased in the ventral striatum/​ accumbens; this data-​driven dissociation supports the idea that these corticostriatal circuits are differently affected in OCD. Notably, although the ventral striatum exhibited decreased global connectivity degree, a follow-​up seed-​ based analysis showed a specific increase in ventral-​striatal functional connectivity with the ventromedial prefrontal cortex region (ventral anterior cingulate; Figure 24.2), which is in agreement with most studies using a seed-​based approach. 266

Figure 24.2  ALTERED FUNCTIONAL CONNECTIVITY BETWEEN NU CLEUS

ACCUMBENS AND MEDIAL PREFRONTAL CORTEX.  In another resting-​ state study, whole-​brain cluster-​corrected analysis of resting-​state functional connectivity to an anatomically defined seed in the ventral striatum (left) revealed a specific increase in the medial PFC/​anterior cingulate cortex, consistent with the earlier findings of Harrison et al.  (Adapted with permission from Anticevic et al., 2014.)

Other studies (Hou et al., 2014; Tian et al., 2015) have also reported alterations congruent with the model of corticostriatal dysfunction in OCD, showing increased functional connectivity strength in hub regions located throughout the corticostriatal circuits. Alterations are not limited to regions within these circuits, but also extend to parietal, temporal, occipital, and cerebellar regions, although, there is some discrepancy between studies regarding the nature of these alterations (i.e., increased vs. decreased functional connectivity strength). Interestingly, in one of these studies (Hou et al., 2014) it was shown that first-​ degree relatives also showed overlapping increased functional connectivity strength in hubs, the bilateral caudate nucleus, and the left orbitofrontal and middle temporal cortices, suggesting that indices derived from graph theory approaches may be used to identify heritable neuroimaging endophenotypes of OCD. Finally, graph theory techniques have also been used in the context of treatment protocols. Shin et  al. (2014) showed that OCD patients showed an overall decrease in small-​world efficiency and modularity at baseline, with the default mode and the fronto-​parietal networks clustered into a single module. After 16 weeks of treatment with SSRIs, however, these alterations were reversed, in parallel with clinical improvement. Changes in connectivity degree of the right ventral frontal cortex were correlated with improvement of OCD symptoms. Feusner et  al. (2015) showed increased small-​worldness and clustering O bsessive - C ompulsive D isorder

 

coefficient after 4 weeks of intensive cognitive-​behavioral therapy, although intriguingly, patients entering therapy with already high network efficiency were at greater risk of relapse at follow-​up. Similarly, Göttlich et  al. (2015) observed that a lower degree centrality (a measure of functional connectivity strength) of basolateral amygdala was associated with a diminished response to CBT, probably as a consequence of alterations in the fear circuitry affecting fear extinction mechanisms.

activity on information processing by other networks (for a review, see Stern & Taylor, 2014). On the basis of altered connectivity between different brain networks, the interfering or modulatory effects of affective or motivational processes on core OCD symptoms have also been suggested (see Fontenelle et al., 2012 or Jung et al., 2013). Likewise, functional connectivity studies have also provided evidence of the deficient cortical regulation on subcortical activity in patients with OCD (see Dunlop et  al., 2015; Zhang et al., 2011). There are relatively few reports of altered functional C ONCL US IO N S connectivity in pediatric OCD samples (Bernstein et  al., 2016; Fitzgerald et  al., 2010, 2011; Gruner et  al., 2014; Across different analysis approaches, the analysis of resting-​ Weber et  al., 2014). Results of these studies have generstate fMRI data in OCD patients has provided consistent ally been in agreement with the findings of adult samples. evidence of altered functional connectivity within cortico- Hence, assessments of functional connectivity may provide striatal and default mode networks, which is in line with a stable marker of brain network level alterations in OCD, prevailing neurobiological models of the disorder (Menzies and, as such, they have been proposed as neuroimaging et al., 2008, Milad & Rauch, 2012; Stern & Taylor, 2014). endophenotypes of the disorder (Hou et al., 2014) as well Most studies have reported findings consistent with as candidate biomarkers for predicting and monitoring enhanced functional connectivity between the ventral part treatment response (Feusner et  al., 2015; Göttlich et  al., of the striatum and the orbitofrontal and ventromedial pre- 2015; Shin et al., 2014). frontal cortices (see, for example, results in Beucke et  al., 2013; Harrison et  al., 2009; 2013; or Sakai et  al., 2011; R E F E R E NC E S Figure 24.1, 24.2, ), although there appears to be some impact of the effect of antidepressant medication on these findings (see results in Posner et al., 2014 vs. Beucke et al., Abe, Y., Sakai, Y., Nishida, S., Nakamae, T., Yamada, K/​, Fukui, K., & Narumoto, J. (2015). Hyper-​influence of the orbitofrontal cortex 2013 and Anticevic et al., 2014). Likewise, results of studies over the ventral striatum in obsessive-​compulsive disorder. European showing alterations in functional connectivity within dorNeuropsychopharmacology, 25(11), 1898–​1905. sal corticostriatal circuits have been somewhat heterogene- Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and ous (see Harrison et al., 2009 vs. Fitzgerald et al., 2011 and cortex. Annual Review of Neuroscience, 9, 357–​381. Posner et al., 2014). It is also not clear whether local and Andrews-​Hanna, J. R., Reidler, J. S., Sepulcre, J., Poulin, R., & Buckner, R. L. (2010). Functional-​anatomic fractionation of the brain’s default distant estimates of functional connectivity within these network. Neuron, 65(4), 550–​562. circuits may provide a different pattern of results. Although Anticevic, A., Hu, S., Zhang, S., Savic, A., Billingslea, E., Wasylink, S., striatal regions seem to shown increased functional connecRepovs, G., Cole, M. W., Bednarski, S., Krystal, J. H., Bloch, M. H., Li, C. S., & Pittenger, C. (2014). Global resting-​state functional tivity at the local or proximal level, results are less clear at the magnetic resonance imaging analysis identifies frontal cortex, striadistant level (see results in Beucke et al., 2013 vs. Anticevic tal, and cerebellar dysconnectivity in obsessive-​compulsive disorder. et al., 2014). Similarly, results are far from clear regarding Biological Psychiatry, 75(8), 595–​605. the connectivity the orbitofrontal cortex with the rest of Baxter, L. R., Jr, Phelps, M. E, Mazziotta, J. C., Guze, B. H., Schwartz, J. M., & Selin, C. E. (1987). Local cerebral glucose metabolic rates in the frontal lobe or the rest of the brain (see, for instance, obsessive-​compulsive disorder. A comparison with rates in unipolar results in Beucke et  al., 2013 vs. Meuner et  al., 2012 and depression and in normal controls. Archives of General Psychiatry, 44(3), 211–​218. Anticevic et al., 2014). Bernstein, G. A., Mueller, B. A., Schreiner, M. W., Campbell, S. M., Although the DMN has been comparatively less studRegan, E. K., Nelson, P. M., Houri, A. K., Lee, S. S., Zagoloff, A. D., ied, results from these studies seem to be more consistent, Lim, K. O., Yacoub, E. S., & Cullen, K. R. (2016). Abnormal striatal resting-​state functional connectivity in adolescents with obsessive-​ showing a decreased functional connectivity within the compulsive disorder. Psychiatry Research, 247, 49–​56. network in association with an increased connectivity with Beucke, J. C., Kaufmann, C., Linnman, C., Gruetzmann, R., Endrass, T., Deckersbach, T., Dougherty, D. D., & Kathmann, N. (2012). Altered other brain networks, including corticostriatal networks cingulostriatal coupling in obsessive-​ compulsive disorder. Brain (see Beucke et al., 2014; Cheng et al., 2013; Fitzgerald et al., Connectivity, 2(4), 19–​202. 2010; Jang et  al., 2010; Peng et  al., 2014; or Stern et  al., Beucke, J. C., Sepulcre, J., Eldaief, M. C., Sebold, M., Kathmann, N., & Kaufmann, C. (2014). Default mode network subsystem alterations 2012). These findings suggest an interfering effect of DMN B rain F unctional C onnectivity

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25. NEUROTRANSMITTER DYSREGULATION IN OCD Ilse Graat, MD, Martijn Figee, MD PhD, and Damiaan Denys, MD PhD

N

eurotransmitter dysregulation may play an important role in the pathophysiology of obsessive-​ compulsive disorder (OCD); targeting presumptive neurotransmitter abnormalities is central to its pharmacological treatment (see c­ hapters 40, 41). Forty to sixty percent of OCD patients respond to pharmacotherapy with drugs that increase intrasynaptic serotonin (Denys, 2006; Soomro et  al., 2008), suggesting that OCD is related to dysfunction of serotonin (also called 5-​hydroxytryptamine, or 5-​HT). Dopaminergic systems are likely to be involved as well, because patients who do not respond to treatment with serotonin reuptake inhibitors (SRIs) can be successfully augmented with dopamine receptor antagonists (Bloch et al., 2006; Fineberg et al., 2006). Recent evidence for the potential efficacy of glutamate modulating drugs in OCD suggest glutamatergic abnormalities in OCD (Denys, 2006). Finally, analogs of γ-​aminobutyric acid (GABA) have shown to augment SRI treatment for OCD (Corá-​Locatelli et al., 1998; Oulis et al., 2011). Functional imaging studies consistently show involvement of the cortico-​ striatal–​ thalamic–​ cortical circuit (CSTC, also named corticostriatal or frontostriatal circuit) in the pathophysiology of OCD (Menzies et  al., 2008; Saxena & Rauch, 2000) (see c­ hapter 21). Within this circuitry, the neurotransmitters serotonin, dopamine, glutamate, and GABA are important regulators of neuronal activity. CSTC circuits consist of an excitatory direct pathway that is modulated by an inhibitory indirect pathway. It is generally presumed that these pathways are imbalanced in OCD patients, with less indirect inhibition and more direct excitation (Menzies et  al., 2008; Saxena & Rauch, 2000). The resulting hyperactivation of the orbitofrontal cortex (OFC) might be associated with obsessive thoughts, for example, about harm, danger, or hygiene, whereas striatal overactivation could be related to a compulsive drive to act upon these potential dangers. The exact function of

serotonin, dopamine, glutamate, and GABA in this model, remains, however, unclear. Importantly, the efficacy of pharmacological treatments that target serotonin and other neurotransmitter systems provides only weak evidence for their involvement in pathophysiology. Dysfunctional neurotransmission may be primary, causing OCD, or secondary, as a consequence of other pathophysiological processes; neurotransmitter abnormalities could even be compensatory, mitigating changes in other systems. This chapter reviews clinical studies investigating the role of serotonin, dopamine, glutamate, and GABA in OCD, with a focus on treatment studies, genetic studies, and neurochemical imaging studies. Considering all evidence, it introduces an integrated neurotransmitter model of OCD (Figure 25.1). T H E S E ROT ONE R GIC   S YS T E M The strongest evidence for involvement of 5-​ HT in OCD has been the robustly documented effectiveness of selective serotonin reuptake inhibitors (SSRIs) and the SRI clomipramine in OCD (Soomro et  al., 2008)  (see ­chapter 40). Tricyclic drugs with a primarily noradrenergic mechanism of action, such as desipramine, are ineffective (Goodman, 1990). SEROTONERGIC MECHANISMS OF OCD TREATMENT

In serotonergic neurons, 5-​ HT is synthesized in two steps:  tryptophan is converted into 5-​hydroxytryptophan by tryptophan hydroxylase, and 5-​hydroxytryptophan is converted into 5-​HT. Once synthesized, 5-​HT is packaged into presynaptic vesicles via vesicular monoamine transporters. These vesicles fuse with the presynaptic membrane 271

 

= HYPO ACTIVITY = HYPER ACTIVITY

THALAMUS/ MIDPONS 5HT – GABA –

OFC/ PFC GABA GLU +

GENES 5HT = SEROTONIN GLU = GLUTAMATE DA = DOPAMINE

CAUDATE NUCLEUS GLU +

STRIATUM DA +

Figure 25.1  An integrative model of neurotransmitter dysregulation in OCD. Convergent abnormalities in 5-​HT, DA, glutamate, and GABA are implicated in OCD, as detailed in the text.

and release 5-​HT into the extracellular space when the neuron is stimulated. There, 5-​HT interacts with postsynaptic serotonin receptors, including 5-​HT2A and 5-​HT2C receptors, but also with terminal (5-​HT1B/​D) and somatodendritic (5-​HT1A) auto-​ receptors that presynaptically regulate its release. The serotonin transporter (SERT, or 5-​HTT) transports 5-​HT back into the presynaptic neuron; this is the most important mechanism for modulating serotonin’s extracellular effects, and thus an important drug target. 5-​HT is broken down intracellularly by monoamine oxidase (MAO). Pharmacological agents used for treating mood and anxiety disorders interact with different parts of the serotonergic cycle. MAO-​inhibitors affect the action of monoamine oxidase; 5-​HT1A partial agonists stimulate 5-​HT1A; and SSRIs and SRIs occupy the SERT, preventing 5-​HT from binding. Drugs targeting the SERT have proved to be particularly effective in OCD (Pizarro et al., 2014). Blocking the SERT leads to a decrease of serotonergic reuptake and thereby an increase of intrasynaptic 5-​HT concentrations, augmenting serotonin’s postsynaptic and presynaptic actions, which decrease 5-​HT release. SRIs are the primary pharmacological treatment for OCD (see c­ hapter 40). SRIs are also used for anxiety disorders, major depressive disorder (MDD), and a range of other indications; however, SRI treatment for OCD takes longer and requires higher doses than other conditions (Bloch et  al., 2010; Tollefson, 1994). During the initial phase of SRI admission to guinea pigs, desensitization of 5-​ HT1A receptors leading to 5-​HT release in the OFC and the head of caudate nucleus, two regions of relevance for OCD, can take up to 2 months. In regions of greater relevance for MDD, such as the dorsolateral prefrontal cortex, hippocampus, and hypothalamus, desensitization may take only two weeks (el Mansari et  al., 1995). Furthermore, 5-​HT release in the OFC could be obtained only when the guinea pigs where given the double dose of SRI. These findings 272

suggest that the anticompulsive mechanism of SRIs differs from their antidepressive and anxiolytic effects: SRI effects on compulsivity may require serotonergic effects specifically in the ventral frontostriatal network, which requires higher doses and a longer delay of onset. Delayed desensitization of OFC 5-​HT1A receptors by SRIs might also be a possible explanation for the ineffectiveness of SRI augmentation with a 5-​HT1A agonist, like buspirone, to treat OCD (Aouizerate et al., 2005). SEROTONERGIC GENETICS OF OCD

Candidate gene studies investigating serotonergic polymorphisms have provided some support for involvement of serotonin-​related genes in the pathogenesis of OCD (see ­chapter 19). Just as most pharmacological studies have focused on the SERT, most genetic studies have focused on the serotonin transporter gene (also called SLC6A4), which maps to chromosome 17q11.1–​ q12 (Nakamura et al., 2000). The SERT gene-​linked polymorphic region (5-​ HTTLPR), found in the promoter, has multiple alleles, of which the La-​and S-​alleles (long and short, respectively) are the most common and most studied; results to date have, however, been variable, and effect sizes have not been large. A comprehensive metaanalysis by Taylor et al. (2012) confirms association of the 5-​HTTLPR-​La allele with OCD, with an odds ratio of 1.25. Polymorphisms of the HTR2A gene, coding for the serotonin 2A receptor, have also been associated with OCD, by candidate gene studies and metaanalysis. The metaanalysis of Taylor et al. (2012) found an odds ratio of 1.24 for the rs6311 A  allele. This is consistent with studies suggesting involvement of 5-​HT2A in effective pharmacotherapy for OCD (Marek et al., 2003). However, some individual studies have found no significant association between HTR2A polymorphisms and OCD, or found one only in females (Enoch et al., 2001; Hemmings et al., 2003). O bsessive - C ompulsive D isorder

 

A polymorphism in the MAO-​A gene has been associated with OCD only in males, who more frequently had the gain-​of-​function EcoRV variant of the MAO-​A gene, causing higher 5-​HT turnover in serotonergic neurons. Although MAO-​inhibitors are not as effective in OCD as SSRIs ( Jenike et al., 1997), there might be a role for the MAO-​A gene in the pathogenesis of OCD. Some studies have also reported an association between OCD and polymorphisms of the genes for the 5HT1B receptor, but these results are not as often replicated (Mundo et al., 2000, 2002). IMAGING STUDIES OF THE SEROTONERGIC SYSTEM

Positron emission tomography (PET) and single-​photon emission computerized tomography (SPECT) using radiotracers that bind to SERT have been used to examine SERT availability in OCD. Simpson et al. (2003) used the PET tracer [11C]McN 5652, which is a potent and selective SERT ligand. Comparing 11 patients with 11 controls, they found no statistically significant differences in SERT binding within striatal, limbic, or cortical areas. The patients in this study were not highly symptomatic (mean Y-​B OCS scores of 20 ± 4 points), which may have attenuated effects. A contemporaneous study using SPECT imaging with iodine-​123-​labeled 2ß-​carbomethoxy-​3ß-​(4-​iodophenyl)tropane ([123I]ß-​CIT) found an increase of SERT availability in midbrain-​pons, but this was only statistically significant for the early-​onset patients (25% of CY-​B OCS scores and a Clinical Global Impression-​Improvement score of much or very much improved). S R IS A ND RELAPSE PREVEN TI O N A recent study in an epidemiological adult sample suggested that approximately 50% of cases of OCD achieved sustained remission by the age of 50 years (Fineberg et al., 2013). In contrast, OCD as seen in the clinic is usually characterized by a chronic and relapsing course. Follow-​up studies of treatment-​seeking cases suggest that full remission is infrequent, even in specialist treatment centers. For example, in a 5-​year naturalistic follow-​up study of 213 S tandard E v idence - B ased P harmacological T reatment

adults with OCD, only 39% participants entered either partial (22.1%) or full (16.9%) remission, and 59% of participants who remitted subsequently relapsed (Eisen et al., 2013). The long-​term course of pediatric OCD may be more favorable:  In 4  years of prospective follow-​up of 60 young people treated for OCD, 80% achieved either partial (53%) or full (27%) remission, of whom 21% subsequently relapsed (Mancebo et al., 2014). These findings emphasize the importance of relapse prevention in the management of OCD across the lifespan. Controlled studies in adults with OCD have shown that, irrespective of duration of treatment, discontinuation of pharmacotherapy is frequently, but not always, associated with relapse (reviewed in Fineberg et al., 2013). A number of relatively short-​term studies have investigated the effect of stopping clomipramine. In the majority of cases, symptoms reemerged within a few weeks of stopping medication, whereas improvement to a level near to that prior to discontinuation was achieved by reinstatement of clomipramine (reviewed in Fineberg et al., 2007). The effect of discontinuing SSRI in stable adult treatment responders has been subject to more robust controlled investigation. A  metaanalysis of these studies detected overall superiority of continuing treatment with SSRIs compared with switching to placebo in preventing relapse (Fineberg, Tonnoir, et al., 2007). It is noteworthy that the studies testing sertraline (Koran et  al., 2002)  and fluoxetine (Romano et  al., 2001), which may have been underpowered, did not find a significant difference between 449

 

continuing treatment on active drug or switching to placebo, although patients remaining on higher (60 mg/​day) fluoxetine doses showed significantly lower relapse rates than those on placebo (Romano et al., 2001). Together, the results suggest that SSRIs as a group are effective at preventing symptomatic relapse. There also appears to be a positive impact of maintenance SSRI treatment (as opposed to discontinuation) on quality of life and psychosocial functioning (Hollander et al., 2010). Therefore, relapse prevention, through the continuation of pharmacotherapy, represents a rational treatment target for those who have responded to an SSRI or clomipramine. The American Psychiatric Association treatment guidelines (Koran et al., 2007) recommend continuation of pharmacotherapy for a minimum of 1 to 2  years in treatment-​responsive individuals and emphasize the importance of long-​term treatment from the outset. Regular clinic appointments have been shown to enhance adherence (Santana et al., 2010). The recently published international standards of care for obsessive compulsive disorder centers (Menchon et  al., 2016, in press) emphasize the importance of providing clinical follow-​up as a means of reducing relapse

As OCD responds to SRI in a slow, gradual way and some patients respond more slowly than others, it is important not to anticipate treatment failure prematurely. Individuals with OCD are not always accurate in reporting change in symptoms, and it is therefore helpful to include a close relative or friend in the assessment. There remains controversy as to the length of an adequate treatment trial before judging whether a treatment has succeeded or failed. Expert consensus guidelines suggest at least 12 weeks at optimised dosages are needed (Baldwin et al., 2005, www. nice.org.uk); longer may be required in some cases. For practical purposes, patients experiencing less than a 25% reduction of their baseline Y-​B OCS score, after completing 12 weeks of SRI treatment, of which at least 6 weeks should be at maximal tolerated dose, may be considered to have failed to respond (Koran et al., 2007). EXTENDED TRIAL OF ORIGINAL SRI

The American Psychiatric Association (APA; Koran et al., 2007) recommended continuing with an SSRI for 8 to 12 weeks, of which 6 should be at maximum tolerated dose, before a change in pharmacological treatment is considered. However, this may result in patients enduring inefTR EATM ENT O PTI O N S FO R PATI EN TS WH O DO fective treatment for longer than necessary. A few studies NOT R ES P OND TO  SRI TREATMEN T have examined whether it may be possible to identify likely treatment nonresponders within a shorter time frame, Although most individuals with OCD respond well to first-​ based upon their early treatment response. For example, line treatment with SRIs, for most the treatment response is in the study by Da Conceicao et al. (2013) (see Onset of not complete. In at least 30% of cases, residual symptoms SRI Efficacy), clinical improvement at 4 weeks was strongly remain in spite of prolonged treatment (Eddy et al., 2004). associated with treatment response, emphasizing the The clinical management of treatment-​resistant OCD is an importance of measuring early treatment-​related changes area that has not yet been thoroughly investigated, although and hinting that change could be considered earlier than 12 there is much interest in the area, and studies indicating weeks into the course of treatment. However, as only 55% promising treatment strategies are starting to appear in the of those who showed early improvement were responders even at 12 weeks, and data from another extended trial sugscientific literature. Research into treatment-​resistant OCD has been com- gest a full clinical response may occur in some cases only promised by the lack of validated definitions of treatment after several months of treatment (Rasmussen et al., 1997), response and treatment failure. Studies have chosen various it may be appropriate to persist for longer than 12 weeks different criteria; some included only extremely refractory with a given SRI in patients who have shown some signs patients who had failed to respond to successive sustained of improvement but who have not yet fully responded. The treatments with more than one SRI, whereas others included study by Diniz et al., (2011) tested 54 patients who had not those who had made a partial response to treatment with a responded to 8 weeks of fluoxetine monotherapy by ransingle drug. Pallanti and colleagues (2002) proposed research domizing them to one of three treatment arms: fluoxetine criteria based on expert consensus opinion. Treatment-​ and placebo, fluoxetine and clomipramine, or fluoxetine failure was suggested as less than 25% improvement from and quetiapine. At the 12-​week study end-​point, those in baseline in total Y-​BOCS scores. Levels of nonresponse, both the fluoxetine and placebo and fluoxetine and clomipaccording to the numbers of failed treatments, were also ramine treatment groups had improved equally and signifdefined and the term “treatment-​refractory” was reserved icantly when compared with the fluoxetine and quetiapine group, suggesting delayed benefit occurs from extended for those who did not respond to “all available treatments.” 450

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treatment with fluoxetine. Importantly, the patients in this study were not necessarily fully SSRI resistant at baseline (exposed to only 8 weeks of SSRI). Notwithstanding, an extended trial of monotherapy with the original SSRI may be a rational option for SSRI nonresponders or partial responders, particularly if the treatment is well tolerated, given the limited documented benefit of other treatment strategies.

risk of dose-​related serious adverse events, including cardiotoxicity and seizures. In contrast, some evidence suggests SSRIs may show better efficacy and are well tolerated by OCD patients when given at doses exceeding the licensed recommendations. A  metaanalysis (Bloch et  al., 2010)  involving 2,268 adult patients demonstrated that higher doses of SSRIs were associated with greater clinical efficacy, as determined by improvement in Y-​B OCS scores or by the proportion of treatment responders. However, higher doses of SSRIs were also S W I T C H B E T W E E N S R I S / ​S R I T O   S E R O T O N I N -​ associated with a significantly higher number of drop-​ NOREPINEPHRINE REUPTAKE INHIBITOR outs as a result of side effects. Similarly, in the metaIf the response to the first SRI is inadequate (assuming good analysis by Issari et  al. (2016), higher doses of SSRIs adherence) or poorly tolerated, switching to another SRI were also associated with larger improvements in OCD is another acceptable option. However, there is very lim- symptoms. This effect tends to be seen after 3 to 6 weeks ited data to support this practice. March et al. (1997) rec- of treatment. It is important to highlight that in both ommended switching to another SRI if the clinical effect the metaanalyses cited (Bloch et  al., 2010; Issari et  al., is incomplete after 8 to 12 weeks on the maximum dose. 2016)  the dosages in the studies included were within They estimated the chance of responding to a second SRI licensed ranges at the time that the studies were conat 40%, and to a third at even less. They also proposed ducted; it is no longer recommended that citalopram is switching to clomipramine after two or three failed SSRI prescribed at dosages exceeding 40 mg daily, due to contrials. However, in an open-​labeled study, switching from cerns about possible QT prolongation. one SSRI to another resulted in a lower response rate (0%–​ Early case studies (Bejerot & Bodlund, 1998; Byerly 20%) than switching to clomipramine (33%–​40%) (Koran et  al., 1996)  were followed by two open-​label studies et al., 2002). In another study, in which patients who failed that tested a “higher than usual” dose of escitalopram to respond to at least two trials of an SSRI (excluding cita- over 16 weeks. The study by Rabinowitz et  al. (2008) lopram) were randomized to 12 weeks of clomipramine, found that 64% of 67 patients receiving escitalopram venlafaxine, or citalopram, 37.5% patients switched to clo- in the range of 20 to 50 mg daily (mean 33.8 mg/​day) mipramine and 42% switched to venlafaxine responded, achieved responder status. Escitalopram was well tolercompared with 14% on citalopram (Ravizza et al., 2001). ated, with no discontinuations within the higher dose The authors suggested that switching to a drug with a differ- phase. Dougherty et al. (2009) randomized 30 patients ent mode of action may be more beneficial than switching to either 20 mg or 30 mg per day escitalopram. At the end-​ to a third SSRI. In contrast, Denys et al. (2004) performed point, those taking 30 mg per day showed a significantly a double-​blind switch study of paroxetine and venlafax- greater improvement in Y-​B OCS scores and response ine in 43 patients who had failed to respond in an earlier rate than those taking 20 mg per day. Interestingly, the trial. At the end of 12 weeks, 42% patients benefited from a difference disappeared when the results were analyzed switch to the alternate agent. Responder rates were 56% for with baseline depression and anxiety scores included as switching to paroxetine (15/​27) and just 19% for switch- covariates, suggesting that OCD patients with comoring to venlafaxine (3/​16). Altogether, after two consecu- bid depression or anxiety may specifically benefit from tive trials of these treatments, 109 of 150 patients (73%) a higher SSRI dosage. achieved a Y-​B OCS decrease of at least 25%. The results A double-​blind study (Ninan et al., 2006) has investiaffirm switching SRIs in case of refractoriness may be con- gated the use of higher doses of sertraline in OCD patients sidered a useful strategy for patients with OCD and suggest who had failed to respond to standard doses of sertraline that paroxetine is more efficacious than venlafaxine in the monotherapy. Sixty-​six patients were randomized to contreatment of nonresponders to a previous SRI trial. tinue with sertraline 200 mg per day or to receive 250 to 400 mg par day. Although responder rates did not significantly differ between the two groups, at the end-​point, INCREASE SRI DOSAGE symptom improvement (on Y-​B OCS and CGI) was sigThe maximum recommended dose (250 mg/​day) of clo- nificantly greater for the high-​dose group. Both groups dismipramine is not usually exceeded, due to the increased played similar levels of adverse events, suggesting sertraline S tandard E v idence - B ased P harmacological T reatment

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is comparatively more effective and well tolerated at doses higher than 200 mg per day. A systematic, retrospective, naturalistic case-​notes review (Pampaloni et  al., 2010), conducted in a specialist OCD outpatient service, found that patients receiving higher doses of SSRI (n  =  26) demonstrated clinical improvement over time. However, both baseline and endpoint Y-​B OCS scores for the high-​dose group exceeded those of a control group treated in parallel with formulary doses, indicating limited benefit for high-​dose SSRI treatment. The frequency of adverse event reporting did not differ significantly between the two groups, suggesting that higher dosages of SSRIs are well tolerated. The APA OCD Guideline (Koran et al., 2007; updated in Koran & Simpson, 2013) provides a list of upper doses of SSRI that exceed licensed limits and that are occasionally prescribed for those who have failed to respond to conventional doses or are recognized to be “fast metabolizers.” As long as the patient is not experiencing undue adverse effects, the Guideline (Koran et  al., 2007)  recommends “occasionally prescribed” doses of up to 120 mg per day of fluoxetine, 450 mg per day of fluvoxamine, 100 mg per day of paroxetine, and 400 mg per day of sertraline. Such doses seem most warranted when the patient has had a partial response to a lower dose and is tolerating the medication well. However, such an approach is not without risk. In the case of some SSRIs—​for example, citalopram and perhaps also escitalopram, which are recognized to have a dose-​dependent effect on extending the ECG QT interval (U.S. Food and Drug Administration, 2012)—​caution is required if the maximum dose is exceeded, although a recent study did not show an elevated cardiac risk on higher doses of citalopram (Zivin et al., 2013). The elderly or those with a cardiac history may be at particular risk from higher doses of these compounds. If exceeding the licensed daily dosage, it may be advisable to monitor for adverse effects on cardiac conduction (e.g., by ECG monitoring). The elderly may also be susceptible to SSRI-​induced electrolyte disturbances and bleeding tendencies, and for those on anticoagulant therapy, especially if using high dose fluoxetine, the International Normalized Ratio may require more stringent monitoring. INTRAVENOUS ADMINISTRATION OF SSRIS

There is evidence to suggest a role for intravenous (IV) administration of SRIs in those who have failed to respond to oral administration, though this approach is highly

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dependent on the configuration of health systems and may have limited practicality outside inpatient settings. In a study of 54 oral clomipramine-​refractory OCD patients (Fallon et  al., 1998), participants were randomized to receive either IV clomipramine (starting at 25 mg/​ day and increasing up to 250 mg/​day) or IV placebo. In the IV clomipramine treatment arm, 21% of patients were treatment responders (compared with 0% in the placebo group); significant improvements were evident on the National Institute of Mental Health Obsessive Compulsive Scale and the CGI scale, but not on the Y-​BOCS. IV clomipramine was not associated with any serious adverse events. In another recent open-​label study (Karameh & Khani, 2015), in 30 SRI-​resistant cases, IV clomipramine was administered for 1 week on an inpatient basis and was followed by oral clomipramine dosed up to 225 mg per day. At discharge, 23 patients (76.7%) had a decrease in Y-​BOCS ≥25% and were considered responders; however, only 18 (60%) were still responders at 24 weeks. No relevant persistent side effects were reported. The results suggest IV clomipramine could be of at least short-​term benefit for severe OCD cases that have not adequately responded to several therapies, but the long-​term advantages need further exploration. An open-​trial (Pallanti et  al., 2002)  of IV citalopram in 39 patients, who had failed at least two adequate trials of SRIs (excluding citalopram), showed the treatment was well tolerated even at high doses (up to 80 mg daily). Fifty-​ nine percent of the patients responded rapidly. Twenty-​ seven patients who had an improvement of at least 20% in Y-​B OCS scores continued treatment with oral citalopram, and by day 84 all of these patients demonstrated significant further improvement. Consequently, the authors suggested that IV citalopram could be a useful method of accelerating response for OCD patients and for predicting response to oral citalopram treatment. COMBINING DIFFERENT SRIS

For OCD patients resistant to SRI monotherapy, the combination of clomipramine with an SSRI has been found to be helpful in a few studies, but this combination should be prescribed with caution as potentially dangerous pharmacokinetic interactions on the hepatic P450 cytochrome isoenzymes may occur, resulting in elevated clomipramine plasma levels (see ­chapter 42). A small study of 22 patients with a mixture of diagnoses (Szegedi et  al., 1996)  found that the combination of fluvoxamine and clomipramine was efficacious and generally well tolerated, although high plasma levels of clomipramine were associated with a higher frequency

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of clinically relevant adverse effects. The authors therefore recommended ECG and EEG monitoring, as well as clomipramine plasma level monitoring for comedicated patients. Compared with other SSRIs, citalopram and escitalopram are potentially less likely to pharmacokinetically interact with clomipramine. Another small open-​label trial (Pallanti et al., 1999) investigated the efficacy of citalopram (40 mg daily) in combination with clomipramine (150 mg daily) compared with citalopram (40 mg daily) monotherapy. All nine patients in the combination therapy group showed decreased Y-​BOCS scores, by at least 35% from baseline, compared with just one patient in the citalopram monotherapy group. Adverse effects were similar in both groups, suggesting that clomipramine in combination with citalopram might be used effectively and safely in patients with OCD. However, two more recent small studies, with methodological weaknesses, have found no benefit from combining clomipramine with an SSRI and have emphasized the potential for adverse effects associated with this combination. A  small open-​label study of 21 SSRI nonresponders (Diniz et  al., 2010)  found that combining an SSRI with clomipramine did not produce symptomatic improvement. One patient had to withdraw because of serotonin syndrome. A  further double-​blind, placebo-​controlled study (Diniz et al., 2011) of 54 patients who had not responded adequately to 8 weeks SSRI monotherapy found that combining fluoxetine with adjunctive clomipramine was no better than giving adjunctive placebo. Three patients on adjunctive clomipramine developed a prolonged ECG QTc interval and were withdrawn. Taken together, these results suggest limited benefits for such combinations and, if they are contemplated, that ECG and plasma level monitoring are advisable. AUGMENTING SRI WITH ADJUNCTIVE ANTIPSYCHOTIC

On the basis of current limited evidence, antipsychotics when administered as monotherapy do not appear to be effective in OCD (with the possible exception of aripiprazole) (e.g., McDougle et al., 1995). In contrast, they may play an important adjunctive role when administered with SRIs (Keuneman et al., 2005). Studies of adjunctive antipsychotic agents have produced the strongest evidence of effectiveness in SRI-​resistant OCD. Even so, the evidence is largely based on results from small, randomized controlled trials and open case series. The use of antipsychotics needs to be balanced against their adverse event profile. Metabolic, neuromuscular, and cardiovascular

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side effects are common in patients receiving antipsychotic medications for any indication, so thorough initial evaluation to ensure that their use is clinically warranted and ongoing monitoring to ensure that adverse effects are identified and managed are recommended (http://​ www.choosing wisely.org/ ​ c linician- ​ l ists/ ​ a merican-​ psychiatric- ​ a ssociation- ​ a ntipsychotic- ​ m edications-​ without-​appropriate-​and-​ongoing-​evaluation/​). There have been no dose-​finding studies of antipsychotic in OCD. Moreover, we have limited understanding of the optimal duration of antipsychotic treatment, the role in relapse prevention (Maina et  al., 2003), and the place of routine metabolic monitoring for this patient group (Albert et al., 2013).

First Generation Antipsychotic A double-​ blind, placebo-​ controlled study (McDougle et  al., 1994)  demonstrated significant Y-​B OCS improvements for haloperidol (mean dose 6.2 mg) added to fluvoxamine. Eleven of 17 patients receiving the active drug achieved “responder” status within 4 weeks, compared with none receiving placebo. A better response was reported for patients with comorbid tics. In a case series by the same authors, McDougle et  al. (1990) reported a benefit from adding open-​label pimozide (6.5 mg) in 17 patients unresponsive to fluvoxamine. Those with comorbid chronic tics or schizotypal disorder responded best. However, dose-​ dependent extrapyramidal side effects, such as akathisia, occurred to the extent that in some of the studies (e.g., McDougle 1990, 1994)  up to half the patients required coadministration of beta blockers and/​or anticholinergics. Another study that demonstrated efficacy of adjunctive haloperidol 2 mg per day (Li et al., 2005) noted that out of the 12 patients, 5 had to terminate the treatment prematurely owing to dystonia and severe lethargy. It is therefore recommended to start treatment with low dosages, and increase cautiously subject to tolerability (e.g., 0.25–​0.5 mg daily haloperidol, titrated slowly to 2–​4 mg daily; McDougle & Walsh, 2001). Due to their propensity for extrapyramidal side effects, first-​generation antipsychotic agents are usually reserved as a third-​line treatment after a trial of a second-​ generation antipsychotic.

Second Generation Antipsychotic Second-​generation antipsychotics that modulate serotonin and dopamine neurotransmission also offer promise in SRI-​resistant OCD.

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Risperidone Several randomized controlled trials have demonstrated efficacy for adjunctive risperidone in SSRI-​resistant OCD. In a double-​blind, placebo-​controlled trial (McDougle et  al., 2000), 36 SRI-​resistant patients were assigned to either adjunctive risperidone (mean dose 2.2 mg daily) or placebo for 6 weeks. Risperidone was superior at reducing the symptoms of OCD, anxiety, and depression. 50% of those in the risperidone group became responders. Patients in the placebo group were subsequently given a similar open-​label trial of risperidone; within this group, 50% were found to respond. Risperidone was generally well tolerated, with the main adverse event recorded being mild transient sedation (85%). A smaller study (Hollander et al., 2003c) of 16 patients with treatment-​refractory OCD (defined as failing two adequate trials of SRIs) found that after 8 weeks of treatment, 40% of the risperidone group had responded, compared with none in the placebo group. A  third trial (Erzegovesi et  al 2005)  enrolled 45 drug-​naïve subjects in a 12-​week open label fluvoxamine phase, after which 10 fluvoxamine nonresponders were randomized to 6 weeks low dose (0.5 mg daily) risperidone and 10 to placebo augmentation. The study lacked a formal between-​group analysis, but five risperidone-​ treated cases responded compared with two on placebo. Taken together, these data suggest that risperidone augmentation is an effective strategy for SSRI-​resistant OCD. However, a fourth study (Simpson et  al., 2013)  that treated 100 SSRI partial or nonresponders with adjunctive intensive CBT, adjunctive risperidone (up to 4 mg daily), or adjunctive pill placebo, found no benefit for risperidone over placebo in an 8-​week randomized controlled trial. These data suggest that the benefits of adding risperidone may be limited to patients with clear evidence of SSRI resistance.

placebo-​controlled study (Bystritsky et al., 2004) randomized 26 patients to either olanzapine (mean dose 11.2g/​day) or placebo augmentation for 6 weeks. Six out of 13 patients (46%) in the olanzapine treatment arm were responders, compared with none in the placebo group. Two patients (15%) withdrew from the study due to adverse effects from olanzapine (weight gain and sedation). A similar study (Shapira et  al., 2004)  compared the effect of augmenting fluoxetine with olanzapine or placebo. However, in this study there was no benefit from adjunctive olanzapine, as both groups improved significantly after 6 weeks. The study probably failed because the study population was not truly SSRI-​resistant; the majority of patients had only been taking 40 mg per day fluoxetine, with one taking just 20 mg per day prior to entering the trial.

Quetiapine Studies investigating adjunctive quetiapine in treatment-​ resistant OCD have also yielded mixed results. In one double-​ blind, placebo-​ controlled study (Carey et  al., 2005)  with 42 participants, quetiapine (mean dose 169 mg) was found to be no more effective than placebo. After 6 weeks, 40% in the quetiapine treatment arm responded compared with 47.6% in the placebo group. Again, the study may have failed because the study population did not have established SRI-​resistance. In contrast, in another study (Denys et  al., 2004)  of 40 OCD patients characterized by greater SRI-​resistance (at least two previous trials of SRIs at maximum tolerated doses), adjunctive quetiapine (up to 300 mg daily) was efficacious. In the quetiapine treatment group, 40% were responders (decrease in baseline Y-​B OCS score ≥35% and CGI-​Improvement scale rating of “improved” or “very much improved”) compared with 10% in the placebo group. Paliperidone Another smaller study of adjunctive quetiapine in 21 An 8-​week double-​blind study (Storch et al., 2013) investi- cases of highly treatment-​resistant OCD (at least two pregated the use of adjunctive paliperidone (9-​OH-​risperidone-​ vious trials of SRIs at maximum tolerated doses) (Fineberg the primary active metabolite of risperidone) (≤9 mg/​day) et al., 2005) found that quetiapine (mean 215 mg/​day) was or placebo in 34 SSRI-​resistant OCD cases. There was a sig- numerically advantageous (quetiapine showed a mean 14% nificant reduction in Y-​B OCS scores (mean 7.98 points) improvement in Y-​B OCS compared with 6% on placebo), in the paliperidone arm; however, similar reductions (not but the results did not reach statistical significance. as great) were also evident in the placebo group (mean 4.02 A further small randomized controlled study (Kordon points), and the difference did not reach statistical signifi- et al., 2008) investigated adjunctive quetiapine (up to 400 cance. The study was described as a pilot and the results sug- mg daily) in 40 cases with severe OCD unresponsive to 12 gest that a better-​powered study is needed to unequivocally weeks of SRI and found no significant difference between demonstrate efficacy. quetiapine and placebo (mean decrease in Y-​B OCS 5.2 in the quetiapine group and 3.9 in the placebo group). Olanzapine A small randomized, open-​label trial with some methSome evidence suggests that adjunctive olanzapine is also odological limitations compared the use of adjunctive queeffective in SRI-​ resistant OCD. A  small double-​ blind, tiapine (200 mg) with adjunctive clomipramine (75 mg) in 454

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SSRI-​treated patients (Diniz et al., 2010). Quetiapine produced a significantly lower Y-​B OCS score at the end-​point of the study compared with baseline; this was not the case in the clomipramine group. In addition, 4 (out of 11) quetiapine patients were responders, compared with 1 (out of 10) patients taking clomipramine. A meta-​analysis (Fineberg et  al., 2006)  incorporating results from three of the controlled trials (Carey et al., 2005; Denys et al., 2004; Fineberg et al., 2005) indicated efficacy for quetiapine, measured by improvements on Y-​B OCS scores. Furthermore, in a pooled analysis (Denys et  al., 2007)  of data from the same placebo-​controlled quetiapine trials involving 102 patients (Carey et al., 2005; Denys et  al., 2004; Fineberg et  al., 2005)  quetiapine appeared superior to placebo. The best results were seen when quetiapine was used in combination with specific SRIs (i.e., clomipramine, fluoxetine or fluvoxamine), and when the SRI dose was lower, suggesting quetiapine may be of most benefit in those patients who are unable to take maximal doses of SRI.

efficacious in an open-​label study of eight OCD patients (Connor et al., 2005). These results suggest promise for aripiprazole in treatment resistant OCD across the lifespan, and argue for further exploration of the effect of antipsychotic monotherapy in OCD. W H IC H ANT IPS YC H OT IC IS B E S T IN  S R I-​R E S IS TANT   OC D? HEAD TO HEAD STUDIES

A retrospective analysis of naturalistic treatment (Savas et al., 2008)  compared 24 SRI-​resistant OCD patients treated with adjunctive quetiapine or ziprasidone. The results indicated that clinical improvement was more frequent in the quetiapine (80%) compared with the ziprasidone cohort (44.4%), and at 2, 3, and 6 months follow-​up, Y-​B OCS and CGI scores were higher in the ziprasidone group. A single-​blind, randomized trial (Maina et al., 2008) of Aripiprazole 50 treatment-​resistant OCD patients compared adjuncA small, 12-​week open-​label study (Pessina et al., 2009) used tive olanzapine (mean dose 5.3 mg/​day) and risperidone flexible doses of adjunctive aripiprazole (mean daily dose (mean dose 2.1 mg/​day). Patients in both groups showed a 11.2 mg) in 12 SRI-​resistant OCD patients. At the 12-​ significant postbaseline response without evident between-​ week end-​point the patients showed a significant improve- group differences. Discontinuation rates were also similar. ment in their Y-​B OCS scores compared with baseline. Although the proportion of patients reporting adverse A  subsequent 16-​week double-​blind, placebo-​controlled events did not differ, the profile of adverse experiences diftrial (Muscatello et  al., 2011)  of 30 treatment-​resistant fered significantly, with risperidone being associated with adult OCD patients indicated that adjunctive aripiprazole restlessness or amenorrhea and olanzapine with weight gain. (15 mg/​day) was superior to placebo (mean decrease of Another small, double-​blind trial of 44 patients (Shoja 28.5% in Y-​B OCS score with aripiprazole compared with Shafti & Kaviani, 2015) who had not responded to fluvox0.6% with placebo). A  similar 12-​week randomized con- amine monotherapy (300 mg daily) compared adjunctive trolled study in 39 patients (Sayyah et al., 2012) also found aripiprazole (10 mg/​day) and quetiapine (300 mg/​day). a significant reduction in Y-​B OCS scores with adjunctive No participants in the study demonstrated a full response; aripiprazole (10 mg/​day) compared with placebo (30.6% however, there was a significantly higher number of partial for aripiprazole compared with 4.14% for placebo). responders in the quetiapine (54.4%) group compared with Aripiprazole has also been studied in young people with the aripiprazole group (27.3%). The results may be difficult SRI-​resistant OCD. Masi et al. (2010) reported a case series to extrapolate, as all participants were female inpatients. of 39 severely impaired adolescents, for whom aripiprazole (mean daily dosage 12.2 ± 3.4 mg) augmentation of SRIs M E TA A N A LY S I S was well tolerated and effective in more than half of the patients. Another interesting recent open-​label study inves- Although studies on the previously mentioned antipsytigated aripiprazole monotherapy (2–​7.5 mg/​day) in 16 chotics have demonstrated effectiveness as augmentation children with OCD resistant to at least 12 weeks of treat- agents in OCD, the overall effect size is modest, and only ment with at least two SSRIs and CBT. Aripiprazole dem- around one third of patients are noted to respond to such onstrated striking improvement in CGI scores (all subsets, treatments. p ≤ .002) for 13 of 16 children, and halved all CY-​B OCS A metaanalysis (Skapinakis et  al., 2007)  combining subscores after approximately 12 weeks of treatment. results from 10 randomized, placebo-​ controlled studAripiprazole monotherapy was also found to be potentially ies involving haloperidol, risperidone, olanzapine, and S tandard E v idence - B ased P harmacological T reatment

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quetiapine found adjunctive antipsychotics as a group were effective compared with placebo (RR = 3.31). There was inadequate evidence to recommend one antipsychotic over another. A  subsequent metaanalysis by Dold et  al. (2013) included 12 studies (incorporating 394 patients). The analysis showed that significantly more participants responded to augmentation with antipsychotics compared with placebo (RR = 2.1). Risperidone was found to be efficacious, whereas the results for aripiprazole and haloperidol were inconsistent. This analysis did not support efficacy for quetiapine or olanzapine. The authors suggested that risperidone should therefore be the first-​choice adjunctive antipsychotic in OCD. The most recent metaanalysis (Veale et  al., 2014), which restricted itself to second-​generation antipsychotics and included 14 studies and 493 patients, produced a rather similar result. Antipsychotics as a class were efficacious, as were the specific agents aripiprazole and risperidone, whereas there was insufficient evidence to suggest that quetiapine or olanzapine were superior to placebo. It is also worth noting that augmentation with antipsychotics appears to have a greater benefit in patients with comorbid tic disorder. A metaanalysis by Bloch et al. (2006) highlighted this observation; in their analysis involving data from nine studies, the absolute risk difference for the subgroup of OCD patients with comorbid tic disorder was 0.43 compared with 0.22 for the entire population of OCD patients. A mixed model metaregression analysis of 13 RCTS (Ducasse et  al., 2014)  attempted to correlate the effectiveness of each antipsychotic compound (as standardized mean difference in Y-​B OCS score) with the neurotransmitter receptor binding affinities of each drug. The authors found a significant positive correlation between dopamine receptor (D2R, D3R) affinity and clinical efficacy, suggesting antipsychotics may exert their clinical effects in OCD through this mechanism. P HA R M ACOLO G I CAL TREATMEN T O F O C D IN P REGNA NCY AN D BREASTFEED I N G Women who are pregnant or within the postnatal period (up to 1 year after birth) are 1.5 to 2 times more likely to experience OCD symptoms compared with the general population (Russell et al., 2013; see ­chapter 27). The UK National Institute for Health and Care Excellence (NICE) recently performed a detailed analysis of the use of antidepressants in pregnancy (NICE, 2014). NICE advised that there should be a higher threshold for pharmacological treatment with antidepressants such as SSRIs and TCAs 456

in pregnant or breastfeeding women and, where appropriate, psychological intervention should be offered in the first instance (NICE, 2014). Acquiring robust data on the use of pharmacological treatments in pregnancy and breastfeeding women is challenging. It was acknowledged by NICE (2014) that there is insufficient evidence to make recommendations regarding the use of pharmacological interventions in specific anxiety disorders (including OCD). However, based on the existing evidence, it was thought reasonable for certain pregnant women whose symptoms have not responded to psychological treatments to receive pharmacological treatment with antidepressants. Decisions about initiating or continuing pharmacological treatment in pregnancy and breastfeeding need to be made on an individual benefit versus risk analysis. It was also recommended that pregnant and breastfeeding women should be given access to the available information pertaining to the risks and benefits of both continuing and stopping medication, and should be supported in the decisions that they make surrounding their treatment. Ideally, such discussions should take place well in advance of pregnancy, to facilitate effective care planning. Given the high rates of relapse observed following SSRI discontinuation in the placebo-​referenced trials (see earlier; risk of relapse was shown to be 2.74 times greater on placebo compared with escitalopram; Fineberg, Tonnoir et al., 2007), for those women whose OCD is stabilized on SRI, any medication changes need to be managed with caution. For those choosing to discontinue SRI, the creation of a robust relapse-​management plan, including consideration of treatment with CBT and support for the partner or carer, is advisable. For detailed advice relating to prescribing in pregnancy and breastfeeding, including the risks associated with specific agents, we refer the reader to the 2014 NICE guideline. In summary, the risks were found to include a small but significant association between SSRIs and the rate of preterm delivery and miscarriage. SSRI exposure in late pregnancy is associated with a small but significant risk of persistent pulmonary hypertension in the neonate (additional 2 cases per 1,000 pregnancies). Neonatal adaptation syndrome, respiratory distress, and tremor are seen more frequently following maternal treatment with any antidepressant; in the NICE analysis the absolute risk differences ranged from 34 to 333 more per 1,000. However, such difficulties are usually perceived as mild and self-​limited. There was also evidence of a small but statistically significant association between maternal SSRI use and congenital malformations, including cardiac malformations (major and minor combined; additional 9 per 1,000 O bsessi v e - C ompulsi v e D isorder

 

pregnancies). However, the association between major congenital malformations and SSRI treatment did not turn out statistically significant. Sertraline appeared to be associated with fewer congenital malformations than the other SSRIs and for this reason is often the SSRI of choice for pregnant women. Interestingly, analysis by NICE of the association between TCAs with congenital malformations favored the group prescribed TCA (20 fewer per 1,000) compared with the nonexposed group. This finding could be interpreted to support the use of clomipramine for OCD in pregnancy. However, in the NICE analysis there was an unusually high rate of congenital malformations in the nonexposed group, which may have confounded the result. Moreover, TCAs such as clomipramine should be prescribed with caution in pregnant women due to their potential toxicity in overdose. It has been reported that parental mental health disorders can be associated with an increased risk of neurodevelopmental disorder such as autistic spectrum disorder in the offspring (Daniels et  al., 2008). Evidence of neurodevelopmental disorder related to maternal antidepressant was not included in the overall NICE metaanalysis but was independently searched for and analyzed. One study that looked at children prenatally exposed to maternal depressive symptoms, children with prenatal SSRI exposure, and unexposed children (El Marroun et  al., 2014)  found that children exposed in utero to SSRIs showed more autistic traits and were at increased risk of developing pervasive developmental disorders, compared with children who were only exposed to maternal depressive symptoms during pregnancy (odds ratio of 1.91). It is not clear whether any of the children were exposed to prenatal maternal OCD symptoms. It can be argued that naturalistic studies such as this are unable to conclusively demonstrate a causal link because of the potential for ascertainment bias, as the more complex and severely ill cases are more likely to be treated pharmacologically (Viswanathan et al., 2013). The NICE guidelines concluded there is currently limited evidence for associations between pervasive developmental disorders in the offspring and maternal antidepressant treatment. There currently are no published studies looking at maternal OCD in relation to subsequent neurodevelopmental disorders in offspring. For patients requiring antipsychotics in pregnancy, NICE concluded that the data do not favor the use of any particular antipsychotic agent. The available limited data suggest a possible association exists between maternal antipsychotic use and congenital malformation (major congenital malformation; additional 13 per 1,000 pregnancies) and with gestational diabetes (19 additional cases per 1,000 S tandard E v idence - B ased P harmacological T reatment

women). Therefore, NICE advocates that all women prescribed antipsychotics in pregnancy should be offered glucose tolerance testing. Apart from those taking lithium or clozapine, NICE recommends that all women should be encouraged to breastfeed. Sertraline occurs at relatively low levels in breast milk, whereas citalopram and fluoxetine occur at higher levels. Therefore sertraline appears the preferred SSRI for breastfeeding mothers.

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41. THE PHARMACOLOGICAL TREATMENT OF REFRACTORY OCD Christopher Pittenger, MD, PhD

S TA NDA R D TREATMEN TS A ND THEIR LI MI TATI O N S Obsessive-​ compulsive disorder (OCD) affects approximately one person in 40 over the course of a lifetime and produces profound morbidity (Kessler, Petukhova, Sampson, Zaslavsky, & Wittchen, 2012) (see ­chapters 4, 6). New and effective therapeutic tools to alleviate this suffering were developed starting in the 1980s, with the introduction of evidence-​ based psychotherapies based on extinction (­chapter 37) and of pharmacotherapy with serotonin reuptake inhibitors (SRIs): first clomipramine (Insel et al., 1983) and subsequently the selective serotonin reuptake inhibitors, such as fluvoxamine, fluoxetine, and sertraline (Goodman et  al., 1989; Koran et  al., 2007; Soomro, Altman, Rajagopal, & Oakley-​Browne, 2008) (­chapter 40). Contemporary OCD treatment deploys these strategies, either individually or together, and provides substantial symptomatic relief for many (­chapter 36). The greatest barrier to improving the lives of individuals with OCD is the inefficient deployment of these proven treatments, which many patients are unable to access. However, even with optimal delivery of proven first-​and second-​line interventions, a substantial minority of patients experience little improvement. Furthermore, many who improve enough to be categorized as treatment “responders” continue to have significant symptoms, and concomitant suffering and disability. The clinician is therefore often faced with the challenge of treatment-​refractory OCD and must turn to less well proven treatment strategies. There are several approaches to the treatment of refractory OCD. For sufficiently motivated patients, one option is to engage in more intensive cognitive-​behavioral therapy (CBT), in an intensive outpatient or inpatient setting (­chapter  47). For the most profoundly refractory patients, anatomically targeted invasive

treatments are sometimes an option (­chapters 45, 46). The current chapter reviews pharmacological approaches to refractory OCD. These strategies are not as well established in controlled studies as the standard-​of-​care pharmacotherapeutic strategies reviewed in c­ hapter 40, but they are nevertheless frequently necessary in clinical practice. The bedrock of pharmacotherapy for OCD is the use of selective serotonin reuptake inhibitors, or SSRIs:  fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram (Soomro et  al., 2008). Details of the use of these agents and the evidence base behind them are reviewed in c­ hapter  40; a few principles are briefly noted here. First, all SSRIs appear to be equally efficacious, at the population level (though a particular patient may respond better to one than to another). The initial choice between them is thus generally guided by patient preference, side effects, pharmacokinetic factors, and other considerations, rather than by efficacy. Second, although standard SSRI doses can be of benefit, optimal response often requires the use of high doses, for an extended period of time (Issaria, Jakubovski, Bartley, Pittenger, & Bloch, 2016). Third, remission of moderate to severe illness after SSRI treatment is not the norm; response in treatment studies is typically defined as a 25% to 35% reduction in symptoms, which is enough to produce a substantial improvement in quality of life but often leaves substantial residual symptoms. When initial SSRI monotherapy is ineffective or is limited by side effects, it is often advisable to try a second SSRI (Koran et  al., 2007); although they are similarly efficacious overall, in individual cases one agent may provide relief when another has not. When SSRI pharmacotherapy is inefficacious, there are several second-​line approaches with clear support in controlled studies. First, CBT should always be considered, either alone or as augmentation of partially effective or ineffective SSRI treatment (Simpson et al., 2013). Sometimes 463

 

patients who are unable to engage effectively in CBT at baseline, or are unwilling to try, will respond better to psychotherapeutic interventions after a modest “softening” of symptoms with medication. Second, the older SRI clomipramine is efficacious (Insel et al., 1983), and even appears to be more potent than the SSRIs, at the population level (Koran et  al., 2007)—​though it is typically not used as a first-​line agent because of its side effects. Third, augmentation with low doses of neuroleptics, especially risperidone and aripiprazole, is beneficial in some patients (Veale et al., 2014). This may be especially true in those with a history of tics (Bloch et al., 2006). When all of these strategies have been tried (or considered and rejected) and a patient continues to exhibit substantial symptoms and suffering, then they may be considered treatment refractory. Several factors need to be carefully considered before reaching this conclusion. First, is the diagnosis correct? Subtle diagnostic distinctions can arise with autism (­chapter 58), anxiety disorders (­chapter 54), tic disorders (­chapter  53), and obsessive-​compulsive personality disorder (­chapter  59), among others; although conventional diagnostic categories should not be over-​reified and gray areas are common, misdiagnosis may lead to inappropriate treatment selection. Second, were trials of CBT adequate? Many practitioners are not familiar with the details of CBT for OCD, or do not apply them consistently and robustly (­chapters  37, 38). Third, was SSRI dosing adequate? It is common for psychopharmacological generalists to use suboptimal doses and/​or to not extend trials for an adequate length of time before ending them, and some “refractory” patients will respond when SSRI treatment is optimized. Fourth, are there comorbidities or significant environmental factors that are limiting treatment response? Examples may include trauma-​ associated symptomatology (­chapter  55), depression, and family accommodation (­chapter  43). Sometimes alleviation of such auxiliary factors will facilitate response to first-​line OCD treatments. Estimates of the prevalence of refractory OCD vary; systematic exploration of this question is complicated by the fact that different authors have used different definitions of “refractory.” Most estimates cluster around 30%; for our purposes in this chapter, greater precision is not essential. When a patient is refractory to the best evidence-​based treatments, it is important to consider the full gamut of possible interventions, including most specifically higher-​ intensity CBT, and not just pharmacological measures. With that caveat, the remainder of this chapter discuses pharmacological options for refractory disease; other options are addressed elsewhere in this volume. 464

DU AL R E U PTAK E INH IB IT OR S Tricicyclics with high specificity for noradrenergic reuptake blockade are inefficacious for OCD in controlled studies (Foa, Steketee, Kozak, & Dugger, 1987; Thoren, Asberg, Cronholm, Jornestedt, & Traskman, 1980). On the other hand, clomipramine is efficacious a monotherapy for OCD, and may even be superior to the SSRIs (Insel et al., 1983; Koran et al., 2007). This has led to the idea that an appropriately titrated balance between SRI and noradrenergic reuptake inhibitor activity might produce an optimal clinical response in OCD (Dell’Osso, Nestadt, Allen, & Hollander, 2006). However, trials of newer dual reuptake inhibitors have produced mixed results. A small, early open-​label study of venlafaxine monotherapy suggested that it was highly effective in SSRI-​refractory OCD, with a response rate of 76% in 29 subjects (Hollander et  al., 2003). A  smattering of subsequent uncontrolled reports have similarly suggested benefit. However, a later double-​blind crossover study with paroxetine reported clinical response to venlafaxine but suggested that venlafaxine may actually be less efficacious than paroxetine as monotherapy for OCD: The fraction of venlafaxine responders who responded upon crossing over to paroxetine was substantially higher than the fraction of paroxetine nonresponders who responded upon crossing over to venlafaxine (Denys, van Megen, van der Wee, & Westenberg, 2004). Recent studies of duloxetine are weakly positive:  Duloxetine monotherapy showed benefit in an open-​label study (Dougherty et al., 2015) and was equivalent to paroxetine in a blinded active comparator study (Mowla, Boostani, & Dastgheib, 2016). Overall, data on these agents are weak, and they should not be considered alternatives to the SSRIs for initial treatment. However, they may be of benefit to some patients when SSRI monotherapy fails, especially in the presence of comorbid depression.

OT H E R MONOAMINE R GIC   AGE NT S The robust data for the efficacy of the SSRIs in OCD (Soomro et al., 2008) motivates interest in whether other medications that primarily target the brain’s serotonin system may be of benefit. The literature here is mixed. Clearly, improved understanding of the pathophysiology of OCD, and whether and how serotonin imbalance contributes to its pathophysiology, could inform a rational pharmacotherapy. As we do not yet have such an understanding, O bsessi v e - C ompulsi v e D isorder

 

investigations in this area have been largely empirical. Both agents that act specifically on serotonin receptors and antidepressants with broader or indirect serotonergic effects have been investigated. CLOMIPRAMINE AUGMENTATION

Clomipramine augmentation of SSRI treatment, or SSRI augmentation of clomipramine, has been explored in an effort to capture the benefits of clomipramine while limiting the side effects that can emerge at higher doses. Controlled data on these strategies are sparse (Marazziti et al., 2008) and do not provide clear guidance as to their efficacy. The combination of clomipramine with fluvoxamine can be problematic and must be approached with care. Fluvoxamine is a potent inhibitor of the liver enzyme CYP2C19 and thus inhibits the metabolism of clomipramine to desmethylclomipramine. This can result in marked elevations of serum clomipramine when the two agents are coadministered (Szegedi, Wetzel, Leal, Hartter, & Hiemke, 1996). On the other hand, it has been proposed that the combination of clomipramine with low-​ dose fluvoxamine may be beneficial, as increasing the ratio of clomipramine to desmethylclomipramine, which has greater noradrenergic activity, may optimize therapeutic response and reduce the incidence of some side effects (see ­chapter  42). Careful monitoring of serum drug levels is essential if such an approach is used. BUSPRIONE

Busprione (Buspar) is a partial agonist of the 5-​HT1A serotonin receptor; it also has affinity for the D3 and D4 dopamine receptors. It is most often used in the treatment of generalized anxiety disorder. Controlled data in the treatment of OCD are quite limited and largely negative (Koran et al., 2007). Despite this, some experts advocate the use of high-​dose buspirone as augmentation of SSRI therapy in refractory cases. This high-​dose augmentation strategy had not yet been rigorously tested in controlled studies. PINDOLOL

Pindolol is a beta-​ adrenergic antagonist and 5-​ HT1A antagonist. Small controlled studies have reported some benefit from either monotherapy or augmentation of SSRI treatment (Koran et  al., 2007). A  recent metaanalysis of controlled augmentation studies showed a nonsignificant trend toward symptom improvement with pindolol augmentation (Sassano-​Higgins & Pato, 2015). More research P harmacological T reatment of R efractory   O C D

is needed to establish the role of this agent, but it may be of benefit in some cases. MIRTAZEPINE

Mirtazepine is an alpha-​ 2 adrenergic antagonist that enhances norepinephrine release and indirectly enhances serotonergic neurotransmission. A  small open-​label trial followed by double-​blind, placebo-​controlled discontinuation suggested benefit (Koran, Gamel, Choung, Smith, & Aboujaoude, 2005). A  placebo-​controlled trial of mirtazapine augmentation of citalopram suggested that this combination may accelerate therapeutic response, although symptom improvement by the end of the trial (12 weeks) was not different between groups (Pallanti, Quercioli, & Bruscoli, 2004). Side effects can be limiting with mirtazapine: in particular, sedation and weight gain can be prominent. More research is needed to establish the role of this agent, if any, in the pharmacotherapy of OCD. ONDANSETRON

Ondansetron is a 5-​HT3 agonist; it is used in the treatment of nausea, especially in the context of chemotherapy. It has been investigated in five augmentation studies; there is some evidence for benefit (Serata et al., 2015). There has been a single controlled study of the related agent granisetron, which also suggested benefit. These studies have generally used doses substantially lower than those used in the treatment of nausea. A  larger multisite controlled trial was recently completed by Transcept Phamaceuticals (NCT01275248); results have not yet been reported. GLU TAMAT E MODU LAT OR S : T H E NMDA R E C E PT OR There has been substantial interest over the past decade in the hypothesis that imbalance in glutamate, the primary excitatory neurotransmitter in the brain, may contribute to OCD. Evidence in support of this idea comes from genetic studies, work in animal models, neurochemical imaging investigations, and examination of cerebrospinal fluid from patients (Pittenger, Bloch, & Williams, 2011); this literature is discussed in detail elsewhere in this volume (see ­chapters 19, 25, 33). Because glutamate is ubiquitous in the brain and is implicated in numerous brain processes and neurological diseases, a number of pharmacological agents have been described that modulate it; many of these have been tested in OCD, with some early signs of efficacy 465

 

(Pittenger, 2015). It is important to note, however, that no glutamate modulator can be said to have been clearly proven to be effective in OCD. Many early studies have been small and uncontrolled, and controlled studies have been small and have yielded mixed results. Clinically, therefore, it is only appropriate to consider the use of a glutamate modulator once better-​proven approaches, especially CBT and SSRI monotherapy, have been exhausted (Koran et al., 2007). Particular attention has focused on the NMDA glutamate receptor. The NMDA receptor is unusual for two reasons. First, it is not activated by glutamate alone; rather, it is maximally activated when presynaptically released glutamate binds to it as the same time as the postsynaptic neuron in which it is situated is already active. This allows it to serve as a coincidence detector. Second, NMDA activation lets calcium enter the postsynaptic cell. Calcium interacts chemically with a number of substrates in the postsynaptic cell and thereby triggers molecular changes above and beyond its acute effects on neuronal electrical activity. Depending on the amount and specific dynamics of calcium influx, this can trigger synaptic changes, neurotrophic processes, cell damage, or even cell death. Because of this characteristic, the NMDA receptor is thought to be a central player in varied neuronal processes, including brain development, learning, and memory, as well as psychopathology and neurodegeneration. NMDA receptors found outside the synapse have different effects than those at the synapse and may contribute importantly to cell damage when they are excessively activated (“excitoxicity”). MEMANTINE

Memantine is an noncompetitive pore-​blocking NMDA antagonist; it is approved by the US Food and Drug Association (FDA) for Alzheimer’s disease of moderate severity (Yang, Zhou, & Zhang, 2013). In Alzheimer’s disease, it is thought to be neuroprotective by reducing NMDA-​mediated calcium influx and thus limiting excitoxicity (Parsons, Stoffler, & Danysz, 2007). Memantine’s low affinity for the receptor and rapid on-​off kinetics are thought to lead to its preferentially targeting extrasynaptic NMDA receptors, leaving the critical functions of synaptic receptors relatively unperturbed (Parsons et al., 2007). Off-​label use of memantine use in OCD has been described in a number of case series and uncontrolled studies, with generally good tolerability and many reports of benefit (Pittenger et al., 2011; Sani et al., 2012). Individual studies have for the most part been small and not placebo-​ controlled, and so caution in generalizing from these reports 466

is needed. There have been two recent placebo-​controlled studies of memantine augmemtation in OCD, one in outpatients and one in inpatients, from a single center in Iran; both reported dramatic and statistically significant benefit (Ghaleiha et al., 2013; Haghighi et al., 2013). The effects reported in these studies were more robust than those of any other controlled study of any medication in OCD—​ 100% response in one case—​which raises questions about whether the investigators were diagnosing and assessing OCD in the same way as others. These questions aside, memantine is FDA-​approved and has a relatively benign side effect profile and thus may be reasonable to consider in refractory cases, once better-​proven agents have been exhausted. KETAMINE

Ketamine is a much more potent noncompetitive antagonist of the NMDA receptor than memantine, and its effects are quite different. Ketamine is used clinically as an anesthetic; it also has abuse potential. Neuropsychiatric interest in ketamine derives from its effects at subanesthetic doses, which are psychotomimetic, dissociative, and  –​remarkably –​produce an almost immediate antidepressant effects that last for up to 2 weeks after a single infusion (Krystal, Sanacora, & Duman, 2013). This striking observation has spurred interest in whether ketamine infusion might be of similar benefit in OCD. Results have been mixed. An open-​label trial in 10 treatment-​refractory patients showed benefit to comorbid depression but a clinically insignificant effect on OCD symptoms (Bloch et  al., 2012). However, a subsequent placebo-​controlled crossover trial in unmedicated, nondepressed patients suggested significant benefit (Rodriguez et al., 2013). Both of these studies were small. It remains to be determined whether a single ketamine infusion will prove to be of benefit in a subset of patients. Excitement over ketamine’s antidepressant effects, both at the level of clinical studies (Krystal et al., 2013) and at the level of mechanistic investigations (Duman & Aghajanian, 2012), is driving significant investment by pharmaceutical companies, and new NMDA-​modulating agents are likely to become available in the near future; off-​label use of these new agents in OCD will be of great interest. G LY C I N E

Glycine is an amino acid and an obligatory cotransmitter at the NMDA receptor: Glycine cannot open the receptor by itself, but it is necessary for glutamate’s effects. Modulating brain glycine is therefore an indirect way to affect the O bsessi v e - C ompulsi v e D isorder

 

activity of the receptor. A small controlled study of glycine itself suggested benefit; unfortunately, large amounts of glycine are required and it produces significant nausea, which led to frequent dropouts (Greenberg et al., 2009). Glycine is unlikely to be a widely useful treatment, even if it proves efficacious, due to these side effects. Glycine levels can be indirectly modulated, however, by an inhibitor of the primary glycine transporter, GLY-​T1. The naturally occurring compound sarcosine inhibits GLY-​T1, and an uncontrolled study suggests that it may be of benefit in refractory OCD (Wu, Tang, Lane, Tsai, & Tsai, 2011). A placebo-​controlled study of the more specific GLY-​T1 inhibitor bitopertin was recently completed (clinicaltrials.gov:  NCT01674361); results have not yet been publicly reported. D -​C Y C L O S E R I N E

D-​cycloserine (DCS) is a modified amino acid that acts as an agonist at the glycine site on the NMDA receptor. It has been used in a rather different way than glycine itself. Because the NMDA receptor is critical for the mechanisms of synaptic plasticity that underlie learning, potentiating its function can enhance learning. This has been clearly shown in animal studies, in which D-​cycloserine can potentiate extinction learning (Walker, Ressler, Lu, & Davis, 2002). Because CBT is a form of structured learning, potentiating its mechanisms may enhance its speed or efficacy (Krystal et al., 2009; Myers, Carlezon, & Davis, 2011). An initial study in patients with acrophobia validated this approach: D-​cycloserine given prior to computerized exposure therapy significantly improved clinical response (Ressler et al., 2004). Several studies have applied this approach to the treatment of OCD, with mixed results (McGuire, Wu, Piacentini, McCracken, & Storch, 2016; Norberg, Krystal, & Tolin, 2008) (see c­ hapter 37). Variables that explain the heterogeneity of response may include the DCS dose, the timing (i.e., how long before psychotherapy sessions it is given), the nature of the CBT, and the nature of the target patient population. Some studies suggest that benefit from D-​cycloserine is limited to early in treatment, such that the net effect is an acceleration of CBT, rather than a change in ultimate efficacy (Norberg et al., 2008). The benefit of DCS augmentation of CBT is sufficiently unclear that it has not entered widespread use; indeed, the efficacy reported in a subset of early studies appears to be decreasing in subsequent work, and recent metaanalyses suggest a small and nonsignificant benefit (McGuire et  al., 2016). A  recent study suggests that it may augment CBT only in otherwise unmedicated patients, not in those concurrently taking an P harmacological T reatment of R efractory   O C D

SSRI (Andersson et  al., 2015); however, this moderating effect was not replicated in a separate study in pediatric OCD (Storch et al., 2016) or in metaanalysis across all published studies (McGuire et al., 2016). Although the utility of DCS in the treatment of OCD remains questionable, the concept of using a pharmacological strategy to increase the efficacy of CBT is an exciting one, and further advances in this area may make a qualitative difference in the efficacy of care in the future. T H E H E T E R O G E N E I T Y O F   N M D A - ​T A R G E T I N G STRATEGIES IN THE TREATMENT OF OCD

The broad range of strategies that have been investigated in OCD, each of which has some data supporting its efficacy, merits comment. The treatment strategies summarized modulate the NMDA receptor in four distinct ways. Memantine treatment represents chronic antagonism of the NMDA receptor. Ketamine infusion, in contrast, achieves more potent, acute antagonism. Glycine (and GLY-​T antagonism) chronically potentiates NMDA function, whereas D-​cycloserine transiently potentiates it prior to CBT. It seems unlikely, though not impossible, that such disparate strategies could all be of benefit in the same patients. Another possibility is that varied pathophysiologies lead to clinically similar presentations of OCD, and different pharmacological mechanisms are efficacious in each. Alternatively, some of these approaches may prove in the end not to be effective after all—​the studies summarized are small, and many are uncontrolled, making false positive results a real danger. Only further research will resolve these questions and establish the role, if any, of NMDA modulation in the pharmacological treatment of OCD. OT H E R GLU TAMAT E MODU LAT OR S RILUZOLE

The first glutamate modulator to be tested in refractory OCD was not an NMDA modulator, but rather the drug riluzole, a unique medication that is approved by the FDA for the treatment of amyotrophic lateral sclerosis (Pittenger, Coric, et  al., 2008). Riluzole has several mechanisms of action; it appears to have a net glutamate-​lowering effect, by reducing glutamate release from axon terminals and by potentiating glutamate uptake by transporters on glial cells (EAAT2 and EAAT3) (Pittenger, Coric, et al., 2008). An initial case report and two follow-​up, open-​label studies suggested benefit in a substantial fraction of patients whose 467

 

OCD is refractory to standard pharmacotherapy (Coric et al., 2003, 2005; Pittenger, Kelmendi, Wasylink, Bloch, & Coric, 2008). Unfortunately, a follow-​up controlled study showed only trend-​level, statistically insignificant benefit (Pittenger et al., 2015); if this trend is real, it would require much larger studies to definitively prove. More recently, a similar study from Iran did suggest statistically significant benefit, when riluzole and an SSRI (fluvoxamine) were started simultaneously (Emamzadehfard et  al., 2016). A  study in children produced more definitively negative results: A placebo-​controlled investigation of riluzole in 60 patients showed no evidence of benefit (P. J. Grant et al., 2014). Although riluzole may be of benefit in some adults, therefore, the evidence does not at present support its widespread use until better-​proven options have been exhausted. N -​A C E T Y L C Y S T E I N E

N-​acetylcysteine, or NAC, is a modified form of the amino acid cysteine and an antioxidant. It can also modulate extrasynaptic glutamate levels through its interaction with the glial cystine-​glutamate antiporter (Pittenger et  al., 2011). This, together with the fact that it is cheap, is available without a prescription, and has a benign side-​effect profile, has motivated trials in OCD, as well as in several other neuropsychiatric conditions (see also ­chapter  44). An early case report suggested benefit from the addition of NAC to ongoing SSRI treatment (Lafleur et al., 2006). Controlled studies from Iran have suggested benefit of NAC augmentation (Afshar et al., 2012; Paydary et al., 2016); but a controlled trial from Australia found no benefit (Sarris et al., 2015), and a recent trial from Brazil suggested benefit for anxiety symptoms but not for OCD (Costa et al., in press). It is possible that particular subgroups of patients respond, and that larger studies with clear subgroup analyses will be needed to clarify effects. NAC has also been studied in trichotillomania, with mixed results. One high-​quality study suggested substantial benefit in adults ( J. E. Grant, Odlaug, & Kim, 2010), but a subsequent study in adolescents showed no benefit (Bloch, Panza, Grant, Pittenger, & Leckman, 2013). More research is needed to clarify the benefits of NAC. That said, its low cost and benign side-​effect profile make it a potentially attractive agent to try, especially in pediatric patients and others in whom side effects may be of particular concern.

levels (in addition to other effects). Controlled trials have suggested modest benefit from topiramate; the effect may be greater on compulsions than on obsessions (Berlin et al., 2011). Benefit from topiramate augmentation was modest in a recent study from Iran, reaching statistical significance at a midpoint analysis but not at the end of 12 weeks (Afshar, Akuchekian, Mahaky, & Zarean, 2014). Side effects, especially cognitive slowing, can be limiting with this agent. LAMOTRIGINE

Lamotrigine is an antiepileptic and mood stabilizer; like riluzole, it reduces glutamate outflow through inhibition of certain presynaptic voltage-​gated sodium channels. (It is not thought to potentiate glutamate reuptake, as riluzole does.) Early work showed no improvement from lamotrigine treatment in OCD (Kumar & Khanna, 2000), but more recent controlled trials suggest benefit (Bruno et al., 2012; Khalkhali, Aram, Zarrabi, Kafie, & Heidarzadeh, 2016), and a number of case reports describing long-​term treatment have been published. More work is needed. OT H E R PH AR MAC OLOGIC AL AU GME NTAT ION S T R AT E GIE S A number of other agents have been investigated in the pharmacotherapy of refractory OCD. As with the agents described, all of these have been examined in small and/​or uncontrolled studies and cannot be considered to be proven treatments for OCD. OPIOID AUGMENTATION

The endogenous opioid system has been postulated to be involved in OCD pathogenesis ever since it was noted that administration of the opioid antagonist naloxone can exacerbate OCD symptoms (Insel & Pickar, 1983). A  double-​blind, placebo-​controlled crossover trial of 23 treatment-​refractory OCD patients demonstrated a significant benefit from weekly oral morphine compared with placebo: 2 weeks of oral morphine produced a median decrease in Y-​B OCS severity of 13%, with 7 of the 23 subjects (30%) being treatment responders (Koran, Aboujaoude, et  al., 2005). Tramadol hydrochloride, an opioid agonist with lower abuse potential than morphine, has been studied as TOPIRAMATE an augmentation agent for treatment refractory OCD in an The antiepileptic drug topiramate interacts with voltage-​ open-​label trial. The six treatment-​refractory OCD patients gated calcium channels and thereby modulates glutamate included in this study experienced an average decline of 468

O bsessi v e - C ompulsi v e D isorder

 

Y-​B OCS scores of 26% (Shapira et al., 1997). Sedation was a problematic side effect of tramadol treatment. Further double-​blind studies are needed to establish the efficacy of tramadol as an augmentation agent in OCD. The addictive potential and other side effects of opioid agents are important considerations. CAFFEINE

Caffeine was included as an active control in a pilot study of amphetamine augmentation in OCD. Both dextroamphetamine and caffeine led to significant improvements in refractory patients, over the course of 5 weeks (Koran, Aboujaoude, & Gamel, 2009). The potential clinical use of these stimulants has not yet been followed up in larger studies. NUTRACEUTICALS

A range of over-​the-​counter supplements and other “nutraceuticals” have been tested in the treatment of OCD, with mixed results. These are further discussed in ­chapter 44.

Because of the relatively weak data base for the use of these pharmacological strategies, the choice between them is often based more on individual practitioner experience and preference than on a clear algorithm. In general, the weight of evidence supporting a particular agent should be weighed against potential side effects, in the context of practical factors. For example, although the evidence supporting N-​acetylcysteine augmentation is fairly weak, with two recent controlled studies showing no statistically significant benefit, its low cost and benign side effect profile may make it a reasonable thing to try in some cases. Conversely, although there is evidence for benefit from morphine treatment, the abuse potential and other side effects associated with opiate agents appropriately limit their use. In sum, much more research is needed to clarify the optimal treatment strategies for patients whose OCD symptoms are refractory to first-​and second-​line pharmacological and psychotherapeutic strategies. It is to be hoped that in the coming years advances in our understanding of the pathophysiology of the disorder will lay the groundwork for a more rational pharmacotherapy for refractory disease.

C ONCL US IO N S R E F E R E NC E S OCD that is refractory to first-​and second-​line treatments is a distressingly common clinical challenge. A  wide variety of pharmacological strategies have been employed in this context. Unfortunately, the literature available to guide their use is quite limited; studies have been small, often uncontrolled, and of variable quality. As a result, as noted repeatedly in the discussion, none of the agents described here are supported by sufficiently definitive evidence for them to be considered part of the standard treatment of OCD. That said, they may be of benefit in some individuals and are often considered when better-​proven first-​and second-​line treatments have failed. Modulators of glutamate neurotransmission and homeostasis have been a focus of particular attention in recent years. Here, too, the evidence base is weak. Of note, agents with contrasting and even opposite mechanisms of action have been investigated; in particular, both positive and negative modulators of the NMDA glutamate receptor have been tested in the treatment of refractory OCD, and they have been used both acutely and chronically. Because glutamate is involved in virtually every part of the brain and is subject to many layers of homeostatic regulation (Pittenger et al., 2011), it is conceivable that such heterogeneous pharmacological mechanisms could all be of benefit, perhaps in different subsets of patients, by targeting different aspects of glutamate imbalance. P harmacological T reatment of R efractory   O C D

Afshar, H., Akuchekian, S., Mahaky, B., & Zarean, E. (2014). Topiramate augmentation in refractory obsessive-​compulsive disorder:  A  randomized, double-​blind, placebo-​controlled trial. Journal of Research in Medical Sciences, 19(10), 976–​981. Afshar, H., Roohafza, H., Mohammad-​ Beigi, H., Haghighi, M., Jahangard, L., Shokouh, P., . . . Hafezian, H. (2012). N-​acetylcysteine add-​on treatment in refractory obsessive-​compulsive disorder: A randomized, double-​blind, placebo-​controlled trial. Journal of Clinical Psychopharmacology, 32(6), 797–​803. Andersson, E., Hedman, E., Enander, J., Radu Djurfeldt, D., Ljotsson, B., Cervenka, S., . . . Ruck, C. (2015). D-​Cycloserine vs placebo as adjunct to cognitive behavioral therapy for obsessive-​compulsive disorder and interaction with antidepressants:  A  randomized clinical trial. JAMA Psychiatry, 72(7), 659–​667. Berlin, H. A., Koran, L. M., Jenike, M. A., Shapira, N. A., Chaplin, W., Pallanti, S., & Hollander, E. (2011). Double-​blind, placebo-​ controlled trial of topiramate augmentation in treatment-​resistant obsessive-​compulsive disorder. Journal of Clinical Psychiatry, 72(5), 716–​721. Bloch, M. H., Landeros-​ Weisenberger, A., Kelmendi, B., Coric, V., Bracken, M. B., & Leckman, J. F. (2006). A systematic review:  Antipsychotic augmentation with treatment refractory obsessive-​compulsive disorder. Molecular Psychiatry, 11(7), 622–​632. Bloch, M. H., Panza, K. E., Grant, J. E., Pittenger, C., & Leckman, J. F. (2013). N-​Acetylcysteine in the treatment of pediatric trichotillomania:  A  randomized, double-​blind, placebo-​controlled add-​on trial. Journal of the American Academy of Child and Adolescent Psychiatry, 52(3), 231–​240. Bloch, M. H., Wasylink, S., Landeros-​Weisenberger, A., Panza, K. E., Billingslea, E., Leckman, J. F.,  .  .  .  Pittenger, C. (2012). Effects of ketamine in treatment-​ refractory obsessive-​ compulsive disorder. Biological Psychiatry, 72(11), 964–​970. 469

 

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42. TREATMENT OF PEDIATRIC OCD S. Evelyn Stewart, MD and Clare Bleakley, MBBS

P

ediatric OCD is a common condition, affecting between 0.5% and 2% of youth (Heyman et al., 2003, Rasmussen & Eisen, 1992; see ­chapter 3). In a 1997 study, OCD was listed among the 10 most disabling medical illnesses by the World Health Organization, illustrating its severe impact (Murray & Lopez, 1997). Despite this morbidity, OCD is frequently underrecognized, with symptoms that often remain hidden or misunderstood by affected youth (Stewart et al., 2012). Although several treatment approaches have demonstrated efficacy for decreasing pediatric OCD severity, remission rates continue to be suboptimal. This chapter summarizes proven first-​line pharmacological and psychological treatments, discusses potential switching and augmentation strategies, and suggests practical management tips for pediatric OCD.

trials have consistently demonstrated its efficacy, although reported effect sizes vary (d  =  0.78 to 4.38) (O’Kearney, 2007). Over the past two decades, increased attention has focused on evaluating CBT techniques that are modified specifically for pediatric patients. ERP is the cornerstone of CBT treatment for pediatric OCD (Barrett et al., 2008; Chu et al., 2015); it is central to the majority of manualized CBT programs examined in controlled trials (Bolton & Perrin, 2008). Despite the plethora of evidence to support its use, however, a survey of pediatric OCD practitioners found that only one third regularly used exposure techniques (Geller & March, 2012). Moreover, access to appropriately qualified or experienced practitioners may be limited in many areas. Non-​ERP elements of CBT that have been incorporated within manualized treatment programs for pediatric OCD include psychoeducation and anxiety management, FIRS T- L​ INE TREATMEN T O F PED I ATRIC   OC D utilizing techniques such as progressive muscle relaxation (Turner, 2006). Cognitive techniques have varied in comAlthough some variability exists, it is important to note plexity across pediatric OCD protocols, ranging from that most OCD treatment studies define clinically signif- focusing on simple coping statements such as, “Boss back icant treatment response as a 25% to 35% decrease in CY-​ the OCD,” to modifying thought appraisal (Himle et  al., BOCS (Children’s Yale-​ Brown Obsessive-​ Compulsive 2003; March & Mulle, 1998; Turner, 2006). The most scale) or Y-​B OCS score (Walsh & McDougle, 2011; see promising CBT treatment protocols are multicompo­chapter  14). This implies that a patient could be consid- nent programs incorporating ERP, cognitive strategies, ered a “responder” and still have substantial and impairing and relapse prevention, while employing developmentally symptoms. Remission is typically defined by a CY-​B OCS appropriate modifications such as family member inclusion or Y-​B OCS score of less than 11 (March et al., 2004; Storch (Barrett et al., 2008; Rosa-​Alcazar et al., 2015). The impact of CBT delivery method, frequency, and et al., 2011). intensity has also been investigated. Barrett et  al. (2004) found equally superior symptom reduction in group-​ PSYCHOLOGICAL TREATMENT delivered (61% decrease) and individual-​delivered (65% Cognitive behavioral therapy (CBT), including exposure/​ decrease) CBT when compared with wait-​list controls. In response prevention (ERP), is the recommended first line a small trial (n  =  31), Storch et  al. (2011) found greater treatment for pediatric OCD (Geller & March, 2012; see remission rates in those receiving Web-​cam-​delivered CBT ­chapters  37, 38). Metaanalyses of pediatric OCD CBT (51%) compared with wait-​list controls (13%). A  study 473

 

comparing intensive (14 daily sessions) versus weekly (14 sessions) CBT found no difference in outcome (Storch et  al., 2007). Intensive treatment has been suggested for those with more severe or impairing illness, given the shorter time to treatment completion. In another study, a greater number of treatment sessions was advised for those with higher baseline OCD severity (Torp et al., 2015). Active involvement of family members has been examined in CBT trials of pediatric OCD, much more than in the treatment of adults. Family interventions are typically designed to reduce family accommodation of OCD symptoms (enabling of OCD-​trigger avoidance and rituals; see ­chapter  43), and may run concurrently with individual (Freeman et al., 2014; Piacentini et al., 2011) or group CBT (Stewart et al., 2014), or as an addition following standard treatment. Family education has also been delivered via Internet (Comer et al., 2014). Early evidence suggests that parental involvement is especially beneficial in therapy for young children (Lewin, 2014; Waters et al., 2001). Specific challenges of conducting OCD-​focused CBT in children include their decreased insight (Storch et  al., 2010a) and limited ability to reflect upon obsessional thoughts (O’Kearny, 2007). Practical adaptations of therapeutic approach include emphasis on behavioral over cognitive techniques to improve engagement (Lewin, 2014). Previously agreed-​upon rewards for effort, given promptly following ERP (Turner, 2006), are advised, along with reinforcing parent and therapist praise (Gryczkowski & Whiteside, 2014; Walther et  al., 2014). Externalizing the OCD (March & Mulle, 1998) and integrating parent management training (Lewin, 2014)  may also help to limit OCD-​related family conflict. Other techniques that are being explored include mindfulness skills training (Edalati et al., 2014; see ­chapter 39) and motivational interviewing (Merlo et al., 2010).

PHARMACOLOGICAL TREATMENT

Serotonin reuptake inhibitors (SRIs), including clomipramine and selective serotonin reuptake inhibitors (SSRIs), represent the mainstay of pharmacological treatment for pediatric OCD (see also ­chapter 40). Clomipramine, a tricyclic antidepressant, was the first medication identified to decrease OCD severity; this is presumed to relate to its relatively specific inhibition of serotonin reuptake (Ivarsson et al., 2015). This hypothesis was strengthened by negative trials of other tricyclic antidepressants, such as desipramine, that have less effect on serotonin reuptake and have no observable impact on OCD (e.g., Zohar & Insel, 1987).

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Selective Serotonin Reuptake Inhibitors Following introduction of the SSRI medication class in the 1980s, these were also identified as effective in pediatric OCD treatment; clearly, this further supports the centrality of serotonergic effects in the previously documented efficacy of clomipramine. Because of their superior side-​effect profile (relative to clomipramine), SSRIs are currently the first-​line pharmacological treatment approach for pediatric OCD, although some have argued that these should be redefined as second-​line following a CBT trial (Ivarsson et al., 2015; NICE Guidelines, 2005). Although all SSRIs are commonly used in clinical management of pediatric OCD, those specifically labelled by the US Food and Drug Administration (FDA) for this indication are fluoxetine (for children over 7 years old), sertraline (for children over 6 years old), and fluvoxamine (for children over 8 years old). Paroxetine is approved for treatment of adult OCD, but not in children. Although citalopram and escitalopram are not FDA approved for OCD in either children or adults, they have shown promising results (Zohar, 2008) and are frequently used off-​label. Any of these six SSRI medications may be prescribed for pediatric OCD at the prescriber’s discretion, based on clinical judgement (Stewart et al., 2012). Details of these medications are included in Table 42.1. No significant efficacy differences between specific SSRIs have been identified, on a population level (Geller et al., 2003; Ivarsson et al., 2015). However, clinical experience suggests differing efficacy in individual patients, which suggests that a trial with alternative SSRI is appropriate following initial treatment failure with a first agent. An adult study of nonresponders to a first SSRI reported a 40% response rate for a second SSRI trial (March et al., 1997). A pragmatic approach for the selection of an SSRI should consider side-​effect profiles, potential interactions with other medications, and family history of responsiveness to a particular agent (Stewart et al., 2012). As for CBT administration, the effects of the intensity and duration of SSRI treatment have also been examined. Two crucial elements for optimizing SSRI response in OCD include sufficient dosage (maximum tolerated within range, presuming remission has not yet occurred) and duration (12 weeks, with 3 weeks at highest tolerated dose). In OCD-​ affected adults, an increase from medium to high SSRI dosage resulted in an additional 7% to 9% improvement in OCD severity (Bloch et al., 2010). This contrasts with SSRI use in depression, which has a nonlinear dose–​response curve. Although higher SSRI doses also correlate with increased adverse effects in OCD, the fairly benign side-​ effect profile of this medication class indicate that this dose O bsessi v e - C ompulsi v e D isorder

 

TA B L E   4 2 . 1  

SR I M E D I C AT I O N S F O R   F I R S T- L​ I N E P HA R M AC OTHER A P Y O F P ED I ATR I C  O C D

Medication

Starting dose (mg/​d)

Target Dose (Range)

Notes on Adverse Effects

Selected Details

*Fluoxetine capsule, liquid

Adolescents: 10–​20 Children 2.5–​10

80 (10–​80)

** Insomnia/​agitation/​ rash possibly more common; weight gain less common; May alter insulin requirements

Prolonged half-​life (may be useful if compliance is poor).

*Fluvoxamine tablet

Adolescents: 25–​50 Children: 12.5–​25

300 (50–​300)

**SSRI class AE Nausea more common

Give in divided doses with meals and bedtime to avoid side effects. Metabolized by CYP1A2 and 2D6. Inhibits CYP1A2 and 2C19.

*Sertraline 25,50,100,150, 200 mg tablet

Adolescents: 25–​50 Children: 12.5–​25

200 (50–​200)

**SSRI class AE Diarrhea more common

Citalopram 10, 20, 40 mg tablet, liquid (10 mg/​5 mL)

Adolescents: 10–​20 Children: 2.5–​10

40 (10–​40)

**SSRI class AE Risk of QTC prolongation above 40 mg daily (d/​c if QTc >500 ms)

Escitalopram tablet, liquid

Adolescents: 5 Child: 5

20 (10-​20)

**SSRI class AE

Paroxetine 10,20,30,40 mg tablet, liquid

Adolescents: 10 Children: 2.5–​10

60 (10–​60)

**SSRI class AE More weight gain/​sexual dysfunction more common

Short half life Metabolized by and inhibits CYP2D6. Discontinuation symptoms common—​withdraw slowly.

*Clomipramine 25,50,75 mg capsules

Adolescents: 25 Children: 6.25–​25

250 (50–​250)

Dry mouth, constipation, dizziness, postural hypotension, sexual, weight gain, tremor, sedation, hyperhidrosis, EKG changes, seizures.

EKG monitoring and monitoring of blood levels is required.

*FDA approved for treatment of pediatric OCD. **SSRI class adverse effects: Common: insomnia, anxiety, gastrointestinal symptoms, sexual dysfunction, dizziness, sedation, behavioral activation. Rare: headache, suicidal ideation/​ behavior, manic switch, increased bleeding time.

escalation strategy is often preferable to the use of augmenting agents with higher associated risks (Bloch & Storch, 2015). That said, it important to note that the net benefit of SSRI doses beyond the usual FDA-​approved range is less well established for pediatric patients than it is for adults. To guide treatment decisions in pediatric OCD, risks versus benefits must be weighed in discussion with the family, considering the risks both of medication use and of ongoing unmanaged OCD pathology. Unfortunately, medication adverse effects almost always precede observable benefits. Common and rare yet serious SSRI adverse effects are included in Table 42.2, with potential management strategies. Children with brain injury or intellectual impairment may be more sensitive to the dose effects of medication or “paradoxical reactions” (Stewart & Stachon, 2014). Although concerns have been raised regarding SSRI effects on the developing brain, no evidence currently suggests that these medications negatively affect neurodevelopment (Cousins & Goodyer, 2015). T reatment of P ediatric   O C D

Antidepressants, including SSRIs, have been associated with increased risk of suicidal ideation among youth, resulting in a 2004 black box warning for suicidality for all antidepressants in those under 18  years old. Specifically, a metaanalysis of antidepressants in depressed youth had found a 4% increase in suicidality compared with 2% in those taking placebo, with no increase in completed suicide (Hammad et al., 2006). However, a reanalysis of fluoxetine data (n = 708) found no effect on suicidality when considering mediating effects of depressive symptoms (Gibbons et al., 2015). In pediatric OCD, a metaanalysis by Bridge et  al. (2007) found that SSRI-​induced benefits outweigh risks of a suicidal event, with a number needed to harm (NNH: suicidal ideation) of 200 versus a number needed to treat (NNT: efficacy) of six. This contrasts with major depression, for which NNH = 112 and NNT = 10. Bridge et al. (2007) also found no significant absolute risk difference (0.5%) between SSRIs and placebo regarding suicidality in pediatric OCD. Therefore, although close monitoring

475

 

TA B L E   4 2 . 2  

SSR I - ​R E L AT E D A DV E R S E E F F E C T S A N D M A N AGEM EN T S TR ATEGI ES Specifics

Management strategies

Often transient, first few weeks

Take with meals

Special notes

Common Nausea/​diarrhea Headache

*Divide dose, start low

Insomnia Sedation Sexual side effects

Typically do not spontaneously resolve

Requires direct questioning

Behavioral activation

Hyperactivity/​ talkativeness/​ impulsivity, may present after several weeks

Decrease dose,* titrate very slowly

SRI-​emergent mania

Uncommon in youth

Close monitoring

Potential suicidality (not completion)

2% increase noted in pediatric depression, no significant increase in OCD

Monitor, especially in first few months

For OCD: Number needed to harm = 200 versus number needed to treat = 6

For citalopram: prolonged QT interval

Risk at >40 mg daily**

Consider EKG

FDA black box warning

Agitation, irritability, gastro-​ intestinal or flu-​like symptoms and sleep disturbance

Gradual dose tapering

Mostly in younger children

Rare but serious Low dose

Vigilence required with bipolar family hx

Special circumstances Sudden discontinuation

Consider fluoxetine (long half-​life) if adherence is poor or unreliable.

Describe to families prior to trial

*Murphy et al., 2008 **US FDA, 2011

and counselling of patients and parents regarding the possible emergence or worsening of suicidal thoughts is appropriate, this concern should not in most cases mitigate against consideration of medication.

Clomipramine Clomipramine is the only non-​SSRI serotonin reuptake inhibitor specifically labelled for use in pediatric OCD by the FDA. With an effect size of d = 1.305, it has superior benefit compared with SSRIs (d = 0.644) in pediatric OCD (Sánchez-​Meca et al., 2014). This was also confirmed in a recent metaanalysis reporting significant differences in effect (p =.009) (Ivarsson et al., 2015). Despite its higher reported efficacy versus SSRIs, clomipramine is not recommended for initial pharmacological treatment of pediatric OCD due to the associated increased frequency and seriousness of adverse effects (Ivarsson et al., 2015). These can be divided into anticholinergic (dry 476

mouth, blurred vision, constipation, urinary hesitancy), antihistaminergic (sedation and weight gain), autonomic antiadrenergic (postural hypotension, intracardiac conduction slowing, sweating, increased blood pressure, tremor), antiserotonergic (sexual dysfunction, nausea), and general central nervous system (confusion, myoclonic twitches, seizure) effects. Prior to initiating clomipramine, these potential adverse effects should be discussed, and personal or family history of cardiac events or seizures should be sought to inform consideration of risks versus benefits. Electrocardiograms should be collected at baseline, 1 to 2 weeks following dose adjustments of clomipramine (or medications that influence clomipramine metabolism), and annually (Stewart & Stachon, 2014). In contrast to SSRI trials, optimizing clomipramine dosage should be guided by serum levels of clomipramine and its metabolite, desmethylclomipramine (DCMI), collected 12 hours post dose. These are significantly influenced by individual hepatic metabolic profiles. O bsessi v e - C ompulsi v e D isorder

 

Tolerability of adverse effects and impact on OCD symptoms must be taken into consideration at each step of dosage management. In spite of its adverse effect profile and the requirement for monitoring, the potential benefits of clomipramine as an alternative following one or two failed SSRI trials should not be underestimated. C O M P A R I S O N O F   C B T, S R I , A N D COMBINED CBT+SRI APPROACHES

The choice between a trial of CBT, an SRI, or a combination of the two in pediatric OCD depends on several variables, not least of which is the practical matter of the availability of a skilled therapist who can provide effective CBT. Outcome predictors for CBT and SRIs have been identified that may be of use in individual management decision making. A recent review of randomized trials directly comparing SRIs with CBT found the latter to be statistically more effective in achieving response in youth with OCD (Ivarsson et al., 2015), when delivered by well-​trained clinicians. The landmark Pediatric Obsessive Compulsive Treatment Study (POTS) trial reported that combined CBT and sertraline produced a superior response to either monotherapy. The remission rate for combined treatment (54%) was significantly greater than that for sertraline alone (21%); it was nominally greater than for CBT alone (39%), thought this latter difference was not statistically significant (March et al., 2004). More recent metaanalyses have confirmed superior response to combined treatment as compared to medication alone, but not as compared with CBT alone (Ivarsson et  al., 2015; O’Kearney, 2007). For those demonstrating a partial response to an SSRI, a follow-​up to the original POTS study (POTS-​II) demonstrated superiority of full CBT augmentation, compared with medication monotherapy or to medication management with brief instruction in CBT by a psychiatrist. These results highlight the need for widespread availability of OCD-​trained CBT therapists to enable effective management of pediatric OCD (Franklin et  al., 2011). Unfortunately, therapist availability is often limited. Treatment selection for individual patients is dependent on several factors, including family perspective, CBT accessibility and clinical characteristics. Several predictive factors have been identified that may be beneficial in this decision (see Figure 42.1). Across both SSRI and CBT treatment types, positive response predictors include lower OCD severity and related impairment, greater insight, and less family accommodation (see c­ hapter  43). The absence of comorbid externalizing symptoms is a positive predictor T reatment of P ediatric   O C D

of treatment response, more so in youth with OCD than in adults (Lebowitz & Bloch, 2012). Comorbid tics are a negative predictor of response to SSRIs. For CBT, family-​related factors have prognostic significance; poorer response is associated with OCD, other psychopathology, and other types of dysfunction within the family structure (Chu et al., 2015; Garcia et al., 2010; Ginsburg et al., 2008; Peris et al., 2012; Torp et al., 2015). In summary, SRIs, CBT, and combined treatments are all more effective in achieving response and remission than placebo. SRI treatment appears to be less effective than CBT or combined treatments, especially with respect to achieving remission. If an initial course of CBT has failed or produced only a partial response, either further CBT or addition of an SRI may be of benefit. Treatment decisions in specific cases are dependent upon the wishes of the family, safety concerns, and co-​morbidities. (Sánchez-​Meca et al., 2014). S E C OND- ​L INE T R E AT ME NT S T R AT E GIE S IN  R E F R AC T OR Y PE DIAT R IC   OC D Unfortunately, even gold-​standard treatment for pediatric OCD (expert CBT and SRI combination) achieves symptom remission in only half of cases (Bloch & Storch, 2015; March et  al., 2004). After confirming that sufficient and appropriate CBT and SRI treatments have been delivered for an individual patient, if clinical response is still inadequate a number of augmenting and alternative treatment strategies may be considered, although the evidence base for them is generally less solid than it is for SRIs and CBT. These include augmenting SSRIs with clomipramine, or augmenting SRIs with antipsychotics, benzodiazepines, or newer agents such as glutamate modulators (Geller & March, 2012). A first consideration in refractory cases is whether first-​ line treatments—​CBT and SRI medication—​have been optimally delivered. Medication trials should include two SRI trials of a minimum of 10 weeks, with at least 3 weeks at the maximum recommended (or tolerated) dose (Geller & March, 2012). CBT can be optimized by increasing its intensity, with multiple weekly sessions. Inpatient admission may also be considered, particularly if this offers the opportunity for intensive CBT therapy in a supportive setting. CLOMIPRAMINE AND FLUVOXAMINE COMBINATION

One pharmacological strategy for refractory disease is the combination of clomipramine with an SSRI (Bloch & 477

 

Diagnosis of OCD

CBT with emphasis on ERP ongoing moderate to severe symptoms 1st SSRI trial (not fluvoxamine)

Unsuccessful trial and moderate illness

Unsuccessful trial and severe illness

2nd SSRI trial (not fluvoxamine) Switch to fluvoxamine

Unsuccessful trial

Unsuccessful trial Decrease fluvoxamine to 100 mg daily. Complete EKG and blood work.

Continue fluvoxamine. Commence clomipramine (CMI) 12.5–25 mg daily

Repeat EKG and blood work including CMI and metabolite levels

Increase CMI by 12.5 – 25 mg as tolerated. Aim for CMI+metabolite level 1 kg) to enable a stable supply throughout the year. S T.  JOH N’ S   WOR T St. John’s wort (SJW; Hypericum perforatum) is a perennial herb with flowering tops that have a long history of medicinal use. Substantial evidence has accumulated supporting 497

 

the efficacy of SJW as an antidepressant; metaanalyses have found SJW to be superior to placebo in reducing depressive symptoms, and of similar efficacy to SSRIs and tricyclics, with fewer adverse effects (Linde, Berner, & Kriston, 2008; Rahimi, Nikfar, & Abdollahi, 2009). The main bioactive compounds in SJW are thought to include hyperforin, hypericin and pseduohypericin, as well as several flavonoids (Butterweck, 2003). Theories of antidepressant mechanism include monoamine oxidase inhibition, benzodiazepine receptor binding, and inhibition of serotonin, norepinephrine, and dopamine reuptake (Butterweck & Schmidt, 2007; Nathan, 2001). There is, however, little clinical evidence to support efficacy in OCD. An initial open-​label study by Taylor & Kobak (2000) provided favorable pilot data: 12 OCD patients were administered SJW 900 mg per day monotherapy for 12 weeks; YBOCS scores improved by 7.4 points. Five (42%) of the twelve patients were rated as being “much” or “very much improved” on the clinician-​ rated CGI. However, a subsequent placebo-​controlled trial by the same group (Kobak et al., 2005), with a much larger sample size (n = 60 OCD patients), failed to replicate. SJW was administered for 12 weeks using a flexible dose of 600 mg–​1800 mg. A high quality hydro alcoholic extract (LI-​160), which has been found to be effective for depression in a number of studies, was used, and levels of hypericin and hyperforin were confirmed. There was no difference at study endpoint in Y-​BOCS, Y-​BOCS subscales, or the percentage of participant’s rated as “much” or “very much” improved. There has not been a subsequent trial of SJW in OCD; it is difficult to draw any firm conclusions regarding its efficacy on the basis of only two studies from the same laboratory. Further controlled studies are needed. M IL K THIS TLE Milk thistle (Silybum marianum), a Mediterranean plant, has been used in the Middle East for the treatment of obsessive and compulsive symptoms for many generations (Sayyah, Boostani, Pakseresht, & Malayeri, 2010). The flavonolignan complex from milk thistle, known as silymarin (rich in silibinin), is believed to be the main bioactive compound; it has hepatoprotective effects and acts as a monoamine oxidase inhibitor (Mazzio, Harris, & Soliman, 1998), and has been documented to increase cortical serotonin levels (Osuchowski, Johnson, He, & Sharma, 2004). In a human study of methamphetamine abusers, prefrontal decreases in dopamine and serotonin were ameliorated by silymarin (Lu et al., 2010). 498

The only RCT of milk thistle for the treatment of OCD published to date was conducted by Sayyah et  al. (2010) in Iran. The authors compared milk thistle (600 mg/​day methanolic leaf extract) with 30 mg/​day of fluoxetine, rather than with placebo (i.e., a noninferiority design). Thirty-​five participants with a Y-​B OCS score of >21 (moderate–​severe OCD) were randomly assigned to treatment over an 8-​week period. Both interventions were found to result in a highly significant reduction in YBOCS score (p  =  .0001), with no significant difference between the two at endpoint. The reporting in this published trial is unconventional; baseline Y-​B OCS was reported to be 41, but the Y-​B OCS scale as usually applied extends only to 40. This study used the leaf of S. marianum, and not the seeds (which have the richest content of silymarin). There was no reported measurement or standardization of the bioactive flavonolignan complex. Noninferiority designs such as this typically need a larger sample size than that more conventional placebo-​controlled trials (D’Agostino Sr, Massaro, & Sullivan, 2003). A  placebo-​controlled RCT is needed to establish efficacy of milk thistle above and beyond placebo. Grant and Odlaug (2015) published three case studies of patients with OCD and related disorders treated with silymarin. In the first of these case studies, an 18-​year old woman with TTM was treated with >300 mg per day milk thistle for 4 months and reported almost complete cessation of hair pulling. In the second case, a 30-​year old woman with moderately severe (Y-BOCS 22 points) contamination obsessions and washing compulsions received 600 mg per day milk thistle, and reported a marked improvement after 8 weeks (Y-BOCS 12 points, mild). In the final case, a 25-​year old man with pathological nail biting took >150 mg per day milk thistle for 4 weeks and reported cessation of the urge to bite his nails. After stopping milk thistle treatment, the nail biting returned to baseline levels 2 weeks later; and then with re-​introduction of treatment, symptoms disappeared again after 4 weeks. These case studies, together with the initial comparator study by Sayyah et al. (2010), provide encouraging initial support for the efficacy of milk thistle in OCD. It is also noteworthy that milk thistle is typically well tolerated, and few side effects have been reported (Grant & Odlaug, 2015; Sayyah et al., 2010). B OR AGE Borage (Echium amoenum) is a traditional Persian anxiolytic and thymoleptic plant medicine. Preclinical studies have provided evidence to suggest that borage has anxiolytic, antidepressant (Sayyah, Sayyah, & Kamalinejad, 2006), O bsessi v e - C ompulsi v e D isorder

 

and sedative effects (Rabbani, Sajjadi, Vaseghi, & Jafarian, 2004). Sayyah et al. (2009) compared borage extract (500 mg/​day) to placebo in 44 moderate-​severe OCD patients over a 6-​week period. Change in Y-BOCS over 6 weeks did not significantly differ between the two groups overall, although toward the end of the intervention period, at week 4 and week 6, Y-BOCS scores were nominally lower for borage in comparison with placebo. There was a significant decrease in anxiety for borage when compared with placebo (p = .021). No adverse effects were recorded. This initial study provides only weak evidence of efficacy for borage as a treatment for OCD, with further research warranted. N-​A C ETY L CYSTEI N E Of all the nutraceutical substances to emerge in recent years as potential treatments for OCD, N-​Acetylcysteine (NAC) has perhaps generated the most intensive research interest (Oliver et  al., 2015). It increases extrasynaptic glutamate and inhibits synaptic glutamate release via actions at the cystine-​glutamate antiporter on glial cells in regions of the brain implicated in OCD (Pittenger, Bloch, & Williams, 2011). It also increases endogenous production of glutathione, which results in a reduction of brain oxidative stress and inflammation (Berk, Ng, Dean, Dodd, & Bush, 2008). There is evidence for NAC efficacy across a range of psychiatric disorders, including bipolar disorder, substance abuse, pathological gambling, and schizophrenia (Camfield, 2013). It is readily available over-​the-​counter and is typically well tolerated, with a negligible side-​effect profile (Atkuri, Mantovani, & Herzenberg, 2007; Miller & Rumack, 1983). Lafleur et al. (2006) described the first evidence for NAC benefit in OCD, in a case report of a 58-​year-​old woman with treatment-​resistant OCD who experienced a large reduction in YBOCS symptom severity (from a baseline score of 32 to an end-​point score of 9) when administered 3000 mg per day NAC over a 12-​week period. However, in a subsequent case series of patients with severe OCD (Van Ameringen, Patterson, Simpson, & Turna, 2013), only one patient out of six displayed a response to NAC, using a maximum dose of 3000 mg per day NAC for 4 weeks. Two RCTs of NAC in OCD have been described. Afshar et al. (2012) compared 2400 mg per day NAC to placebo over a 12-​week period and found a significantly greater decrease in Y-BOCS in the NAC group from 8 weeks onwards, and a full clinical response in 10 out of 19 patients in the NAC group. In contrast, Sarris et al. (2015) N utraceutical and A lternati v e T reatments

treated 44 adult participants with DSM-​V diagnosed OCD with NAC (3000 mg/​day) or placebo over 16 weeks, and found no significant benefit of NAC; only 20% (4) of the participants in the NAC group were classified as responders (Y-BOCS ≥35% reduction). However, it is noteworthy that younger patients under 34 years were found to have Y-BOCS reductions (p = .037), and OCD duration (yrs) was found to be a significant negative predictor of YBOCS reduction at endpoint (Sarris, Oliver, Camfield, & Dean, in press). The Y-BOCS compulsions subscale was also found to be reduced at 12 weeks, although the effect dissipated by 16 weeks. At the time of this review, two other NAC placebo-​controlled clinical trials for OCD were being conducted: a 12-​week RCT in pediatric OCD by Bloch et al. at Yale University (NCT01172275) and a 16-​week RCT in treatment refractory OCD patients by Shavitt et al. at the University of Sao Paulo (NCT01555970). A larger 16-​week RCT in OCD by Sarris et al. at the University of Melbourne has also recently been funded (NHMRC APP1104460). A handful of studies have examined NAC in the treatment of grooming disorders. An initial case report by Berk et al. (2009) described three patients participating in a 7-​ month clinical trial for NAC in bipolar disorder who had compulsive nail-​biting. By the end of the study 2000 mg per day of NAC was found to result in reductions in nail biting in all three patients, with one patient reporting a complete cessation of nail biting from 2 weeks onward. In a subsequent 12-​week RCT in 25 children and adolescents, it was reported that 800 mg per day NAC was associated with a significant initial increase in nail length in comparison to placebo, but the effect had dissipated by the end of the second month (Ghanizadeh, Derakhshan, & Berk, 2013). An initial case report by Odlaug and Grant (2007) described two patients with TTM who responded favorably to NAC (1800–​2400 mg/​day), with significant reductions in hair pulling behaviors after only 2 to 3 weeks of treatment. A  subsequent case series by Rodrigues-​Barata et  al. (2012) reported similar findings, with two females with chronic, treatment-​ resistant TTM displaying complete regrowth of their hair within 3 months of initiating 1200 mg per day NAC. Favorable findings were also reported following a 12-​week RCT in 50 adult TTM patients, with a significant reduction in hair pulling symptoms after 1200 to 2400 mg NAC per day (Grant, Odlaug, & Suck, 2009). However, a subsequent, very similar study in 35 pediatric TTM patients (aged 8–​17) found no significant difference between NAC and placebo, over a 4-​week period (Bloch, Panza, Grant, Pittenger, & Leckman, 2013). 499

 

NAC has also been investigated as a treatment for compulsive skin picking (excoriation). Silva-​Netto et al. (2014) described three patients with treatment-​resistant skin picking, with “major improvements” in skin picking with 1200 to 1800 mg per day NAC. In a 12-​week open label study in 35 children and adults investigating excoriation in association with Prader-​Willi Syndrome, Miller & Angulo (2014) reported that 450 to 1200 mg NAC per day brought about a significant improvement in skin picking behaviors, with 71% of participants reporting complete resolution of self-​ mutilating behaviors. In sum, there is promising evidence supporting the use of NAC in OCD and related disorders, though much remains unresolved (Oliver et al., 2015). Patients with more chronic and severe forms of OCD may not benefit as much, and it is unclear whether it is more effective as monotherapy or augmentation to existing SSRI treatments. Preclinical data suggest that NAC can interact with antidepressants, altering their effective dose (Cost-​Campos et al., 2013). Further randomized studies are required to confirm the efficacy of NAC and to evaluate these other questions. GLY CINE The amino acid glycine is a coagonist, together with glutamate, of the NMDA glutamate receptor (NMDAR) (Clements & Westbrook, 1991). Chronic dosing of glycine at 60 g per day produces a two-​fold increase in glycine levels within the central nervous system ( Javitt, 2006); this level cannot be obtained from dietary sources (U.S. Department of Agriculture, 2010). With an increased supply of available glycine in the brain, NMDAR function may be potentiated (Pittenger et al., 2006). Animal models suggest that activation of NMDA receptors may have an anticompulsive effect (Albelda, Bar-​On, & Joel, 2010). In an initial placebo-​controlled study of glycine in OCD, Greenberg et al. (2009) administered 60 g per day glycine (or placebo) to 24 adult OCD patients as augmentation to their current treatments over a 12-​ week period. Patients receiving glycine had an average 0.82 point decrease in Y-​B OCS scores for each week they remained in the study in comparison with placebo; this difference approached significance in an analysis of completers (p  =  0.053). Unfortunately, the trial was hampered by a high rate of noncompliance due to the unpleasant taste and nausea associated with daily consumption of such a large daily dose of glycine. Cleveland and colleagues (2009) presented the case study of a patient with severe treatment-​ resistant OCD who ingested glycine over a 5-​year period. 500

The patient, who was largely housebound prior to starting to use glycine, reported a large reduction in OCD symptoms and resumed education and social functioning following treatment. These preliminary findings are encouraging; further randomized placebo-​controlled trials are needed, as is the development of more palatable modes of glycine ingestion.

S AR C OS INE Sarcosine is an inhibitor of glycine reuptake and thus makes glycine more readily available at the synapse, potentiating NMDA receptor function (Pittenger & Bloch, 2014). Pharmacological evidence suggests that sarcosine may be more potent than glycine, as it may also act directly as a coagonist of NMDARs and leads to less NMDAR desensitization (Zhang, Lyons-​ Warren, & Thio, 2009). There has only been one study to investigate the clinical efficacy of sarcosine for the treatment of OCD. Wu et al. (2011) administered 500 to 2000 mg per day sarcosine to 26 moderate-​severe (>16 YBOCS) OCD patients in a 10-​week, open-​label trial. A  mean decrease of 19.8% in YBOCS score was observed at study endpoint, with eight participants regarded as responders with a >35% reduction in YBOCS score. A subgroup of participants who had discontinued use of SRIs for at least 8 weeks prior to the study (n = 8) were found to display the strongest response to sarcosine, suggesting that it may act better as monotherapy rather than augmentation. These initial findings are encouraging. Sarcosine can be administered in smaller quantities than glycine and has been found to be well tolerated (Wu et al., 2011).

PS ILOC YB IN Psilocybin (4-​phosphoryloxy-​dimethyltrypamine) is a potent indoleamine hallucinogen found naturally in a number of wild mushroom species world-​wide (e.g., Psilocybe cyanescens and Psiolocybe subaeuruginosa). Due to psilocybin’s acute psychoactive effects, it is currently listed as a scheduled substance in many countries. There have been a number of intriguing recent reports suggesting that psilocybin may have therapeutic value in the treatment of anxiety in the terminally ill (Grob, Bossis, & Griffiths, 2013; Grob et al., 2011), as well for the reduction of clinical symptoms in OCD (Grob et  al., 2011; Moreno & Delgado, 1997a). Of particular interest are O bsessi v e - C ompulsi v e D isorder

 

reports suggesting that rapid and long-​lasting reductions in obsessive-​compulsive symptoms may be observed after a single dose (Wilcox, 2014). When ingested orally, psilocybin is converted into the active compound psilocin, with acute perceptual and subjective effects reliably induced using doses of 20 to 30 mg/​70  kg p.o. (285 µg/​k g–​428 µg/​k g ) and lasting up to 6 hours (Griffiths et al., 2011). The acute psychoactive effects of psilocybin are due to a serotonergic mechanism of action (Passie, Seifert, Schneider, & Emrich, 2002). Psilocin binds with high affinity to postsynaptic 5-​HT2A receptors, and to a lesser extent 5-​HT1A receptors, with widespread effects on activity in prefrontal cortical networks (Halberstadt & Geyer, 2011; Vollenweider, Vollenweider-​ S cherpenhuyzen, Bäbler, Vogel, & Hell, 1998). Downstream effects on the release of striatal dopamine have also been documented (Vollenweider, Vontobel, Hell, & Leenders, 1999). Both of these effects may be relevant in the context of OCD. Preclinical evidence (Matsushima, Shirota, Kikura-​ Hanajiri, Goda, & Eguchi, 2009) suggests that acute psilocybin administration may lead to a reduction in OCD-​related behaviors. Psilocybe argentipes, a variety of psychedelic mushroom containing psilocybin, produced a significant reduction in marble-​burying activity, a commonly used animal model of compulsive behavior (see ­chapter 35). Two case reports and one open-​label study have examined psilocybin’s effects in patients with OCD. Moreno and Delgado (1997a) described a 34 year-​old man who had suffered from OCD since adolescence. He reported that the repeated use of psilocybe mushrooms consistently led to freedom from obsessions and compulsions during the period of intoxication and eventually led to a remission that lasted several months. In a follow-​up, open-​label study, Moreno et al. (2006) investigated the effects of psilocybin over a range of doses in nine patients with a DSM-​I V diagnosis of OCD. All patients had also experienced at least one SSRI treatment failure related to the use of SSRIs and were free of antidepressants for at least 2 weeks. Over a series of 4 study weeks, participants were administered one of four doses of psilocybin (25, 100, 200, and 300 µg/​kg) and then monitored overnight. A 25% or greater decrease in Y-​B OCS score was observed for 88.9% of patients at 24 hours posttreatment for at least one of the doses. Psilocybin was well tolerated, with no significant adverse physical or psychological effects. Although formal OCD measurements did not extend past 24 hours, two of the

N utraceutical and A lternati v e T reatments

patients reported that symptom relief lasted for most of the following week. Symptom relief in this study was not related to dosage, suggesting that even the lowest dose could produce a clinical benefit. There was no placebo. The lowest dose (25 µg/​kg) produced no psychotomimetic effects, suggesting that benefits in OCD symptoms could be dissociated from the acute psychoactive effects of psilocybin. Even at the highest dose (300 µg/​kg), no significant adverse effects were reported. This is line with previous findings (Passie et  al., 2002). Adverse reactions, including strong dysphoria and/​or anxiety/​panic, have been reported in a small proportion of participants only at high doses of psilocybin:  7.3% of participants at 315 µg/​kg, and 5.7% of participants at 250 to 260 µg/​kg (Studerus, Kometer, Hasler, & Vollenweider, 2011). Perhaps the most unique characteristic of psilocybin in these studies is that its effects have been reported to be rapid, with a lingering period of symptom reductions following a single dose that may last for days or weeks. This contrasts with SSRI treatments which require several weeks of daily dosing in order to begin to ameliorate obsessive-​ compulsive symptoms (see ­chapter 40). This acute effect was corroborated in a recent case report (Wilcox, 2014). A 38-​year old male with severe treatment-​resistant OCD that interfered with his social and occupational functioning consumed approximately 2 grams of Psilocybe cubensis intermittently over the course of a year and reported a significant reduction in intrusive thoughts for about 3 weeks following each ingestion. At 1-​year follow-​up the patient reported being symptom free during that time (Wilcox, 2014). These initial studies and case reports provide intriguing preliminary evidence suggesting possible acute and chronic efficacy for psilocybin in the treatment of OCD. However, further clinical studies are needed before any firm conclusions can be drawn. Research with psilocybin is logistically challenging, due to the current legal status and difficulties in blinding psilocybin trials, but the potential benefits of a rapidly acting treatment are substantial. C ONC LU S IONS AND F U T U R E DIR E C T I O N S Despite widespread usage of nutraceutical, herbal, and over-​ the-​counter substances by patients with OCD and related disorders, clinical research has only begun to investigate the efficacy of these substances in a systematic and scientific manner. Myo-​inositol and St. John’s wort showed initial

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promise in the treatment of OCD, but investigations were abandoned on the basis of nonsignificant findings in studies that may have been underpowered. Milk thistle (Silybum marianum) has a long history of traditional usage in OCD in the Middle East, yet properly designed RCTs to investigate its efficacy are still lacking. Similarly, borage (Echium amoenum) is also in need of further research. Psilocybin, although currently a scheduled substance, represents a possible means of acute symptom reduction in OCD symptoms, probably via activity involving 5-​HT2A receptors. Recent interest in glutamatergic treatments for OCD has motivated studies of the NMDA modulators glycine and sarcosine, which have shown promise in early studies. Perhaps the most promising glutamatergic nutraceutical treatment for OCD and related disorder to emerge in recent years is N-​Acetylcysteine. In comparison with other treatments, NAC has received the greatest research focus, and we will hopefully be in a position within the coming decade to definitively determine whether it has overall efficacy in the treatment of OCD, and if so under which conditions it is most effective. A number of factors complicate this literature and make it difficult to draw firm conclusions. As is typically the case in nascent research involving alternative therapies, many early observations are in the form of case reports, and these typically present more favorable evidence than properly controlled clinical studies, due to reporting bias and uncontrolled placebo effects. In studies of nutraceuticals, in particular, the quality of the herbal extract/​nutraceutical administered may vary substantially. The titration schedule followed, the duration of the intervention, and the careful selection of a representative patient sample are additional sources of variability. Adequate pharmacokinetic data is rarely available for nutraceuticals, and the determination of titration schedules and adequate dosage has been largely a matter of guesswork. For this reason, in subsequent research it may be advantageous to conduct dose escalation studies. Set against this uncertainty is the fact that many of the nutraceutical compounds described in this chapter are quite well tolerated and may be more acceptable to some patients than conventional pharmacotherapeutics. Even though the benefit is not as firmly established as it is for the SSRIs or for appropriate CBT, the low risk makes these interventions plausible clinical alternatives in some cases. In summary, the investigation of nutraceutical and herbal treatments for the treatment of OCD and related disorders is still at an early stage, with much further research needed. However, even at this early stage there is some evidence to suggest that certain treatments may be of use in reducing

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OCD symptoms among those with mild–​moderate symptoms and also may be associated with a more favorable side-​ effect profile than commonly prescribed pharmaceutical alternatives. Future issues that are in need of resolution, in addition to overall efficacy, include the optimal dosages required for best effect, whether monotherapy or augmentation strategies are most appropriate, and for which disorders (e.g., OCD, TTM, excoriation, nail biting) the best results are obtained. The next decade of research holds great promise in providing patients with much-​needed evidence regarding the efficacy of alternative OCD treatments.

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45. FUNCTIONAL NEUROSURGERY IN SEVERE AND TREATMENT-​R EFRACTORY OCD Erica C. Keen, MD, PhD, Alik S. Widge, MD, PhD, and Darin D. Dougherty, MD

HIS TOR IC AL CO N TEX T The first functional neurosurgical procedures performed on human patients date back to the Stone Age, from which we have archaeological records of trephination, the intentional opening of the skull to relieve pain or release demons of the spirit. Trephination was performed for a range of indications and continued sporadically into at least the 17th century. In the early 19th century, the observed clinical sequelae of brain injuries, such as those suffered by Phineas Gage, led to inferences about the localization of particular brain regions to specific functions. This trend motivated early, focused neurosurgical ablations, including those of Burckhardt in the 1890s and Puusepp in the 1930s. Moniz and Lima developed the first standardized neurosurgery for psychiatric conditions in the 1930s. In their prefrontal leukotomy, they injected absolute alcohol into the centrum ovale of the frontal lobes bilaterally through holes in the lateral surfaces of the skull (Moniz, 1937). Moniz’s trials lacked objective and long-​term follow-​up data. Yet his results were enthusiastically accepted by the medical community, ultimately resulting in receipt of the 1949 Nobel Prize in Medicine and Physiology. Influenced by Moniz, Freeman and Watts subsequently developed the transorbital leucotomy, termed the lobotomy in the United States, which was widely accepted in the 1940s–​1950s despite nonstandardized and subjective data reporting and a 4% mortality rate (Freeman, 1948; Freeman & Watts, 1942). Due to its favorable publicity—​and in the context of significant societal pressures on the psychiatrically ill population—​the lobotomy began to be abused by poorly skilled and minimally regulated practitioners. Indiscriminately performed,

it is estimated that more than 60,000 procedures were performed between 1936 and 1956, with unacceptably high morbidity and mortality rates (El-​Hai, 2007; Feldman & Goodrich, 2001). Concern about the lack of objective documentation, the sheer number of procedures performed, and the unacceptable risk/​benefit profile grew during the 1950s, with a resultant decline in the popularity of neurosurgical interventions for psychiatric disease. In the aftermath of this dark and unregulated era in psychiatric neurosurgery arose legislation mandating critical protections and rights for human subjects (US DOH, 1977), advances in surgical technique such as the stereotactic frame and CT-​MRI guidance, an empirically based psychiatric nosology codified in DSM III (1980) and IV (1994), quantitative diagnostic instruments, and an explosion of neuroscientific research highlighting the neural basis of OCD and identifying specific brain pathways that could be targeted for treatment (see ­chapters  20, 21). Together, these developments set the stage for renewed interest and support for the careful, highly regulated application of surgical interventions for OCD. In the current era of neurosurgery for OCD, four procedures are performed in highly specialized centers: anterior cingulotomy, subcaudate tractotomy, limbic leukotomy, and anterior capsulotomy (Figure 45.1). Each approach incorporates bilateral lesions using modern stereotactic localization techniques and yields substantial improvement in patients’ symptoms and function in 40% to 70% of cases. These procedures have lower morbidity and mortality than earlier approaches and involve progressively more accurate and smaller lesions, with correspondingly lower risk.

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CINGULOTOMY Anterior Cingulate Gyrus

CAPSULOTOMY Anterior Limb of Internal Capsule

SUBCAUDATE TRACTOTOMY Substantia Innominata

Figure 45.1  SCHEMATIC ILLUSTRATION OF STEREOTACTIC LESIONS USED

Exclusion criteria include potentially interfering psychiatric comorbidities (especially severe personality or substance use disorders), neurocognitive disorders, medical contraindications, structural brain lesions or significant CNS injuries, and imminent suicidal intent. A history of past seizures is a risk factor for perioperative seizures, but not a strict exclusion criterion. Similarly, a history of bipolar disorder is a relative contraindication, with more distant and milder manic episodes preferable. Subjects less than 18 years of age require additional scrutiny, given the complications regarding consent in such cases. After surgical candidacy has been confirmed, preoperative evaluation should include serum electrolytes, complete blood count, coagulation testing, urine analysis, ECG, brain MRI, EEG, and extensive neuropsychological testing. Several months postoperatively, brain MRI should be used to document the location and extent of surgical lesions. Close follow-​up should be established, with an intensive behavioral therapy and pharmacological regimen occurring as soon as possible and preferably within the first postoperative month.

IN THE TREATMENT OF  SEVERE OCD.  Limbic leukotomy combines cingulotomy and subcaudate tractotomy.  (From Lipsman et al., 2007)

ANT E R IOR C INGU LOT OMY C A NDIDATE SELECTI O N Because of the invasive nature of the procedure and the abuses of the past, neurosurgical treatment of OCD involves close institutional oversight at a limited number of highly specialized centers with sufficient expertise and experience to perform these procedures both proficiently and ethically. It is imperative that investigators and clinicians remain cautious, and cognizant of the checkered past of psychiatric neurosurgery. Potential surgical candidates must be carefully evaluated by a multidisciplinary team of psychiatrists, neurosurgeons, psychologists, and neurologists in consultation with ethicists. Stringent criteria are applied such that the number of appropriate surgical candidates is small, limited to those who meet clearly defined and systematized rigorous inclusion and exclusion criteria. Inclusion criteria include evidence of severe symptomatology (Y-​BOCS score >25) refractory to an exhaustive array of available and established treatment options (including several adequate trials of appropriate pharmacological agents and robust evidence-​based cognitive-​behavioral therapy), rigorously assessed decisional capacity to freely consent to the surgery without coercion, and agreeability and ability to engage in long-​term follow-​up (Garnaat et al., 2014). 508

Anterior cingulotomy was initially developed to treat intractable pain, but it was subsequently noticed that patients with comorbid anxiety and depressive symptoms had better results. This led H.  Thomas Ballantine, a neurosurgeon at Massachusetts General Hospital (MGH), to explore anterior cingulotomy as a treatment for a range of psychiatric indications, including OCD, in the early 1960s (Ballantine, Bouckoms, Thomas, & Giriunas, 1987). Since 1962, the group at MGH has performed over 1,000 anterior cingulotomies, with those after 1990 performed under MRI guidance. The surgical targets are within the bilateral dorsal anterior cingulate cortices (Brodmann areas 24 and 32) at the margin of their connecting fibers in the cingulum white matter bundle. Two or three ~1.0  cm3 lesions are formed bilaterally by thermocoagulation through burr holes in the skull under local anesthesia. Anterior cingulotomy has been the most widely used psychiatric neurosurgical procedure in North America for the past several decades due to its low morbidity and evidence for clinical efficacy in refractory OCD. In a retrospective review of 198 cases with a mean follow-​ up time of 8.6 years, Ballantine and colleagues reported symptom improvement in 56% of cases (Ballantine et al., 1987). Reevaluation of these data using more stringent O b sessive - C ompulsive D isorder

 

response criteria concluded that 33% of these patients received “substantial benefit” and that delayed response was common, with 3 to 6  months required for beneficial effects to emerge in most cases (Cosgrove, 2000). Another review of 34 cases of MRI-​g uided stereotactic anterior cingulotomy classified 27% as clear responders and an additional 27% as “possible” responders (Spangler et al., 1996). A prospective study of 44 patients who received anterior cingulotomy with a mean follow-​up of 32 months found that 45% responded favorably, classified as full or partial responders to the procedure (Dougherty et al., 2002). When categorizing responders strictly as those with at least a 35% reduction in Y-​B OCS score, a smaller study found that 6 of 14 cases met responder criteria at 12 months, with a mean reduction of 36% in Y-​B OCS score (C. H. Kim et al., 2003). In a study published several years later, this group found that 8 of 17 cases met responder criteria at 12 months, with a mean reduction of 48% in Y-​B OCS score and no significant adverse events ( Jung et al., 2006). Sheth and colleagues followed 64 patients who received anterior cingulotomy, with full and partial response defined as Y-​B OCS score reductions of greater than 35% and 25%–34%, respectively (Sheth et al., 2013). At the first postoperative evaluation with a mean follow-​ up duration of 10.7 months, 42% had achieved at least a partial response. Response rate climbed to 69% after either repeat anterior cingulotomy (involving additional lesions to the dorsal anterior cingulate cortex) or subcaudate tractotomy in 30 patients at a mean follow-​up duration of almost 5 years (see later). Bourne and colleagues also reported improvement in response rate after repeat anterior cingulotomy, with full responders rising from 17% to 38% in the repeat anterior cingulotomy group (Bourne et al., 2013). In addition to the evidence for its efficacy in OCD, anterior cingulotomy is associated with a low rate of side effects. Of the more than 1,000 anterior cingulotomies performed at MGH, there have been no reported deaths and only one postoperative stroke since the introduction of MRI guidance. In a long-​term prospective follow-​up of patients who received anterior cingulotomy, Dougherty and colleagues reported no serious long-​term adverse events (Dougherty et al., 2002). Short-​term adverse events, such as headache, nausea, difficulty urinating, and subjective memory issues usually resolve within several days. The most common serious adverse event associated with anterior cingulotomy is seizure, with rates ranging from 1% to a maximum of 9% in the literature, and an increased risk in those with a prior seizure history (Binder & Iskandar, 2000). F unctional N eurosurgery

S U B C AU DAT E T R AC T OT OMY Subcaudate tractotomy, developed by Knight in the United Kingdom in the early 1960s, targets the substantia innominata inferior to the head of the caudate nucleus, interrupting white matter tracts that connect prefrontal cortical regions to subcortical structures. The procedure historically involved placing an array of radioactive Yttrium-​90 seeds at the target location, yielding lesion volumes of ~2  cm3 surrounding each seed. Since 1995, however, lesions have been generated by radiofrequency thermocoagulation, thus improving the spatiotemporal resolution of the procedure. Within 10 years of its inception, subcaudate tractotomy had been performed in more than 650 cases of OCD, anxiety, and depression, with reported improvement in approximately 50% of subjects with OCD (Knight, 1973). A further review of patients who received subcaudate tractotomy similarly reported a 50% improvement in “obsessional neurosis” (Goktepe, Young, & Bridges, 1975). In 1994, Bridges and colleagues reviewed 1,300 cases of patients with anxiety, OCD, major depressive disorder, or bipolar disorder treated with subcaudate tractotomy, reporting that 40% to 60% benefited to the point of resuming normal or near-​normal lives (Bridges et al., 1994). In addition, the suicide rate fell from 15% to 1% among these patients. A single case study has reported clinical improvement in a patient who received subcaudate tractotomy using a “frameless” stereotactic procedure in 2006 (Woerdeman, Willems, Noordmans, Berkelbach van der Sprenkel, & van Rijen, 2006). Side effects of subcaudate tractotomy, as with other stereotactic interventions, are mostly minimal and transient. These include somnolence, often lasting for several days, lethargy, and confusion that may persist for up to 1 month. Temporary decreases in cognitive function have also been described. As with anterior cingulotomy, the most common major adverse event is seizure, reported in approximately 1% to 2% of cases (Greenberg, Dougherty, & Rauch, 2011). At least one surgery-​related death, attributed to Yttrium-​90 seed migration, has been reported in the literature. LIMB IC LE U KOT OMY Limbic leukotomy, pioneered by Kelly and colleagues in the United Kingdom in the early 1970s, combines the subcaudate tractotomy and anterior cingulotomy procedures, thus disrupting fiber tracts in two discrete regions associated with OCD pathophysiology (Kelly et  al., 1973). Lesions are typically formed either by thermocoagulation or with a cryoprobe. This is often a “staged” procedure, with patients 509

 

offered the subcaudate operation only after receiving and failing to respond to anterior cingulotomy. An early report of 40 OCD patients treated with limbic leukotomy reported improvement in 89%, as estimated with a 5-​point rating scale (Kelly et al., 1973). In the same year, this group reported a similar rate of improvement for 30 patients who were retrospectively followed for a mean duration of 16 months. The authors noted that clinical improvement was often delayed for several months postoperatively. More recently, Hay and colleagues reported moderate to marked improvement in 38% of 26 patients who had received limbic leukotomy (Hay et al., 1993). Kim and colleagues reported dramatic improvement in 12 patients treated with limbic leukotomy whose mean Y-​B OCS score decreased postoperatively from 34 to 3 (Kim, Lee, & Choi, 2002). Montoya and colleagues followed 21 patients with either OCD or MDD for 26 months postoperatively, reporting a 36% to 50% response rate in both disorders (Montoya et al., 2002). Price and colleagues have reported efficacy of limbic leukotomy in five cases with severe self-​mutilation and repetitive tic-​like behaviors, suggesting particular benefit for this phenotypic subset of OCD patients (Price et al., 2001). Bourne and colleagues compared the efficacy of subcaudate tractotomy with repeat anterior cingulotomy in patients deemed poorly responsive to an initial anterior cingulotomy procedure. Those who received subcaudate tractotomy as the second procedure (effectively a staged limbic leukotomy) improved and fared better than those who received a repeat anterior cingulotomy, with 64% full responders in the subcaudate tractotomy group compared with 38% full responders in the repeat anterior cingulotomy group (Bourne et al., 2013). Adverse events associated after limbic leukotomy include those relevant for each of its component procedures. Short-​term adverse events include confusion, headache, and lack of sphincter control that resolve within days to weeks postoperatively. Several papers have reported enduring lethargy. As with other procedures, perioperative seizure is an additional risk. Limbic leukotomy tends to require a longer postoperative stay than either anterior cingulotomy or subcaudate tractotomy alone. No deaths have been reported in the literature. A NTER IOR CAPSULO TO MY Anterior capsulotomy was developed by Talairach and colleagues in France in parallel with Lars Leksell and 510

colleagues in Sweden. The procedure, in use since the late 1940s, focuses lesions on the anterior limb of the internal capsule at the level of the intercommissural plane, impinging on the ventral striatum immediately inferior to the internal capsule. The objective is to interrupt fibers connecting the prefrontal cortex, especially the orbitofrontal cortex and subgenual anterior cingulate cortex, and the thalamus, including the dorsomedial thalamus. The original procedure was performed with thermocoagulation (“open” or “thermocapsulotomy”) through burr holes in the skull. For more than 20 years, a variation known as gamma ventral capsulotomy (GVC) has also been performed, using the “gamma knife” radiosurgery technique. In GVC, gamma radiation focuses multiple rays through a collimator helmet to converge on a single location, creating smaller lesions than those with thermocoagulation. GVC lesions generally remain within the middle to ventral portion of the anterior capsule. Reports on thermocapsulotomy have indicated substantial efficacy in OCD. Herner published a report of 116 cases performed in the 1950s, documenting a “favorable” response in 50% of patients with OCD (Herner, 1961). Bingley and colleagues reported “satisfactory outcomes” in approximately 70% of 35 patients with OCD (Bingley, Leksell, Meyerson, & Rylander, 1977). A review of 253 OCD patients who received anterior capsulotomy suggested that 67% exhibited significant improvement (Waziri, 1990). A review of 213 psychiatric cases in the literature published prior to 1994 found that 64% had satisfactory outcomes, with OCD patients demonstrating the greatest benefit from the procedure (Mindus, Rasmussen, & Lindquist, 1994). D’Astous and colleagues followed 24 OCD patients who had anterior capsulotomy for a mean duration of seven years (D’Astous, Cottin, Roy, Picard, & Cantin, 2013). The authors classified 37% as full responders and 11% as partial responders. Adverse events associated with thermocapsulotomy are more common and severe than for other ablative procedures, and include confusion in up to three-​quarters of patients that typically resolves within 1 week postoperatively, weight gain, and rare intracranial hemorrhage (Bingley, Leksell, Meyerson, & Rylander, 1977). Other reported side effects include incontinence, fatigue, memory difficulties, and seizure, each of which may be rare but more lasting (Feldman, Alterman, & Goodrich, 2001). In contrast to thermocapsulotomy, GVC involves smaller lesions, quicker recovery times, and potentially fewer risks. Rück and colleagues compared thermocapsulotomy and GVC in a cohort of 25 patients (16 undergoing thermocapsulotomy, 9 undergoing GVC), with a mean O b sessive - C ompulsive D isorder

 

follow-​up duration of 10.9 years (Ruck et al., 2008). Twelve patients were deemed responders, with a reduction in Y-​ BOCS score of at least 35%, and 9 of these 12 patients were considered to be in remission, with Y-​B OCS scores of less than 16. There were no significant differences in clinical efficacy between the two procedures. However, fewer adverse events were noted with smaller lesions in GVC. Sheehan and colleagues followed five patients treated with GVC for 24 months and reported that four demonstrated symptomatic improvement, with a median reduction in Y-​B OCS score from 32 to 13 (Sheehan, Patterson, Schlesinger, & Xu, 2013). Lopes and colleagues followed five patients treated with GVC and reported that three met response criteria at 48 months postoperatively (Lopes et al., 2014). Though the rate and severity of adverse events associated with GVC are lower than with thermocapsulotomy, one disadvantage of GVC is that potential lesion sites cannot be transiently cooled to reveal unanticipated motor or sensory effects prior to lesioning, as can be done with thermocapsulotomy. In addition, radiation-​induced edema and the formation of delayed cysts are risks specifically associated with GVC. Late cysts (more than 5  year postoperatively) have been reported in 1.6% to 3.6% of patients after gamma knife surgery for arteriovenous malformations (Pan, Sheehan, Stroila, Steiner, & Steiner, 2005). In another study, delayed cysts were reported in 2.2% to 9.0% of patients who had received radiosurgery for cerebral arteriovenous malformations, with permanent complications noted in 1% (Foroughi et al., 2010). OCD patients treated with GVC should therefore be closely monitored for several years postoperatively for the development of such cysts. The closed nature of GVC has permitted the ability to design blinded, placebo-​controlled, randomized clinical trials (RCTs) to assess more objectively the risks and benefits of psychiatric neurosurgical procedures for the first time. As of this writing, two reports have been published from a single RCT. Sixteen OCD patients were randomized to receive either GVC or sham surgery (Lopes et  al., 2014). At the conclusion of a 12-​month blinded period, two of eight (20%) patients who received GVC were clinical responders, whereas none of those who received the sham treatment met responder criteria. In a second, open phase of the study, four patients from the sham group elected to receive GVC. Two of these four were classified as responders at 12  months. In addition, two patients from the original active group converted to responder status at the 54-​month follow-​up time point, leading to an overall response rate of 58.3% in the GVC group. The lack of response in the sham group during the blinded phase suggests an absence of placebo effect and F unctional N eurosurgery

supports the efficacy of GVC in OCD. The most serious adverse event in this study was cerebral edema and a subsequent radiation-​induced cyst in one patient. A further analysis of the same RCT cohort by Batistuzzo and colleagues investigated the effects of GVC on the neuropsychological profile of these 16 OCD patients (Batistuzzo et al., 2015). By evaluating patients at baseline and 1 year postoperatively, the authors determined that GVC did not lead to a decline in cognitive or motor function, as had been previously speculated. Rather, GVC unexpectedly improved visuospatial memory performance. No significant adverse events were noted. C OMPAR IS ON OF   NE U ROS U R GIC AL PROC E DU R E S The choice of which neurosurgical intervention to perform tends to follow institutional expertise; thus, direct head-​to-​ head comparisons of neurosurgical approaches for OCD are rare. However, a few metaanalyses and comparisons of secondary procedures after anterior cingulotomy have been reported in the literature. Brown and colleagues examined ten studies with a total of 193 patients treated with either anterior cingulotomy or anterior capsulotomy (Brown et al., 2015). The authors found that a significant number of patients met criteria for treatment response at the 12-​month and long-​term follow-​ up time points, based on mean reductions in baseline Y-​ BOCS scores, after both procedures. These procedures were also efficacious in reducing comorbid depression and anxiety symptoms, as measured with symptom-​specific rating scales. Both efficacy and adverse event rates were higher for anterior capsulotomy than for anterior cingulotomy. However, considerable heterogeneity in technique across study sites may have skewed these results, as with other metaanalytic studies in the field. Because the objective of anterior cingulotomy is to make the smallest possible lesion necessary to generate a positive clinical response, patients may return several months after the first operation for a second procedure if the clinical response is deemed inadequate. Bourne and colleagues reported on a cohort of 31 nonresponders to anterior cingulotomy who received either extension of the initial anterior cingulotomy or a subcaudate tractotomy as a second procedure (Bourne et al., 2013). Of the 19 patients who elected to have either second procedure, 53% were full responders (at least a 35% decrease in Y-​B OCS score) and 21% were partial responders (25%–​34% decrease in Y-​B OCS score), compared with 17% full responders and 511

 

25% partial responders for those who did not have a second procedure. When comparing response to a repeat anterior cingulotomy versus subcaudate tractotomy, 64% became full responders after subcaudate tractotomy versus 38% after repeat anterior cingulotomy, suggesting that following anterior cingulotomy with subcaudate tractotomy (effectively resulting in a limbic leukotomy) might confer a higher response rate for initial nonresponders. Regardless of the type of second procedure, the authors found that a second lesion surgery was both safe and effective. NEUROC IR CUI TRY/​P O TEN TI AL M EC HA NIS MS O F ACTI O N Resurgent interest in psychiatric neurosurgery has been motivated by translational research that informs our understanding of the clinical benefits obtained from these surgeries. That surgeries targeting different brain structures produce symptomatic improvement fits well with models in which cortico-​striato-​thalamo-​cortical (CSTC) circuits connecting the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), striatum, and thalamus are central to OCD pathophysiology and treatment response (Figure 45.2; see ­chapter 21). As currently conceptualized, spiraling loops facilitate the flow of information across topographically organized CSTC circuits, each of which consists of a specific cortical region connecting to a particular striatal region which then communicates with a unique section of thalamus and back again to the cortex (Alexander, Crutcher, & DeLong, 1990; Dougherty, Rauch, & Greenberg, 2010; Haber, Fudge, & McFarland,

2000; Milad & Rauch, 2012; see c­hapter  20). OCD is believed to involve an imbalance in neural activity in specific CSTC circuits, in which those involving the OFC, ACC, thalamus, and caudate are tonically overactive (Saxena, Brody, Schwartz, & Baxter, 1998). Neuroimaging studies suggest that activity in these circuits is amplified during symptom provocation and diminished after clinically effective treatment (Baxter et al., 1992; Cannistraro et  al., 2004). Findings in human subjects have been bolstered by work in rodent models of OCD, in which neural activity levels can be manipulated while monitoring OCD-​ like behavior. Accordingly, altering activity in CSTC circuits seems to promote or inhibit OCD-​like behavior (e.g., excessive grooming) in these animal models (Ahmari & Dougherty, 2015; Ahmari et  al., 2013; Burguiere, Monteiro, Feng, & Graybiel, 2013). Currently employed neurosurgical procedures entail lesions at varying nodes of the CSTC circuitry, thus putatively disrupting disease-​related pathological neural activity in relevant brain pathways. Anterior cingulotomy targets the dorsal ACC, including gray matter in the cingulate gyrus and white matter cingulum bundle, thus putatively modifying cingulo-​striatal projections and bidirectional signaling between the dorsal ACC and the OFC, ventral striatum, and limbic structures. Neuroimaging studies have found evidence for altered connectivity patterns between the ACC and ventral striatum when OCD patients anticipate punishment (Beucke et al., 2012) and increased fractional anisotropy in the cingulum bundle and anterior limb of the internal capsule in patients with OCD compared with healthy controls (Cannistraro et al., 2007). No published studies have demonstrated postoperative shifts in

Cortical

ACC/vmPFC

Dorsal lateral prefrontal cortex

Lateral-orbitofrontal cortex

Striatal

Nucleus accumbens

Caudate nucleus

Putamen

Thalamus Thalamic

Figure 45.2  Schematic illustration of cortico-​striato-​thalamo-​cortical (CSTC) pathways implicated in the pathophysiology of OCD.  (From Milad & Rauch, 2012)

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O b sessive - C ompulsive D isorder

 

functional activity in these pathways, though Banks and colleagues have reported that preoperative increased connectivity between the right ACC, striatum, and thalamus correlates with improved clinical outcomes to anterior cingulotomy (Banks et al., 2015). Subcaudate tractotomy involves bilateral orbitomedial lesions that disrupt fibers connecting the OFC and subgenual ACC to the thalamus, thus potentially reducing overactive OFC-​caudate pathways. Using two-​tensor tractography, Yang and colleagues have beautifully characterized OFC tracts disrupted in subcaudate tractotomy and confirmed that the surgery disrupts these connections, consistent with this mechanism (Yang et al., 2015). Limbic leukotomy, combining the lesions of anterior cingulotomy and subcaudate tractotomy, has been reported to alter regional cerebral blood flow in the medial prefrontal cortex, cingulate, and striatum (Kim, Lee, Son, Choi, & Lee, 2001). Sawle and colleagues have reported the case of one patient with OCD/​Tourette in whom reduced activity in the caudate nucleus postoperatively correlated with symptom reduction (Sawle, Lees, Hymas, Brooks, & Frackowiak, 1993). Finally, anterior capsulotomy involves lesions of the ventral portion of the anterior limb of the internal capsule, thus disrupting fibers that connect the OFC/​subgenual ACC to thalamic and striatal regions. Accordingly, this procedure may interrupt pathological CSTC circuitry involving OFC-​caudate or reciprocal OFC-​thalamus communication. Neuroimaging studies have suggested that clinical benefit requires lesions in the right anterior capsule that reduce neural activity in the orbitomedial frontal cortex (Lippitz, Mindus, Meyerson, Kihlstrom, & Lindquist, 1999). Clinical improvement has also been correlated with reduced activity in bilateral dorsal ACC, medial dorsal thalamus, and caudate, as measured with positron emission tomography (PET) (Zuo et al., 2013). In another PET study, postoperative metabolic decreases were reported in ACC, PFC, OFC, mediodorsal thalamus, caudate, and cerebellum after anterior capsulotomy (Suetens, Nuttin, Gabriels, & Van Laere, 2014). FUTUR E DI RECTI O N S Neurosurgical interventions are invasive and not without risk, and so the ability to identify candidates who are likely responders is of great importance. The field has begun to determine predictors of response by analyzing correlations between preoperative neuroimaging data or clinical presentation and treatment response (Borairi & Dougherty, F unctional N eurosurgery

2011). Rauch and colleagues reported that hypermetabolism in the right posterior cingulate predicted greater treatment response to anterior cingulotomy (Rauch et al., 2001). Banks and colleagues found that decreased gray matter in the right ACC and increased structural connectivity between the right ACC and the caudate, putamen, pallidum, thalamus, and hippocampus correlated with improved clinical outcomes to anterior cingulotomy (Banks et al., 2015). Thus, both neurophysiological and neuroanatomical characteristics may preoperatively aid identification of candidates and lesion sites to improve response. Clinical presentation may also provide predictive information. Obsessions and compulsions are heterogeneous: Factor analysis has delineated up to six independent dimensions of symptomatology (Baer, 1994; Goodman et al., 1989; Leckman, Zhang, Alsobrook, & Pauls, 2001; Pinto et al., 2008; see ­chapter 8), and different symptom dimensions are likely to have partly separable neural correlates (Mataix-​Cols et al., 2004; van den Heuvel et al., 2009; Widge, Deckersbach, Eskandar, & Dougherty, 2015). To date, only one group has reported on symptom dimensions with respect to surgical outcomes, noting that patients with hoarding symptoms have worse clinical outcomes after anterior cingulotomy or anterior capsulotomy (Gentil et al., 2014). Further exploration of correlations between symptom dimensions and outcomes are likely to reveal clinical predictors of response that could improve candidate selection. Technical advances will lead to refinement of lesion areas and reduced invasiveness, both of which will lessen risk and reduce recovery times. Targeting of specific neuronal projections (rather than anatomical regions) may improve specificity and minimize unwanted side effects. Individualized treatment may be guided by preoperative neuroimaging that delineates patient-​ specific biomarkers of disease and lesion foci. Newer techniques such as focused ultrasound are being explored. A  recently published case study of four patients who underwent anterior capsulotomy with MR-​g uided focused ultrasound reported clinical improvement and no significant side effects ( Jung et al., 2014). Focused ultrasound has also been proposed as a screening technique to identify viable candidates prior to ablative neurosurgery. Neurosurgical devices capable of reversibly modulating neural activity may provide additional advantages. Deep brain stimulation (DBS) is a nonablative technique that involves surgical implantation of bilateral electrodes that permit the polarity, amplitude, and frequency of stimulation to be dynamically adjusted (see ­chapter  46). DBS is performed clinically in a small number of OCD patients 513

 

annually in the United States under a Humanitarian Device Exemption from the US Food and Drug Administration. There is a growing literature demonstrating safety and efficacy of DBS, comparable to ablative neurosurgeries. A  recent metaanalysis reviewed 20 studies with 160 patients (62 with DBS and 108 with anterior cingulotomy) and reported that anterior cingulotomy was slightly more effective than DBS, with those who received anterior cingulotomy 9% more likely to go into remission and with a 10% greater mean reduction in Y-​B OCS score (Pepper, Hariz, & Zrinzo, 2015). No significant difference in side effect profile was noted between the two procedures. Of note, however, the DBS target has been drifting posteriorly in recent protocols, and outcomes from this more posterior site may be better than those previously reported. Further, dynamic optimization is possible with DBS, and real-​time closed loop feedback driven by disease-​specific biomarkers is in development (Widge, Arulpragasam, Deckersbach, Dougherty, 2015; Widge, Dougherty, & Moritz, 2014). Finally, a move toward greater standardization, more objective documentation, and collaboration will benefit the field. The invasiveness of ablative surgical interventions has, with the notable exception of GVC, precluded the use of RCTs. With the advent of GVC and other less invasive procedures, the placebo response and objective risks and benefits of neurosurgeries for OCD may be better assessed (Lopes et al., 2014). Measurement of clinical response based on standardized quantifiable scales and documentation of symptom dimensions and neuropsychological profiles will enhance the value of data obtained. Head-​to-​head comparisons of surgical procedures, perhaps even blinded, may reveal subtle differences in response and contribute to further individualization of treatment. Lastly, the field would benefit from the establishment of an international registry in which to collect systematic and accessible data on subjects, procedures, and outcomes. C ONCL US IONS Modern neurosurgical approaches to the treatment of OCD are important options for carefully selected patients with severe, chronic, treatment-​ refractory OCD. The four currently accepted procedures have demonstrated—​ and improving—​efficacy and safety. On the horizon are advances in candidate selection and response prediction, individualization of treatment based on clinical presentation and preoperative neuroimaging, and development of less invasive and dynamically modulated techniques.

514

Clinical and translational research that employ the latest advances in neuroimaging, electrophysiology, and parallel behavioral models in humans and other animals, will continue to illuminate the pathophysiology of OCD, the mechanisms by which psychiatric neurosurgery produces its therapeutic benefits, and paths toward further improvements in these valuable treatment tools.

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tractomy. An indispensable treatment. British Journal of Psychiatry, 165(5), 599–​611; discussion 612-​593. Brown, L. T., Mikell, C. B., Youngerman, B. E., Zhang, Y., McKhann, G. M., 2nd, & Sheth, S. A. (2016). Dorsal anterior cingulotomy and anterior capsulotomy for severe, refractory obsessive-​ compulsive disorder:  A  systematic review of observational studies. Journal of Neurosurgery, 124(1), 77–​89. Burguiere, E., Monteiro, P., Feng, G., & Graybiel, A. M. (2013). Optogenetic stimulation of lateral orbitofronto-​striatal pathway suppresses compulsive behaviors. Science, 340(6137), 1243–​1246. Cannistraro, P. A., Makris, N., Howard, J. D., Wedig, M. M., Hodge, S. M., Wilhelm, S., . . . Rauch, S. L. (2007). A diffusion tensor imaging study of white matter in obsessive-​compulsive disorder. Depresion and s Anxiety, 24(6), 440–​446. Cannistraro, P. A., Wright, C. I., Wedig, M. M., Martis, B., Shin, L. M., Wilhelm, S., & Rauch, S. L. (2004). Amygdala responses to human faces in obsessive-​compulsive disorder. Biological Psychiatry, 56(12), 916–​920. Cosgrove, G. R. (2000). Surgery for psychiatric disorders. CNS Spectrums, 5(10), 43–​52. D’Astous, M., Cottin, S., Roy, M., Picard, C., & Cantin, L. (2013). Bilateral stereotactic anterior capsulotomy for obsessive-​compulsive disorder: Long-​term follow-​up. Journal of Neurology, Neurosurgery, and Psychiatry, 84(11), 1208–​1213. Dougherty, D. D., Baer, L., Cosgrove, G. R., Cassem, E. H., Price, B. H., Nierenberg, A. A.,  .  .  .  Rauch, S. L. (2002). Prospective long-​term follow-​up of 44 patients who received cingulotomy for treatment-​ refractory obsessive-​ compulsive disorder. American Journal of Psychiatry, 159(2), 269–​275. Dougherty, D. D., Rauch, S. L., & Greenberg, B. D. (2010). Pathophysiology of obsessive-​compulsive disorders. In D. J. Stein, E. Hollander, & B. O. Rothbaum (Eds.), Textbook of anxiety disorders (2nd ed., pp. 287–​309). Washington, DC: American Psychiatric Publishing. El-​Hai, J. (2007). The lobotomist: A maverick medical genius and his tragic quest to rid the world of mental illness. Hoboken, NJ: Wiley. Feldman, R. P., & Goodrich, J. T. (2001). Psychosurgery:  A  historical overview. Neurosurgery, 48(3), 647–​657; discussion 657–​659. Feldman, R. P., Alterman, R. L., & Goodrich, J. T. (2001). Contemporary psychosurgery and a look to the future. Journal of Neurosurgery, 95(6), 944–​956. Foroughi, M., Kemeny, A. A., Lehecka, M., Wons, J., Kajdi, L., Hatfield, R., & Marks, S. (2010). Operative intervention for delayed symptomatic radionecrotic masses developing following stereotactic radiosurgery for cerebral arteriovenous malformations-​-​case analysis and literature review. Acta Neurochirurgica (Wien), 152(5), 803–​815. Freeman, W. (1948). Transorbital leucotomy. Lancet, 2(6523), 371–​373. Freeman, W., & Watts, J. W. (1942). Prefrontal lobotomy: The surgical relief of mental pain. Bulletin of the New York Academy of Medicine, 18(12), 794–​812. Garnaat, S. L., Greenberg, B. D., Sibrava, N. J., Goodman, W. K., Mancebo, M. C., Eisen, J. L., & Rasmussen, S. A. (2014). Who qualifies for deep brain stimulation for OCD? Data from a naturalistic clinical sample. Journal of Neuropsychiatry and Clinical Neuroscience, 26(1), 81–​86. Gentil, A. F., Lopes, A. C., Dougherty, D. D., Ruck, C., Mataix-​Cols, D., Lukacs, T. L., . . . Miguel, E. C. (2014). Hoarding symptoms and prediction of poor response to limbic system surgery for treatment-​ refractory obsessive-​compulsive disorder. Journal of Neurosurgery, 121(1), 123–​130. Goktepe, E. O., Young, L. B., & Bridges, P. K. (1975). A further review of the results of sterotactic subcaudate tractotomy. British Journal of Psychiatry, 126, 270–​280. Goodman, W. K., Price, L. H., Rasmussen, S. A., Mazure, C., Fleischmann, R. L., Hill, C. L., . . . Charney, D. S. (1989). The Yale-​ Brown Obsessive Compulsive Scale. I.  Development, use, and reliability. Archives of General Psychiatry, 46(11), 1006–​1011.

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Greenberg, B. D., Dougherty, D. & Rauch, S. L. (2011). Neurosurgical lesion procedures and deep brain stimulation. In B. J. Sadock, V. A. Sadock, & P. Ruiz (Eds), Kaplan and Sadock’s comprehensive textbook of psychiatry (pp. 3314–​3322). Philadelphia, PA:  Lippincott Williams and Wilkins. Haber, S. N., Fudge, J. L., & McFarland, N. R. (2000). Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. Journal of Neuroscience, 20(6), 2369–​2382. Hay, P., Sachdev, P., Cumming, S., Smith, J. S., Lee, T., Kitchener, P., & Matheson, J. (1993). Treatment of obsessive-​compulsive disorder by psychosurgery. Acta Psychiatrica Scandinavica, 87(3), 197–​207. Herner, T. (1961). Treatment of mental disorders with frontal stereotaxic thermo-​lesions: a follow-​up study of 116 cases. Acta Psychiatrica Scandinavica, 36(supplement 158), 7–​149. Jung, H. H., Kim, C. H., Chang, J. H., Park, Y. G., Chung, S. S., & Chang, J. W. (2006). Bilateral anterior cingulotomy for refractory obsessive-​ compulsive disorder:  Long-​term follow-​up results. Stereotactic and Functional Neurosurgery, 84(4), 184–​189. Jung, H. H., Kim, S. J., Roh, D., Chang, J. G., Chang, W. S., Kweon, E. J., . . . Chang, J. W. (2014). Bilateral thermal capsulotomy with MR-​ guided focused ultrasound for patients with treatment-​refractory obsessive-​compulsive disorder: A proof-​of-​concept study. Molecular Psychiatry, 20(10), 1205–​1211. Kelly, D., Richardson, A., Mitchell-​Heggs, N., Greenup, J., Chen, C., & Hafner, R. J. (1973). Stereotactic limbic leucotomy: A preliminary report on forty patients. British Journal of Psychiatry, 123(573), 141–​148. Kim, C. H., Chang, J. W., Koo, M. S., Kim, J. W., Suh, H. S., Park, I. H., & Lee, H. S. (2003). Anterior cingulotomy for refractory obsessive-​ compulsive disorder. Acta Psychiatrica Scandinavica, 107(4), 283–​290. Kim, M. C., Lee, T. K., & Choi, C. R. (2002). Review of long-​term results of stereotactic psychosurgery. Neurologica Medico-​Chirurgica (Tokyo), 42(9), 365–​371. Kim, M. C., Lee, T. K., Son, B. C., Choi, C. R., & Lee, C. (2001). Regional cerebral blood flow changes in patients with intractable obsessive compulsive disorders treated by limbic leukotomy. Stereotactic and Functional Neurosurgery, 76(3-​4), 249–​255. Knight, G. (1973). Further observations from an experience of 660 cases of stereotactic tractotomy. Postgraduate Medical Journal, 49(578), 845–​854. Leckman, J. F., Zhang, H., Alsobrook, J. P., & Pauls, D. L. (2001). Symptom dimensions in obsessive-​compulsive disorder:  Toward quantitative phenotypes. American Journal of Medical Genetics, 105(1), 28–​30. Lippitz, B. E., Mindus, P., Meyerson, B. A., Kihlstrom, L., & Lindquist, C. (1999). Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-​ compulsive disorder:  Relevance of the right hemisphere. Neurosurgery, 44(3), 452–​458; discussion 458–​460. Lipsman, N., et  al. (2007). Deep brain stimulation for treatment-​ refractory obsessive-​compulsive disorder: The search for a valid target. Neurosurgery, 61, 1–​13. Lopes, A. C., Greenberg, B. D., Canteras, M. M., Batistuzzo, M. C., Hoexter, M. Q., Gentil, A. F., . . . Miguel, E. C. (2014). Gamma ventral capsulotomy for obsessive-​compulsive disorder:  A  randomized clinical trial. JAMA Psychiatry, 71(9), 1066–​1076. Mataix-​ Cols, D., Wooderson, S., Lawrence, N., Brammer, M. J., Speckens, A., & Phillips, M. L. (2004). Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessive-​ compulsive disorder. Archives of General Psychiatry, 61(6), 564–​576. Milad, M. R., & Rauch, S. L. (2012). Obsessive-​compulsive disorder: Beyond segregated cortico-​striatal pathways. Trends in Cognitive Science, 16(1), 43–​51. Mindus, P., Rasmussen, S. A., & Lindquist, C. (1994). Neurosurgical treatment for refractory obsessive-​compulsive disorder: Implications for understanding frontal lobe function. Journal of Neuropsychiatry and Clinical Neuroscience, 6(4), 467–​477.

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Moniz E. (1937). Prefrontal leucotomy in the treatment of mental disorders. American Journal of Psychiatry, 93, 1379–​1385. Montoya, A., Weiss, A. P., Price, B. H., Cassem, E. H., Dougherty, D. D., Nierenberg, A. A., . . . Cosgrove, G. R. (2002). Magnetic resonance imaging-​g uided stereotactic limbic leukotomy for treatment of intractable psychiatric disease. Neurosurgery, 50(5), 1043–​1049; discussion 1049–​1052. Pan, H. C., Sheehan, J., Stroila, M., Steiner, M., & Steiner, L. (2005). Late cyst formation following gamma knife surgery of arteriovenous malformations. Journal of Neurosurgery, 102(Suppl), 124–​127. Pepper, J., Hariz, M., & Zrinzo, L. (2015). Deep brain stimulation versus anterior capsulotomy for obsessive-​compulsive disorder: A review of the literature. Journal of Neurosurgery, 122(5), 1028–​1037. Pinto, A., Greenberg, B. D., Grados, M. A., Bienvenu, O. J., 3rd, Samuels, J. F., Murphy, D. L., . . . Nestadt, G. (2008). Further development of YBOCS dimensions in the OCD Collaborative Genetics study: Symptoms vs. categories. Psychiatry Research, 160(1), 83–​93. Price, B. H., Baral, I., Cosgrove, G. R., Rauch, S. L., Nierenberg, A. A., Jenike, M. A., & Cassem, E. H. (2001). Improvement in severe self-​ mutilation following limbic leucotomy:  A  series of 5 consecutive cases. Journal of Clinical Psychiatry, 62(12), 925–​932. Rauch, S. L., Dougherty, D. D., Cosgrove, G. R., Cassem, E. H., Alpert, N. M., Price, B. H., . . . Fischman, A. J. (2001). Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder. Biological Psychiatry, 50(9), 659–​667. Ruck, C., Karlsson, A., Steele, J. D., Edman, G., Meyerson, B. A., Ericson, K., . . . Svanborg, P. (2008). Capsulotomy for obsessive-​compulsive disorder:  Long-​term follow-​up of 25 patients. Archives of General Psychiatry, 65(8), 914–​921. Sawle, G. V., Lees, A. J., Hymas, N. F., Brooks, D. J., & Frackowiak, R. S. (1993). The metabolic effects of limbic leucotomy in Gilles de la Tourette syndrome. Journal of Neurology, Neurosurgery, and Psychiatry, 56(9), 1016–​1019. Saxena, S., Brody, A. L., Schwartz, J. M., & Baxter, L. R. (1998). Neuroimaging and frontal-​ subcortical circuitry in obsessive-​ compulsive disorder. British Journal of Psychiatry Suppl(35), 26–​37. Sheehan, J. P., Patterson, G., Schlesinger, D., & Xu, Z. (2013). Gamma knife surgery anterior capsulotomy for severe and refractory obsessive-​compulsive disorder. Journal of Neurosurgery, 119(5), 1112–​1118. Sheth, S. A., Neal, J., Tangherlini, F., Mian, M. K., Gentil, A., Cosgrove, G. R., . . . Dougherty, D. D. (2013). Limbic system surgery for treatment-​ refractory obsessive-​compulsive disorder:  A  prospective long-​term follow-​up of 64 patients. Journal of Neurosurgery, 118(3), 491–​497. Spangler, W. J., Cosgrove, G. R., Ballantine, H. T., Jr., Cassem, E. H., Rauch, S. L., Nierenberg, A., & Price, B. H. (1996). Magnetic

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46. DEEP BRAIN STIMULATION FOR INTRACTABLE OCD Wayne K. Goodman, MD, Nigel Kennedy, MBBS, PhD, MSc, Kyle Lapidus, MD, PhD, and Brian H. Kopell, MD

O

bsessive-​compulsive disorder (OCD) is a common, persistent, and oftentimes disabling disorder marked by unwanted and distressing thoughts (obsessions) and irresistible repetitive behaviors (compulsions) (American Psychiatric Association, 2013; Rasmussen & Eisen, 1992). OCD affects 2% to 3% of the US population (Ruscio, Stein, Chiu, & Kessler, 2010) and is responsible for substantial functional impairment (Adam, Meinlschmidt, Gloster, & Lieb, 2012; Norberg, Calamari, Cohen, & Riemann, 2008) and increased risk of early mortality (Meier et al., 2016). The only established first-​line treatments for OCD are cognitive-​behavioral therapy (CBT) with exposure/​response prevention (ERP) (Deacon & Abramowitz, 2004; Koran et al., 2007; see ­chapter 37) and serotonin reuptake inhibitor medications (SRIs) (Ackerman & Greenland, 2002; W. K. Goodman et al., 1990; Koran et al., 2007; Pigott & Seay, 1999; Pittenger & Bloch, 2014; see ­chapter 40). Approximately 30% to 40% of patients fail to respond to either modality (Ost, Havnen, Hansen, & Kvale, 2015; Romanelli, Wu, Gamba, Mojtabai, & Segal, 2014), and few patients experience complete symptom resolution (Simpson, Huppert, Petkova, Foa, & Liebowitz, 2006). Adjunctive antipsychotics may be beneficial in SRI partial responders, especially those with concomitant tics (Bloch et al., 2006; McDougle et al., 1994). Noninvasive devices like repetitive transcranial magnetic stimulation are showing promise in non–​ reatment-​ resistant OCD (Dunlop et al., 2016; Modirrousta, Meek, Sareen, & Enns, 2015). However, for the most severe and refractory cases, ablative neurosurgery, either cingulotomy (Dougherty et al., 2002; Jenike et al., 1991; Jung et al., 2006) or anterior capsulotomy (Lopes et al., 2014; Lopes, Greenberg, Pereira, Noren, & Miguel, 2015; Mindus, Edman, & Andreewitch, 1999; Ruck et al., 2008) has long been the option of last resort

(Greenberg, Rauch, & Haber, 2010; Pressman, 1998; see ­chapter 45). In contrast to ablative procedures, deep brain stimulation (DBS) has the advantages of being adjustable, nondestructive, and potentially reversible (explantable) (Rezai et al., 2008; see Table 46.1). These features have led to DBS supplanting lesioning techniques for the neurosurgical treatment of medication-​refractory Parkinson’s disease (PD), essential tremor, and dystonia (Hariz & Hariz, 2013; see Table 46.2). In psychiatric disorders, in which less is known about the optimal targets for neurosurgical intervention, reversibility and adjustability are even more critical (Goodman & Insel, 2009). Both DBS and ablative procedures are invasive and associated with significant safety risks (Table 46.1). However, the available data from postmortem tissue and electron microscopy of explanted electrodes suggest that the pathological changes produced by chronic DBS are limited to mild gliosis along the electrode track and giant cell reaction adherent to the lead (Moss, Ryder, Aziz, Graeber, & Bain, 2004). In 1999, DBS targeting the anterior limb of the internal capsule (ALIC) was found beneficial in three of four cases of intractable OCD (Nuttin, Cosyns, Demeulemeester, Gybels, & Meyerson, 1999). Since then, the DBS literature for OCD has evolved to larger studies, several small randomized sham-​controlled clinical trials, and targeting of brain regions outside the ventral capsule/​ventral striatum (VC/​VS). Anatomic targets for DBS in OCD have included the ALIC (Abelson et al., 2005), neighboring targets (i.e., the VS; Goodman et al., 2010; Greenberg, Gabriels, et al., 2010) or nucleus accumbens (NAc; Denys et al., 2010), a subregion of the VS), the bed nucleus of the stria terminalis (Islam, Franzini, Messina, Scarone, & Gambini, 2015), the subthalamic nucleus (STN; Mallet et

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TA B L E   4 6 . 1  

C O M PAR I S O N O F   N E URO S UR GI C A L A P PROAC HES Ablative*

DBS

Comments and Caveats

Stereotactic

Yes

Yes

Destructive

Yes

No

In DBS, evidence from postmortem tissue suggests mild gliosis around electrode track after chronic placement.

Reversible

No

Yes

Although DBS is a reversible procedure, there are risks (e.g., hemorrhage) associated with explantation of the intracranial hardware.

Invasive

Yes

Yes

Craniotomy

No

Yes

Adjustable

No

Yes

Serious A/​Es

Yes

Yes

In DBS, additional risks (e.g., infection) are associated with craniotomy and lead placement. Both approaches are associated with risk of intracranial hemorrhage. Late onset radiation necrosis (Tripathi et al., 2014) has been reported with Gamma Knife surgery.

Cost

High

Higher

Operative, device and follow-​up (programming) requirements make DBS significantly more expensive.

With radiosurgery (e.g., Gamma Knife or LINAC) no craniotomy is necessary.

*  In the past, ablative surgery was often performed using thermolytic lesions; modern approaches use radiosurgery. Gamma Knife uses sources of cobalt 60 to produce γ rays, whereas LINAC refers to a linear accelerator that emits high-​energy x-​rays. DBS, deep brain stimulation; A/​E, adverse event. Table adapted with permission from Table 1 of Goodman, W. K., & Insel T. R. (2009). Deep brain stimulation in psychiatry: Concentrating on the road head. Biological Psychiatry, 65, 263–​266.

al., 2008), and the inferior thalamic peduncle (ITP; Jimenez et al., 2013). In 2010, the FDA approved a Humanitarian Device Exemption (HDE) for up to 4,000 people a year in the US to receive VC/​VS DBS for intractable OCD, based upon the device’s safety and its probable benefit. This is the same regulatory status assigned to DBS for intractable dystonia (see Table 46.2). As of this writing, the outcome data for DBS in OCD continue to look promising, with a recent metaanalysis showing response rates averaging 60% across different targets (Alonso et al., 2015). This chapter reviews the current state of the field of DBS for intractable OCD and discusses future innovations in DBS technology that may further enhance outcomes. The emphasis herein on ventral striatal targets (ALIC, VC/​VS, and NAc) reflects several considerations: (1) these procedures have received limited regulatory approval (i.e., VC/​VS DBS for OCD is performed under HDE approval in the United States and, in Europe, under a Conformité Européene [CE] approval); (2) they comprise the majority of published reports (Alonso et al., TA B L E   4 6 . 2  

F DA APP ROVA L S TAT US F O R   D B S

Full FDA Approval

Humanitarian Device Exemption (HDE)* Approval

Essential Tremor

Dystonia

Refractory Parkinson’s Disease

Intractable OCD (January 2010)

Refractory Epilepsy *About HDEs: 1. intended for fewer than 4,000 people in the US every year; 2. demonstrated product safety and probable benefit; 3. IRB approval and written informed consent is required at each center.

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2015); and (3) the first author has nearly 15 years of experience with this intervention for severe, treatment-​resistant OCD. We begin with a brief history of psychiatric neurosurgery and the use of ablative procedures for patients with OCD. T H E LE GAC Y OF   “ PS YC H OS U R GE R Y” Investigators who are developing neurosurgical approaches for psychiatric disorders should be cognizant of past mistakes and careful not to repeat them (Goodman & Insel, 2009; Lapidus, Kopell, Ben-​Haim, Rezai, & Goodman, 2013). Consequently, a description of modern stereotactic neurosurgical interventions for psychiatric disease is incomplete without discussion of lessons learned from the dark era of frontal lobotomy (Goodman & Insel, 2009; Pressman, 1998). Inspired by the nonhuman primate research of Yale’s John Fulton, the Portuguese neurologist Egas Moniz introduced frontal leucotomy in 1936 (Lapidus et  al., 2013; Lerner, 2005). A  surgical instrument called a “leucotome” was inserted through a burr hole and manipulated to sever white matter tracts of the prefrontal cortex (Heller et  al., 2006; Mashour, Walker, & Martuza, 2005). Moniz, who coined the term “psychosurgery” (Heller et  al., 2006), theorized that disrupting the neuronal circuits that caused psychiatric illness would “… change the corresponding thoughts and … force them into other channels (Gross & Schafer, 2011).” In 1949, he won the Nobel prize for discovering “the therapeutic value of leucotomy in certain psychoses (Moniz, 1949).” O b sessive - C ompulsive D isorder

 

pharmacological milestone—​more so than public outcry (Valenstein, 1974)—​led to an abrupt end to the practice of frontal lobotomy (Pressman, 1998). However, this infamous period lives long in public memory through literature and movies, such as One Flew Over the Cuckoo’s Nest (Kesey, 1962). The specter of lobotomy remains a source of trepidation despite the vast changes that have taken place in the field of neurosurgery for neuropsychiatric disorders. One small but important change is discarding the term “psychosurgery,” a misnomer that implies the surgical target is the “mind” or “psyche” (Kopell & Rezai, 2003). The intended target is the neural substrate of the disorder, and the goal is restoration of normal emotional, behavioral, and cognitive function. Figure 46.1  ILLUSTRATION OF TRANSORBITAL OR “ICE PICK” LOBOTOMY

PROCEDURE DEVELOPED BY WALTER FREEMAN.  A metal spike is passed underneath the eyelid and driven by a mallet through the roof of the orbit into the brain. Frontal fiber tracts are severed by a sweeping motion of the surgical instrument. This outpatient procedure used the postictal state induced by electroconvulsive therapy as anesthesia.  (Reproduced with permission from Lerner, B. H. (2005). Last-​ditch medical therapy –​revisiting lobotomy. The New England Journal of Medicine, 353, 119–​121.)

In the United States, the neurologist Walter Freeman championed frontal lobotomy at a time when there was a dearth of treatment options for the severely mentally ill and over 400,000 patients were housed in mental asylums (Glied & Frank, 2009). Between 1939 and 1951, a staggering 18,000 frontal lobotomies were performed in the United States alone (Goodman & Insel, 2009; Mashour et al., 2005; Braslow, 1999). Freeman parted company from his neurosurgical colleague James Watts to develop “ice pick” lobotomy, a rapid but imprecise procedure for severing fiber tracts of the frontal lobes using a transorbital approach (Lerner, 2005; Figure 46.1). Although this procedure allowed many patients to be discharged from the hospital to the community, it was associated with high mortality and morbidity, including radical changes in personality (Pressman, 1998). The problems of this first period in psychiatric neurosurgery were not limited to the crudeness of the surgical procedures and cavalier behavior of Freeman, who paraded around the country in his “lobotomobile” (Heller, 2006; Lapidus et al., 2013; Rogers, 2009). Despite the call for rigorous clinical trials, none was performed. No data were published that approach our current standards for reliable and objective reporting of therapeutic outcome or adverse events. Furthermore, the protection of human subjects was woefully inadequate, if not entirely absent (Goodman & Insel, 2009). With the advent of chlorpromazine in 1953 came a safer, more effective method of managing psychosis. This D eep Brain S timulation

S T E R E OTAC T IC NE U ROS U R GE R Y Although lobotomies stopped being performed, stereotactic neurosurgical approaches that produced more precise and circumscribed lesions led to a resurgence of interest in psychiatric indications (Lapidus et al., 2013). Stereotactic neurosurgery refers to a method for navigating the brain using an external, three-​dimensional frame of reference. This technique enhances accuracy of reaching the intended target and minimizes side effects from injury to surrounding brain tissue. Marriage of stereotactic techniques with high-​resolution brain imaging and computer guidance systems led to further refinements in targeting. Between 1947 and 1949, Wycis and Spiegel (Spiegel, Wycis, Marks, & Lee, 1947) introduced the first subcortical stereotactic neurosurgical procedure for a psychiatric condition (Lapidus et al., 2013). By combining a head-​ mounted apparatus with pneumoencephalography to visualize intracranial landmarks, they were able to chart trajectories to the targets of interest. Using this procedure, they tried unsuccessfully to treat psychotic agitation with thermolytic dorsomedial thalamotomy (Kopell & Rezai, 2003). In 1949, the Swedish surgeon Lars Leksell invented a stereotactic head frame (Figure 46.2a) that is remarkably similar to the type still in use today (Figure 46.2b; Leksell, 1949). This advance, together with his later innovation of “Gamma Knife” radiosurgery, was aimed at minimally invasive treatment of neurological and psychiatric disorders (Heller, 2006). Several different stereotactic ablative procedures have been applied to the treatment of OCD (Lapidus et  al., 2013). These are described in detail in ­chapter 45. 519

 

he programmed the device to deliver continuous high frequency stimulation to the target region, leading to improved clinical symptoms during chronic treatment (Benabid, Pollak, Louveau, Henry, & de Rougemont, 1987). An implanted DBS device consists of four components (Figure 46.3): (1) the stimulating lead, placed stereotactically within the desired brain target and equipped with multiple (typically four) electrode contacts for delivering therapeutic stimulation; (2) a locking device, which anchors the lead and covers the burr hole through which the lead is placed; (3) an implantable pulse generator (IPG) placed under the skin of the chest; and (4) an extension cable, tunneled under the skin connecting the IPG to the lead. DBS surgery is a two-​stage procedure: first, implantation of the leads in the brain; and second, implantation of (B) the IPG and extensions. For bilateral DBS, some neurosurgeons perform the first stage on two different days, one for each brain hemisphere. Because the brain parenchyma does not contain pain receptors, the first stage can be performed with local anesthesia of the scalp and conscious sedation. In some cases, the patient is awakened for a portion of the procedure to allow for initial behavioral testing of DBS stimulation using externalized leads. The second stage is carried out under general anesthesia and involves the implantation of the IPG under the skin of the chest wall, below the clavicle, akin to a cardiac pacemaker. Once implanted, the IPG can be interrogated and controlled externally by telemetric communication with a hand-​held programming device. Titration of the stimulator typically begins 1 to 2 weeks postoperatively, when the patient has recovered from surgery. The specialist—​a neurologist in the case of movement disorders or a psychiatrist in treatment of mental disorders—​works with the patient to adjust stimulation settings. Although the position of the Figure 46.2  A. The original Leksell stereotactic frame from 1949. B. The modern version.  (Courtesy of Elekta) lead in the brain is fixed, the center of the electrical field can be shifted along the axis of the lead by activating different contacts. In addition to changing the electrode configuraDBS DEVICES tion, signal amplitude, frequency (typically high frequency 130–​180 Hz), and pulse width can all be varied. Thousands DBS research has advanced primarily through work in of permutations are possible for the device settings. To movement disorders, as memorialized by the 2014 Lasker-​ manage this daunting task, programming algorithms have Debakey Clinical Medical Research Award to Mahlon been developed to systematically and efficiently survey the DeLong and Alim-​Louis Benabid (DeLong & Benabid, therapeutic space and identify boundaries defined by side 2014). In 1987, Benabid, a French neurosurgeon, per- effects. Over repeated programming sessions, settings are formed the first case of DBS, implanting a neurostimulator optimized to enhance clinical benefit while minimizing with an electrode in the thalamus of a patient with intrac- DBS-​induced adverse effects. Of note, the on/​off status of table tremor (Okun, 2014). Based on previous experience stimulation can be masked to allow for active/​sham ranfrom intraoperative testing prior to making lesions, Benabid domization necessary for double-​blind controlled studies. found that high-​and not low-​frequency stimulation supPatients need to be followed closely during the inipressed tremor (DeLong & Benabid, 2014). In this case, tial titration phase, to allow early recognition of adverse (A)

520

O b sessive - C ompulsive D isorder

 

Figure 46.3  DEEP BRAIN STIMULATION (DBS) IMPLANTED HARDWARE.  Electrodes attached to a lead are implanted into a brain target (subthalamic

nucleus in illustration) through a burr hole in the skull. The insulated is tunneled under the skin to a programmable pulse generator that lies under the skin in the chest wall and delivers therapeutic current.  (Illustration by Cassio Lynn)

effects such as hypomania (Haq et al., 2010; Widge et al., 2016)  and readjustment of the parameters as necessary. The patient is also given a limited-​functionality access device, allowing him or her to check the status of the IPG. The access device can give the patient a restricted range of control over the parameters (e.g., amplitude) of the stimulation field, as determined safe by the programming specialist. EFFICACY OF D BS I N  O CD VENTRAL STRIATUM AND NEIGHBORING TARGETS

The first reports of DBS treatment primarily for psychiatric disorders, OCD (Nuttin et  al., 1999)  and Tourette Syndrome (TS) (Vandewalle, van der Linden, Groenewegen, & Caemaert, 1999), were published in 1999 (Lapidus et al., 2013). Bart Nuttin in Belgium implanted DBS leads bilaterally “down the barrel” of the ALIC in four patients with severe OCD. This electrical stimulation target was selected primarily on the basis of the area ablated during gamma knife cingulotomy. Beneficial effects were observed in three of the four cases during acute stimulation (Nuttin et al., 1999). A subsequent publication from the same group D eep Brain S timulation

tested the effects of chronic DBS stimulation in a blinded crossover fashion (Nuttin et  al., 2003). The most ventral Contact 0 was placed in or near to the NAc. Superiority of active stimulation over the “Off ” condition was demonstrated in three of four cases (Nuttin et al., 2003). The original “follow the lesion” (Nuttin et al., 1999) rationale for ALIC DBS in OCD is compatible with converging lines of evidence that OCD involves cortico-​striato-​ thalamo-​cortical circuit dysfunction (Greenberg, Rauch, et al., 2010; Harrison et al., 2009; Milad & Rauch, 2012; see ­chapters 20, 21). Preclinical (McCracken & Grace, 2009) and clinical data (Harrison et al., 2009), particularly from functional brain imaging studies (Dougherty et al., 2016; Figee et al., 2013), suggest that increased connectivity between the PFC and the VS plays a role in the pathophysiology OCD. DBS therapy in the region of the VS may modulate pathways coursing through the ALIC that have been implicated in neurocircuitry models of OCD (Milad & Rauch, 2012). In a seminal study of NAc DBS in OCD, repeated resting-​state fMRI scans showed that DBS normalized (increased) NAc activity and reduced excessive connectivity between NAc and prefrontal cortex (Figee et al., 2013). Emerging evidence suggests that white matter fibers connecting the VS with medial prefrontal cortical regions are the main target of the DBS electrodes (Lehman, Greenberg, McIntyre, Rasmussen, & Haber, 2011). 521

 

Following the initial report of Nuttin (Nuttin et  al., 1999), other groups have published on their experience with DBS of the ALIC in intractable OCD (Abelson et al., 2005) or neighboring brain regions, including the ventral capsule/​ventral striatum (VC/​VS) (Goodman et al., 2010; Greenberg, Gabriels, et al., 2010) and NAc (Denys et al., 2010; Huff et  al., 2010). Many of the findings are from uncontrolled, open-​label studies or case reports (Goodman & Alterman, 2012). Several studies included a double-​blind period with an on/​off phase (Denys et al., 2010; B. J. Nuttin et  al., 2003)  or staggered-​onset design (Goodman et  al., 2010). A long-​term, open-​label follow-​up study of VC/​VS DBS included 26 patients who were followed for a mean of 31.4 months (Greenberg, Gabriels, et al., 2010). Using stringent outcome criteria (≥35% decrease in Y-​B OCS scores), more than 60% of these patients showed a response (Greenberg, Rauch, et al., 2010). Reductions in symptom severity were accompanied by improvements in measures of functioning and quality of life (Greenberg, Rauch, et al., 2010). Denys and colleagues published findings on NAc DBS in 16 patients with treatment-​resistant OCD (Denys et al., 2010). Nine (56%) of the patients met criteria for response following 8 months of open-​label DBS. Patients were then entered in a double-​blind crossover phase with random assignment to 2 weeks of either active or sham stimulation. During the sham phase, patients exhibited a rapid worsening in symptoms of OCD and depression (Denys et al., 2010). An NIMH-​ funded multi-​ center randomized sham-​ controlled trial of VC/​VS DBS in OCD has been completed, but the results have yet to be published. It should be noted, however, that that study was not powered to be a pivotal test of efficacy (Benjamin Greenberg, 2016 personal communication). The relative course of VS DBS-​induced changes in mood and OCD symptoms is noteworthy. Positive effects on mood and motivation invariably precede improvement in OCD (Goodman et al., 2010). Reductions in OCD symptom severity are generally not observed for weeks or months, and optimal benefit is not achieved until after at least 6 months of stimulation. The failure to detect changes on the Y-​B OCS may be partially related to insensitivity of this instrument at the higher end of the severity range (Denys et al., 2010). Future studies of DBS in OCD may benefit from use of the Y-​B OCS II, which was designed to be more granular at the upper range of symptom severity (Storch et al., 2010; see ­chapter 14). Nevertheless, it is evident that major reductions in OCD symptom severity take time to develop. Clinical research from the Amsterdam 522

group suggests that the VS DBS enhances the therapeutic effects of ERP (Mantione, Nieman, Figee, & Denys, 2014). Preclinical studies show that NAc DBS enhances fear extinction (Rodriguez-​Romaguera, Do Monte, & Quirk, 2012), which may explain how it augments ERP in humans (Mantione et al., 2014). The gradual course of improvement in OCD, difficulty in generalizing gains outside of clinic, and risk of relapse (when DBS is discontinued) may reflect impairment in extinction learning and retention (Baas et al., 2014; Britton, Evans, & Hernandez, 2014; Craske, Treanor, Conway, Zbozinek, & Vervliet, 2014; Figee et al., 2011; Mantione et al., 2014; Milad & Quirk, 2012; van Westen, Rietveld, Figee, & Denys, 2015). SUBTHALAMIC NUCLEUS

In 2002, Mallet and colleagues reported on results of STN DBS in two patients with comorbid PD and OCD (Mallet et al., 2002). In both cases, DBS alleviated symptoms of PD and reduced severity of obsessive-​compulsive symptoms, as reflected by >50% decrease of Y-​B OCS scores (Mallet et  al., 2002). Based on these and other (Fontaine et  al., 2004)  encouraging results from open-​ label studies, a randomized, double-​blind crossover trial of STN DBS was conducted in 16 patients with refractory OCD (Mallet et al., 2008). The active and sham treatment arms were each 3 months long and the total duration of the study was 10  months. Y-​B OCS scores were significantly lower at the end of the active phase compared with the end of the sham phase. Because of placement variations, four patients in this study were actually stimulated in areas outside the STN; however, each patient had at least one electrode contact in the STN. In marked contrast to experience with VS DBS in OCD, no changes in mood or anxiety symptoms were noted in this study (Mallet et al., 2008). OTHER TARGETS

Other anatomical sites that have been tested as potential DBS targets for OCD include the ITP, the ventral caudate nucleus, and the bed nucleus of the stria terminalis (Islam et al., 2015; Table 46.3). The number of cases targeting each of these other targets remains very small, making it hard, as of yet, to draw conclusions as to their efficacy. M E TA A N A LY S E S

A 2011 review concluded that the overall response rate was >50% across all published papers on the various DBS O b sessive - C ompulsive D isorder

 

ADV E R S E   E V E NT S

PU BLI S HE D S T UD I E S O F   D B S F O R  O C D : TARG E T S A N D N UM B E R O F   S UB J E C T S TA B L E   4 6 . 3  

ALIC VC/​VS NAc # Studies (32) # Patients (122)

STN

ITP

BNST VCN

9

6

7

5

1

1

2

14

34

35

27

6

6

2

N = 83

N = 27

ALIC = Anterior Limb Internal Capsule; VC/​VS = Ventral Capsule/​Ventral Striatum; STN = Subthalamic Nucleus; ITP = Inferior Thalamic Peduncle; BNST = Bed Nucleus Stria Terminalis; VCN = ventral caudate nucleus.

targets (de Koning, Figee, van den Munckhof, Schuurman, & Denys, 2011). Lower response rates were seen with unilateral stimulation to the NAc (Huff et al., 2010). A more recent metaanalysis (Alonso et  al., 2015)  examined data from 116 patients across 31 studies. Of these, 83 patients had DBS in striatal regions (ALIC, VC/​VS, NAc), 27 patients received treatment in the STN, and 6 patients in the ITP (see Table 46.3). The global Y-​B OCS reduction was calculated to be 45.1% and the overall response rate was 60% (see Figure 46.4). No statistically significant differences in treatment outcomes were found in the comparison of the VS and STN areas. Better response was associated with older age of OCD onset. Study

The risks associated with DBS are generally divided into three categories related to: (1) the surgery, (2) hardware malfunctions, and (3) the effects of stimulation (or its interruption). Worldwide experience with over 120,000 cases of DBS for movement disorders serves as an ample database for predicting surgical and hardware-​related side effects in psychiatric disorders. The implanted hardware is identical and the surgical procedures differ only with respect to entry point, trajectory, and targets, which generally do not entail higher risks. COMPLICATIONS OF SURGERY

The most dreaded risk of DBS therapy is that of brain hemorrhage during implantation of the DBS leads (Bronstein et al., 2011). Hemorrhage rates of 0 %–​10% are reported in the literature (Bronstein et al., 2011), though larger series report hemorrhage rates of ~2% (Follett et al., 2010; Foltynie & Hariz, 2010). Depending on the size and location, these hemorrhages may be inconsequential or may cause a variety of neurological deficits or even death. The risk of hemorrhage may be correlated with larger numbers of microelectrode recording trajectories (employed

Events Total

Proportion

95%-Cl w(fixed) w(random)

Mallet et al., 2002 Nuttin et al., 2003

2 4

2 8

1.00 [0.16; 1.00] 0.50 [0.16; 0.84]

1.9% 9.2%

1.9% 9.2%

Sturm et al., 2003

3

4

0.75 [0.19; 0.99]

3.5%

3.5%

Aouizerate et al., 2004 Abelson et al., 2005

2 2

2 4

1.00 [0.16; 1.00] 0.50 [0.07; 0.93]

1.9% 4.6%

1.9% 4.6%

Greenberg et al., 2006 Mallet et al., 2008

6 12

10 16

0.60 [0.26; 0.88] 0.75 [0.48; 0.93]

11.1% 13.9%

11.1% 13.9%

Jiménez et al., 2009

5

5

1.00 [0.48; 1.00]

2.1%

2.1%

Servello et al., 2009

2

4

0.50 [0.07; 0.93]

4.6%

4.6%

Huff et al., 2010

1

10

0.10 [0.00; 0.45]

4.2%

4.2%

Greenberg et al., 2010 (UF) Greenberg et al., 2010 (LV)

3 4

5 7

0.60 [0.15; 0.95] 0.57 [0.18; 0.90]

5.5% 7.9%

5.5% 7.9%

Denys et al., 2010

9

16

0.56 [0.30; 0.80]

18.2%

18.2%

Franzini et al., 2010 Tsai et al., 2012

1 2

2 4

0.50 [0.01; 0.99] 0.50 [0.07; 0.93]

2.3% 4.6%

2.3% 4.6%

Chabardès et al., 2012 Roh et al., 2012

1 4

2 4

0.50 [0.01; 0.99] 1.00 [0.40; 1.00]

2.3% 2.1%

2.3% 2.1%

105

0.60 [0.49; 1.69] 0.60 [0.49; 1.69]

100% ..

.. 100%

Fixed effect model Random effects model

Heterogeneity: l-squared = 0%, tau-squared = 0, p = 0.6381

0

0.2

0.4

0.6

0.8

1

Figure 46.4  Forest Plot for percentage of responders according to standardized criteria (≥35% reduction in posttreatment Y-​BOCS scores).

D eep Brain S timulation

523

 

to electrophysiologically identify the therapeutic target) (Foltynie & Hariz, 2010; Mikos et al., 2010) and implantation trajectories that traverse sulci and/​or the lateral ventricles (Gologorsky et al., 2011; Sansur et al., 2007). A low risk of hemorrhage (1%–​4%) is expected in DBS procedures for psychiatric disorders, because the ventricles are easy to avoid when approaching these targets, and target localization is not dependent on microelectrode recording (Goodman & Alterman, 2012). The most common complication of DBS surgery is infection, which is reported to occur in 0% to 15% of cases (Bronstein et  al., 2011). Infection can spread along the implanted brain lead and result in meningitis, cerebritis, or brain abscess; but these are uncommon occurrences. In our experience, most infections occur at the chest pocket, allowing for preservation of the brain lead if one acts quickly to remove the infected IPG and extension (Goodman & Alterman, 2012). DBS surgery is associated with about 4% risk of seizures during the postoperative period, mostly within 48 hours of surgery (Pouratian, Reames, Frysinger, & Elias, 2011). Postoperatively, the patient may experience transient confusion and memory loss. These adverse events are more common in older patients and those with preexisting cognitive impairment. Overall, the published neuropsychological data available to date indicate that DBS for OCD is safe from the perspective of long-​term cognitive functioning. Neuropsychological outcome in 21 patients (10 OCD and 11 TRD [treatment resistant depression]) who received VC/​VS DBS found no significant declines in cognitive function (Kubu et al., 2013). In a different study of NAc DBS for OCD (n = 16), cognitive functioning remained stable after 8  months on most but not all measures (Mantione et al., 2015). Some measures of visual organization and verbal fluency showed worse performance postoperatively (Mantione et  al., 2015). It is unclear whether these were effects of surgery or of stimulation. A study of STN DBS in 16 subjects with OCD found no significant changes on neuropsychological testing (Mallet et al., 2008). A 2015 article reviewed the adverse events reported from all published reports of DBS for OCD, TRD, and TS (Saleh & Fontaine, 2015). Of 272 patients, with a mean follow up of 22 months, the surgical mortality was zero. There were two suicides within the TRD cohort. For the combined group, the rate of intracranial hemorrhage was 2.2%, and infections developed in 7.7% of the cases. Of the 94 OCD patients, 3 (3.2%) experienced intracranial hemorrhages and 4 (4.3%) developed infections. Two of the intracranial hemorrhages occurred within VC/​VS: one detected on postoperative images was 524

asymptomatic (Greenberg et al., 2006); the other resulted in apathy that resolved in 3 months (Greenberg, Gabriels, et  al., 2010). The third intracranial haemorrhage was in the STN and produced permanent finger palsy (Mallet et al., 2008). No seizures were reported among the entire multidiagnostic group. Similar rates of surgically related side effects were found in a 2015 metaanalysis of the literature that included a somewhat larger sample of 116 patients with OCD who underwent DBS (Alonso et al., 2015). The number of cases and rates of adverse events were as follows: intracranial hemorrhage: n = 3 (2.6%); wound infection: n = 5 (4.3%); seizures: n = 1 (0.9%); and memory complaints: n = 9 (7.8%). COMPLICATIONS RELATED TO CHRONIC HARDWARE IMPLANTATION

The Medtronic ActivaTM deep brain stimulation system has been commercially available in the United States and the EU for about 20 years, and so the long-​term risks associated with implanting these devices are well established (Goodman & Alterman, 2012). Overall, chronic implantation of these devices is well tolerated. Although hardware-​related complications are reported to occur in as many as 25% of patients at some point in time, the annualized risk is approximately 4%, and most of the complications are readily managed (Boviatsis, Stavrinou, Themistocleous, Kouyialis, & Sakas, 2010; Doshi, 2011; Oh, Abosch, Kim, Lang, & Lozano, 2002; Paluzzi, Belli, Bain, Liu, & Aziz, 2006). Breakage of a stimulating lead or an extension wire can lead to loss of efficacy and require revision surgery. This adverse event occurred in 3 (2.6%) of 116 patients with OCD who underwent DBS (Alonso et al., 2015). Erosion of the scalp tissue overlying the burr hole cap is another potential long-​term complication of the implanted device and is most commonly observed in balding men and the elderly, whose scalps are more atrophic. These devices are battery-​powered and must therefore be replaced periodically. Before the introduction of rechargeable systems, the IPGs of patients with OCD required replacement every 12 to 36 months, depending upon device settings. This contrasts with the much longer effective battery life in patients with movement disorders and reflects the higher current densities used in VC/​VS DBS for OCD. Although battery replacement surgery is a short, simple, ambulatory procedure during which only the IPG pocket is accessed, it is an expensive surgery, and frequent battery change surgeries pose both health and financial concerns (Goodman & Alterman, 2012). In some patients who O b sessive - C ompulsive D isorder

 

were implanted under the HDE for OCD, we have been able to conserve battery life by having the patients turn off their PGs during sleep (Goodman & Alterman, 2011). This strategy provides added benefit to those patients who find that the energizing effect of VS DBS interferes with sleep onset. The advent of IPGs with rechargeable batteries remedies one problem while introducing a new burden: the time spent recharging the devices. STIMULATION RISKS

DBS “On Effects” The side effects of DBS vary according to the brain area targeted and the stimulation settings. According to the previously mentioned metaanalysis of 116 OCD patients, the most common adverse behavioral effects of DBS were anxiety (21.6%), hypomania (19.8%), disinhibition (6%), impulsivity (1.7%), and panic attacks (0.9%) (Alonso et al., 2015). Acute effects of DBS on mood and anxiety are more prominent with ventral striatal targets (ALIC, VC/​VS, and NAc) compared with the STN target (Mallet et  al., 2008). Other side effects of DBS included paresthesias (3.4%), olfactory illusions/​hallucinations (3.4%), jaw tightness (1.7%), and speech disturbances (1.7%) (Alonso et al., 2015). In all cases, the unwanted acute effects of stimulation were reversible with adjustments in programming parameters. Stimulation using monopolar settings can cause tingling or vibration sensations in the region of the IPG. This side effect will resolve by lowering intensity or changing to a bipolar configuration. The most problematic behavioral side effect of VS DBS is induction of hypomania, with or without impulsivity (Haq et  al., 2010; Lapidus et  al., under review; Luigjes et al., 2011; Widge et al., 2016). One review of the literature found that 44% (32/​73) of OCD cases experienced mood changes during VS DBS (Saleh & Fontaine, 2015). Management of hedonic effects of VS DBS are discussed in the following.

DBS “Off Effects”

the device automatically turning itself off. When patients report rapid clinical deterioration, it is important to check the status of the device and its usage history.

Drug–​Device Interactions Little attention has been paid in the literature to the possibility of drug–​device interactions contributing to adverse events. An example is a patient who was tolerating high dose SSRI but then developed insomnia when VS DBS was initiated (Goodman et al., 2010). The insomnia resolved when the dose of SSRI was lowered while the DBS settings were held constant. Based on anecdotal clinical impressions, antipsychotic medications may attenuate the mood enhancing effects of VS DBS in OCD (Goodman & Alterman, 2012).

E LIGIB ILIT Y F OR   DB S   IN  OC D Neurosurgery for OCD is appropriate only in a subgroup of patients who remain severely ill despite having failed ERP and adequate trials of multiple medications including SSRIs, clomipramine, and adjunctive antipsychotics. The following inclusion and exclusion criteria are used at our treatment center in accord with the FDA HDE for VC/​ VS DBS.

Inclusion Criteria •

Men and women (nonpregnant) between ages 21 and 70

•

The patient has had at least a 5-​year history of treatment-​ refractory OCD that causes substantial subjective distress and impairment in functioning.

•

The patient has a minimum score of 28 on the Y-​B OCS.

•

The patient has failed an adequate trial of at least three of the following SSRIs: •

Fluoxetine; fluvoxamine; citalopram; escitalopram; sertraline; paroxetine

• The patient has failed an adequate trial of clomipramine. Abrupt interruption of chronic VS DBS stimulation • The patient has failed augmentation of one or more has resulted in clinical worsening of both obsessive-​ of the aforementioned drugs with at least one of the compulsive and depressive symptoms in patients with following antipsychotics: haloperidol; risperidone; OCD (Greenberg, Gabriels, et al., 2010). Typically, depresquetiapine; ziprasidone; aripiprazole. sive symptoms emerge first as soon as 24 hours following discontinuation. Inadvertent interruptions are usually the • The patient must have failed an adequate trial of CBT for OCD, defined as 25 hours of documented ERP by result of battery depletions at end of service life (Goodman an expert therapist. et al., 2010) or because of delays in recharging that result in

D eep Brain S timulation

525

 

•

The psychotropic medication regimen has been stable for the month preceding surgery

Exclusion Criteria •

The patient has a lifetime diagnosis of psychotic disorders such as schizophrenia.

•

Alcohol or substance abuse/​dependence within 6 months, excluding nicotine

•

The patient is deemed at high risk of suicidal behavior or impulsivity.

•

There is any neurological or medical condition/​disorder that makes the patient, in the opinion of the surgeon, a poor candidate to undergo the surgical procedures of the study.

•

The patient is pregnant or plans to become pregnant in the next 24 months.

•

There is a need for diathermy, which can interfere with the stimulator.

For patients meeting these criteria, a robust informed consent procedure is required, involving detailed explanation of the procedure, alternative treatments, and a full explanation of the risks and acknowledgement of the limited evidence for efficacy. Patients are encouraged to have a family member or close friend attend the consent process. A friend or family member is identified who will inform the clinical team regarding the patient’s clinical status, particularly if there is a worsening. Patients are carefully screened for other psychiatric pathology.

may include modulation of axonal tracts (Gradinaru, Mogri, Thompson, Henderson, & Deisseroth, 2009; McCracken & Grace, 2007). High-​frequency DBS may produce inhibition of the local area but activation of efferent and afferent axons that affect nuclei upstream and downstream from the site of stimulation (McCracken & Grace, 2007). In the case of NAc DBS for OCD, the Amsterdam group suggests that the mechanisms of action of DBS represent “a combination of excitatory and inhibitory as well as local and distal effects (van Westen et al., 2015).” NE E DS , GAPS , AND F U T U R E DIR E C T ION S Although VS DBS is an important option for intractable OCD, there is much room for improvement in outcome rates, magnitude of response, and mitigation of DBS-​ induced side effects (Goodman & Alterman, 2012). Even among DBS “responders,” as defined by a 35% reduction in symptom severity on the Yale-​Brown Obsessive Compulsive Scale (Y-​B OCS; Goodman et al., 1989), few achieve remission, response of OC symptoms is delayed (typically no earlier than a month), and maximal benefit is not achieved until 6 months or later (Goodman et al., 2010; Greenberg, Gabriels, et al., 2010). PROGRAMMING

Programming adjustments are made largely on the basis of acute beneficial effects on “anxiety,” “mood” and “energy,” as described by the patient and observed by the clinician. In contrast to DBS for tremor, immediate effects on the core symptoms of OCD (i.e., obsessions and compulsions) are not discernable in the acute programming sesM EC HA NIS MS O F ACTI O N  O F D BS sion. Instead, parameters are adjusted, in a trial-​and-​error fashion, based on changes in OCD symptom severity In 1987, while preparing to perform a thalamotomy in since the last visit, as reported by the patient or informpatient with essential tremor, Benabid discovered that high-​ ant. Importantly, VS DBS-​induced elevated mood is also frequency (>100 Hz) electrical stimulation of the target used as surrogate marker for OCD, as some studies (and could reversibly stop tremor (DeLong & Benabid, 2014). the author’s [WKG] clinical experience) suggest it may be Similarities in the clinical effects of both approaches (lesion a positive predictor of eventual OCD outcome (Denys et and stimulation) led to the view that high frequency DBS al., 2010; Goodman & Alterman, 2012; Haq et al., 2011; was acting as “functional ablation.” The original hypothesis Okun et al., 2004; Tsai et al., 2014). The “mirth response” that high frequency DBS silenced the target nucleus—​by can be dramatic (Haq et al., 2010). Mood is experienced depolarization blockade, increase in local GABAergic as congruent with the intensity of the smile or laughter transmission, local synaptic inhibition, or synaptic depres- (Gibson et al., 2016; Okun et al., 2004). Sustained posision (Lee, Blaha, & Bledsoe, 2009)—​has been challenged tive effects of DBS on mood invariably precede any clinby emerging basic neuroscience research showing that the ically apparent improvement in OCD (Goodman et al., therapeutic mechanisms of DBS are far more complex and 2010). On the other hand, improvement in mood does

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not guarantee a successful outcome for OCD. Clinician-​ and patient-​ rated measures of increased energy (e.g., higher “vitality” and lower “fatigue” on the Profile Of Mood States) accompany positive mood effects of VS DBS in OCD (Goodman et al., 2010). Apart from its possible predictive value (Gibson et  al., 2016; Widge et  al., 2016), DBS-​induced mirth also represents a potential risk: development of hypomania or mania (Haq et al., 2010; Widge et al., 2016). Despite the programmer’s best efforts to titrate the dose of stimulation, some patients go on to exhibit a behavioral syndrome marked by elevated mood, increased energy, pressured speech, decreased need for sleep, and sometimes impulsivity (Haq et al., 2010; Lapidus et al., under review). These signs and symptoms are reversible with adjustments in DBS settings. However, turning down the amplitude or reducing the pulse width may lead to a loss of clinical benefit. Striking the right balance between overshooting (high amplitude induction of hypomania) and undershooting (low amplitude insufficient to improve OCD) is often challenging. In some cases, patients are prescribed “mood stabilizers” like lithium or antipsychotic medication to manage the hypomania and allow stimulation to proceed at an effective dose (Lapidus et  al., under review). Risk of developing DBS-​induced hypomania is unrelated to history of bipolar disorder (Widge et al., 2016). The aforementioned challenges in optimizing programming reflect in part the limitations of current DBS technology. Existing open-​loop DBS, which delivers fixed stimulation irrespective of the changing state of the patient, is an inherent barrier to further progress. In contrast, new generation closed-​loop or adaptive DBS (aDBS) systems can record, stimulate, and use signals from the brain—​local field potentials (LFPs)—​to make responsive adjustments to the patient’s behavioral state (Afshar et al., 2012; Carron, Chaillet, Filipchuk, Pasillas-​Lepine, & Hammond, 2013; Priori, Foffani, Rossi, & Marceglia, 2013). Such aDBS systems are already approved for epilepsy (Morrell & Group, 2011)  and undergoing testing in movement disorders (Qasim et  al., 2016)  and Tourette Syndrome (Almeida et  al., 2015). Accomplishing the next step of automatically adjusting VS stimulation in response to emergence of adverse effects (e.g., hypomania) or for better control over fluctuating OC symptoms would represent a major improvement over the fixed dose approach. TARGETING

A recent trial of DBS for treatment-​resistant depression targeting the subcallosal cingulate cortex (SCC; the St.

D eep Brain S timulation

Jude trial) was a high-​profile failure (Cavuoto, 2013). This failure may be explained, in part, by overreliance of structural images and the absence of consideration of fiber tracts in surgical planning (Lujan et al., 2013). As noted earlier, therapeutic effects of DBS may be mediated by actions on fibers of passage rather than local effects on the intended gray matter target such as the STN (Gradinaru et al., 2009). Delineating critical white matter pathways at the individual subject level may help predict the target regions most likely to produce maximum clinical benefit with DBS. For example, in one recent study, preoperative diffusion tensor imaging data were acquired in 16 patients with TRD to produce patient-​specific white matter tractography maps (Riva-​Posse et  al., 2014). Postoperative field modelling analysis showed that the activation volumes of all responders to SCC DBS impacted a particular combination of fiber bundles (Riva-​Posse et  al., 2014). Nonresponders did not consistently share this association between activation volume and fiber connections. A similar approach can be applied to investigations of DBS for OCD. In a proof-​of-​concept study, structural connectome mapping in healthy subjects was used to characterize high levels of variability in fiber tracts in the VC/​ VS and then combined with preoperative diffusion imaging to guide target selection in an OCD patient (Makris et al., 2015). Another group investigated tractography activation patterns in a cohort of six patients with OCD who received VC/​VS DBS (Goodman et al., 2010; Hartmann et al., 2016). They created computational models to simulate activation of fiber tracts and to identify their cortical connections. Modulation of dorsolateral prefrontal cortex was associated with the best clinical response (Hartmann et al., 2016). Together, these findings suggest that DBS surgical planning may benefit from consideration of electrode placement in relation to location of fiber tracts. PAT I E N T S E L E C T I O N

Gender and duration of OCD symptoms do not predict response to DBS (Alonso et  al., 2015). A  metaanalysis found that better response to DBS (all targets) was associated with older age at OCD onset (Alonso et al., 2015). Extant data are insufficient to predict which clinical subtypes of OCD are best suited for DBS. There is one case report that OCD comorbid with TS did not respond well to VS DBS (Burdick et al., 2010). Moreover, the preferred DBS anatomic targets for TS are different (Almeida et al., 2015). Given the relative absence of clinical predictors of response, more research needs to be done with putative

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biomarkers such as resting state functional connectivity that might reveal evidence of circuit pathology responsive to DBS (O’Halloran et al., 2016).

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47. INTENSIVE TREATMENT APPROACHES FOR OCD Joshua M. Nadeau, PhD, Bradley C. Riemann, PhD, and Eric A. Storch, PhD

O

bsessive-​ compulsive disorder (OCD) is characterized by obsessions (recurrent or persistent thoughts, urges, or images that are perceived as distressing and intrusive) and/​or compulsions (repetitive overt or mental rituals typically initiated as a response to an obsession; American Psychiatric Association [APA], 2013). It is an impairing psychological disorder that affects approximately 1% to 2% of youth (Lewin & Piacentini, 2009)  and adults (Crino, Slade, & Andrews, 2005; see ­chapter  4). Obsessive-​compulsive symptoms are associated with significant functional impairment across occupational, social, interpersonal, and family domains ( Jacoby et al., 2014; Piacentini et al., 2003; Storch et al., 2014) and diminished quality of life (Kugler et al., 2013; Lack et al., 2009; Nadeau et  al., 2013). Several factors predict clinically severe and refractory disease, including obsessive-​ compulsive symptom severity (Lack et  al., 2009; Storch et  al., 2010; Valderhaug & Ivarsson, 2005), presence of comorbid psychiatric disorders (Garcia et al., 2010; Storch et al., 2008), and a variety of clinical characteristics such as patient insight and family accommodation ( Jacoby et al., 2014; Storch et al., 2007). TR EATM ENT  O F O CD There are two evidence-​based treatment modalities for OCD:  cognitive-​b ehavioral therapy (CBT) incorporating exposure and response prevention (ERP; see ­chapter  37) and pharmacotherapy with serotonin reuptake inhibitors (SRI; see ­chapter  40). CBT has been recommended as a monotherapy for mild and moderate cases of OCD, and in combination with SRI medications for more severe patients (Geller &

March, 2012; Koran & Simpson, 2013). CBT for OCD includes three critical components:  exposure, wherein the patient is placed in anxiogenic situations (whether imaginal or in vivo); response prevention, in which the patient is unable to access escape-​ or avoidance-​b ased compulsions (preventing negative reinforcement); and cognitive restructuring, in which anxiogenic thoughts are illuminated and challenged (Manassis, Russell, & Newton, 2010; Velting, Setzer, & Albano, 2004; see ­chapters 37, 38). SRIs (both the selective serotonin reuptake inhibitors and the older tricyclic drug clomipramine) are first-​line medications for OCD (Ivarsson et al., 2015; Mataix-​Cols et al., 2014; see ­chapter 40). However, SRI treatment has modest effect sizes overall and as compared with CBT (Öst et al., 2015), high relapse rates upon termination (Albert et al., 2014), the potential for mild (Peluso et al., 2012) to more significant side effects (e.g., behavioral activation; Goodman et al., 2007), and variable response depending upon the presence comorbid psychiatric conditions (Geller et al., 2003). Despite the evidence supporting the utility of CBT, fewer than 10% of patients with OCD receive CBT with ERP (e.g., Blanco et  al., 2006; Marques et  al., 2010). Research has identified several treatment barriers, including therapist reluctance to utilize exposure-​based protocols, unfounded therapist fears related to patient decompensation (Cahill et al., 2006), relative scarcity of CBT-​trained practitioners (Goodwin et  al., 2002), patient fears of exposure-​based therapy, and the cost of specialized care. This chapter discusses the potential for intensive treatment to address many of these barriers, and provides a review of existing research studies to support the utility of an intensive approach to treatment of OCD.

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INTENS IVE TREATMEN T O F O CD A concentrated course of CBT with ERP, often termed “intensive CBT” (Abramowitz et al., 2003; Storch et al., 2007), may be appropriate in cases in which severe OCD symptoms do not show a sufficient response to traditional weekly/​biweekly sessions (Geller & March, 2012). The intensive treatment approach often allows patients to relocate (temporarily) to a specialty treatment setting with highly trained and proficient providers, thereby facilitating a more rapid reduction in both symptoms and functional impairment, compared with traditional treatment frequency (Storch et  al., 2007, 2008; Whiteside et al., 2008; Whiteside & Jacobsen, 2010). Intensive treatment has shown efficacy in studies of both youth and adults. Among adults, Foa et  al. (2005) compared intensive ERP (15 daily 2-​hour sessions over 3 weeks), clomipramine monotherapy, combined intensive ERP and clomipramine, and placebo treatment among 122 adults. Although all three treatment groups outperformed placebo, both ERP and combined therapy were more effective than clomipramine alone. Combined therapy did not differ significantly from ERP monotherapy. Abramowitz et al. (2003) compared two groups of adults receiving 15 sessions of ERP:  one group (n  =  20) receiving daily sessions for 3 weeks, and the other (n = 20) receiving twice-​ weekly sessions for 8 weeks. Both regimens were effective, and daily sessions showed more improvement at posttreatment (85% response rate for daily, vs. 70% response rate for biweekly), but no differences were found at follow-​up. Among youth, Storch et al. (2007) compared the efficacy of intensive and weekly family-​based ERP among 40 children and adolescents (ages 7–​17) over 14 sessions. At posttreatment, intensive CBT (90% response rate, 75% remission rate) was at least as effective as weekly CBT (65% response rate, 50% remission rate), with high maintenance of gains exhibited by both groups at 3-​month follow-​up. Similarly, Storch et  al. (2010) reported on an open trial of intensive family-​based CBT among children and adolescents (n = 30, ages 7–​19) who were partial or nonresponders to medication for OCD. After 14 sessions, CBT was effective at posttreatment (80% response rate, 56.6% remission) and 3-​month follow-​up (80% response rate, 53.3% remission). Of interest, significant reductions were also noted in depressive symptoms, behavior problems, and family accommodation. Whiteside and Jacobsen (2010) conducted a 5-​day intensive CBT trial among youth (n  =  15, ages 10–​18) and their parents. ERP was found effective at posttreatment (83.3% response rate), with maintenance of gains observed at 5-​month follow-​up.

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C ONT INU U M OF   C AR E Treatment hours involving exposure activities correlate with treatment response (Fisher & Wells, 2005). This relationship is moderated by therapist specialization/​competency using CBT with ERP (Fisher & Wells, 2005; Turner, Beidel, Spaulding, & Brown, 1995). The principle that “dosage” of CBT—​particularly of hours focused upon exposure tasks—​ should be associated with increased treatment response for a given level of symptom severity undergirds the organization of specialty treatment centers incorporating “levels” of treatment intensity based on hours of treatment. The three most typical treatment levels—​in order of increasing environmental structure and treatment hours—​are intensive outpatient programming (IOP), partial hospitalization programming (PHP), and residential treatment centers. T R E AT ME NT PLANNING AND T R ANS IT IO N The optimal level of treatment depends on multiple factors. It is generally appropriate to attempt standard (weekly or biweekly) outpatient CBT before considering more intensive treatment. Poor response to standard treatment is associated with symptom severity (Garcia et  al., 2010; Ginsburg et  al., 2008), OCD-​related functional impairment, the presence of symptoms in specific domains (Ferrao et al., 2006; Mataix-​Cols et al., 2002; see ­chapter 8), early onset of symptoms, and duration of symptoms (Kishore et al., 2004). Limited response to standard outpatient CBT may motivate incorporating pharmacotherapy or a higher level of care (Geller & March, 2012; Skarphedinsson & Ivarsson, 2015). Comorbidity has been associated with attenuated treatment response. This includes externalizing disorders (e.g., ADHD, disruptive behavior disorders and/​or noncompliance; Garcia et al., 2010; Storch et al., 2008), tic disorders (Ginsburg et al., 2008) in children, depression in children and adults (Abramowitz et al., 2003; Kishore et al., 2004), anxiety disorders, and autism spectrum disorder (ASDs; Storch et al., 2008). It is unclear whether treatment resistance is more related to specific psychiatric symptoms or to overall psychiatric loading (Stewart et  al., 2006); most likely both contribute (Kishore et  al., 2004; Storch et  al., 2007). In addition to providing a higher dosage, intensive CBT facilitates the combination of CBT strategies targeting different symptoms (e.g., ERP for OCD and behavioral activation for depression; Hollon et  al., 2006)  or modification of standard evidence-​based treatment techniques

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(CBT for anxious youth with ASD; Nadeau et al., 2011). Such individualization of treatment can maximize its value and efficiency. Impaired insight has also been associated with decreased treatment response (Kishore et al., 2004; see c­ hapter 13). Intensive treatment can be of particular benefit for the patient with poor or absent insight. In addition to greater ERP dosage, group and/​or facilitated activities allow for social learning to assist with instillation and bolstering of insight. Family accommodation—​ maladaptive adjustment or modification of family routines in response to a child’s psychiatric symptoms—​has been associated with reduced treatment engagement and response (Peris et  al., 2008; Storch et al., 2008; see ­chapter 43). Parental involvement in child rituals is associated with OCD symptom severity and with parent psychopathology (Peris et al., 2008). Intensive treatment provides opportunities for individual and group activities in which the child is independent from parents, as well as training for parents in accommodation reduction and behavioral management. A challenge to treatment planning, as well as to research, is the difficulty of defining treatment response (Pallanti & Quercioli, 2006). Recent work has sought to define meaningful clinical treatment breakpoints based upon common symptom measures, such as the Yale-​ Brown Obsessive Compulsive Scales (Y-​ B OCS; Goodman et  al., 1989)  and its youth counterpart (CY-​ BOCS; Scahill et al., 1997); however, such work is relatively untested (e.g., Lewin et  al., 2014; Mataix-​Cols et  al., 2016). Treatment facilities offering intensive care vary in their approach to the evaluation of response, even to the point of using proprietary treatment transition guidelines.

minute sessions daily or twice daily (Storch et al., 2007; Whiteside & Jacobsen, 2010). An alternative approach follows a format originally developed for specific phobia treatment, the one-​session treatment (see Ollendick et al., 2009) model, in which sessions are longer (from 2 to 3-​1/​2 hours) but provided once daily. Transition from IOP to weekly or twice-​weekly CBT is predicated upon (1) decreasing OCD symptom severity to within the capacity of a traditional outpatient provider and (2)  increased adaptive functioning, which leads to improved quality of life and conduces to continued treatment adherence (Huppert & Franklin, 2005). As discussed, objective definition of transition metrics is difficult, mainly because symptom severity and impairment are not perfectly related: A patient with significant symptoms may be able to function reasonably well, and one with milder symptoms may be markedly impaired. PA R T I A L H O S P I TA L I Z AT I O N P R O G R A M M I N G

Partial hospitalization programming (PHP), also known as day treatment, indicates an increase in treatment intensity over IOP, with a typical “session” spanning a 5-​to 8-​hour day, 5 days per week (Bystritsky et al., 1999). As with IOP, a large fraction of treatment should include exposure tasks relevant to the patient’s presenting OCD symptoms. The time available at the PHP level allows other activities not normally feasible in shorter sessions, such as CBT-​oriented processing groups, experiential or recreational therapy activities, group-​based exposure activities, and family therapy. PHP is often appropriate in the context of significant functional impairment (Dell’Osso et al., 2007; Munlord, Vapnik, & Wolfson, 1996). For example, if a patient is not able to participate in school or work, PHP care may be appropriate, with a primary goal of restoring function I N T E N S I V E O U T PAT I E N T P R O G R A M M I N G to a level at which they can successfully return to school Intensive outpatient treatment typically indicates three or work as soon as possible. At that point, ongoing IOP or more therapy sessions per week, with multiple hours may be appropriate to provide ongoing treatment around per session. Intensive outpatient programming (IOP)-​ their school or work schedule. Although academic and/​or level care is appropriate for moderate to severe OCD occupational functioning is an important factor in treatsymptoms associated with significant impairment and ment decisions, it should be noted that other factors often distress. Several studies of intensive CBT for OCD have affect or overshadow its importance (i.e., distance or availbeen published over the last 15  years (e.g., Foa et  al., ability of trained providers, financial burden of care, etc.). 2005; Lewin et al., 2005; Storch et al., 2007; Whiteside et al., 2014). There is not a universally agreed upon defiRESIDENTIAL TREATMENT CENTERS nition of what constitutes IOP-​level care (as opposed to standard outpatient care on the one hand and PHP Residential treatment programs have been developed for care on the other). One model incorporates 60 to 90 severe and treatment-​refractory symptoms that cannot be

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managed in a less intense setting and require continuous monitoring and supervision. Residential care differs from a typical psychiatric inpatient admission in that the latter is indicated for those in acute crisis, such as suicidality or an inability to provide self-​care (Stewart et  al., 2005). Residential programs provide the highest “dose” of CBT. They allow CBT activities to be practiced for all day-​to-​day activities, such as social interaction and personal hygiene. Increased staffing allows for close monitoring of all treatment activities, making the treatment less dependent on patients’ ability to perform “homework” on their own. Community-​based activities (e.g., shopping, church/​worship, social outings) can be structured to maximize patient success and symptom management. Generally speaking, patients treated in residential programs have higher symptom acuity, increased comorbidity (e.g., depression, eating disorders; Leonard et al., 2015; Stewart et  al., 2006), and decreased insight when compared with patients in less intensive settings. Similarly, patients in residential treatment often have a history of noncompliance and/​or lack of response to previous (lower intensity) levels of care. Residential level treatment for OCD can be successful among patients who have shown poor treatment response at lower dosage levels (Leonard et  al., 2015; Stewart et  al., 2006). Treatment resulted in significant decreases in OCD and depression symptom severity for the majority of patients in the sample. In a follow-​up study by Stewart et  al (2009) of residential treatment patients (n = 61), improvements in OCD and depressive symptoms were maintained 1, 3, and 6 months after discharge. Continuing care after discharge from a residential program must be carefully managed. PHP/​day-​treatment programs are often used as a step-​down for patients who show response to treatment at the residential level. As treatment dosage decreases, target behaviors are tracked to determine the extent to which a patient utilizes adaptive coping skills/​behaviors in the absence of the structured residential setting. S UM M A RY AN D FUTURE D I RECTI O N S There are a number of common barriers to successful ERP treatment for OCD, including variables specific to the patient (e.g., noncompliance, symptom severity), the provider (e.g., training in ERP, comfort with specific presentation, cost), and the environment (e.g., geographic availability of providers, financial constraints). Intensive treatment programming seeks to address these barriers and 536

thereby to provide symptom relief and restoration of adaptive functioning in patients who do not benefit from less intensive care. Objective and valid metrics of treatment response are essential to the stepped care model, as they constitute the foundation upon which treatment planning decisions should be made. There have been recent attempts to build consensus with respect to common terminology and metrics in OCD assessment and treatment (Mataix-​Cols et al., 2016). In the search for best practices in OCD treatment, this common ground and language is essential to inform decisions regarding appropriate levels of care, and thereby to maximize patients’ response to treatment.

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Peris, T. S., Bergman, R. L., Langley, A., Chang, S., McCracken, J. T., & Piacentini, J. (2008). Correlates of accommodation of pediatric obsessive-​ compulsive disorder:  Parent, child, and family characteristics. Journal of the American Academy of Child and Adolescent Psychiatry, 47, 1173–​1181. Piacentini, J., Bergman, R. L., Keller, M., & McCracken, J. (2003). Functional impairment in children and adolescents with obsessive-​compulsive disorder. Journal of Child and Adolescent Psychopharmacology, 13, 61–​69. Scahill, L., Riddle, M. A., McSwiggin-​Hardin, M., Ort, S. I., King, R. A., Goodman, W. K., Cicchetti, D., & Leckman, J. F. (1997). Children’s Yale-​Brown Obsessive Compulsive Scale:  Reliability and validity. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 844–​852. Skarphedinsson, G., & Ivarsson, T. (2015). Evidence-​based treatments in treatment-​ naïve and treatment-​ resistant pediatric obsessive-​ compulsive disorder. Current Behavioral Neuroscience Reports, 2, 127–​136. Stewart, S. E., Stack, D. E., Farrell, C., Pauls, D. L., & Jenike, M. A. (2005). Effectiveness of intensive residential treatment for severe, refractory obsessive-​ compulsive disorder. Journal of Psychiatric Research, 39, 603–​609. Stewart, S. E., Stack, D. E., Tsilker, S., Alosso, J., Stephansky, M., Hezel, D. M., Jenike, E. A., Haddad, S. A., Kant, J., & Jenike, M. A. (2009). Long-​term outcome following intensive residential treatment of obsessive-​compulsive disorder. Journal of Psychiatric Research, 43, 1118–​1123. Stewart, S. E., Yen, C. H., Stack, D. E., & Jenike, M. A. (2006). Outcome predictors for severe obsessive-​compulsive patients in intensive residential treatment. Journal of Psychiatric Research, 40, 511–​519. Storch, E. A., Geffken, G. R., Merlo, L. J., Jacob, M. L., Murphy, T. K., Goodman, W. K., Larson, M. J., Fernandez, M., & Grabill, K. (2007). Family accommodation in pediatric obsessive–​compulsive disorder. Journal of Clinical Child and Adolescent Psychology, 36, 207–​216. Storch, E. A., Geffken, G. R., Merlo, L. J., Mann, G., Duke, D., Munson, M., Adkins, J., Grabill, K. M., Murphy, T. K., & Goodman, W. K. (2007). Family-​ based cognitive-​ behavioral therapy for pediatric obsessive-​compulsive disorder: Comparison of intensive and weekly approaches. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 469–​478. Storch, E. A., Larson, M. J., Muroff, J., Caporino, N., Geller, D., Reid, J. M., . . . & Murphy, T. K. (2010). Predictors of functional impairment in

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pediatric obsessive-​compulsive disorder. Journal of anxiety disorders, 24, 275–​283. Storch, E. A., Merlo, L. J., Larson, M. J., Geffken, G. R., Lehmkuhl, H. D., Jacob, M. L., Murphy, T. K., & Goodman, W. K. (2008). Impact of comorbidity on cognitive-​behavioral therapy response in pediatric obsessive-​compulsive disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 47, 583–​592. Storch, E. A., Merlo, L. J., Lehmkuhl, H., Geffken, G. R., Jacob, M., Ricketts, E., Murphy, T. K., & Goodman, W. K. (2008). Cognitive-​ behavioral therapy for obsessive-​ compulsive disorder:  A  non-​ randomized comparison of intensive and weekly approaches. Journal of Anxiety Disorders, 22, 1146–​1158. Storch, E. A., Milsom, V. A., Merlo, L. J., Larson, M., Geffken, G. R., Jacob, M. L., Murphy, T. K., & Goodman, W. K. (2008). Insight in pediatric obsessive-​compulsive disorder:  Associations with clinical presentation. Psychiatry research, 160, 212–​220. Storch, E. A., Wu, M. S., Small, B. J., Crawford, E. A., Lewin, A. B., Horng, B., & Murphy, T. K. (2014). Mediators and moderators of functional impairment in adults with obsessive–​compulsive disorder. Comprehensive Psychiatry, 55, 489–​496. Turner, S. M., Beidel, D. C., Spaulding, S. A., & Brown, J. M. (1995). The practice of behavior therapy: A national survey of cost and methods. Behaviour Therapist, 18, 1. Valderhaug, R., & Ivarsson, T. (2005). Functional impairment in clinical samples of Norwegian and Swedish children and adolescents with obsessive-​compulsive disorder. European child & adolescent psychiatry, 14, 164–​173. Velting, O. N., Setzer, N. J., & Albano, A. M. (2004). Update on and advances in assessment and cognitive–​behavioral treatment of anxiety disorders in children and adolescents. Professional Psychological Research and Practice, 35, 42–​54. Whiteside, S. P., Brown, A. M., & Abramowitz, J. S. (2008). Five-​day intensive treatment for adolescent OCD:  A  case series. Journal of Anxiety Disorders, 22, 495–​504. Whiteside, S. P., & Jacobsen, A. B. (2010). An uncontrolled examination of a 5-​day intensive treatment for pediatric OCD. Behavior therapy, 41, 414–​422. Whiteside, S. P., McKay, D., De Nadai, A. S., Tiede, M. S., Ale, C. M., & Storch, E. A. (2014). A baseline controlled examination of a 5-​ day intensive treatment for pediatric obsessive-​compulsive disorder. Psychiatry Research, 220, 441–​446.

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S ECT I O N 6. O C D - R E L AT E D DI SORDERS

 

 

48. OBSESSIVE-​C OMPULSIVE AND RELATED DISORDERS A N E W CAT EGORY I N DSM - ​5

Katharine A. Phillips, MD

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he category of Obsessive-​Compulsive and Related Disorders (OCRDs) is new to DSM-​5 and was one of the more interesting and potentially impactful changes in the revised manual. This new DSM-​5 chapter contains OCD, body dysmorphic disorder (BDD), hoarding disorder, trichotillomania (hair-​ pulling disorder), and excoriation (skin-​picking) disorder (American Psychiatric Association, 2013), which are the focus of this discussion. The DSM-​5 OCRD chapter also contains substance/​ medication-​ induced OCRD, OCRD due to another medical condition, other specified OCRD, and unspecified OCRD; these four categories are analogous to those included in other chapters of DSM-​5 (American Psychiatric Association, 2013). The addition of OCRDs to DSM-​5 draws attention to similarities in these disorders’ key clinical features of obsessions/​preoccupations and/​or driven repetitive behaviors, as well as other shared features. This substantial change in diagnostic structure has both clinical and research implications. Optimally grouping disorders into categories may usefully guide assessment and treatment. For example, adaptations of the Yale-​Brown Obsessive Compulsive Scale (Y-​B OCS; Goodman, Price, Rasmussen, et  al., 1989)  are used to assess the severity of most of the OCRDs, and effective treatment approaches for some of these disorder are very similar (Phillips & Stein, 2015a). Furthermore, related disorders may be highly comorbid with one another and may have an increased prevalence in family members; thus, when a patient has one of these disorders, clinicians may be reminded to inquire about the presence of other OCRDs in the patient and family members. From a research perspective, this new grouping may encourage research on these disorders’ similarities, differences, and relatedness (Phillips & Stein, 2015b).

Most of the disorders in the new chapter were not included in the earliest editions of DSM. They gradually appeared in later editions but were scattered around the manual in different chapters. In DSM-​IV, published in 1994, OCD was classified as an anxiety disorder, BDD as a somatoform disorder, and trichotillomania as an impulse control disorder not elsewhere classified (American Psychiatric Association, 1994). DSM-​IV did not include hoarding disorder or excoriation (skin-​picking) disorder. Because DSM attempts to classify related disorders in the same chapter, DSM-​IV’s approach implied that OCD, BDD, and trichotillomania were unrelated conditions, which now appears incorrect. However, in the early 1990s, very little research had been done on these disorders (with the exception of OCD itself ), or on their relationship to one another. By the time DSM-​ 5 was developed (2007–​ 2012), research on the putative OCRDs had dramatically increased. Available data indicated that BDD is closely related to OCD and that trichotillomania also has shared features with OCD (Phillips, Stein, Rauch, et al., 2010). Based on this evidence, as well as clinical utility considerations, OCD, BDD, and trichotillomania were moved to the new OCRD chapter. Hoarding disorder and excoriation (skin-​picking) disorder, which are new to DSM-​5, were then put in this chapter. Although this specific grouping of disorders is new to DSM-​5, the concept of such a cluster of conditions is old. For more than a century, it has been proposed that some disorders in the OCRD category are closely related to one another (Phillips, 1991). For example, in the early 1900s, Pierre Janet noted BDD’s similarities to OCD ( Janet, 1903), and in 1949 William Stekel emphasized the obsessional preoccupation and compulsive behaviors that characterize

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BDD, describing BDD as “the peculiar group of compulsive ideas which concern the body” (Stekel, 1949). For the past several decades, the term “obsessive-​compulsive (OC) spectrum disorders” has been used to refer to a group of disorders characterized by repetitive thoughts and/​or behaviors, which are presumed to be related to OCD, while also being distinct from one another (Phillips, 2002; Stein & Hollander, 1993). The term “spectrum” implies that shared, underlying psychobiological mechanisms may account for their similar symptoms and that a continuum of genotypes, endophenotypes, or other related constructs lead to the various symptoms and dimensions seen in clinical practice (Hyman, 2002; Insel, Cuthbert, Garvey, et al., 2010). The term “spectrum” additionally implies that related disorders along a spectrum vary continuously in relation to one another in some underlying construct, such as “impulsivity” or “compulsivity.” The term OCRD, adopted in DSM-​5, avoids this theoretical assumption. This category of OC-​spectrum disorders evolved from an understanding of compulsivity as a symptom dimension arising from abnormalities in tightly regulated brain circuits (cortical-​striatal-​thalamic-​cortical circuits) that give rise to partially overlapping diagnostic entities (Hollander, 2015). Certain animal behaviors that involve these circuits, such as excessive grooming, that could be considered “motoric” compulsions or “lower-​order, repetitive behaviors,” have some phenomenological and psychobiological overlap with tics, hair-​pulling in trichotillomania, and compulsive skin-​picking in excoriation (skin-​picking) disorder and BDD (see ­chapter 29; Joel, Stein, & Schrieber, 2008; Feusner, Hembacher, & Phillips, 2009). The more complex symptoms of cognitively focused OCRDs (OCD, BDD, and hoarding disorder), which could be considered “cognitive” or “higher-​order” obsessive-​compulsive symptoms, may focus on harm avoidance, cleanliness, order, hoarding of possessions, appearance (appeal to potential mates), and health, all of which may reflect evolutionarily based needs (see ­chapter 61; Feusner, Hembacher, & Phillips, 2009). The corresponding compulsions aim to reduce anxiety or to neutralize future threat. Researchers have embraced the concept of a cluster of OC-​related disorders since the early 1990s, when Hollander (1993) drew attention to it. In 2007, an international survey of experts also endorsed this construct (Mataix-​Cols, Pertusa, & Leckman, 2007). Further support came from an international DSM-​5 research planning conference that preceded the formal development of DSM-​5; based on an examination of available scientific evidence, the conference participants recommended that a new OCRD chapter be added to DSM-​5 (Hollander, Kim, & Zohar, 2007; 542

Hollander, Zohar, Sirovatka, & Regier, 2011). Hollander’s (1993) early proposal regarding the OC-​spectrum included a broader range of disorders, some characterized by greater obsessionality and others by greater impulsivity, but later conceptualizations included a narrower range of disorders characterized by obsessions and/​ or repetitive behaviors (Mataix-​Cols et al., 2007). W H Y AND H OW T H E NE W C H APT E R WAS ADDE D T O  DS M- 5 ​ As just noted, when the formal development of DSM-​ 5 began in 2007, historical tradition, views of experts, and available evidence all largely supported the inclusion of a new chapter of OCRDs in DSM-​5. There was general agreement that some disorders, such as BDD, should be included in this new chapter; there was some disagreement about the inclusion of others (Mataix-​Cols et  al., 2007). These early perspectives and recommendations very usefully informed the formal DSM-​5 development process. In addition, the DSM-​5 OC-​Spectrum Sub-​Workgroup (a subworkgroup of the DSM-​5 Work Group on Anxiety, Obsessive–​ Compulsive Spectrum, Posttraumatic, and Dissociative Disorders) conducted its own rigorous, more in-​depth reviews of the scientific literature in order to make formal recommendations. The Sub-​Workgroup commissioned field trials (studies) and secondary data analyses of existing data sets, sought input from many individuals and groups, and considered thousands of comments posted on DSM5.org to inform its recommendations. One challenge that the OC-​Spectrum Sub-​Workgroup (and other DSM-​5 workgroups) faced was that although DSM attempts to classify closely related disorders together in the same chapter, there is currently no perfect way to determine the exact nature of mental disorders’ true relatedness to one another, and thus how they should be classified. Ideally, our nosology should classify disorders together based on shared underlying mechanisms and etiology (Hyman, 2002, 2003). However, mechanisms and etiology of mental disorder are enormously complex, and our field is still very far from identifying them. Thus, as a proxy, the DSM-​5 workgroups and Task Force were guided by several principles in order to determine (1) what chapters should be included in DSM-​5 and what the overall structure (the “metastructure”) of the manual should look like, and (2) which disorders should be included within each chapter. These principles were: (1) The approach should have face validity. (2) The approach should O b sessive - C ompulsive D isorder

 

have clinical utility; for example, the groupings should be helpful to clinicians in assessing patients, formulating diagnoses, selecting appropriate interventions, and enhancing communication with patients and among clinicians. (3) The approach should be evidence based and reflect the apparent relatedness of disorders to one another (First, Pincus, Levine, 2004; Phillips et al., 2010). Regarding the third guideline, because the etiology and pathophysiology of mental disorder is still largely unknown, the DSM-​5 process used 11 “validators” to infer the relatedness of disorders to one another. These eleven validators expanded upon those that Robins and Guze proposed in their seminal 1970 paper (Robins & Guze, 1970), which other authors subsequently expanded (Kendler, Gardner, & Prescott, 2002). The 11 validators were: shared symptomatology, neural substrates, biomarkers, course of illness, temperamental antecedents, familiality, cognitive and emotional processing abnormalities, genetic risk factors, environmental risk factors, comorbidity, and treatment response. The guiding principle was that the more similar disorders are to one another in terms of these 11 validators, the more closely related they are presumed to be. Disorders with similarities across multiple validators were candidates for inclusion in the same chapter (Phillips et al., 2010). Although imperfect, these validators provided a useful guide to how disorders should be grouped together in DSM-​5. Based on these validators, as well as clinical utility, face validity considerations, surveys, and reviews, the DSM-​5 OC-​Spectrum Disorders Sub-​Workgroup published an initial review in 2010 that concluded that a number of putative OCRDs appeared more closely related to OCD than to other near-​neighbor disorders, and concluded that there was merit to including a new chapter of OC-​spectrum disorders (subsequently called OCRDs) in DSM-​5 (see Phillips et al., 2010 for details). In addition, discussions on harmonization of the metastructure in DSM-​5 and ICD-​ 11 reached some consensus, which included the proposal that the OCRDs should be a separate category in both classification systems. The DSM-​5 Sub-​Workgroup initially proposed that DSM-​5 include a chapter of “anxiety and obsessive-​compulsive-​spectrum disorders,” with two subgroups (one for anxiety disorders and one for OCRDs), which reflected similarities between some OCRDs and some anxiety disorders (see Stein et al., 2010 for details). However, the Sub-​ Workgroup later recommended that DSM-​ 5 instead contain separate chapters for anxiety disorders and OCRDs. This new proposal was made possible by a change in DSM-​5’s coding approach, which allowed O b sessive - C ompulsive R elated D isorders

DSM-​5 to contain more chapters than DSM-​IV did. Splitting these two chapters reflected important differences between some disorders contained within them (for example, between social anxiety disorder and excoriation [skin-​picking] disorder; Stein et al., 2010). At the same time, the Sub-​Workgroup recommended that the OCRD chapter directly follow the anxiety disorders chapter in order to reflect the close relationship between some of the OCRDs and anxiety disorders (for example, between OCD and number of anxiety disorders, and between BDD and social anxiety disorder; Stein, Craske, Friedman, & Phillips, 2011). DSM-​5 aims to put related chapters of disorders near one another; this contrasts with the approach used in DSM-​IV, in which the chapter order instead emphasized differential diagnosis considerations (for example, in DSM-​ IV substance-​ related disorders preceded categories such as mood disorders and anxiety disorders because substance-​related causes of depression and anxiety should be ruled out before diagnosing a mood or anxiety disorder; American Psychiatric Association, 1994). IS T H E   GROU PING OF   OC R DS OPT IMA L ? Although there was strong support from the literature and the field for including a new chapter of OCRDs in DSM-​5, a more challenging issue was which specific disorders should be included in it. As Stein has stated, any nosology is only one potential solution to the conundrum of classification, and far from the last word. At the same time it should reflect a careful weighing of different options, and a real striving to come up with a well-​reasoned product (Stein, 2008). The DSM-​5 process involved exhaustive weighing of various considerations, in addition to a painstaking review of existing evidence and commission of new studies. However, our field is not yet at the point where we can carve nature precisely at its joints, because we do not yet fully understand mechanisms and causes of mental disorders. In addition, the validator approach—​although valuable—​ has limitations. Ideally, using validators to determine disorder relatedness should be based upon studies that directly compare each and every disorder in the OCRD chapter to one another and to disorders in other chapters that have characteristics in common with each OCRD. Such studies should be done for all validators. But studies such as these would be very costly and have not been done. Many studies, for example, indicate that BDD has many similarities to OCD (as well as some 543

 

differences), but very few studies have directly compared BDD to social anxiety disorder, eating disorders, or other “near neighbor” disorders. Even then, unless all of these disorders and all validators are included in the same study, judgment is required to compare findings across studies in order to determine the degree of disorder relatedness, especially if findings differ across studies and validators. Because of these complexities and judgment calls, although ICD-​11 is likely to include a chapter of OCRDs that looks very similar to that in DSM-​5, it may also have a few differences (Stein, Kogan, Atmaca, et al., 2016). Tourette’s disorder has long been considered to be closely related to OCD, based upon the similarity of tics to OCD compulsions, its close genetic relationship to OCD, and other similarities (Phillips et al., 2010). However, a new neurodevelopmental disorders chapter was added to DSM-​5, and it can be argued that tic disorders have more in common with other neurodevelopmental disorders than with some disorders in the OCRD chapter (Walkup, Ferrão, Leckman, Stein, & Singer, 2010). For example, first-​line pharmacotherapy for OCD (SRIs) differs notably from that of tic disorders (alpha adrenergic agonists or neuroleptics). As another example, hypochondriasis is a heterogeneous condition, with some forms appearing more similar to OCD and others more similar to the anxiety disorders or somatic symptom disorders. Evidence regarding its optimal placement in DSM-​5 was inconclusive (Phillips et al., 2010). Although less well studied, obsessive-​compulsive personality disorder has some similarities to OCD and might have been placed in the OCRD chapter, rather than the personality disorder chapter (Phillips et al., 2010). The bar for change in DSM-​5 was high; in the absence of clear evidence, there was an explicit bias toward keeping classification as it had been in DSM-​I V, so as not to needlessly disrupt clinical practice. Ultimately—​ even after considering validators, clinical utility, and face validity—​judgment was needed to decide where these disorders should be placed. In collaboration with other DSM-​5 workgroups, the recommendation was to classify tic disorders with neurodevelopmental disorders, to keep hypochondriasis (renamed as illness anxiety disorder) in the somatic symptom chapter, and to keep obsessive-​compulsive personality disorder in the personality disorder chapter. Of note, a tic specifier was added to OCD’s diagnostic criteria; this specifier highlights the close relationship between OCD

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and tic disorders and also has clinical utility in that it may remind clinicians to assess for tics in patients with OCD, which has important clinical implications (Leckman, Denys, Simpson, et  al., 2010). (Because of this important relationship, tic disorders are included in the section on OCD-​related disorders in the current text; see ­chapter  53). All of these recommendations were subsequently reviewed and approved by the DSM-​ 5 Task Force and ultimately by the American Psychiatric Association Board of Trustees. It could be argued that the OCRD chapter should have better reflected the more inclusive concept of a compulsive-​ impulsive spectrum (Fineberg, Potenza, Chamberlain, et al., 2010), by including disorders characterized by high levels of impulsivity (such as pathological gambling). However, more recent data suggest important differences in their phenomenology, psychobiology, and other diagnostic validators, and excluding them from the OCRD chapter is consistent with more recent views of experts in the field (Mataix-​Cols et al., 2007). Taken together, many would agree that OCRD-​related changes in DSM-​5 are a step in the right direction. They improve upon DSM-​IV by reflecting evidence that accumulated since DSM-​IV was developed. Indeed, some important studies published after DSM-​5 offer further support for this grouping of disorders (Monzani, Riisdijk, Harris, & Mataix-​Cols, 2014). However, DSM-​5 is not perfect. To improve the grouping, much more research needs to be done on these disorders and their relationship to many other disorders across DSM. The OCRDs may look somewhat different in ICD-​11 and in future editions of DSM. These manuals may incorporate some disorders that were excluded from the DSM-​5 OCRD section, such as hypochondriasis/​illness anxiety disorder. In addition, in these future manuals, some of the conditions currently classified as an “other specified obsessive-​compulsive and related disorder” may perhaps be elevated to full-​fledged disorders with diagnostic criteria. Olfactory reference syndrome (ORS; distressing or impairing preoccupation with emitting a foul body odor, which others cannot perceive) is a case in point. The DSM-​5 OC-​Spectrum Sub-​Workgroup recommended that ORS be included in the section on Conditions for Further Study, a required prelude to inclusion as a full-​fledged disorder in the OCRD chapter (Feusner, Phillips, & Stein, 2010); however, the bar for adding new disorders with full criteria sets to DSM-​5, even to the Conditions for Further Study section, was high, so ORS and some other candidate conditions were

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instead more simply and briefly listed, without criteria sets, as “other specified” OCRDs.

CONS

(1) Some of the OCRDs, such as excoriation (skin-​picking) disorder and hoarding disorder, may not be closely related to one another (although this is also the case for the some of S OM E P RO S AN D CO N S O F THE N EW the disorders grouped together in other chapters in DSM-​5). OCR D C HA PTER (2) It may have been better to include some excluded disorders, such as tic disorders and illness anxiety disorder For the reasons just discussed, there are both pros and cons (hypochondriasis), in the OCRD chapter. (3)  Classifying to the current grouping (Phillips & Stein, 2015b). OCD and BDD in a different chapter than the anxiety disorders may imply that they are not closely related to the anxiety disorders, although they probably actually are. The PROS fact that the OCRD chapter directly follows the anxiety (1) The new chapter reflects advances in knowledge since disorders chapter highlights these close relationships (Stein the early 1990s, when DSM-​IV was developed, and it et  al., 2011). (4)  Some might consider the chapter name likely classifies these disorders more accurately than DSM-​ too “OCD-​centric” (although it is worth noting that the IV did. For example, BDD appears more similar to OCD name includes “obsessive-​compulsive” but not “obsessive-​ than to the somatic symptom disorders, and trichotilloma- compulsive disorder”). (5) Some clinicians and researchers nia appears more similar to OCD than to impulse control might incorrectly assume that all OCRDs are “just OCD,” disorders such as pyromania and intermittent explosive which could lead to incorrect identification of symptoms disorder (Phillips et al., 2010). (2) This grouping of disor- and disorders in research studies and incorrect treatment of ders draws attention to similarities among the OCRDs and patients. Furthermore, although some effective treatments may increase awareness of these underrecognized disorders. for some of these disorders overlap, others meaningfully (3) Grouping these disorders together highlights similarities differ (Phillips & Stein, 2015a). For example, the SRIs are in approaches to assessment; adaptations of the Y-​BOCS selectively efficacious for OCD, and probably also for BDD, (Goodman et  al., 1989; Keuthen, Wilhelm, Deckersbach, but their effectiveness for hoarding disorder, trichotilloet  al., 2001; O’Sullivan, Keuthen, Hayday, et  al., 1995; mania, and excoriation (skin-​picking) disorder is less clear. Phillips, Hollander, Rasmussen, et  al., 1997)  and DSM-​ As another example, unlike OCD, hoarding disorder and 5’s new cross-​cutting measures for the OCRDs (LeBeau BDD do not respond well to simple exposure and response RT, Mischel, Simpson, et  al., 2013), based on the Florida (ritual) prevention; modified cognitive-​behavioral intervenObsessive-​ Compulsive Inventory (Storch, Kaufman, tions and motivational interviewing are usually needed. This Bagner, et al., 2007), can be applied to all of the OCRDs. issue also arises among the disorders grouped together in (4) When patients present with an OCRD, clinicians may be other chapters in DSM-​5; for example, pharmacotherapy for more likely to screen for other OCRDs in the patient and in anorexia nervosa and bulimia nervosa meaningfully differs. family members. (5) Clinicians may be reminded that there are some similarities in treatment approach among some of the OCRDs—​for example, pharmacotherapy of BDD and C ONC LU DING T H OU GH T S OCD, and use of habit reversal training for trichotillomania and excoriation (skin-​picking) disorder (Phillips & Stein, 2015a). (6)  Researchers may be encouraged to study mul- In summary, the addition of a the concept of the OCRDs tiple OCRDs in an attempt to elucidate their relationship to DSM-​5 reflects increased understanding since DSM-​IV was developed, and many would agree that these changes to one another. There are substantial advantages to adding both hoard- are an advance over DSM-​IV. However, the current classiing disorder and excoriation (skin-​picking) disorder to fication is not perfect, and much more research is needed. DSM and to the OCRDs. Prior to DSM-​5, both disor- Such research should examine a variety of validators and a ders were underdiagnosed and often treated as if they were range of categorical and dimensional constructs, drawing OCD, even though a modified treatment approach is on both proximal and distal explanations (Nesse & Stein, needed (Phillips & Stein, 2015a). Their addition to DSM-​5 2012; Stein & Lochner, 2006). This work should also aim may help clinicians better identify, diagnose, and treat them to elucidate underlying mechanisms and etiology. In the meantime, it is hoped that the changes in DSM-​5 yield (Phillips & Stein, 2015a).

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advances in research and, most importantly, improvements in patient care.

Mataix-​Cols, D., Pertusa, A., & Leckman, J. F. (2007). Issues for DSM-​ V: How should obsessive-​compulsive and related disorders be classified? American Journal of Psychiatry, 164, 1313–​1314. Monzani, B., Riisdijk, F., Harris, J., & Mataix-​Cols, D. (2014). The structure of genetic and environmental risk factors for dimensional representations of DSM-​5 obsessive-​compulsive spectrum disorders. JAMA Psychiatry, 71, 182–​189. R EF ERENCES Nesse, R. M., & Stein, D. J. (2012). Towards a genuinely medical model for psychiatric nosology. BMC Medicine, 10, 5. American Psychiatric Association. (1994). Diagnostic and statistical O’Sullivan, R. L., Keuthen, N. J., Hayday, C. F., et  al. (1995). The Massachusetts General Hospital (MGH) hairpulling manual of mental disorders (4th ed.). Washington, DC: Author. scale:  2.  Reliability and validity. Psychotherapy and Psychosomatics, American Psychiatric Association. (2013). Diagnostic and statistical 64, 146–​148. manual of mental disorders (5th ed.). Arlington, VA: Author. Feusner, J., Hembacher, E., & Phillips, K. A. (2009). The mouse who Phillips, K. A. (1991). Body dysmorphic disorder: The distress of imagined ugliness. American Jornal of Psychiatry, 148, 1138–​1149. couldn’t stop washing: Pathologic grooming in animals and humans. Phillips, K. A. (2002). The obsessive compulsive spectrums. Psychiatric CNS Spectrums, 14, 503–​513. Clinics of North America, 25, 791–​809. Feusner, J. D., Phillips, K. A., & Stein, D. J. (2010). Olfactory reference syndrome: Issues for DSM-​V. Depression and Anxiety, 27, Phillips, K. A., Hollander, E., Rasmussen, S. A., et al. (1997). A severity rating scale for body dysmorphic disorder: development, reliabil592–​599. ity, and validity of a modified version of the Yale-​Brown Obsessive Fineberg, N. A., Potenza, M. N., Chamberlain, S. R., et al. (2010). Probing Compulsive Scale. Psychopharmacology Bulletin, 33, 17–​22. compulsive and impulsive behaviors, from animal models to endophePhillips, K. A., & Stein, D. J. (Eds.). (2015a). Handbook on obsessive-​ notypes: A narrative review. Neuropsychopharmacology, 35, 591–​604. compulsive and related disorders. Arlington, VA: American Psychiatric First, M. B., Pincus, H. A., Levine, J. B., et  al. (2004). Clinical utility Publishing. as a criterion for revising psychiatric diagnoses. American Journal of Phillips, K. A., & Stein, D. J. (2015b). Introduction and major changes Psychiatry, 161, 946–​954. for the obsessive-​compulsive and related disorders in DSM-​5. In K. Goodman, W. K., Price, L. H., Rasmussen, S. A., et al. (1989). The Yale-​ A. Phillips, & D. J. Stein (Eds.), Handbook on obsessive-​compulsive and Brown Obsessive Compulsive Scale II: Validity. Archives of General related disorders (pp. 1–​24). Arlington, VA:  American Psychiatric Psychiatry, 46, 1012–​1016. Publishing; 2015. Hollander, E. (2015). Forward. In K. A. Phillips, & D. J. Stein (Eds.), Handbook on obsessive-​compulsive and related disorders (pp. xi–​xiii). Phillips, K. A., Stein, D. J., Rauch, S. L., et al. (2010). Should an obsessive compulsive spectrum grouping of disorders be included in the DSM-​ Arlington, VA: American Psychiatric Publishing. V? Depression and Anxiety, 27, 528–​555. Hollander, E. (Ed.). (1993). Obsessive-​ compulsive related disorders. Robins, E., & Guze, S. B. (1970). Establishment of diagnostic validity in Washington, DC: American Psychiatric Press. psychiatric illness: Its application to schizophrenia. American Journal Hollander, E., Kim, S., & Zohar, J. (2007). OCSDs in the forthcoming of Psychiatry, 126, 983–​987. DSM-​V. CNS Spectrums, 12, 320–​323. Hollander, E., Zohar, J., Sirovatka, P., & Regier, D. (Eds). (2011). Stein, D. J. (2008). Is disorder X in category or spectrum Y? General considerations and application to the relationship between obsessive-​ Obsessive compulsive spectrum disorders: Refining the research agenda compulsive disorder and anxiety disorders. Depression and Anxiety, for DSM-​V. Washington, DC: American Psychiatric Publishing. 25, 330–​335. Hyman, S. (2003). Forward. In K. A. Phillips, M. B. First, & H. Pincus (Eds.), Advancing DSM: Dilemmas in psychiatric diagnosis (pp. xi–​ Stein, D. J., Craske, M. G., Friedman, M. J., & Phillips, K. A. (2011). Meta-​structure issues for the DSM-​5:  How do anxiety disorders, xix). Washington DC: American Psychiatric Association. obsessive-​compulsive and related disorders, post-​traumatic disorders, Hyman, S. E. (2002). Neuroscience, genetics, and the future of psychiatand dissociative disorders fit together? Current Psychiatry Reports, ric diagnosis. Psychopathology, 35, 139–​144. 13, 248–​250. Insel, T., Cuthbert, B., Garvey, M., et al. (2010). Research domain criteria (RDoC): Toward a new classification framework for research Stein, D. J., Fineberg, N. A., Bienvenu, O. J., et al. (2010). Should OCD be classified as an anxiety disorder in DSM-​V ? Depresion and Anxiety, on mental disorders. Ametrican Journal of Psychiatry, 167, 748–​751. 27, 495–​506. Janet, P. (1903). Les obsessions et la psychasthenie. Paris: Felix Alcan. Joel, D., Stein, D. J., & Schrieber, R. (2008). Animal models of obses- Stein, D. J., & Hollander, E. (1993). The spectrum of obsessive-​ compulsive related disorders. In E. Hollander (Ed.), Obsessive-​ sive compulsive disorder: From bench to bedside via endophenotypes compulsive related disorders. Washington, DC:  American and biomarkers. In R. A. McArthur, & F. Borsini (Eds.), Animal and Psychiatric Press. Translational Models for CNS Drug Discovery, Vol 1: Psychiatric disorStein, D. J., Kogan, C. S., Atmaca, M., et al. (2016). The classification of ders (pp. 133–​164). Amsterdam: Elsevier. obsessive-​compulsive and related disorders in the ICD-​11. Journal of Kendler, K. S., Gardner, C. O., & Prescott, C. A. (2002). Toward a comAffective Disorders, 190, 663–​674. prehensive developmental model for major depression in women. Stein, D. J., & Lochner, C. (2006). Obsessive-​compulsive spectrum disAmerican Journal of Psychiatry, 159, 1133–​1145. orders:  A  multidimensional approach. Psychiatric Clinics of North Keuthen, N. J., Wilhelm, S., Deckersbach, T., et  al. (2001). The Skin America, 29, 343–​351. Picking Scale: Scale construction and psychometric analyses. Journal Stekel, W. (1949). Compulsion and doubt. (E. A. Gutheil, Trans.). of Psychosomatic Research, 50, 337–​341. New York: Liveright. LeBeau, R. T., Mischel, E. R., Simpson, H. B., et al. (2013). Preliminary assessment of obsessive-​ compulsive spectrum scales for DSM-​ 5. Storch, E. A., Kaufman, D. A., Bagner, D., et al. (2007). Florida Obsessive-​ Compulsive Inventory: Development, reliability, and validity. Journal Journal of Obsessive-​Compulsice and Related Disorders, 2, 114–​118. of Clinical Psychology, 63, 851–​859. Leckman, J. F., Denys, D., Simpson, H. B., et  al. (2010). Obsessive-​ compulsive disorder:  A  review of the diagnostic criteria and pos- Walkup, J. T., Ferrão, Y., Leckman, J. F., Stein, D. J., & Singer, H. (2010). Tic disorders: Some key issues for DSM-​V. Depression and Anxiety, sible subtypes and dimensional specifiers for DSM-​V. Depression and 27, 600–​610. Anxiety, 27, 507–​527.

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49. CLINICAL FEATURES, ASSESSMENT, AND TREATMENT OF BODY DYSMORPHIC DISORDER Lisa Zakhary, MD, PhD, Hilary Weingarden, MA, Alexandra Sullivan, BA, and Sabine Wilhelm, PhD

B

ody dysmorphic disorder (BDD) is a common yet underrecognized disorder, characterized by a distressing preoccupation with an imagined or slight defect in appearance. It can lead to tremendous suffering and dysfunction. Epidemiological research shows an estimated prevalence of 1.7% to 2.4% in the general population (Buhlmann et al., 2010; Koran, Abujaoude, Large, & Serpe, 2008; Rief, Buhlmann, Wilhelm, Borkenhagen, & Brahler, 2006). Prevalence estimates are higher among dermatology (14%; Conrado et al., 2010) and cosmetic surgery patients (24.5%; Alavi, Kalafi, Dehbozorgi, & Javadpour, 2011). BDD has been described in the literature for over a century, but it was only introduced in the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (DSM-​III) in 1980, as “dysmorphophobia,” an example of an atypical somatoform disorder with no diagnostic criteria (American Psychiatric Association, 1980). It was given a separate diagnosis within somatoform disorders in DSM-​IIIR with full diagnostic criteria and was renamed body dysmorphic disorder (American Psychiatric Association, 1987). The diagnosis was maintained with few changes in DSM-​IV-​TR (American Psychiatric Association, 2000). However, to reflect the growing evidence that BDD and OCD share many features, BDD has been reclassified as an obsessive-​ compulsive and related disorder in DSM-​5 (American Psychiatric Association, 2013; see chapter 49). The DSM-​5 defines BDD as a preoccupation with one or more perceived appearance flaws that either are not observable or appear minor to others, causing significant distress or dysfunction (American Psychiatric Association, 2013). A new diagnostic requirement in DSM-​5 is the performance

of repetitive behaviors, such as mirror checking or grooming. A diagnosis of BDD is excluded if the preoccupation is mainly with body fat or weight, concerns more typically seen with eating disorders (EDs; see c­ hapter 56). Finally, as with OCD, the DSM-​5 has introduced a new specifier for insight—​good, poor, or absent insight/​delusional beliefs—​ to reflect the wide range of insight impairment in patients with BDD. C LINIC AL F E AT U R E S A P P E A R A N C E P R E O C C U PAT I O N S

The most common areas of concern include skin, hair, and nose, although any physical attribute can become a target of preoccupation (Phillips & Diaz, 1997; Phillips, Menard, Fay, & Weisberg, 2005). As an example, muscle dysmorphia is a subtype of BDD in which the area of concern is inadequate musculature (Olivardia, Pope, & Hudson, 2000; C. G. Pope et al., 2005; H. G. Pope, Jr., Gruber, Choi, Olivardia, & Phillips, 1997). Individuals with BDD are commonly preoccupied with several different aspects of their appearance (Phillips & Diaz, 1997; Phillips, Menard, Fay, & Weisberg, 2005). An estimated 40% of individuals with BDD spend 3 to 8 hours per day thinking about their appearance; 25% think about their appearance for more than 8 hours per day (Phillips, 2009). Appearance preoccupations, like intrusive thoughts in OCD, are typically difficult to control and lead to significant distress, particularly since patients often feel deformed and ashamed (Phillips, 2009).

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VARIABLE INSIGHT

Individuals with BDD demonstrate variable insight regarding these perceived defects. Insight ranges from awareness that appearance concerns are excessive to complete conviction of being physically deformed. A  majority of patients experience delusions of reference, believing that others are staring or laughing at them due to their appearance flaw (Phillips, 2009). Two studies of insight found that 36% to 39% of patients with BDD were delusional (Eisen, Phillips, Coles, & Rasmussen, 2004; Phillips, Menard, Pagano, Fay, & Stout, 2006). Studies comparing delusional and nondelusional BDD suggest that they are variations of the same disorder, though the delusional form is associated with greater clinical impairment (Mancuso, Knoesen, & Castle, 2010; Phillips, McElroy, Keck, Hudson, & Pope, 1994; Phillips, Menard, Pagano, et  al., 2006). The medication treatment of delusional and nondelusional BDD, discussed later, is the same.

Carter, 1998). In fact, for as many as 30% of BDD sufferers, impairment and avoidance can be so severe that individuals become housebound (Phillips, McElroy, Keck, Pope, & Hudson, 1993). In one study of adolescents with BDD, 11% of patients had permanently dropped out of school (Phillips, Didie, et al., 2006). Unemployment rates in BDD are high, ranging from 21.4% to 57% (Didie, Menard, Stern, & Phillips, 2008; Frare et  al., 2004; Perugi et  al., 1997; Phillips et al., 1993; Rief et al., 2006; Veale, Boocock, et al., 1996), with nearly a quarter (22.7%) of individuals receiving disability payments (Didie et al., 2008). Among adults with BDD who are able to work, nearly 90% in one study reported work-​related impairment due to appearance preoccupations (Didie et al., 2008). An estimated 75% to 90% of individuals with BDD are single or divorced (Fontenelle et al., 2006; Phillips et al., 1993; Phillips, Menard, Fay, & Pagano, 2005). SUICIDALITY

COMMON REPETITIVE BEHAVIORS

To reflect the extent to which individuals with BDD engage in repetitive behaviors, compulsive behaviors are required for a BDD diagnosis in the DSM-​5 (American Psychiatric Association, 2013). Compulsive behaviors may include excessively checking mirrors or reflective surfaces (Phillips, 2009). Many patients report getting “stuck” in the mirror for hours, examining themselves in close detail (Phillips, 2009). They may also camouflage the region of concern (e.g., by wearing a hat or concealing clothing), seek frequent reassurance from friends and family about their appearance, and physically check the disliked body part (e.g., repeatedly touching it; Phillips, 2009). Other behaviors include excessive grooming (e.g., hair removal, makeup), frequently comparing oneself to others, compulsive skin picking, and excessive tanning (Phillips, 2009). Individuals with concerns about muscularity may engage in excessive exercise and use of anabolic steroids or supplements (Olivardia et al., 2000; C. G. Pope et al., 2005; H. G. Pope, Jr. et al., 1997). About 40% of patients spend 1 to 3 hours per day, and 40% spend 3 to 8 hours per day, performing these behaviors (Phillips, 2009).

Alongside functional impairment, risk of suicide is a distinct clinical issue for BDD sufferers. Nearly 80% of adults with BDD may experience suicidal ideation in their lifetime (Phillips, Coles, et  al., 2005; Phillips, Didie, et  al., 2006)  and a substantial proportion (22-​28%) of adults with BDD attempt suicide (Phillips, 2007; Phillips, Coles, et  al., 2005; Phillips & Diaz, 1997; Phillips, Didie, et  al., 2006; Veale, Boocock, et  al., 1996). One prospective study of suicidality in BDD found that, over the course of 4 years, 57.8% of the adult sample (n = 185) experienced suicidal ideation, 2.6% made at least one attempt, and two individuals completed suicide (Phillips & Menard, 2006). These findings are striking; the suicide completion rate in this sample was approximately 45 times greater than that of the general population, and it exceeded suicide completion rates documented for other serious psychiatric illnesses including major depressive disorder (MDD), bipolar disorder, and EDs (Phillips & Menard, 2006). Moreover, suicide attempts among adolescents with BDD may be significantly more frequent (44.4%) than among adults (Phillips, Didie, et al., 2006). Taken together, there is an evident need for clinicians to assess and address suicide risk when treating patients with BDD.

F U N C T I O N A L I M PA I R M E N T A N D A VO I DA N C E

COMORBIDITY

BDD is associated with extensive functional impairment, which is often worse than in other, phenomenologically similar disorders like OCD (Frare, Perugi, Ruffolo, & Toni, 2004; Phillips, Gunderson, Mallya, McElroy, &

Comorbid psychiatric disorders are common in individuals with BDD. With an estimated lifetime prevalence of ~75% across three large studies, MDD is the most common comorbidity (Gunstad & Phillips, 2003; Phillips & Diaz,

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1997; Phillips, Menard, Fay, & Weisberg, 2005). Other common comorbid disorders include substance use disorders (30%–​50%), social phobia (36%–​40%), OCD (30%–​ 39%), and EDs (7%–​25%) (Grant, Menard, Pagano, Fay, & Phillips, 2005; Gunstad & Phillips, 2003; Phillips, Menard, Fay, & Weisberg, 2005). DEMOGRAPHICS AND COURSE

BDD typically begins during early adolescence, with a mean age of onset of 16; however, it has been reported to occur as early as 5 years old (Albertini, Phillips, & Guevremont, 1996; Bjornsson et  al., 2013; Gunstad & Phillips, 2003; Phillips, Menard, Fay, & Weisberg, 2005). Investigations into sex differences have mostly demonstrated that BDD is slightly more common in women (Koran et  al., 2008; Phillips & Diaz, 1997; Phillips, Menard, & Fay, 2006; Rief et al., 2006), although one study in a clinical sample indicated a roughly equal sex ratio (Phillips & Diaz, 1997). A  recent 4-​year prospective study illustrates that BDD is a chronic disorder with a low probability of full remission (20%) and high probability of relapse (Phillips, Menard, Quinn, Didie, & Stout, 2013). Earlier onset and more severe BDD increase the risk of relapse (Phillips, Menard, et al., 2013). A S S ES S M E N T SCREENING AND SCALES

Despite being relatively common, BDD is underdiagnosed. Individuals with BDD may be too embarrassed to disclose appearance concerns, making it particularly important for mental health clinicians to systematically screen all patients for such preoccupations (Phillips & Hollander, 2008). There are several useful scales for BDD assessment. The Body Dysmorphic Disorder Questionnaire is a 4-​question screening tool for clinicians and patients (Phillips, 2005a). For diagnosis, the BDD Diagnostic Module, a clinician-​administered scale that maps onto DSM-​IV BDD criteria, can be administered (Phillips, 2005a). The Yale-​ Brown Obsessive Compulsive Scale Modified for BDD (BDD-​YBOCS) is a 12-​item clinician-​administered scale to assess BDD severity (Phillips et al., 1997). The BDD-​YBOCS is often readministered throughout treatment to assess changes in BDD symptom severity (Phillips et al., 1997). For insight, the Brown Assessment of Beliefs Scale, a 7-​item clinician-​ administered scale, is often used (Eisen et  al., 1998; Body D ysmorphic D isorder :   C linical

Phillips, Hart, Menard, & Eisen, 2013). Finally, the BDD Symptom Scale (BDD-​SS) is a detailed self-​report scale that identifies BDD symptoms, cognitions, and severity (Wilhelm, 2006). DIFFERENTIAL DIAGNOSIS

BDD may mimic OCD based on the presence of repetitive intrusive thoughts and compulsive behaviors, but there are important differences. The content of obsessions and compulsions in OCD ranges widely (e.g., contamination, symmetry, harm); for those with BDD, obsessions focus on perceived defects in one’s appearance, and compulsions are aimed at diminishing or concealing the perceived defect (Chosak et  al., 2008). Another distinguishing feature is that, whereas individuals with OCD tend to have good insight, those with BDD often have poor or absent insight (Chosak et al., 2008). Although EDs and BDD have clear similarities, including the core feature of body dissatisfaction, there are also distinguishing features. In EDs, body dissatisfaction is most often focused on weight and shape, whereas in BDD it is more commonly focused on specific body parts (Hartmann, Greenberg, & Wilhelm, 2013; Kittler, Menard, & Phillips, 2007; Phillips & Diaz, 1997; Phillips, Menard, Fay, & Weisberg, 2005). Moreover, one study found that although 29% of a BDD sample (n = 200) had concerns with weight and shape, their primary appearance concerns typically focused on other body areas, and they appeared to represent a more ill population (Kittler et al., 2007). Additionally, the presence of eating pathology can distinguish EDs from BDD (Fang & Wilhelm, 2015; Hartmann et al., 2013). BDD and ED can cooccur, and in comorbid cases, both diagnoses should be made (Hartmann et al., 2013). T R E AT ME NT The first-​ line treatments for BDD include serotonin reuptake inhibitors (SRIs) and cognitive behavioral therapy (CBT), although data are limited (Ipser, Sander, & Stein, 2009; National Collaborating Centre for Mental Health, 2006). SEROTONIN REUPTAKE INHIBITORS

Currently, there are no medications with FDA approval for the treatment of BDD. However, SRIs—​medications widely used in the treatment of OCD, including selective serotonin 549

 

reuptake inhibitors and clomipramine (see ­chapter  40)—​ have consistently shown reductions in BDD symptoms. Case reports of fluoxetine and clomipramine (Brady, Austin, & Lydiard, 1990; Hollander, Liebowitz, Winchel, Klumker, & Klein, 1989) paved the way for case series and open-​label studies with fluvoxamine (n = 30, n = 15, respectively, in Perugi et al., 1996; Phillips, Dwight, & McElroy, 1998), citalopram (n  =  15; Phillips & Najjar, 2003), and escitalopram (n = 15; Phillips, 2006), with overall response rates ranging from 63% to 73% (Phillips, 1991). The SRI clomipramine was more efficacious than the non-​SRI antidepressant desipramine in a double-​blind crossover trial (n = 29) in reducing BDD symptoms and overall dysfunction (Hollander et al., 1999). To date, there has been only one double-​blind randomized placebo-​controlled SRI trial for BDD. In this 12-​week trial of fluoxetine (n = 67), fluoxetine was significantly more efficacious than placebo, with ultimate response rates of 53% for fluoxetine and 18% for placebo (Phillips, Albertini, & Rasmussen, 2002). There are no studies directly comparing SRIs, although all are thought to be equally effective (as is the case for OCD). SRIs are also effective for the treatment of delusional BDD or those with poor insight (Hollander et  al., 1999; Phillips et  al., 2002; Phillips, McElroy, Dwight, Eisen, & Rasmussen, 2001; Phillips et al., 1994). This contrasts with other disorders where insight is impaired to a delusional extent, in which antipsychotics are often a mainstay of treatment. In the fluoxetine randomized control trial (RCT), fluoxetine was as effective for delusional BDD patients as for nondelusional BDD patients (Phillips et al., 2002). Similar results were seen in open-​label studies of fluvoxamine, citalopram, and escitalopram and in the clomipramine crossover study (Hollander et al., 1999; Phillips, 2006; Phillips, McElroy, et  al., 2001; Phillips & Najjar, 2003). Data on antipsychotic monotherapy for BDD is lacking. However, augmentation of SRIs with antipsychotics is under exploration, as summarized.

Serotonin Reuptake Inhibitor Dosing and Duration Studies specifically comparing different SRI doses or duration for BDD are lacking; however, clinically, most patients require high, in many cases maximum, SRI dosing (Phillips, 2009; Phillips & Hollander, 2008). As a result of high dose requirements, SRI tolerability becomes a central issue of treatment. Clinical experience suggests that SRIs with more favorable side effect profiles may be preferable to begin. Citalopram is generally well tolerated, but its overall utility in BDD has been limited since 2011 following the FDA’s reduction in maximum dose from 60 mg per day to 550

40 mg per day due to potential QTc prolongation (FDA, 2011). The merit of this change has been questioned in several later studies including a large cohort study showing no elevated risk of ventricular arrhythmia, cardiac, or noncardiac mortality on citalopram dosages greater than 40 mg per day (Zivin et al., 2013). As a result, some practitioners will prescribe citalopram at above maximum dosing with EKG monitoring, particularly in cases with severe symptomatology. Response to SRIs appears to be delayed but has not been studied systematically. Mean time to response in the fluoxetine RCT (Phillips et  al., 2002)  and one fluvoxamine open-​label study were roughly 6 to 8 weeks (Phillips, Dwight, et al., 1998). Faster response times were reported in the citalopram and escitalopram open-​ label studies (~5weeks) (Phillips, 2006; Phillips & Najjar, 2003). Full response may require 12 to 16 weeks (Phillips & Hollander, 2008). Because of delayed response and high dose requirements, fairly rapid titration is recommended (Phillips & Hollander, 2008). If a patient has not had significant symptom reduction on an adequate SRI trial (high dose, 12–​16 weeks) or if the SRI is intolerable, a switch to a different SRI is indicated. Because of high dose requirements and tolerability issues, several SRI trials may be required. Research on non-​SRI monotherapies is very limited and includes two small open-​ label studies of venlafaxine (n = 17; Allen et al., 2008), a serotonin norepinephrine reuptake inhibitor, and levetiracetam (n = 17; Phillips & Menard, 2009), an antiepileptic medication, both of which showed reduction in BDD symptoms.

Partial Response to a Serotonin Reuptake Inhibitor Patients who have shown only a partial response to a maximum SRI dose may benefit from above-​maximum dosing, as in OCD. No major studies or guidelines regarding above-​maximum dosing exist. In the clinical experience of the first author, the following doses are routinely helpful and tolerable: escitalopram, 30 mg/​day; sertraline, 300 mg/​day; and fluoxetine, 120 mg/​day (L Zakhary, unpublished data, 2015). However, even higher doses have been reported: escitalopram, 60 mg/​day; sertraline, 400 mg/​day; and fluvoxamine, 400mg/​day (Phillips, 2009). Given the risk of seizure and QTc prolongation, clomipramine should not exceed 250 mg per day, and regular monitoring of blood levels is advisable at higher doses. Although the FDA has not warned of significant QTc prolongation with escitalopram, there have been reports of escitalopram-​induced QTc prolongation in the literature, so EKG monitoring O b sessive - C ompulsive D isorder

 

with above-​ maximum escitalopram dosing is prudent (FDA, 2012). Augmentation is also an option for partial responders, although augmentation data is sparse. In one small open-​ label study (n  =  13), 46% of patients with BDD showed improvement with buspirone, a 5-​HT1A partial agonist (mean dose 60 mg/​day), when added to an ineffective or partially effective SRI (Phillips, 1996). There have also been reports of patients showing benefit with clomipramine augmentation, a strategy useful in OCD treatment. However, combined SRI/​clomipramine treatment should be undertaken with care, because selective SRIs can unpredictably increase clomipramine levels (Phillips, Albertini, Siniscalchi, Khan, & Robinson, 2001). If clomipramine and selective SRIs are used together, clomipramine should be started at a low dose and EKG and clomipramine level monitored frequently (Phillips & Hollander, 2008). Antipsychotics are being explored for use in augmentation, in part due to their benefit in OCD; however, so far results have been mixed and limited. The only randomized placebo-​controlled study of augmenting agents found no difference between pimozide, a typical antipsychotic, and placebo when added to fluoxetine (Phillips, 2005c). There has been one positive case report with aripiprazole (10 mg/​day) (Uzun & Ozdemir, 2010), no studies with risperidone or quetiapine, and mixed case reports with olanzapine (Nakaaki, Murata, & Furukawa, 2008; Phillips, 2005b). This area requires further study, although atypical antipsychotics are suspected to be more effective than typicals (Nakaaki et al., 2008; Phillips, 2005b, 2005c; Phillips, Albertini, et al., 2001; Uzun & Ozdemir, 2010). In addition, and intuitively, augmentation appears to be more robust when an SRI is at least partially effective (Phillips, Albertini, et al., 2001). COGNITIVE BEHAVIORAL THERAPY

The preferred psychotherapy for BDD is cognitive behavioral therapy (CBT). Behavioral therapy (BT) for BDD includes exposure and response prevention (see ­chapter 40), during which patients are exposed to stimuli or situations that are anxiety provoking or avoided, in the absence of completing rituals (e.g., running errands on a sunny day without applying makeup or camouflaging body parts of concern; Marks & Mishan, 1988; McKay, Todaro, Neziroglu, & Campisi, 1997). CBT combines BT with cognitive components (e.g., identifying and challenging distorted beliefs related to BDD) and also typically includes perceptual retraining and mindfulness skills (e.g., mirror retraining, in which patients are taught to observe Body D ysmorphic D isorder :   C linical

their appearance from a holistic and nonjudgmental view, rather than focusing attention critically and narrowly on a perceived flaw; Fang & Wilhelm, 2015; Geremia & Neziroglu, 2001; Neziroglu & Yaryura-​Tobias, 1993; Veale, Gournay, et al., 1996; Wilhelm, Phillips, Fama, Greenberg, & Steketee, 2011; Wilhelm et al., 2014). One manualized CBT treatment also includes “modular” interventions, which consist of optional additions to treatment that address common cooccurring issues (e.g., skin picking or hair pulling, cosmetic surgery seeking, muscle dysmorphia, mood management; Wilhelm et al., 2011, 2014). Single studies have also been published assessing cognitive therapy (CT; Geremia & Neziroglu, 2001), metacognitive therapy (Rabiei, Mulkens, Kalantari, Molavi, & Bahrami, 2012), acceptance and commitment therapy (ACT; Linde et al., 2015), and Internet-​based CBT for BDD (Enander et al., 2014). Although these intervention approaches showed varying promise for treating BDD, additional studies that corroborate initial findings are needed.

Efficacy of Therapy A metaanalysis of treatment studies for BDD evaluated the efficacy of CT, BT, and CBT (Williams, Hadjistavropoulos, & Sharpe, 2006). When examined together, therapy interventions had a large weighted mean effect size (Cohen’s d  =  1.63; Williams et  al., 2006). CBT had a larger effect (d = 1.78) than BT (d = 1.43), which suggests that combining cognitive and behavioral techniques may be the best psychotherapy approach (Williams et al., 2006). However, differences in effect sizes between BT and CBT were not statistically significant (Williams et  al., 2006). Therefore, additional RCTs would better elucidate whether CBT offers distinct advantages over BT for BDD. In addition to case series (Neziroglu & Yaryura-​Tobias, 1993; Wilhelm, Otto, Lohr, & Deckersbach, 1999)  and open trials (McKay et  al., 1997; Neziroglu, McKay, Todaro, & Yaryura-​Tobias, 1996; Wilhelm, Phillips, Fama, Greenberg, & Steketee, 2011) that provide support for both BT and CBT for BDD, three randomized, no-​treatment (Rosen, Reiter, & Orosan, 1995)  or wait list-​controlled (Veale, Gournay, et al., 1996; Wilhelm et al., 2014) studies of CBT have been conducted (ns ranging from 19–​54). Across studies, participants in the CBT condition showed significantly greater reductions in BDD symptoms compared with no-​treatment or wait-​list conditions, and 78% to 81.5% of participants receiving CBT showed clinically significant reductions in treatment (Rosen et al., 1995; Veale, Gournay, et al., 1996; Wilhelm et al., 2014). Studies have 551

 

shown that patients maintained their gains 4.5 to 6 months post-​treatment (Rosen et al., 1995; Wilhelm et al., 2014). Furthermore, one recent study compared CBT (n  =  21) with an anxiety management (n  =  25) comparison treatment (Veale et al., 2014). At post-​treatment (12 weeks), the CBT group showed significantly greater symptom reduction compared with the anxiety management group, with large effects (d = .99; Veale et al., 2014). Considering these data together, CBT appears to be an effective treatment for BDD in comparison with no treatment, a wait list, or an anxiety management treatment. However, the duration of treatment (8–​22 sessions) in these four studies varied substantially, and the number of RCTs testing psychotherapy for BDD remains quite small, underscoring the need for much more research in this area. COGNITIVE BEHAVIORAL THERAPY VERSUS MEDICATION TREATMENT

No studies have been conducted that directly compare CBT with psychopharmacologic treatments, nor have studies been conducted that compare these monotherapies with combination therapy. A metaanalysis compared effect sizes from CBT and pharmacologic studies, finding that CBT had a significantly stronger overall effect (weighted mean effect sizes  =  1.78 and .92, respectively; Williams et  al., 2006). However, the metaanalysis is limited by the small number of included studies, and larger RCTs are necessary to validate these results. Therefore, to date we do not know whether CBT, pharmacologic treatments, or combined therapies offer the strongest approach to treating BDD. COSMETIC TREATMENT

In two large studies (n = 200, n = 289), it was found that 71% to 76% of individuals with BDD seek cosmetic treatments to correct their perceived appearance defects (Crerand, Phillips, Menard, & Fay, 2005; Phillips, Grant, Siniscalchi, & Albertini, 2001). Common nonpsychiatric treatments for BDD include acne treatments, breast augmentation, rhinoplasty, collagen injections, and microderm abrasion (Crerand, Menard, & Phillips, 2010; Crerand et  al., 2005). Despite these treatments, BDD symptoms do not typically improve. In one study of 200 individuals with BDD who underwent a cosmetic procedure, only 3.6% reported a reduction in BDD symptoms (Crerand et  al., 2005). Postoperative dissatisfaction is often high, and a survey of cosmetic surgeons found that 29% had been threatened legally by a patient with BDD (Sarwer, 2002). There are also four case reports of surgeons 552

murdered by patients with BDD (Cotterill, 1996; Crerand, Franklin, & Sarwer, 2006; Yazel, 1999). Given these issues, it is advised that all patients seeking cosmetic treatments be systematically screened for BDD. Individuals suspected of having BDD should be referred to a mental health professional for further evaluation and cosmetic procedure postponed. In some cases, surgeon refusal is not a strong enough deterrent; there are several case reports of patients attempting self-​surgery (Veale, 2000).

C ONC LU S IONS BDD is a common, yet underrecognized disorder of perceived ugliness leading to severe psychosocial dysfunction, depression, and possible suicide. Although much is known about its clinical presentation and demographic characteristics, large gaps in treatment knowledge remain. Hopefully, research will provide answers to guide more effective treatment of this disabling illness.

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Chosak, A., Marques, L., Greenberg, J. L., Jenike, E., Dougherty, D. D., & Wilhelm, S. (2008). Body dysmorphic disorder and obsessive compulsive disorder:  Similarities, differences and the classification debate. Expert Review of Neurotherapeutics, 8(8), 1209–​1218. Conrado, L. A., Hounie, A. G., Diniz, J. B., Fossaluza, V., Torres, A. R., Miguel, E. C., & Rivitti, E. A. (2010). Body dysmorphic disorder among dermatologic patients:  Prevalence and clinical features. Journal of the American Academy of Dermatology, 63(2), 235–​243. doi: 10.1016/​j.jaad.2009.09.017 Cotterill, J. A. (1996). Body dysmorphic disorder. Dermatologic Clinics, 14(3), 457–​463. Crerand, C. E., Franklin, M. E., & Sarwer, D. B. (2006). Patient safety: Body dysmorphic disorder and cosmetic surgery. Plastic and Reconstructive Surgery, 118(70), 167e–​180e. Crerand, C. E., Menard, W., & Phillips, K. A. (2010). Surgical and minimally invasive cosmetic procedures among persons with body dysmorphic disorder. Annals of Plastic Surgery, 65(1), 11–​16. doi: 10.1097/​SAP.0b013e3181bba08f Crerand, C. E., Phillips, K. A., Menard, W., & Fay, C. (2005). Nonpsychiatric medical treatment of body dysmorphic disorder. Psychosomatics, 46(6), 549–​555. doi: 10.1176/​appi.psy.46.6.549 Didie, E. R., Menard, W., Stern, A. P., & Phillips, K. A. (2008). Occupational functioning and impairment in adults with body dysmorphic disorder. Comprehensive Psychiatry, 49(6), 561–​569. doi: 10.1016/​j.comppsych.2008.04.003 Eisen, J. L., Phillips, K. A., Baer, L., Beer, D. A., Atala, K. D., & Rasmussen, S. A. (1998). The Brown Assessment of Beliefs Scale: Reliability and validity. American Journal of Psychiatry, 155(1), 102–​108. Eisen, J. L., Phillips, K. A., Coles, M. E., & Rasmussen, S. A. (2004). Insight in obsessive compulsive disorder and body dysmorphic disorder. Comprehensive Psychiatry, 45(1), 10–​15. doi:  10.1016/​ j.comppsych.2003.09.010 Enander, J., Ivanov, V. Z., Andersson, E., Mataix-​Cols, D., Ljótsson, B., & Rück, C. (2014). Therapist-​ g uided, Internet-​ based cognitive-​ behavioural therapy for body dysmorphic disorder (BDD-​ NET):  A  feasibility study. BMJ Open, 4(9), e005923-​e005923. doi: 10.1136/​bmjopen-​2014-​005923 Fang, A., & Wilhelm, S. (2015). Clinical features, cognitive biases, and treatment of body dysmorphic disorder. Annual Review of Clinical Psychology, 11, 187–​ 212. doi:  10.1146/​ annurev-​clinpsy-​032814-​112849 FDA. (2011). FDA Drug Safety Communication:  Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). Retrieved from http://​www.fda.gov/​Drugs/​DrugSafety/​ ucm269086.htm FDA. (2012). FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. Retrieved from http://​www.fda.gov/​Drugs/​DrugSafety/​ucm297391.htm Fontenelle, L. F., Telles, L. L., Nazar, B. P., de Menezes, G. B., do Nascimento, A. L., Mendlowicz, M. V., & Versiani, M. (2006). A sociodemographic, phenomenological, and long-​ term follow-​ up study of patients with body dysmorphic disorder in Brazil. International Journal of Psychiatry in Medicine, 36(2), 243–​259. Frare, F., Perugi, G., Ruffolo, G., & Toni, C. (2004). Obsessive-​ compulsive disorder and body dysmorphic disorder: A comparison of clinical features. European Psychiatry, 19(5), 292–​298. doi: 10.1016/​ j.eurpsy.2004.04.014 Geremia, G. M., & Neziroglu, F. (2001). Cognitive therapy in the treatment of body dysmorphic disorder. Clinical Psychology & Psychotherapy, 8(4), 243–​251. doi: 10.1002/​cpp.284 Grant, J. E., Menard, W., Pagano, M. E., Fay, C., & Phillips, K. A. (2005). Substance use disorders in individuals with body dysmorphic disorder. Journal of Clinical Psychiatry, 66(3), 309–​316; quiz 404–​405. Gunstad, J., & Phillips, K. A. (2003). Axis I comorbidity in body dysmorphic disorder. Comprehensive Psychiatry, 44(4), 270–​276. doi: 10.1016/​S0010-​440X(03)00088-​9 Body D ysmorphic D isorder :   C linical

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50. BODY DYSMORPHIC DISORDER N E URO BI OLOGY A ND GENET I CS

Jamie D. Feusner, MD and Danyale McCurdy-​McKinnon, PhD

B

ody dysmorphic disorder (BDD) is an often-​serious psychiatric disorder characterized by a preoccupation with perceived flaws in one’s appearance that are minor or imperceptible to others (see ­chapter 49). The disorder is often very distressing and is associated with disability, marked functional impairment, social isolation, depression, and suicidal ideation, with approximately one-​ quarter of those with BDD attempting suicide in their lifetime (Phillips et  al., 2005). The morbidity and mortality of BDD highlight the importance of developing a better understanding of this illness. The etiology and pathophysiology of BDD are undoubtedly complex. Neurobiological factors likely contribute to developmental risk and maintenance of BDD symptoms. Although neurobiological research in BDD is still in its infancy, there are important early clues to be gleaned from the studies that have been published, which may help inform understanding of BDD’s pathophysiology and etiology. This chapter explores the research findings regarding visual processing abnormalities, neurocircuitry, and genetics of BDD. It summarizes studies of visual processing, suggesting disturbances in visual perception, with possible influences from aberrant frontostriatal systems. These abnormalities may contribute to imbalances in local versus global visuospatial information processing, characterized by a heightened attention to detail (local) and impairment in holistic (global) assessment. Local or detailed processing refers to attending to an image in a piecemeal manner. Global or holistic processing refers to viewing an image as a whole and thereby capturing the “big picture”—​that is, the “forest” rather than the “trees.” This chapter then examines evidence of aberrant brain circuitry by synthesizing studies of white matter integrity, structural connectivity, and morphometry (regional brain volumes and cortical thickness).

Also reviewed is the evidence that the susceptibility for BDD may be heritable, and there may be shared genetic factors among the obsessive-​compulsive and related disorders (OCRDs), of which BDD is a member, as a group. A model is then proposed that posits an interaction whereby genetic/​ biological factors and environmental events contribute to the development of BDD (Feusner, Neziroglu, Wilhelm, Mancusi, & Bohon, 2010). This model suggests that more distal genetic and environmental causative factors might contribute to the more proximal factors. Proximal factors include neurobiological imbalances in global versus local visual processing that may influence perceptual distortions and other information processing biases, along with frontostriatal abnormalities that have been tied to obsessive thoughts and repetitive behaviors observed in BDD. V IS U AL PROC E S S ING Abnormal visual information processing is probably the best-​studied neurobiological abnormality associated with BDD. Individuals with BDD experience distortions of self-​perception and appearance. Consequently, they are preoccupied with perceived physical defects, convinced of disfigurement and ugliness, and often have poor insight or even delusional BDD-​related beliefs. These clinical features, along with studies showing impaired performance on tasks pertaining to detailed and global design features, suggest possible disturbances in visual perception and visuospatial information processing. The majority of these studies provide evidence of aberrant global visual processing, with some also demonstrating enhanced local processing.

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Imbalance between local (detail) and global (holistic) processing has been observed in a number of visuospatial and psychophysical studies of BDD. Most of the research suggests enhanced processing of local/​detailed visual information, with some also providing evidence for impaired global/​spatial processing.

Rey-​Osterrieth Complex Figure Test The Rey Osterreith Complex Figure Test is a test of visuospatial construction and memory, in which subjects view a complex figure, copy it, and then reconstruct if from memory. Individuals with BDD (n = 17) performed worse than healthy controls (n = 17) at this task (Deckersbach et al., 2000). The differences on the free recall portion of the test were mediated by deficits in organizational strategies: The BDD group recalled primarily tiny details of the figure instead of larger organizational features (e.g., a large square). This may be due to abnormalities in executive functioning (mediated by frontostriatal systems), which is consistent with findings from morphometric and functional imaging studies reviewed later. Poorer performance in the BDD group may reflect low-​level perceptual abnormalities in global or local visual processing or higher-​level abnormalities in selective attention. A different study did not find abnormalities in the BDD group (n = 14) compared with healthy controls (n = 24) (Hanes, 1998), or in the clinical comparison OCD group (n = 10), which is inconsistent with other previous studies in OCD. Further study will be needed to clarify this discrepancy.

Inverted Faces Task The inverted faces task consists of viewing sets of upright and inverted (upside-​down) faces. Typically, recognition of inverted faces is less accurate and slower. This “face inversion effect” is thought to be due to the fact that humans have a holistic template for normal faces (that is, a preestablished mechanism for recognizing the whole face all at one time), but not for inverted ones (Farah, Tanaka, & Drain, 1995), presumably because inverted faces are not typically encountered in the natural environment. Recognition of inverted faces thus relies on detail-​oriented processing, whereas more efficient holistic processing can be used for upright faces. In one study, the inversion effect on response time was less in individuals with BDD (n = 18) than in control 558

participants (n = 17), for long stimulus presentation time (5,000 ms; Feusner, Moller, et al., 2010). Processing of inverted faces was faster in BDD than in healthy controls. This implies that individuals with BDD may engage in more detailed processing of faces, regardless of the orientation, and thus be less impaired by face inversion. Of note, this effect was not observed at a shorter viewing time. Short ​duration stimuli may provide insufficient time to process details, permitting only global processing. Individuals with BDD typically spend long periods of time viewing their perceived flaws in reflective surfaces, allowing ample encoding and examination of visual detail. A similar study using famous faces also found a reduced inversion effect in individuals with BDD (n = 12) relative to healthy controls (n = 16; Jefferies, Laws, & Fineberg, 2012). The duration of stimuli was not specified. A third study found a reduced inversion effect on response time for faces and bodies in individuals with high body image concerns (n = 40) compared with low body image concerns (n = 40), although diagnostic assessment for DSM BDD was not performed (Mundy & Sadusky, 2014). In this third study, stimulus presentation was brief (for 650 ms), although subjects were given up to 7 seconds to respond to the second stimulus; it is unclear why a differential inversion effect was found at brief stimulus presentation in this study but not the early study in BDD patients described previously (Feusner, Moller, et al., 2010).

Embedded Figures Task and Navon Task The embedded figures task examines global-​local processing in the context of matching and extracting simple shapes embedded within complex figures. The Navon task requires participants to search for global or local stimuli while ignoring distractors at the other level (i.e., participants must ignore detailed distractors and focus on the whole picture, or vice versa). Kerwin and colleagues (2014) examined both of these tasks in a cohort of BDD patients (n = 18) and matched controls (n = 17). Individuals with BDD were slower and less accurate than control participants on both tasks. This suggests that individuals with BDD have a generally slowed processing speed when viewing stimuli that contain both global and local elements. On the Navon task, performance was further impaired when participants were required to shift their attention between detailed and global aspects of the stimuli. Interestingly, those with poorer BDD-​related insight tended to be slower on both tasks. They also had O b sessive - C ompulsive D isorder

 

higher error rates under several conditions in the Navon task. This relationship between poorer insight, assessed dimensionally, and abnormal visuospatial perception suggests a model in which visual processing deficits in BDD may make patients less able to refute what they perceive, which may contribute to poor or absent insight. The Navon task findings of poorer performance for set-​ shifting (the process of updating and shifting cognitive strategies in response to environmental changes) could additionally be an indication of impairment in frontostriatal systems.

Aberrant Flaw Detection The ability to detect asymmetry or flaws in facial features is another aspect of visual processing that has been specifically investigated in BDD. Individuals with BDD (n = 10) or OCD (n = 10) were more apt to perceive distortions in images of their own faces that were not actually present, compared to healthy controls (n = 10; Yaryura-​Tobias et al., 2002). Another study by Reese and colleagues (Reese, McNally, & Wilhelm, 2010) investigated the ability to detect asymmetry in others’ faces; those with BDD (n = 20) were no more likely than healthy controls (n = 20) to detect differences in facial symmetry, suggesting that the abnormality in BDD might be specific to subjects’ own faces. However, a third study by Stangier and colleagues (Stangier, Adam-​ Schwebe, Muller, & Wolter, 2008) determined that individuals with BDD (n = 21) were more accurate in detecting changes in aesthetic features of others’ faces, as compared with two different control conditions (19 patients with disfiguring dermatological conditions and 20 patients with non-​disfiguring dermatological disorders). Those with BDD may perform better than controls due to their enhanced focus on processing visual details. An important difference between these two experiments is that Stangier et  al. (2008) asked subjects to identify changes in facial details, whereas Reese et  al. (2010) asked them to assess facial symmetry, which is likely to engage configural processing. One explanation for the discrepancy between these two studies is that those with BDD may be able to engage configural processing when prompted, although they may not in more naturalistic situations. Integrating these various results is challenging, given the different tasks, the variable time durations, the use of own or others’ face stimuli, and the various endpoint measures. Nevertheless, it seems safe to conclude that heightened detail processing is a likely feature in those with BDD. Body D ysmorphic D isorder :   N euro b iology and G enetics

Identity Recognition of Faces with Emotional Expressions In another facial recognition task, individuals with BDD (n = 12) displayed poor recognition of faces with emotional expressions, compared with healthy controls (n = 11; Feusner, Bystritsky, Hellemann, & Bookheimer, 2010). Poor performance among BDD participants did not depend on the valence of emotional expression: Both positive (e.g., happy) and negative (e.g., angry) expressions resulted in poorer performance. This could be related to an impairment in global visual processing, which may otherwise facilitate identity recognition irrespective of the local facial changes produced by emotional expressions.

Additional Studies of Global Processing of Visual Information Although enhanced detail-​oriented visual processing in BDD is a fairly consistent finding, investigations of global processing have produced more variable results. For example, whereas the emotional faces effect described can be interpreted to suggest a deficit in global processing, another study (n  =  14 BDD and 14 healthy controls) found no abnormalities on the contour integration task, which tests global integration of visual stimuli (Rossell, Labuschagne, Dunai, Kyrios, & Castle, 2014). In the composite face task, tops and bottoms of different faces are presented together, either aligned such that they form a novel composite face, or mis-​aligned. The “composite face effect” refers to the fact that it is generally more difficult to match top halves of faces when they are aligned with mismatched bottom halves than when they are misaligned. Aligned composite faces are processed holistically, as they invoke a facial template; misaligned faces presumably recruit this template less effectively. Individuals who have a deficit in global/​holistic processing are expected to exhibit less of a composite face effect. Monzani and colleagues found no differences between BDD (n = 25) and healthy controls (n = 25) in three tasks of holistic processing: composite faces, face inversion, and the Navon task (Monzani, Krebs, Anson, Veale, & Mataix-​ Cols, 2013). However, the Navon task was administered differently than in the Kerwin et al. (2014) study, which did find a deficit, in that participants were told to focus on the global or local targets before each block, so they were not required to flexibly shift between the two. It is possible that the deficit described by Kerwin et al. relates to difficulty with set shifting, which has been associated with the frontostriatal system (Kerwin et al., 2014). In addition, 559

 

Monzani et al. (2013) presented stimuli for shorter durations; longer exposure to stimuli in the study of Kerwin et al. may have allowed patients enough time to engage more detailed processing, whereas shorter stimulus presentation may permit only holistic processing (a similar point was noted in relation to studies of face processing; Feusner, Moller, et al., 2010). This explanation, however, does not seem to converge with the findings of Stangier et al. (2008) who found that individuals with BDD were more accurate in detecting changes in physical features of others’ faces even after a very short stimulus exposure (200 ms). Other differences in stimuli and other aspects of the methodology hinder comparisons across studies. In addition, all studies had relatively small sample sizes, which raises the possibility of Type II error. NEUROIMAGING STUDIES

A series of studies have used functional neuroimaging to examine the brain correlates of these visual processing abnormalities in BDD. Feusner and colleagues conducted the first functional neuroimaging study examining visual perception in BDD by assessing brain activation during visual processing of others’ faces (Feusner, Townsend, Bystritsky, & Bookheimer, 2007). Participants (n = 12 BDD and 13 healthy controls) underwent functional magnetic resonance imaging (fMRI) while matching photographs of others people’s faces. Some of the faces were digitally altered to remove the high or low spatial frequencies, which created images that contained only low detail (low spatial frequency) or high detail (high spatial frequency) information, respectively (Figure 50.1). Patients exhibited left hemisphere hyperactivity in an extended face-​processing network when processing both normal and low spatial frequency images. This differed from the right hemisphere-​dominant pattern that healthy

controls exhibited, and has been previously described (Haxby et  al., 1994). Controls, as expected, engaged the left hemisphere only when the faces contained only high frequency detail. The recruitment of this detail-​processing circuitry in BDD patients even for low detail faces suggests that their brains may have been attempting to extract high-​ frequency details, even when they are not present in the stimulus. This fits with the clinical observation that BDD patients attempt to extract minute details of appearance “flaws” even though these may not be apparent to others. The BDD participants also displayed abnormally high activation of the amygdala for both the low and high spatial frequency images, compared with the control group. As the amygdala mediates fear responses, as well as other types of emotional arousal, this suggests an aberrant, heightened emotional response in BDD for images that contain low and high levels of detail. A second study by Feusner and colleagues (Feusner, Moody, et al., 2010) utilized fMRI to study own-​face processing in BDD. In this study, participants (n = 17 BDD and 16 healthy controls) viewed their own faces and the faces of another person while being scanned. Abnormal hypoactivity was found in patients in the visual cortex—​ striate and extrastriate regions—​for low spatial frequency images but not for high spatial frequency images, which points specifically to diminished global and configural processing. Similar abnormal hypoactivity for low spatial frequency images was also evident for the control task of viewing others’ faces. This study included a different task than in the previous study (naturalistic viewing vs. a matching task), which precludes a direct comparison. Taken together the two studies provide evidence of imbalances in global vs. local visual processing. In addition, BDD participants showed abnormal hyperactivity in frontostriatal systems (OFC and caudate) when viewing unaltered own-​face images. BDD symptom severity,

Figure 50.1  Example of an unaltered image (left), a digitally altered image that contains only high spatial frequency (middle), and a digitally altered image

that contains only low spatial frequency information (right).

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measured using the Yale–​Brown Obsessive–​Compulsive Disorder Scale Modified for BDD (Phillips et al., 1997), was positively correlated with increased frontostriatal activity and negatively correlated with activity in extrastriate visual cortex. This study offers preliminary evidence of aberrant orbitofrontal-​striatal circuit activity in BDD, similar to that seen in OCD (see c­ hapter 21; Rotge et al., 2008). Increased activity in OFC and caudate could be related to the obsessive thoughts and compulsive behaviors that characterize both BDD and OCD. Moreover, although the BDD group rated the viewing of their own faces as highly aversive, they did not demonstrate corresponding greater amygdala or insula activity while viewing their own faces; this could be considered an abnormal lack of limbic reactivity. Rather, aversiveness was inversely related to brain activity in visual regions, and when aversiveness was controlled for, it explained activity in frontostriatal regions. Together with the previous study, this suggests that the limbic system in BDD is differently activated depending on whether a patient is viewing his or her own or another person’s face. A secondary analysis of the Feusner et al. study (Feusner, Moody, et al., 2010) focused on relationships between anxiety and activity in limbic and visual systems, especially the ventral visual stream, which is a key set of regions involved in image recognition (for example, recognizing that an image is a face or a body) and to the processing of fine details (for example the texture and color of the skin; Bohon, Hembacher, Moller, Moody, & Feusner, 2012). BDD participants (n = 17 BDD and 16 healthy controls) showed a trend nonlinear positive relationship between anxiety and activity in the right ventral visual stream and a linear positive relationship between anxiety and activity in the left ventral visual stream. This relationship was stronger for own-​face stimuli than for familiar-​face stimuli. These findings suggest a relationship between anxiety and activity in visual processing systems in BDD, especially in regard to oneself. In addition, in both BDD and healthy controls, activity in the amygdala was positively associated with activity in ventral visual stream. Signals from the amygdala related to emotional arousal (e.g., anxiety) may enhance ventral visual stream activity, and thereby enhance processing of visual details. Anxiety may thus increase the already heightened perceptual distortions present in BDD. These studies utilized appearance-​related stimuli (faces). It is important to examine whether or not individuals with BDD exhibit abnormal visual processing for other objects as well. The same research group examined visual processing in BDD for non–​appearance-​related stimuli, using fMRI (Feusner, Hembacher, Moller, & Moody, 2011). BDD participants (n = 14) and healthy controls (n = 14) Body D ysmorphic D isorder :   N euro b iology and G enetics

were scanned while they matched photographs of houses that were normal, or contained only high spatial frequency (high detail) or low spatial frequency (low detail) information. The BDD group displayed abnormal hypoactivity in higher order visual processing systems (lingual gyrus, parahippocampal place area, and precuneus) for low spatial frequency images, suggesting global processing deficiencies. These results provide evidence for abnormal global and holistic processing for non–​appearance-​related stimuli, suggesting a more general abnormality in visual processing that extends beyond the processing of individual appearance. A more recent study from the same group examined BDD in relationship to anorexia nervosa (AN; Li et al., 2015). This was the first study to directly compare the neurobiology of BDD to that of AN, which shares many clinical features. Participants (n = 15 BDD, n = 15 AN, n = 15 healthy controls) viewed appearance-​related (faces) and non–​appearance-​related (houses) images while undergoing fMRI and electroencephalography (EEG), in separate sessions. EEG allows characterization of fast-​changing neuronal dynamics with a time resolution in milliseconds; however, it has limited spatial resolution. FMRI has the capability to localize neural activity with higher spatial but lower temporal resolution; thus, the combination of the two provides more precise estimation of both when and where task-​related brain activity is occurring. The analyses were focused on early EEG signals. Both AN and BDD participants displayed hypoactivity in dorsal visual stream systems for low spatial frequency faces, and in early extrastriate regions for low spatial frequency houses. This suggests that a common deficiency in holistic processing is operating early in the visual processing stream and extends later in time into the dorsal higher-​order processing regions. The patterns were not exactly the same in both groups. First, BDD displayed hypoactivity in dorsal visual regions for low spatial frequency faces in comparison with those with AN. Second, BDD but not AN demonstrated hyperactivity when compared with controls in ventral visual stream systems for high spatial frequency houses. Interestingly, activity in this EEG component was correlated with lower attractiveness ratings of others’ face. The latter finding supports the interpretation that enhanced detail processing in BDD may lead to a greater likelihood of flaw detection. This study provides initial evidence of a general pathological visual processing phenotype in both BDD and AN. The nature of the deficit may be slightly different in the two disorders: Abnormalities for low spatial frequency stimuli were more prominent in BDD than in AN, and hyperactivity in the ventral visual stream for high spatial frequency stimuli was seen in BDD but not in AN. 561

 

Taken together, these neuroimaging studies of visual processing point toward deficiencies in global and configural visual processing in the dorsal visual stream in BDD, with the first and the most recent (Feusner et al., 2007; Li et al., 2015) also suggesting enhanced local (detailed) processing in the ventral visual stream. The dorsal visual stream, in general, is responsible for configural (e.g., relative positions of facial features and distance between features) and global (holistic processing of features into a gestalt) visual processing (Goodale & Milner, 1992; Maurer, Grand, & Mondloch, 2002; Tanaka & Farah, 1993). The ventral visual stream, on the other hand, is responsible for detailed visual processing (also known as featural, or local part-​ based, or fragmented-​based processing) and is involved in detection, for example, of visual elements such as skin pores or lines (Bartlett, Searcy, & Abdi, 2003; Goodale & Milner, 1992; Schwaninger, Lobmaier, & Collishaw, 2002) (Figure 50.2). Imbalances between global and local processing in BDD could contribute to visual misperception, such that details are not adequately integrated and contextualized into a whole. This may result in an overall heightened ability to detect “flaws” and inability to determine that most of these “flaws” are, generally, minuscule relative to the whole. Moreover, there is evidence of frontostriatal hyperactivity specifically triggered by an individual viewing her or his own face; similar to that seen upon symptom provocation in OCD (see ­chapter 21). Finally, there is early indication of abnormal limbic (amygdala) activity associated with visual processing, suggesting differences in emotional salience of certain visual stimuli, aberrant emotional reactivity to visual stimuli, and/​or impaired visual-​emotional integration.

Figure 50.2  The dorsal visual stream (blue) in general is responsible for

global and configural visual processing and the ventral visual stream (orange) is responsible for detailed or piecemeal visual processing.

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B R AIN C IR C U IT R Y STRUCTURAL CONNECTIVITY

Understanding abnormalities in brain connectivity may help elucidate the neural bases BDD. Very few studies thus far in BDD have examined brain white matter integrity, connectivity, and organization; however, the findings to date are interesting. The first diffusion tensor imaging (DTI) study to examine white matter in BDD, conducted by Feusner and colleagues, found no significant differences in white matter integrity (n = 14 BDD and 16 healthy controls), but did find correlations between fiber disorganization and poorer BDD-​related insight (on the Brown Assessment of Beliefs Scale) in the inferior longitudinal fasciculus and the forceps major (Feusner et al., 2013). The inferior longitudinal fasciculus connects anterior temporal lobe and occipital cortex, and the forceps major connects right and left occipital cortex. Thus, these results suggest that poor insight is associated with fiber disorganization in the white matter tracts that facilitate communication within the visual cortex and between visual and emotion/​memory systems. This may lead to poorer integration of information between these brain regions. Another DTI study found reductions in white matter integrity in BDD (n = 20) individuals compared with healthy controls (n = 20) bilaterally in the corpus callosum, superior longitudinal fasciculus, and inferior fronto-​occipital fasciculus (Buchanan et al., 2013). These widespread findings suggest that abnormal myelination in many parts of the brain during neurodevelopment may predispose certain people to BDD. Importantly, causality cannot be inferred from these data; symptoms could produce these structural brain abnormalities over time. Differences between these two DTI studies could be due to differences in methodology, including the fact that in the Feusner et al. (2013) study the participants were all unmedicated, whereas in the Buchanan et al. (2013) study the majority were medicated. Medications may alter white matter diffusion properties; alternatively, those who are medicated may represent a clinically more severe cohort who may have had more severe disturbances in white matter. In addition, the former study had a smaller sample size than the latter, which raises the possibility of Type II error. Larger studies are needed. Another study examined structural brain network organization in BDD (n = 14 BDD and 16 healthy controls) (Arienzo et al., 2013b), using a graph-​theoretical approach

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to better understand structural brain connectivity (see ­chapter 24). It found globally abnormal white matter network organization in BDD, with more highly clustered local connections (i.e., a larger clustering coefficient). This may imply higher local information transfer, which may lead to slower information processing, require higher computational “cost,” and may lead to less synchronization across distant regions (Watts & Strogatz, 1998). Individuals with more severe BDD symptoms had less efficiently organized white matter brain connectivity patterns that were unable to maximize both segregation of local connections and integration across long distance connections. BDD individuals also displayed relatively higher network connectivity (“edge betweenness centrality”) between the occipital poles, as well as between anterior temporal and occipital regions, suggesting that information passing between these regions may exert more influence on overall network functioning. This suggests that the brains of individuals with BDD are more dominated by processing of visual stimuli. Overall, this structural connectivity study implicates an aberrant neural network in BDD that may be linked to cognitive, perceptual, and emotional processing deficiencies. Its relationship to the findings in the DTI study are unclear, however, as the DTI studies were designed to examine fiber integrity and organization of individual white matter tracts, rather than the overall pattern of network organization. MORPHOMETRY

Studies of brain morphometry in BDD have been somewhat inconsistent. A small early study found greater total white matter volume and a leftward shift in caudate asymmetry in females with BDD (n = 8) compared with healthy controls (n = 8) (Rauch et al., 2003). A study of males with BDD (n = 12 BDD, 12 controls) also found greater total white matter, as well as smaller anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) volumes, and a trend for larger thalamic volumes (Atmaca et al., 2010). Another volumetric study in BDD (n = 20 BDD and 20 healthy controls) (Buchanan et al., 2014) found reduced volumes in the right OFC and left ACC. However, another study did not find any volumetric differences between groups (Madsen et al., 2015). The largest morphometric study to date included 49 BDD participants and 44 healthy controls, all unmedicated (Madsen et al., 2015). This study examined brain volumes and cortical thickness using whole-​brain voxel-​wise and vertex-​wise approaches, respectively. It additionally used a region-​of-​interest approach for thickness and volumes,

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specifically focusing on frontostriatal regions implicated in the earlier morphometric studies as well as visual regions implicated in visual processing studies. Unlike the previous studies, this larger study found no significant volumetric or cortical thickness differences between BDD and healthy control participants. Several of these morphometric studies found associations between regional brain volumes and symptom severity. Feusner and colleagues (2009) found that symptom severity positively correlated with volumes of the left inferior frontal gyrus and the right amygdala. On the other hand, the Buchanan et al. (Buchanan et al., 2014) study found a negative correlation between left amygdala volume and symptom severity (with a trend for negative correlation in the right amygdala), and a negative correlation between illness duration and right OFC volume. These discrepancies may be due to methodological differences between the two studies. The latter study had a larger sample, but most subjects were medicated; the former had a smaller, unmedicated sample. In the large cortical thickness and volumetric study (Madsen et al., 2015), there were significant associations between anxiety and thinner gray matter in the left superior temporal cortex, which may relate to functional abnormalities also reported in this region (Feusner et al., 2007), and greater gray matter volume in the right caudate nucleus, similarly to what has been reported in OCD (Whiteside, Port, & Abramowitz, 2004). BDD, like all psychiatric disorders, is heterogeneous; correlational analyses such as these may best reveal pathophysiology, though more work is needed. To summarize, although the results of morphometric studies in BDD are discrepant, the largest study to date did not find any significant abnormalities in brain volume or cortical thickness in BDD. However, correlations with symptomatology suggest that certain morphometric anomalies in BDD may be associated with clinical symptoms. Overall, there are still few studies in BDD, and even the largest one to date may have been underpowered to detect subtle abnormalities. Future, larger studies, and the accumulation of additional studies from which to conduct meta-​analyses, will provide more definitive conclusions about brain morphometry in BDD. NE U ROC H E MIS T R Y Disturbances in the serotonin neurotransmitter system have been implicated in multiple OCRDs (Fornaro et al., 2009; see c­ hapter 25). There is limited evidence for a role

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for serotonin in BDD. Both controlled and uncontrolled studies have found that serotonin reuptake inhibitor (SRI) medications are effective treatments many with BDD (see ­chapter 49) (Allen et al., 2008; Ipser, 2010; Phillips & Hollander, 2008), although the mechanisms of this effect are unclear. A case study in which BDD symptoms were exacerbated during dietary depletion of tryptophan (the precursor to serotonin; Barr, Goodman, & Price, 1992) bolsters the argument for a role of serotonin in the pathophysiology of BDD. Another case study found that psilocybin, a serotonin agonist, decreased BDD symptomatology (Hanes, 1996). Preliminary genetic work, described later, suggests that a polymorphism in the serotonin transporter, the target of the SRIs, may contribute to BDD risk. Reduced drug binding to this transporter has been reported in OCD (n = 20) and in a group of patients with OCD related and impulse-​control disorders (n = 23, including 6 with BDD) relative to healthy controls (n = 20; Marazziti, Dell’Osso, & Presta, 1999). Other neurotransmitter systems, including GABA, may also contribute to BDD. The GABA (A)-​gamma-​2 1A allele has been associated with BDD in a preliminary study (see Heritability and Genetics). The antiepileptic medication levetiracetam, which enhances GABA’s effects, showed some benefit for BDD in a small proof-​of-​concept study in BDD (Phillips & Menard, 2009). Overall, however, all of these studies are small and preliminary; much more work is needed to clarify the neurochemical contributors to BDD pathophysiology. HER ITA BIL ITY AN D G EN ETI CS Genetic studies of BDD are in their infancy. Approximately 8% of those with BDD have a family member with BDD, which is four times the prevalence in the general population (Bienvenu et al., 2000). Seven percent of BDD patients have a first-​degree relative with OCD (Phillips, Gunderson, Mallya, McElroy, & Carter, 1998), which is elevated compared with the prevalence of OCD in the general population (about 2%). Another study found that there is a sixfold higher lifetime prevalence of BDD in first-​degree relatives of OCD probands, compared with family members of controls (Bienvenu et  al., 2000). These studies suggest genetic liability for BDD and common heritability in BDD and OCD. Twin studies can better isolate genetic from environmental factors in disease familiality. A twin study of females that assessed “dysmorphic concerns” using a self-​report

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measure found that genetic factors accounted for roughly 44% of the variance of dysmorphic concerns (a construct that is similar to BDD but additionally includes items about body odor and body malfunction; Monzani et al., 2011). The same researchers found in a separate twin sample that up to 64% of the covariation between body dysmorphic and obsessive-​compulsive traits was accounted for by common genetic factors (Monzani et al., 2012). A recent twin study used a multivariate model to examine shared and distinct genetic and environmental risk factors among the OCRDs (Monzani, Rijsdijk, Harris, & Mataix-​Cols, 2014). Heritability was moderate for all of the OCRDs, ranging from 31.6% to 51.1%, with nonshared environment accounting for the rest of the variance. Cooccurrence of OCRDs was best explained by a two-​ factor model. The first latent factor that is largely influenced by genes, had significant loadings on all five OCRDs, but most strongly on OCD, BDD, and hoarding disorder. The second latent factor was specific to trichotillomania and excoriation disorder. These results suggest that the more “cognitive” OCRDs (OCD, BDD, and hoarding disorder) are more closely genetically related, whereas the “body-​ focused repetitive behavior” OCRDs (trichotillomania and excoriation disorder) have additional genetic risk factors. One preliminary study has been conducted using candidate genes in BDD; such candidate gene studies have proven notoriously unreliable in psychiatric genetics but nevertheless deserve mention. An association was reported with the GABA (A)-​gamma-​2 1A allele, although the association did not survive correction for multiple testing (Phillips et al., 2015). A weaker, trend-​level association was also reported with well-​characterized alleles in the promoter of the serotonin transporter (5-​HTTLPR, considering the triallelic structure of this locus), with the s/​s genotype occurring more frequently in BDD participants than in controls. It can be concluded that BDD, like the other OCRDs, is partially heritable. There may be shared genetic factors among the OCRDs, which helps explain their similar phenomenology and/​or frequent co-​occurrence. Much more research is needed to identify specific risk alleles. C ONC LU S IONS AND A PR E LIMINAR Y  MODE L BDD is complex. Heritable factors related to visual processing and obsessive-​compulsive traits, as well as other neurobiological predispositions, may combine with early

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environmental factors to lead to the development of BDD. The behavioral and brain imaging data summarized suggest that abnormalities in the visual processing system are likely to be central to pathophysiology:  A  focus on details in visual processing is seen for both face and nonface stimuli, coupled (in some studies) with a deficiency in more global or holistic visual processing. These observations can be integrated into a tentative explanatory model. Diminished global/​configural processing of visual information may provide an initial distorted precept. The distorted precept is fed to higher levels of information processing in the prefrontal cortex, where it is processed by aberrant frontostriatal systems (involving OFC and caudate). This results in difficulty flexibly shifting attention; consequently, an individual perseverates on the originally misperceived defects. Aberrant frontostriatal systems may also contribute to obsessive thoughts and urges to engage in compulsive behaviors related to these misperceived defects. Impairments in efficient transfer of information across the brain and greater-​than-​normal influence of connections between visual and emotional systems (Arienzo et al., 2013a) may impair integration of new information that would otherwise disconfirm distorted perception. This process may further contribute to poor insight, as patients are unable to refute what they “see.” Current data do not permit clear conclusions as to which of these pathophysiological features is etiological and which develop over time as a consequence of symptoms. Identification of risk factors and early etiological events would be especially clinically relevant, as they may enable early intervention and prevention strategies. New studies are imperative to identify biological targets that can assist in the empirical development of better treatments for this debilitating disorder.

R EF ERENCES Allen, A., Hadley, S. J., Kaplan, A., Simeon, D., Friedberg, J., Priday, L.,  .  .  .  Hollander, E. (2008). An open-​label trial of venlafaxine in body dysmorphic disorder. CNS Spectrums, 13(2), 138–​144. Arienzo, D., Leow, A., Brown, J. A., Zhan, L., Gadelkarim, J., Hovav, S., & Feusner, J. D. (2013a). Abnormal brain network organization in body dysmorphic disorder. Neuropsychopharmacology, 38(6), 1130–​1139. Arienzo, D., Leow, A., Brown, J. A., Zhan, L., Gadelkarim, J., Hovav, S., & Feusner, J. D. (2013b). Abnormal brain network organization in body dysmorphic disorder. Neuropsychopharmacology, 38(6), 1130–​1139. Atmaca, M., Bingol, I., Aydin, A., Yildirim, H., Okur, I., Yildirim, M. A.,  .  .  .  Gurok, M. G. (2010). Brain morphology of patients with body dysmorphic disorder. Journal of Affective Disorders, 123(1-​3), 258–​263.

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Barr, L., Goodman, W., & Price, L. (1992). Acute exacerbation of body dysmorphic disorder during tryptophan depletion. The Americal Journal of Psychiatry, 149(10), 1406–​1407. Bartlett, J., Searcy, J., & Abdi, H. (2003). What are the routes to face recognition? In M. A. Peterson & G. Rhodes (Eds.), Perception of faces, objects, and scenes:  analytic and holistic processes (pp. 21–​52). Oxford: Oxford University Press. Bienvenu, O., Samuels, J., Riddle, M., Hoehn-​Saric, R., Liang, K., Cullen, B., . . . Nestadt, G. (2000). The relationship of obsessive-​compulsive disorder to possible spectrum disorders: Results from a family study. Biological Psychiatry, 48(4), 287–​293. Bohon, C., Hembacher, E., Moller, H., Moody, T. D., & Feusner, J. D. (2012). Nonlinear relationships between anxiety and visual processing of own and others’ faces in body dysmorphic disorder. Psychiatry Research, 204(2-​3), 132–​139. Buchanan, B., Rossell, S., Maller, J. J., Toh, W. L., Brennan, S., & Castle, D. (2014). Regional brain volumes in body dysmorphic disorder compared to controls. The Australian and New Zealand Journal of Psychiatry, 48(7), 654–​662. Buchanan, B. G., Rossell, S. L., Maller, J. J., Toh, W. L., Brennan, S., & Castle, D. J. (2013). Brain connectivity in body dysmorphic disorder compared with controls:  A  diffusion tensor imaging study. Psychological Medicine, 43(12), 2513–​2521. doi:  10.1017/​ s0033291713000421 Deckersbach, T., Savage, C., Phillips, K., Wilhelm, S., Buhlmann, U., Rauch, S.,  .  .  .  Jenike, M. (2000). Characteristics of memory dysfunction in body dysmorphic disorder. Journal of the International Neuropsychological Society, 6(6), 673–​681. Farah, M. J., Tanaka, J. W., & Drain, H. M. (1995). What causes the face inversion effect? Journal of Experimental Psychology. Human Perception and Performance, 21(3), 628–​634. Feusner, J. D., Arienzo, D., Li, W., Zhan, L., Gadelkarim, J., Thompson, P. M., & Leow, A. D. (2013). White matter microstructure in body dysmorphic disorder and its clinical correlates. Psychiatry Research, 211(2), 132–​140. Feusner, J. D., Bystritsky, A., Hellemann, G., & Bookheimer, S. (2010). Impaired identity recognition of faces with emotional expressions in body dysmorphic disorder. Psychiatry Research, 179(3), 318–​323. Feusner, J. D., Hembacher, E., Moller, H., & Moody, T. D. (2011). Abnormalities of object visual processing in body dysmorphic disorder. Psychological Medicine, 41(11), 2385–​2397. Feusner, J. D., Moller, H., Altstein, L., Sugar, C., Bookheimer, S., Yoon, J., & Hembacher, E. (2010). Inverted face processing in body dysmorphic disorder. Journal of Psychiatric Research, 44(15), 1088–​1094. Feusner, J. D., Moody, T., Townsend, J., McKinley, M., Hembacher, E., Moller, H., & Bookheimer, S. (2010). Abnormalities of visual processing and frontostriatal systems in body dysmorphic disorder. Archives of General Psychiatry, 67(2), 197–​205. Feusner, J. D., Neziroglu, F., Wilhelm, S., Mancusi, L., & Bohon, C. (2010). What causes BDD: Research findings and a proposed model. Psychiatry Annals, 40(7), 349–​355. Feusner, J. D., Townsend, J., Bystritsky, A., & Bookheimer, S. (2007). Visual information processing of faces in body dysmorphic disorder. Archives of General Psychiatry, 64(12), 1417–​1425. Feusner, J. D., Townsend, J., Bystritsky, A., McKinley, M., Moller, H., & Bookheimer, S. (2009). Regional brain volumes and symptom severity in body dysmorphic disorder. Psychiatry Research, 172(2), 161–​167. Fornaro, M., Gabrielli, F., Albano, C., Fornaro, S., Rizzato, S., Mattei, C.,  .  .  .  Fornaro, P. (2009). Obsessive-​compulsive disorder and related disorders:  A  comprehensive survey. Annals of General Psychiatry, 8, 13. Goodale, M. A., & Milner, A. D. (1992). Separate visual pathways for perception and action. Trends in Neurosciences, 15(1), 20–​25. Hanes, K. (1996). Serotonin, psilocybin, and body dysmorphic disorder:  A  case report. Journal of Clinical Psychopharmacology, 16(2), 188–​189.

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Hanes, K. (1998). Neuropsychological performance in body dysmorphic disorder. Journal of the International Neuropsychological Society, 4(2), 167–​171. Haxby, J. V., Horwitz, B., Ungerleider, L. G., Maisog, J. M., Pietrini, P., & Grady, C. L. (1994). The functional organization of human extrastriate cortex: A PET-​rCBF study of selective attention to faces and locations. Journal of Neuroscience, 14(11 Pt 1), 6336–​6353. Ipser, J. C., Sander, C., & Stein, D. J. (2009). Pharmacotherapy and psychotherapy for body dysmorphic disorder. Cochrane Database of Systematic Reviews, 2009(1), CD005332. Jefferies, K., Laws, K. R., & Fineberg, N. A. (2012). Superior face recognition in body dysmorphic disorder. Journal of Obsessive-​Compulsive and Related Disorders, 1(3), 175–​179. Kerwin, L., Hovav, S., Hellemann, G., & Feusner, J. D. (2014). Impairment in local and global processing and set-​shifting in body dysmorphic disorder. Journal of Psychiatric Research, 57, 41–​50. Li, W., Lai, T. M., Bohon, C., Loo, S. K., McCurdy, D., Strober, M.,  .  .  .  Feusner, J. (2015). Anorexia nervosa and body dysmorphic disorder are associated with abnormalities in processing visual information. Psychological Medicine, 45(10, 2111–​2122. Madsen, S. K., Zai, A., Pirnia, T., Arienzo, D., Zhan, L., Moody, T. D., . . . Feusner, J. D. (2015). Cortical thickness and brain volumetric analysis in body dysmorphic disorder. Psychiatry research, 232(1), 115–​122. Marazziti, D., Dell’Osso, L., & Presta, S. (1999). Platelet [3H]paroxetine binding in patients with OCD-​related disorders. Psychiatry Research, 89(3), 223–​228. Maurer, D., Grand, R. L., & Mondloch, C. J. (2002). The many faces of configural processing. Trends in Cognitive Sciences, 6(6), 255–​260. Monzani, B., Krebs, G., Anson, M., Veale, D., & Mataix-​Cols, D. (2013). Holistic versus detailed visual processing in body dysmorphic disorder: Testing the inversion, composite and global precedence effects. Psychiatry Research, 210(3), 994–​999. Monzani, B., Rijsdijk, F., Anson, M., Iervolino, A. C., Cherkas, L., Spector, T., & Mataix-​Cols, D. (2011). A twin study of body dysmorphic concerns. Psychological Medicine, 1–​7. Monzani, B., Rijsdijk, F., Harris, J., & Mataix-​Cols, D. (2014). The structure of genetic and environmental risk factors for dimensional representations of DSM-​5 obsessive-​compulsive spectrum disorders. JAMA Psychiatry, 71(2), 182–​189. Monzani, B., Rijsdijk, F., Iervolino, A. C., Anson, M., Cherkas, L., & Mataix-​Cols, D. (2012). Evidence for a genetic overlap between body dysmorphic concerns and obsessive-​compulsive symptoms in an adult female community twin sample. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 159b(4), 376–​382. Mundy, E. M., & Sadusky, A. (2014). Abnormalities in visual processing amongst students with body image concerns. Advances in Cognitive Psychology, 10(2), 39–​48. Phillips, K. A., Coles, M. E., Menard, W., Yen, S., Fay, C., & Weisberg, R. B. (2005). Suicidal ideation and suicide attempts in body dysmorphic disorder. Journal of Clinical Psychiatry, 66(6), 717–​725. Phillips, K. A., Gunderson, C. G., Mallya, G., McElroy, S. L., & Carter, W. (1998). A comparison study of body dysmorphic disorder and

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51. TRICHOTILLOMANIA AND SKIN PICKING DISORDER Jon E. Grant, JD, MD, MPH, Sarah A. Redden, BA, and Eric W. Leppink, BA

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richotillomania (hair pulling disorder) is an often debilitating psychiatric condition characterized by recurrent pulling out of one’s own hair, leading to hair loss and marked functional impairment (Christenson et al., 1991b; Woods et al., 2006). Skin picking (excoriation) disorder is characterized by the repetitive and compulsive picking of skin, causing tissue damage (APA, 2013). Trichotillomania and skin picking disorder appear to have substantial clinical and possibly even neurobiological similarities and, based on these similarities, have been described as body-​ focused repetitive behavior disorders (BFRBs; Grant & Stein, 2014). Although both have been discussed in the medical literature for over a century (Chamberlain et al., 2009; Odlaug & Grant, 2012), they have only recently been grouped together in the 5th edition of the Diagnostic and Statistical Manual (DSM-​5; APA, 2013). Trichotillomania was originally included in DSM-​III-​R in 1987 as an impulse control disorder, not classified elsewhere, and remained in that section until DSM-​5, when it was moved to the chapter on obsessive-​compulsive and related disorders. Prior to DSM-​5, skin picking disorder had not been identified as a specific disorder. Although trichotillomania and skin picking may seem like simple behaviors, research has demonstrated that BFRBs are complex disorders (Mansueto & Rogers, 2012). This chapter reviews the clinical, neurobiological, and genetic characteristics of both disorders and then discusses their treatment. TR IC HOTIL LO MAN I A Nationwide epidemiological studies of trichotillomania are lacking, but small studies examining the prevalence of trichotillomania among college students in the United

States, adolescents in Israel, and older adults within the community have found current rates ranging from 0.5% to 2.0% (Christenson et  al., 1991b; Duke et  al., 2009; King et al., 1995). In adults, trichotillomania appears to have a large female preponderance. In childhood, however, sex distribution has been found to be equal (Cohen et al., 1995; King et al., 1995; Lewin et al., 2009). Hair pulling usually begins at a young age (between ages 10 and 13 years old; Christenson, 1995; Szepietowski et al., 2009), and appears to have a similar presentation across cultures (Duke et al., 2010; Woods et al., 2006). Any site may be the focus of pulling, but the scalp is the most common (72.8%) followed by eyebrows (56.4%; Christenson, 1995; Christenson & Mansueto, 1999). Triggers to pull may be sensory (e.g., hair thickness, length, and location, and physical sensations on scalp), emotional (e.g., feeling anxious, bored, tense, or angry), and cognitive (e.g., thoughts about hair and appearance, rigid thinking, and cognitive errors; Christenson, 1995). Many patients report not being fully aware of their pulling behaviors, a phenomenon known as “automatic” pulling; “focused” pulling, in contrast, generally occurs when the patient sees or feels a hair that is “not right,” that the hair may feel coarse, kinky, or “out of place” (Christenson & Mansueto, 1999). Most patients exhibit varying combinations of focused and automatic pulling, which can fluctuate over time. Psychosocial dysfunction, low self-​esteem, and social anxiety are all associated with trichotillomania, largely due to the alopecia resulting from an inability to stop pulling (Diefenbach et al., 2005; Lewin et al., 2009). Even though trichotillomania interferes with a person’s quality of life, the majority (about 65%) of individuals never seek treatment (Diefenbach et al., 2005). Trichotillomania may result in unwanted medical consequences. Pulling of hair can lead to skin damage if sharp instruments, such as tweezers or scissors, are used to pull

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the hairs. Over 20% of patients also eat the hair after pulling it out (“trichophagia”), which can result in gastrointestinal obstruction and the formation of intestinal hair-​balls (“trichobezoars”), requiring surgical intervention in extreme cases (Grant & Odlaug, 2008). S K IN P IC K IN G D I SO RD ER Skin picking disorder (also called excoriation disorder or dermatillomania) is characterized by the repetitive and compulsive picking of the skin, leading to tissue damage. Erasmus Wilson, in 1875, first coined the term “neurotic excoriation” to describe excessive picking behaviors that were extremely difficult, if not impossible, to control in neurotic patients (Odlaug & Grant, 2012). Two community prevalence studies have found that skin picking disorder is fairly common. In the first study, 354 subjects were recruited, and 19 (5.4%) reported significant picking behavior with associated distress, thereby meeting criteria for skin picking disorder (Hayes et  al., 2009). Sixty-​three percent of the subjects engaged in some form of picking behavior. A second study comprised 2,513 interviews using a phone survey and found that 10% picked to the point of having noticeable skin damage that was not attributable to a medical condition (Keuthen et al., 2010). When distress or impairment was required to meet the threshold for diagnosis, 1.4% met criteria for skin picking disorder. The age of onset for skin picking disorder varies substantially and may occur during childhood, adolescence, or adulthood (Arnold et al., 1998, 1999; Bohne et al., 2002; Calikusu et al., 2003; Flessner et al., 2007; Keuthen et al., 2010; Simeon et al., 1997). The clinical description of skin picking disorder appears essentially the same today as it did when first described by Wilson in 1875. In addition, the disorder presents similarly across cultures—​Europe (Bohne et  al., 2002), Africa (Lochner et  al., 2002), North America (Tucker et  al., 2011), South America (Arzeno Ferrao et al., 2006), and the Middle East (Calikusu et al., 2012). Many individuals with skin picking disorder report that the behavior began with the onset of a dermatological condition such as acne, but the picking continued after the dermatological condition remitted. Individuals with skin picking disorder spend a significant amount of time each day picking their skin, with many reporting that the picking behavior occupies several hours each day (Grant et al., 2007; Keuthen et al., 2007; Tucker

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et al., 2011) or, in some cases, is nearly constant (Lochner et  al., 2002). Due to the amount of time spent picking, individuals report missing or being late for work, school, or social activities (Flessner & Woods, 2006). Triggers to pick vary greatly between patients, and multiple triggers are the norm, not the exception. Stress, anxiety, downtime (e.g., sitting on the couch, watching television, reading, etc.), driving a vehicle, boredom, and feeling tired or angry have all been reported as eliciting a picking episode (Arnold et al., 2001; Grant & Christenson, 2007; Neziroglu & Mancebo, 2001; Neziroglu et al., 2008; Simeon et al., 1997). Picking can also be triggered by the feel (e.g., a bump or unevenness) or look (e.g., blemish or discoloration) of the skin. Picking behavior often begins unconsciously and becomes conscious after a period of time (Grant, Odlaug & Kim, 2007; Odlaug & Grant, 2008). This is similar to trichotillomania (Lochner et al., 2002), wherein the action of pulling has been described as either automatic or focused (Christenson & Mansueto, 1999; see earlier). In samples of skin picking patients, the percentage of time they reported being aware of their behavior has been found to range from 68.9% to 78.1% (Odlaug & Grant, 2007, 2008). In many cases, however, the picking behavior only becomes conscious when someone else brings it to their attention or the site begins to bleed. Although the face is the most common site of picking, other areas, such as the hands, fingers, arms, and legs are also common targets. Most individuals with the disorder pick from more than one body area (Odlaug & Grant 2012). In fact, a study of 60 patients with skin picking disorder found that subjects picked from an average of 4.5 sites (Tucker et al., 2011). For many people, a variety of picking lesions are present, ranging from a few to a few hundred (Gupta, Gupta, & Haberman, 1987; Pusey & Senear, 1920). Picking often results in significant tissue damage and may lead to medical complications such as localized infections and septicemia (Lyell, 1972; Neziroglu et  al., 2008; Odlaug & Grant, 2008). The repetitive, excoriative nature of skin picking may even warrant skin grafting (Arnold et al., 1998; Neziroglu et al., 2008; Odlaug & Grant, 2008); one severe reported case resulted in the development of an epidural abscess and paralysis (Weintraub, Robinson, & Newmeyer, 2000). In rare cases, the behavior can be life-​ threatening, as demonstrated by the case report of a gentleman who required bilateral capsulotomies using gamma knife radiosurgery due to his severe, life-​threatening, picking in which multiple medication trials and skin grafting had been unsuccessful (Kondziolka & Hudak, 2008).

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C L INICA L D I FFEREN CES FRO M O CD

& Grant, 2008). A second study of 40 subjects with skin picking disorder found that 43% had a first-​degree relative Although trichotillomania and skin picking disorder are with skin picking (Neziroglu et al., 2008). In a comparison often grouped in the same general category with obsessive between probands with skin picking and those with OCD, compulsive disorder (OCD), there are some striking differ- individuals with skin picking were significantly more likely ences in terms of clinical presentation. First, these behaviors to have at least one first-​degree relative with skin picking, appear to be more common among females, whereas OCD compared with OCD subjects (Grant et al., 2010); this sughas an even sex ratio. Second, both trichotillomania and gests the presence of genetic risk factors unique to groomskin picking disorder may occur in an automatic fashion—​ ing disorders. In a sample of 2,518 twins from the Twins UK adult that is, there may be few if any obsessional thoughts driving the behaviors. In the case of OCD, compulsions without twin registry, clinically significant skin picking was endorsed obsessions is considered extremely rare. Finally, trichotil- by 1.2%, consistent with the prevalence studies summalomania and skin picking disorder often require medical rized above (Monzani et al., 2012). There were significantly monitoring (due to trichobezoars and picking leading to higher correlations between monozygotic (r = 0.42) versus dizygotic (r = 0.09) twin pairs in skin picking severity, suginfection) to a much greater degree than for OCD. gesting a strong genetic influence. Additive and nonadditive genetic factors accounted for slightly more than 40% of the variance in skin picking, with the remaining variance NEUROBIOLO G Y attributable to non-​shared environmental factors (Monzani et al., 2012). ANIMAL MODELS Several family studies have reported elevated rates of Animal models represent potentially useful tools for trichotillomania in first-​degree relatives of probands with investigating the pathophysiology of trichotillomania and trichotillomania, along with elevated rates of mood and skin picking particularly (Geyer & Markou, 1995, 2002; anxiety disorders (Schlosser et al., 1994). In a recent study, Mckinney, 2001). Several models have been described in Keuthen and colleagues found that the relatives of prowhich mice exhibit excessive grooming. Excessive groom- bands with trichotillomania had higher recurrence risk estiing phenotypes in animals have been variably interpreted mates for hair pulling but not for skin picking, suggesting as recapitulating OCD, Tourette syndrome, autism, and distinct risk genes (Keuthen et al., 2014). Heritability estiother conditions, but they have perhaps the best face valid- mates ranging for BFRBs range from 0.32 to 0.78 (Novak ity for grooming disorders (see ­chapter  29). Three mod- et al., 2009; Monzani et al., 2012). To date there have been els in particular exhibit markedly elevated grooming and no large-​scale genetic studies in BFRBs, and no particular neurobiological change that has been interpreted as reca- candidate genes have emerged from human investigations. pitulating OCD-​related disorders:  the HoxB8 knockout mouse (Greer & Capecchi, 2002), the SAPAP3 knock- N E U R O C O G N I T I O N out mouse (Welch et al, 2007), and the SliTrk5 knockout mouse (Shmelkov et al., 2010). These are discussed in detail Neurocognitive research into BRRBs has focused priin ­chapter 33. The potential relevance of SAPAP3, in par- marily on two domains:  motor impulsivity and cognitive ticular, to grooming disorders is reinforced by the finding flexibility. Data to date are mixed, with some evidence that rare variations in the SAPAP3 gene are associated with suggesting different patterns of deficit in skin picking and human grooming disorders such as skin picking and hair trichotillomania. The repetitive physical symptoms of trichotillomania pulling (Bienvenu et al., 2009). and skin picking disorder suggest an underlying dysfunction of motor inhibitory processes. One test of motor inhibition FA M I LY H I S T O R Y A N D G E N E T I C S is the stop signal task, in which subjects are signaled to make Although the data are limited, existing family history data a simple motor response (like pressing a button) but, on a suggest that both trichotillomania and skin picking may subset of trials, receive a second signal indicating that they be familial (Monzani et al., 2014). In a sample of 60 adults should inhibit the already initiated movement. The relative with skin picking disorder, 28.3% of their first-​ degree timing of these two signals can be titrated to determine the family members also had skin picking disorder (Odlaug stop signal reaction time (SSRT; see ­chapter 22).

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In a first study comparing neurocognitive functioning in 20 patients with skin picking disorder and 20 controls (Odlaug, Chamberlain, & Grant, 2010), SSRT was increased in skin pickers, relative to controls, indicating impaired motor inhibition. A  follow-​up study compared 31 subjects with skin picking disorder, 39 with trichotillomania, and 33 controls and similarly found that an SSRT impairment in individuals with skin picking (Grant et al., 2011). Motor inhibition in trichotillomania may be less severely affected. Two studies found that patients with trichotillomania exhibited impaired inhibitory control compared with healthy controls (Chamberlain et al., 2006; Odlaug et al., 2012), but the three-​group study noted earlier (Grant et al., 2011) found patients with trichotillomania to have SSRT intermediate between skin pickers and controls, such that their performance did not differ significantly from either other group. In a separate study using a go/​ no-​go task, another measure of motor inhibitory control, patients with trichotillomania tended to perform either “fast and inaccurate” or “slow and accurate,” and earlier age of trichotillomania onset was significantly associated with worse inhibitory control (Bohne et al., 2008). The rigid, repetitive behaviors observed in trichotillomania and skin picking disorder may reflect problems with cognitive flexibility, or problems adapting behavior to new information and circumstances (see c­hapters 16, 22, 31). Studies of cognitive flexibility have had mixed results in BFRBs, depending upon the particular task used. For example, when using the CANTAB version of the Intradimensional/​Extradimensional Shift Task, three studies found that individuals with trichotillomania and skin picking disorder did not show deficits in cognitive flexibility (Chamberlain et al., 2006; Grant et al., 2011; Odlaug et al., 2010). However, a study examining response flexibility using the Object Alternation Task, which measures different aspects of flexibility, suggested that individuals with trichotillomania may have difficulties with low-​level response flexibility (Bohne et al., 2005). NEUROIMAGING

A few small studies have examined gray matter volume in trichotillomania. Much of the structural imaging research conducted in patients with trichotillomania has relied on “region of interest” approaches, in which certain brain regions are selected a priori for analysis (see ­chapter 20 for an overview of the brain regions frequently associated with OCD and related disorders). One study measured caudate volumes in trichotillomania (n = 13) versus controls (n = 12), and reported no significant between-​ group 570

differences (Stein et al., 1997). Another study found reduced left inferior frontal gyrus and increased right cuneal volumes in patients with trichotillomania (n = 10) versus controls (n = 10; Grachev, 1997), whereas another found smaller left putamen volumes in patients (n = 10 per group; O’Sullivan et al., 1997). Using parcellation techniques (in which regions of the brain are anatomically demarcated), one study identified reduced cerebellar volumes in trichotillomania subjects (n = 14) compared with controls (n = 12; Keuthen et al., 2007). Finally, using whole-​ brain, voxel-​based morphometry (VBM) in comorbidity free patients, one study found that patients with trichotillomania (n = 18) exhibited gray matter density increases in several brain regions involved in affect regulation, motor habits, and top-​down cognition (i.e., left caudate/​putamen, left amygdalo-​hippocampal formation, bilateral cingulate, and right frontal cortices) compared with controls (n = 19; Chamberlain et al., 2008). Only one study has examined whether trichotillomania is also associated with aberrant white matter tracts, using diffusion tensor imaging (DTI; see c­ hapter  23). Reduced fractional anisotropy (FA), indicating more isotropic (or “random”) water diffusion, is characteristic of disorganized white matter tracts. In parallel with their VBM examination of gray matter, Chamberlain and colleagues (2010) found that individuals with trichotillomania showed reduced FA in white matter tracts associated with bilateral anterior cingulate cortex, bilateral orbitofrontal cortex, presupplementary motor area, the left primary somatosensory cortex, and multiple temporal regions. Together, white matter connectivity and gray matter volumetric results implicate disorganization of neurocircuitry involved in motor habit generation and suppression, along with affective regulation, in the pathophysiology of trichotillomania. There have been three functional neuroimaging studies of BFRBs. In the first study, functional imaging during performance of the serial reaction time task was used to assess striatal and hippocampal activation during implicit sequence learning in participants with trichotillomania (n = 10) compared with healthy controls (n = 10). The study failed to find any significant differences in implicit learning, or in striatal or hippocampal activation, as had been found in OCD (Rauch et al., 2007). In a second functional imaging study in adults, patients with trichotillomania exhibited dampening of nucleus accumbens responses to reward anticipation (but relative hypersensitivity to gain and loss outcomes) as compared with controls (White et al., 2013). Finally, in the only study of children (aged 9–​17 years) with trichotillomania (n  =  9) and healthy controls (n  =  10), those with trichotillomania exhibited significantly greater O b sessive - C ompulsive D isorder

 

activation in left temporal cortex, dorsal posterior cingulate gyrus, and putamen during a visual symptom provocation task, and greater activation in the precuneus and dorsal posterior cingulate gyrus during a visual and tactile provocation (Lee et al., 2010). There have been fewer studies in skin picking disorder. In one study of white matter microstructure, 13 subjects with skin picking disorder were compared with 12 healthy controls using voxelwise analysis with permutation modeling and cluster correction. Subjects with skin picking exhibited significantly reduced FA in tracts distributed bilaterally, which included the anterior cingulate cortices. These findings implicate disorganization of white-​matter tracts involved in motor generation and suppression and were markedly similar to those found in trichotillomania (Grant et al., 2013). In a structural study comparing skin picking disorder with trichotillomania, 17 females with skin picking, 17 with trichotillomania, and 25 healthy female controls participants with skin picking disorder had greater volumes of the ventral striatum bilaterally, reduced cortical thickness in right hemisphere frontal areas, and greater thickness of the cuneus bilaterally, compared with both trichotillomania and controls. The more extensive involvement of the ventral striatum in skin picking may suggest greater involvement of the reward system (Roos et al., 2015). In the only functional neuroimaging study of skin picking disorder described to date, 18 participants with picking and 15 matched healthy controls undertook an executive planning task (Tower of London) during fMRI. Activation during planning was compared between groups using region of interest and whole-​brain permutation cluster approaches. The adults with skin picking disorder exhibited significant functional underactivation in a cluster encompassing bilateral dorsal striatum (maximal in right caudate), bilateral anterior cingulate, and right medial frontal regions. These abnormalities involve neural regions governing habit formation, action monitoring, and inhibition (Odlaug et al., 2015); they overlap significantly with regions that have been shown to be abnormal in OCD (see ­chapter 20–​22). POSSIBLE PSYCHOLOGICAL ETIOLOGIES

Because negative emotions such as anxiety, tension, and sadness often precede pulling and picking episodes, it has been hypothesized that these behaviors have a role in regulating emotional states or stressful events (Bohne et  al., 2002; Duke et  al., 2009). Picking and pulling may function as a means for a person to escape from or avoid aversive experiences, and temporary relief from these negative T richotillomania and S kin P icking D isorder

emotions may maintain the behaviors through a negative reinforcement cycle (Roberts et al., 2013; see ­chapter 60). Studies that have measured emotional regulation in individuals with and without pulling and picking found that these individuals have greater difficulty regulating negative affective states than controls (Shusterman et al., 2009; Snorrason et  al., 2010). Relatedly, boredom may trigger picking and pulling in some individuals (Bohne et  al., 2002; Duke et  al., 2010). This has led some to hypothesize that pulling and picking may similarly help to adjust negative emotions brought on by a feeling of perfectionism characterized by unwillingness to relax (O’Connor et al., 2003). This theory suggests that perfectionism leads to feelings of frustration, impatience, and dissatisfaction when standards are not met, particularly when experiencing boredom because productivity is impossible. Picking and pulling may therefore function as a means of releasing tension generated by these emotions. T R E AT ME NT If untreated, trichotillomania and skin picking disorder appear to be chronic illnesses that may result in substantial psychosocial dysfunction and may even lead to life-​ threatening medical problems (infection; trichobezoar). Controlling skin picking or hair pulling is therefore critical for maintaining long-​term health and quality of life. Clinicians should begin with a thorough psychiatric assessment to establish an accurate diagnosis. Additionally, it is important to work collaboratively with internal medicine and psychiatric management teams for monitoring and rapid intervention if serious medical sequelae result from the picking or pulling. DIAGNOSIS

Thoughtful treatment strategies rely on accurate diagnosis. Misdiagnosis of skin picking disorder and trichotillomania is common. Individuals may be misdiagnosed with OCD, an anxiety disorder, body dysmorphic disorder, or even drug addiction. Approximately 30% of individuals with body dysmorphic disorder also have significant picking behavior. Picking in the case of body dysmorphic disorder is performed to improve appearance. Body dysmorphic disorder, unlike skin picking disorder, responds to selective serotonin reuptake inhibitors (­chapter 49). For these reasons, it is important to differentiate picking secondary to body dysmorphic disorder from picking as the hallmark of 571

 

primary skin picking disorder. Similar diagnostic confusion can occur with OCD. Some people with OCD may pick to remove contaminants from their skin. In those cases, OCD is the more accurate diagnosis. Finally, many individuals who abuse stimulants, prescription or illicit, may pick at their skin as a direct consequence of the drug use. Because treatments of these disorders differ, proper diagnosis is essential. The clinical evaluation of an individual with skin picking disorder should include a comprehensive physical examination. This serves two purposes:  first, to assess the extent of the picking and to develop appropriate dermatological interventions based on the damage to the skin; and second, to assess for possible dermatological or infectious etiologies of skin picking. There are many dermatological conditions that may result in scratching or picking—​for example, scabies, atopic dermatitis, psoriasis, and blistering skin disorders (Mostaghimi, 2012). A  thorough dermatological consultation may include microscopic examination of lesions for scabies, the Wood’s lamp examination for fungal infections, patch testing for allergies, skin biopsies, and laboratory investigations of thyroid, parathyroid, liver, and kidney problems, as these may all result in pruritus, scratching or rubbing of the skin, and resultant excoriations (Mostaghimi, 2012). A physical examination is less often needed in cases of trichotillomania. The one exception, however, is in cases where people report ingesting hair. A physical examination and even abdominal imaging may be needed to rule out a potentially life-​threatening trichobezoar. PSYCHOLOGICAL AND BEHAVIORAL TREATMENTS

The evidence base to guide psychotherapy for BFRBs is small but suggests the use of behavioral therapy for both trichotillomania and skin picking disorder (McGuire et al., 2014). The specific behavioral therapy most often used for these disorders is habit reversal training (HRT); treatment may include components of acceptance and commitment therapy and dialectical behavior therapy as well. There are eight controlled studies of behavioral therapy, using HRT alone or with other components, in trichotillomania and two controlled psychosocial treatment studies for skin picking disorder (Table 51.1), one using HRT and another using cognitive-​behavioral therapy. There are no controlled studies of other psychotherapies. HRT was first developed approximately 40 years ago by Azrin and Nunn for the treatment of nervous habits and tics. The core components of HRT are self-​monitoring (i.e., 572

asking the patient to track his/​her hair pulling, picking), awareness training, competing response training, and stimulus control procedures (i.e., modifying the environment to reduce cues for hair pulling or skin picking). HRT is similar to many other types of behavioral therapy; it differs somewhat from more cognitive approaches in that the focus is on behavioral change and not generally on cognitive strategies to address dysfunctional thoughts that precipitate pulling. HRT can be delivered in person, online using a self-​ help method, or in a group format. Acute treatment gains obtained from HRT are generally maintained for between three to six months. Typically HRT is conducted on a weekly basis, but it can be performed using a more frequent schedule. Although in practice many clinicians use a combination of HRT and more traditional cognitive therapy, the empirical data support HRT as the first-​line psychotherapy for these disorders. To further improve upon HRT, acceptance and commitment therapy as well as elements of dialectical behavior therapy and “decoupling” techniques (where the patient learns to perform actions that unlink the behavioral components involved in hair-​pulling) have all been added to HRT. Behavior therapy has also proven useful for children with trichotillomania. The research on psychotherapy for skin picking disorder is more limited. Preliminary psychosocial treatment studies have provided evidence that HRT and acceptance-​ enhanced behavior therapy elicit significant reductions in skin picking (Table 51.1). For both trichotillomania and skin picking disorder, behavior therapy appears promising. Many questions about treatment, however, remain unanswered. It is unclear how much therapy a person needs; studies range from 1 session to 22 sessions. It is also unclear how lasting the effects of therapy are. Most studies have followed subjects for only 2 or 3 months. Whether booster sessions are needed or whether modifications to the initial therapy would provide longer lasting benefit is still unknown. PHARMACOLOGICAL TREATMENTS

There are currently no pharmacotherapies that would be universally accepted as first-​line treatments for trichotillomania or skin picking disorder (Rothbart et  al., 2013). Nine controlled pharmacological trials have been performed in trichotillomania (Table 51.1). Four of the studies examined serotonin reuptake inhibitor (SRI) antidepressants. Although clomipramine has shown some benefit for trichotillomania, evidence to date does not support the use of SSRI antidepressants. This is in marked contrast to the treatment literature for OCD (see c­ hapter  40) and again O b sessive - C ompulsive D isorder

 

D O U BL E - ​B L I N D, C O N T RO L L E D P HA R M AC OTHER A P Y A N D P S YC HOTHER A P Y TR I A LS FO R  TR I C HOTI LLOMANIA AN D SK I N PI CK I N G D I S O R D E R TA B L E   5 1 . 1  

Trichotillomania—​Controlled Medication Trials Medication

Design/​Duration

Subjects

Mean Daily Dose (±SD)

Outcome

Clomipramine vs. desipramine; Swedo et al., 1989

Crossover, 5 weeks each agent

13 enrolled, 13 completers

CMI: 180 mg (± 56) DMI: 173 mg (± 33)

CMI significantly greater improvement

Fluoxetine; Christenson et al., 1991b

Crossover, 6 weeks fluoxetine and placebo

21 enrolled, 15 completers

Fixed titration to 80 mg

Fluoxetine not significantly different from placebo

Clomipramine vs. fluoxetine; O’Sullivan et al., 1999

Crossover, 10 weeks each agent

12 enrolled; No data on number of completers

CMI: 200 mg ± 15; Fluoxetine: 75 mg ± 5

Similar significant improvement on both agents

Fluoxetine; Streichenwein & Thornby, 1995

Crossover, 6 weeks on fluoxetine and placebo

23 enrolled, 16 completers

70 mg

No differences between groups

Naltrexone; Christenson et al., 1994

Parallel design, 6 weeks

No data on number enrolled; 17 completers

50 mg

Naltrexone significant improvement on one measure

Naltrexone; Grant et al., 2013

Parallel design, 8 weeks

51 enrolled, 44 completers

50 mg, 100 mg, 150 mg

No differences between groups.

N-​acetylcysteine (NAC); Grant et al., 2009

Parallel design, 12 weeks

50 enrolled, 44 completers

1,200 mg to 2,400 mg/​day

NAC group showed significant symptom improvement on all outcome measures

N-​acetylcysteine (NAC); Bloch et al., 2013 (Children)

Parallel design, 12 weeks

39 enrolled, 35 completers

1,200 mg to 2,400 mg/​day

No differences between groups.

Olanzapine; van Ameringen et al., 2010

Parallel design, 12 weeks

25 enrolled, 23 completers

10.8 mg(± 5.7)

Olanzapine significant improvement over placebo on primary measure

Trichotillomania—​Comparison Studies of Medication and Therapy Therapy and medication

Design/​Duration

Subjects

Mean Daily Dose (±SD)

Outcome

Cognitive behavior therapy compared to clomipramine compared to placebo; Ninan et al., 2000

Parallel design, 9 weeks

23 enrolled, 16 completers

116.7 mg

Cognitive behavioral therapy was significantly more effective in reducing the symptoms of trichotillomania than either clomipramine or placebo.

Behavior therapy compared with fluoxetine compared with wait-​list; Van Minnen et al., 2003

Parallel design, 12 weeks

43 enrolled, 40 completers

60 mg

Behavior therapy resulted in statistically significant reductions in trichotillomania symptoms compared with either fluoxetine or wait list.

Behavioral therapy) Behavior therapy and sertraline; Dougherty et al., 2006

2-​week placebo lead-​in followed by 12 weeks of double-​blind medication vs. placebo; nonresponders received two 1-​ hour HRT sessions

42 enrolled, 26 completers

50mg-​200mg

Those receiving both sertraline and HRT improved more than those receiving either modality by itself.

Trichotillomania—​Controlled Psychotherapy Trials

Azrin et al., 1980

Therapy

Subjects

Number of Sessions

Outcome

Habit reversal therapy compared with negative practice

34 enrolled, 34 completers

One 2-​hour session

Habit reversal reduced hair pulling by more than 90% for 4 months, compared with 52%–​68% reduction for negative practice at 3 months. (continued)

 

TA B L E   5 1 . 1  

C O N TI NU E D Trichotillomania—​Controlled Psychotherapy Trials

Woods et al., 2006

Acceptance and commitment therapy/​habit reversal compared to wait list

28 enrolled, 25 completers

10 sessions

Improvement for acceptance and commitment therapy/​habit reversal maintained at 3 months

Franklin et al., 2011 (Children)

Behavioral therapy vs minimal attention control (MAC)

24 enrolled

8 sessions

Behavior therapy resulted in significant improvements compared with MAC.

Moritz & Rufer, 2011

Decoupling compared to muscle relaxation

42 enrolled, 38 completed

Self-​help manual

Decoupling movement resulted in significantly greater reductions in trichotillomania symptoms compared with the muscle relaxation group.

Toledo et al., 2015

Group cognitive-​behavioral therapy or group supportive therapy (control)

48 enrolled, 44 completers

22 sessions

Decrease in hair pulling was significantly greater in the study group than in the control group.

Skin Picking Disorder—​Controlled Medication Trials Fluoxetine; Simeon et al., 1997

Parallel design, 10 weeks

21 enrolled, 17 completers

53.0 mg (± 16.4)

80% of the fluoxetine group were much or very much improved; 27.3% of placebo group were much or very much improved.

Fluoxetine; Bloch et al., 2001

6 weeks open-​label followed by 6 weeks double-​blind for responders

15 enrolled in open-​ label;, 8 responders randomized

20–​60mg

53.3% response rate to open label medication; those assigned to continuation medication had 70% reduction in symptoms, whereas those on placebo returned to baseline.

Citalopram; Arbabi et al., 2008

Parallel design, 4 weeks

46 enrolled, 40 completers

20 mg fixed dose

Citalopram showed greater improvement on one measure.

Lamotrigine; Grant et al., 2010

Parallel design, 12 weeks

35 enrolled, 25 completers

177.2 mg (± 66.1)

7 subjects assigned to lamotrigine (43.8%) were responders compared with 5 (31.3%) assigned to placebo. Those who responded exhibited impaired cognitive flexibility at baseline.

Skin Picking Disorder—​Controlled Psychotherapy Trials Teng et al., 2006

Habit reversal therapy or wait list

25 enrolled, 19 completers

4 sessions

Decrease in hair pulling was significantly greater for HRT than wait list.

Schuck et al., 2011

Cognitive behavioral therapy or wait list

34 enrolled, 28 completers

4 sessions

Participants in the treatment condition showed a significantly larger reduction on all measured variables in comparison with the waiting-​list condition.

suggests a possible difference in pathophysiology between trichotillomania and OCD. Pharmacological agents other than SRIs have been examined for the treatment for trichotillomania, with mixed results. Two studies have examined the opioid antagonist naltrexone, with one finding some modest benefit whereas a second study found that only those subjects with a family history of addiction seemed to benefit from the medication 574

(Grant et al., 2014; Christenson et al, 1994). Similarly, N-​ acetylcysteine, a glutamate modulator, demonstrated marked improvement for adults with trichotillomania (Grant et al., 2009) but failed to show improvement relative to placebo in children (Bloch et al., 2013). Finally, olanzapine demonstrated significant benefit for adults with trichotillomania when using the Clinical Global Improvement scale, but not when using the more usually chosen outcome O b sessive - C ompulsive D isorder

 

measure, the Massachusetts General Hospital Hair Pulling Scale (Van Ameringen et al., 2010). The pharmacotherapy data for skin picking disorder are even more limited, with only four double-​blind, placebo-​ controlled clinical trials to date (Table 51.1). As with trichotillomania, data regarding the efficacy of SRIs have been mixed, with some studies demonstrating improvement on certain measures of picking behavior. Unlike trichotillomania, however, only one non-​SRI agent (lamotrigine) has been studied for skin picking; it was not beneficial (Grant et al., 2010). A few points can be made to summarize the available pharmacological data. First, based on very limited research, behavior therapy seems to be more effective than pharmacotherapy in the treatment of trichotillomania and skin picking disorder. Second, SRI medications (with the possible exception of clomipramine) do not appear particularly beneficial for trichotillomania or skin picking disorder. Other agents, such as N-​acetyl cysteine or olanzapine, may be beneficial for certain individuals with trichotillomania or skin picking disorder. The evidence base is simply too limited to create a pharmacological treatment algorithm at this time. C ONCL US IO N S If untreated, trichotillomania and skin picking disorder are often chronic illnesses and may result in substantial psychosocial dysfunction and even lead to life-​threatening medical problems. Without treatment, spontaneous remission rates in adults are low (approximately 14%; Woods et al., 2006). When diagnosed early and appropriately treated with behavior therapy, however, up to 50% of individuals may experience symptom reduction, at least for the short term (Woods et al., 2006). Therefore, accurate diagnosis followed by evidence-​based treatment is needed to prevent associated disability. Unlike OCD, the BFRBs are not generally driven by obsessional thought. The behaviors of pulling and picking can be very pleasurable for some individuals. They do not seem to respond to SSRIs. Clinicians caring for individuals with trichotillomania or skin picking disorder need to be aware of these salient differences, and not treat these disorders simply as simple variants of OCD. R EF ERENCES American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, DC: Author. T richotillomania and S kin P icking D isorder

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52. HOARDING DISORDER CL I N I CAL P RESENTAT I ON AND TRE ATME NT

Randy O. Frost, PhD, Lucy Graves, BA, and Elizabeth Atkins, BA

A

lthough anecdotal reports of hoarding have existed in the news and in literature for centuries (Penzel, 2014), little scientific research has existed on the topic until recently. Following the first of several systematic investigations in the 1990s, interest has grown exponentially (Mataix-​Cols et al., 2010). One outcome of this work was the addition of hoarding disorder (HD) in the Obsessive Compulsive and Related Disorders chapter of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-​5; American Psychiatric Association [APA], 2013). DIAGNOS IS AN D CLI N I CAL C HA R AC TERI STI CS The DSM-​5 diagnostic criteria for HD include four inclusion and two exclusion criteria (APA, 2013). The first inclusion criterion represents the fundamental characteristic of hoarding: the difficulty discarding or letting go of possessions. This includes any actions that involve parting with possessions, including throwing them away, recycling, donating, or selling (Mataix-​Cols et  al., 2010). The difficulty must be persistent and not limited to short periods of time that might happen, for instance, following the death of a loved one or a move to a smaller home. The difficulty discarding is not limited to items that have no value. This is distinct from the obsessive compulsive personality disorder criterion of an inability “to discard worn-​out or worthless objects even when they have no sentimental value” (p.  679; APA, 2013). Research on hoarding behavior has revealed that people who hoard collect and save all types of objects, including those that can have significant value, such as roomfuls of new and unworn clothing (Frost et al.,

1993). The most commonly hoarded items include books, clothes, and papers, most of which do have value (Pertusa et al., 2008). These items are actively saved in HD because of a perceived need and significant distress if they were to be discarded (APA, 2013). Major motivations for saving among people with HD include concerns about waste, perceived need to retain information, sentimental or emotional attachment, and aesthetic value (Frost et al., 2015). The most visible feature of hoarding is clutter, which congests living areas and makes using them difficult. Emphasis is placed on the active living areas of the home, such as the bedroom or kitchen, in order to distinguish hoarding from simply owning a large number of possessions that are stored in basements, attics, or garages. Clutter results from the hoarding behavior, and it is the feature that represents the biggest threat to the health and well-​being of the sufferer (Tolin, Frost, Steketee, & Fitch, 2008). An exception is made for this criterion if someone other than the sufferer manages the clutter, such as a family member or other authority. In such cases, the living areas may be uncluttered, but the diagnostic criterion is still considered to have been met. The clutter and hoarding behaviors must cause clinically significant distress or impairment for a diagnosis to be made. Symptoms of hoarding vary from mild to severe. Not being able to use the kitchen, sit on chairs, or sleep in the bed due to the clutter are frequent complaints in hoarding cases. More serious impairments include blocked egress and stairways where the clutter can be dangerous to navigate. Clutter has been found to be a significant risk factor for death in residential house fires (Frost et al., 2014). Moreover, these health and safety issues are not restricted to the HD person’s home and can pose problems for neighbors

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or others nearby (Frost et al., 2000). In addition to impairments in the home environment, HD individuals often have significant work impairment (Tolin, Frost, Steketee, & Fitch, 2008). Social functioning appears to be negatively affected, with family members and friends showing hostile attitudes toward individuals with HD (Tolin, Frost, Steketee, Gray, & Fitch, 2008). In addition, embarrassment or shame over the clutter and state of the home can cause people with hoarding to isolate themselves. Hoarding has been found to be associated with lower quality of life and impairment in everyday activities (Saxena et  al., 2011). Hoarding has also been shown to be associated with a variety of medical problems, including obesity, diabetes, ulcers, and high blood pressure (Tolin, Frost, Steketee, & Fitch, 2008). Hoarding can cause significant financial costs to the community as well. Close to 80% of hoarding cases involve multiple agencies and repeated visits (Frost et  al., 2000). The San Francisco Task Force on Compulsive Hoarding (2009) estimated the financial burden to landlords and social service agencies to be over 6 million dollars each year. Several medical conditions are associated with increased accumulation and clutter, including certain types of brain injury and cerebrovascular disease, as well as Prader-​Willi syndrome (APA, 2013). Clutter resulting from these disorders would rule out an HD diagnosis. In addition, several other mental disorders sometimes result in the accumulation of possessions in the home. For instance, some individuals with contamination obsessions in OCD will avoid touching objects in the home that are perceived to be contaminated. Consequently, the home can become severely cluttered. Similarly, people with major depressive disorder can sometimes lose the motivation to organize and discard items. Autism spectrum conditions can result in excessive accumulation, but it is usually explained by the restricted interest pattern seen in conjunction with this disorder. Neurocognitive disorders, such as Alzheimer’s disease, can lead to clutter, squalor, or self-​neglect as well (Snowdon et al., 2010). SPECIFIERS

DSM-​5 criteria contain a specifier for excessive acquisition. Excessive acquisition is defined as excessive buying, collecting, or stealing of objects for which there is no need and/​or no available space (Frost et al., 2009). Several studies have examined the nature and extent of excessive acquisition in hoarding. Frost and colleagues (2011) found that nearly 80% of 217 carefully diagnosed HD clients met criteria for the excessive acquisition specifier. All three forms of acquisition (buying, acquiring for free, and stealing) were greater 580

in HD than OCD patients. Similar frequencies have been found in large Internet studies of hoarding (Frost et  al., 2009, 2013). Family member reports of frequency of excessive acquisition in hoarding relatives are even higher (Frost et al., 2009, 2013). The presence of excessive acquisition is associated with more severe hoarding symptoms (difficulty discarding and clutter) and is the strongest predictor of distress and impairment in HD (Timpano, Keough, et al., 2011). A high frequency of avoidance of acquiring cues in hoarding cases has been noted (Frost et  al., 2013). People with HD often report avoiding certain stores, certain aisles in stores, and even whole cities in order to keep themselves from buying or collecting. Some HD cases have been found to deny current or past acquisition problems, but yet avoid certain stores in order to curtail their acquisition (Frost et  al., 2013). Clinically, this can pose a problem in that HD clients have been reported to deny having acquisition problems at the beginning of treatment only to have them surface later when they begin to confront situations that trigger their acquisition (Frost et al., 2009). Evaluating and treating HD clients for excessive acquisition is crucial to gaining control over their hoarding behavior. As with OCD, the DSM-​5 has a specifier for insight in HD, with three levels based on the extent to which the individual recognizes that the hoarding beliefs and behaviors present a problem. Family members, clinicians, and health officers often describe people who hoard as lacking insight or as “delusional” (Tolin, Frost, Steketee, Gray, & Fitch, 2008). A  number of researchers have found significantly lower insight among hoarding patients than OCD patients (Worden et al., 2014). However, the London field trial for DSM-​5 found that the vast majority of patients diagnosed with HD had “good or fair insight” (85%–​90%), 7% to 10% had poor insight, and only 3.4% were considered to have “absent insight or delusional beliefs” (Mataix-​Cols et al., 2012). Furthermore, Tolin and colleagues found that 85% of people who self-​identified with hoarding problems said they would seek treatment if it were available (Tolin, Frost, Steketee, Gray, & Fitch, 2008). Some have suggested that there may be three aspects of insight that vary independently and color perceptions of insight among people with HD:  anosognosia, overvalued ideation, and defensiveness (Frost et al., 2010). Anosognosia, or the lack of awareness of a problem or the existence of a disorder, may be rare in HD. Even when individuals with severe hoarding deny a problem, they actively work to prevent people from seeing their home, even to the extent of living without functioning appliances or utilities (Kim et  al., 2011). This suggests some O b sessive - C ompulsive D isorder

 

recognition of problems with their living spaces. Those cases with anosognosia in HD may reflect impairments in executive functioning, impairments in perception in which people with HD do not notice the clutter, or the absence of normative information about living spaces (Worden et al., 2014). HD patients frequently live alone, are socially isolated, and often have grown up in a cluttered environment (Frost et al., 2014). These experiences may lead to a lack of recognition of a problem. Observations of poor insight in HD may result from persistent and strong beliefs about the value of possessions that are not shared by the observer. The strongly held belief that a moldy 10-​year old newspaper holds value can appear delusional to a family member or therapist. Yet a person holding such conviction may still recognize that clutter in their home impairs their ability to function. Thus they may have insight with respect to recognizing a problem, but not with respect to beliefs about the value of their objects. These kinds of overvalued ideas in HD typically include beliefs about utility, fear of waste, sentimental attachments, and beliefs about memory and control (Frost et al., 2010). There is ample evidence that these beliefs are core features of HD itself, rather than an indication of poor insight (Frost et al., 2014). Finally, observations about poor insight in HD clients may be influenced by the context in which the observations are made. Many people with HD have experienced decades of criticism from family members and authorities and have had to constantly defend their clutter, acquisition, and saving behavior (Frost et al., 2010). As a result, they may have developed coping strategies to defend themselves and their behavior. Borrowing from the social psychology theory of psychological reactance (Brehm, 1996), it may be that people with HD perceive the relentless criticism of their behavior as restricting their freedom. In response, they resist any suggestion of behavior change or admission of a problem in order to maintain a sense of freedom and control. HD clients have been noted to react negatively to more directive methods by therapists (Frost et al., 2010). EP IDEM IOLO G Y AN D  CO URSE PREVALENCE

Studies of the prevalence of hoarding have relied on varying definitions of what constitutes a hoarding case. Most early studies failed to use operational definitions of hoarding. More recently, five studies have established prevalence H oarding D isorder

rates for hoarding using well-​established measures or criteria. A  study of 5,000 adults in a twin registry in the UK (Iervolino et  al., 2009)  used the Hoarding Rating Scale (HRS; Tolin, Frost, et al., 2010) reported a prevalence rate of 2.3%. Using a German version of the Saving Inventory—​ Revised (SI-​R ; Frost et al., 2004) and a criterion of 2 standard deviations above the mean of community controls revealed a prevalence rate of 4.6% (Mueller et  al., 2009). A second German sample used the HRS cutoff score of 17 and found a prevalence rate of 6.7%. When using DSM-​5 criteria, the rate was 5.8% (Timpano, Exner, et al., 2011). The prevalence rate in a large Italian sample was 6.0% using the recommended criteria on the SI-​R (Bulli et al., 2014). A recent study using the Structured Interview for Hoarding Disorder, which was developed to establish HD diagnoses, found a rate of 1.5% in a London sample (Nordsletten et  al., 2013). However, the authors noted problems with participation rates and solicitation procedures that may have resulted in an underestimation of rates of hoarding. The screening sample was recruited using a targeted door-​ to-​door approach. People with HD may have been less likely to answer the doorbell for unsolicited callers and thus would be less likely to be counted. Together, these studies suggest a prevalence for HD of between 2.0 and 6.0%. Although two studies found hoarding to be more common in men than women, most epidemiological studies have reported no gender differences in prevalence. Women predominate in most clinical studies of hoarding (Steketee et al., 2014). Hoarding has been shown to have a significant impact on social functioning, including family relations and marriage status (Frost et  al., 2014). Family members of those who hoard endorse more rejecting attitudes and feelings of hostility and frustration when compared with family members of those with other mental illnesses (Frost et al., 2014). Furthermore, children of people with HD report feelings of embarrassment and family conflict that negatively influenced their childhood (Tolin, Frost, Steketee, Gray, & Fitch, 2008). Family members report significant caregiver burden and functional impairment as a result of hoarding (Drury et  al., 2014). Several studies have found that people with HD are more likely to be unmarried and live alone in comparison with community controls, collectors, and those with OCD or another anxiety disorder (Steketee et al., 2014). ONSET AND COURSE

Findings regarding age of onset appear to be influenced by the nature of the questions used. In studies that used a single 581

 

question about when symptoms began, the age of onset of hoarding symptoms ranges from 20 to 30 years (Ayers et al., 2010; Pertusa et al., 2008). However, when asked to remember an event that was used as a recollection marker for each decade of life, the age of onset is about a decade earlier, ranging from 11 to 20 years (Ayers et al., 2010; Grisham et al., 2006; Tolin, Meunier, et al., 2010). It appears to take several decades for symptoms to progress from mild to severe. Despite the early age of onset, the age of people in treatment for hoarding, those identified by social service agencies, and those volunteering for research on hoarding, tends to be older than for other disorders such as OCD (Frost et al., 2014). To date there have been no longitudinal studies examining the course of hoarding symptoms. However, only a small number of hoarding participants report symptom remission after onset (Grisham et  al., 2006). In a large sample of HD cases, 73% reported a chronic course, whereas 21% reported increased severity over time, 5% had a fluctuating course, and only 1% reported an improving course (Tolin, Meunier, et al., 2010). EDUCATION, INCOME, AND EMPLOYMENT

Most studies have not found differences in education levels between those with HD versus those with OCD or with nonclinical participants (Steketee et al., 2014). With respect to income, the findings have been mixed, with some studies finding an association and some failing to do so (Frost et al., 2011; Mueller et al., 2009; Wheaton et al., 2008). In a large Internet survey, close to 40% self-​identified hoarding individuals had problems paying their bills, and more than 20% had not filed an income tax return in the last 5 years (Tolin, Frost, Steketee, Gray, & Fitch, 2008). Although this same study found that only a small percentage of those with clinical hoarding were unemployed, 6% reported being fired from their jobs due to their hoarding and the number of work impairment days for those with hoarding was comparable to those with a psychotic disorder. CULTURE AND HOARDING

Although most studies of hoarding come from the Western countries, reports of hoarding have appeared in countries around the world, including Japan (et al., 2010), India (Chakraborty et al., 2012), China (Alcon et al., 2011), Turkey (Tükel et al., 2005), Iran (Mohammadzadeh, 2009), Spain (Fullana et al., 2010), and Brazil (Fontenelle et al., 2004), among others. Two studies to date have looked at hoarding rates across different countries. The first compared OCD symptom dimensions, including hoarding, across six 582

European countries (Belgium, France, Germany, Italy, the Netherlands, and Spain) and found an overall hoarding prevalence in line with past findings (Fullana et al., 2010). The second compared college students’ hoarding symptoms and impulsivity in the United States and Germany (Timpano et al., 2012). They found a slightly higher percentage of the German students had clinically significant hoarding. Little research has examined cultural factors in hoarding. C O M O R B I D I T Y A N D M O D I F Y I N G FAC T O R S

One feature that may affect HD onset and course is the experience of stressful or traumatic events in people with HD. Several studies have reported greater frequency of trauma in those with HD than in community controls or in OCD patients (Frost et al., 2011; Landau et al., 2011; Przeworski et al., 2014). Other studies have found correlations between the frequency of stressful life events and hoarding severity (Timpano, Keough, et al., 2011; Tolin, Meunier, et al., 2010). Several studies have found elevated levels of stressful or traumatic events at or before the onset of symptoms (Grisham et al., 2006; Przeworski et al., 2014). Until recently, hoarding was thought of as a subtype of OCD. However, differences between hoarding and OCD in onset, course, phenomenology, and prevalence led to it being considered a separate disorder (Mataix-​Cols et  al., 2010). HD and OCD still share overlap, however. The largest study of comorbidity in HD found that 18% of 217 diagnosed HD patients met criteria for OCD (Frost et al., 2011). In some cases, hoarding-​like behaviors can be attributed to bona fide OCD (Pertusa et al., 2010). Several other anxiety disorders are also common in HD, including social phobia, and generalized anxiety disorder (Wheaton et al., 2014). Although there is a high rate of experienced trauma in HD, there is little elevation in PTSD among those with HD (Frost et al., 2011). Depression appears to have the greatest overlap with HD. Over 50% of a large HD sample had comorbid depression (Frost et al., 2011); other studies have suggested even higher rates (Wheaton et al., 2008). Impulse control disorders have been implicated in HD, because of their shared focus on acquisition behaviors such as compulsive buying, collecting free things, or kleptomania. Some limited research suggests that hoarding may relate to other problems with impulse control, such as pathological grooming and gambling (Frost et al., 2001; Samuels et al., 2002). Symptoms of attention-​ deficit/​ hyperactivity disorder, particularly inattention, are frequent in HD (Tolin et al., 2011) and are thought to be one form O b sessive - C ompulsive D isorder

 

of information processing deficits that lead to hoarding (Frost et al., 1996). TR EATM ENT E A R LY T R E AT M E N T S T U D I E S

Early studies of psychological treatment for hoarding used standard treatments designed for OCD. Most of these studies reported poor outcomes (Tolin et al., 2015). A comprehensive metaanalysis of treatment outcome studies of OCD patients concluded that the presence of hoarding symptoms in patients with OCD was associated with poor treatment outcomes across all forms of treatment (Bloch et al., 2014). However, studies of this sort suffer from several methodological limitations that restrict the conclusions to be drawn regarding the treatment of hoarding. First, they are limited to cases diagnosed with OCD, and it is not clear what fraction of these patients would meet DSM-​5 criteria for HD. They do not include cases of hoarding without accompanying OCD symptoms; because 80% of HD cases are not comorbid for OCD, these studies may not be representative of most hoarding cases (Frost et al., 2011). Second, these studies focus on treatments for OCD, not treatments designed specifically for hoarding. Finally, the measures employed in these early studies did not include validated measures of hoarding symptoms. More recently, outcome research on HD has featured studies in which participants were solicited and selected based on hoarding and HD diagnosis, treatments have been developed that are based on our current understanding of HD, and measures of hoarding with demonstrated reliability and validity have been employed. TREATMENT OVERVIEW

Group or individual cognitive behavioral therapy (CBT) for hoarding involves 20 to 26 sessions over 6 to 12 months, depending on the severity of symptoms and complexity of the case. Initial assessment is followed by a case formulation using the CBT model for hoarding (Steketee et al., 2013). There are three foci in this treatment: gaining control over acquisition, creating uncluttered living spaces, and reducing the attachment to possessions. In most cases, acquiring is addressed first since progress in creating living space will be limited by the number of new possessions entering the home. The first stages of treatment involve motivational interviewing to address ambivalence. Home visits are an important component and are done as frequently as possible. Friends or family members can be used if they are carefully trained H oarding D isorder

in how to help. Relapse prevention is addressed during the final two sessions (Steketee et al., 2013). TREATING EXCESSIVE ACQUISITION

During acquisition, clients’ attention is typically so narrowly focused on the object in question that other considerations, such as whether they have the money, space, or need for the object, are inaccessible. Consequently, decisions to acquire are not informed by the context of the person’s life. To change this, relevant information must be brought into the decision-​making process. To begin this process, clients generate rules that they agree to follow for any new acquisition (e.g., only acquire if there is a concrete plan to use the object in the next month). Clients generate a set of questions that they think make sense to ask before acquiring something. Typically these are questions most people ask themselves when deciding about an acquisition (e.g., Do I have a specific use for this? Do I already have something like this? Can I get by without this?). Clients carry these questions with them and answer them when faced with an acquiring decision. This strategy brings the context of their lives back into the decision-​making process. Acquiring in HD resembles addictive behaviors. Most often, people with HD can’t resist the urge to acquire. Some cope by avoiding situations in which acquiring might occur (Frost et  al., 2013). Treatment for HD teaches clients to tolerate the urge to acquire, using gradual exposure to acquiring situations that vary in the strength of the urge they induce. Gradual exposure to these situations without acquiring improves the ability to tolerate these urges. Clients keep track of their discomfort and the urge intensity throughout the exposure. These ratings can be graphed to demonstrate the impact of the exercise. For many people with HD, acquiring has become a primary form of pleasure and entertainment. These clients will need help finding alternative sources of pleasure. SORTING AND ORGANIZING SKILLS

In order to increase useable living spaces, therapy for HD includes the development of organizing skills. The task of organizing possessions can be aversive and tax the abilities of HD clients, many of whom have attentional deficits. Maintaining attentional focus is an important organizing skill. Simple strategies can be helpful, including having a support person present or reducing the visibility of other objects in the pile by covering them with a sheet, etc. Training and practice on problem solving may also be necessary. Developing categorizing skills is also important 583

 

for the creation of filing systems. Many HD clients rely on visual cues for memory retrieval, resulting in items collecting in piles in the middle of the room rather than in storage. Putting objects out of sight may create discomfort for HD clients. Strategies for desensitizing clients to this may be necessary. CHANGING ATTACHMENTS TO POSSESSIONS

Sorting and organizing work offers a chance to explore clients’ beliefs about and emotional attachments to possessions. Exploring and changing these features of hoarding disorder are essential. Discussions about the value and meaning of possessions can be worked into these sessions and serve as the beginning of changing attachments to possessions which is the core of CBT for HD. A number of the following cognitive and behavioral strategies can be used in conjunction with sorting and organizing tasks to help clients begin to think differently about their possessions. Thought Listing (TL) is an exercise in which the client is asked to consider the possibility of discarding a specific possession, one they consider difficult to part with, and to describe their thoughts out loud (Steketee et al., 2013). Before beginning, clients are asked to indicate how much distress they anticipate and how long they expect those feelings to last. After a brief time, clients are asked to make a decision about whether to keep or discard the item. If discarded, they are asked to report their thoughts and feelings every 5 minutes or so for the following half-​hour. The exercise is designed to do several things: (1) clarify the nature of the attachment; (2)  increase the time spent processing information about the value of a possession; (3)  expose them to discarding decisions and reduce avoidance of them; and (4) provide practice in sorting and organizing. The Downward Arrow exercise is a variant of TL. It involves a series of repetitive questions concerning what the client anticipates will happen if he or she were to discard a specific item. The exercise begins with the question, “What would happen if you threw that away?” Questions to follow include: What would be so bad about that? If that happened, what would that mean? What would be the worst part of that? Would anything else happen? How long do you think this (feeling) will last? (e.g., discomfort) 584

The goal is to articulate the core fear in the form of a hypothesis. For example, “If I throw this out, I’ll never be able to enjoy myself.” Once a belief is stated in the form of a hypothesis, it can be tested using behavioral experiments, as well as cognitive strategies to identify faulty thinking styles. Hypotheses generated by the Downward Arrow exercise can be tested by setting up experiments. Behavioral experiments (BEs) allow people the opportunity to test their beliefs about their attachments to possessions. The kinds of beliefs and attachments targeted for BEs are outlined in the cognitive behavioral model of HD (Frost et al., 1996). A number of cognitive strategies drawn from other areas of treatment are used in the hoarding treatment protocol. Problematic thinking styles in HD are similar to those seen in anxiety or depression and can be approached in the same way (Beck, 2011). Evaluating the advantages and disadvantages of saving or discarding is commonly used in motivational interviewing and can double here as a strategy for learning how to make decisions. Socratic questioning can be used to help clients recognize the holes in their reasoning. The questions must not be perceived as pushing them into making the decision to discard but rather seen as exploratory, aiming to help discover what possessions are truly important to them. Exercises that take different perspectives about the value of possessions can be powerful to change how people think about their saving and discarding. Cleanouts are generally not recommended in HD. Occasionally, however, they may be necessary for health or safety reasons. It should be noted that although the condition of the home may temporarily change, cleanouts do little to change the hoarding behavior. Lengthy sorting or organizing sessions or using a helper in the home may be beneficial if clients can tolerate them. For these sessions, clients must be in charge and “sign off ” on all objects going into the dumpster or donation pile. OUTCOME RESEARCH ON HOARDING DISORDER TREATMENT

In addition to several case reports, a number of outcome studies show significant improvement in hoarding symptoms following cognitive behavior therapy for HD. A metaanalysis examining pre–​post changes in the studies to date reported significant reductions in HD symptom severity (from 20% to 39%), with large effect sizes (Tolin et  al., 2015). Difficulty discarding showed the largest improvement. Several factors were associated with greater improvement, including being female, younger, and having a larger number of sessions as well as having more sessions in the home. In the two wait list-​controlled studies, large effect O b sessive - C ompulsive D isorder

 

sizes were noted for individual (Steketee et  al., 2010)  as well as group treatment (Muroff et al., 2012). In addition, self-​help groups tightly structured around the CBT protocol have been found to be effective compared to wait list controls (Frost et al., 2012). Despite the promising nature of these outcomes, post-​treatment hoarding severity scores are often still closer to the HD range than to the normal range, suggesting that there is still much room for improvement. Modifications to this treatment may be needed for elderly clients (Ayers et  al., 2011), who may benefit from more emphasis on cognitive rehabilitation and exposure (Ayers et al., 2014). PHARMACOTHERAPY FOR HD

Early studies of pharmacotherapy for hoarding also showed relatively poor response (Bloch et  al., 2014); however, as noted, these studies have severe methodological limitations, reducing their usefulness. Only two studies have examined pharmacotherapy specifically for HD. The first of these studies treated 32 hoarding patients and 47 OCD patients without hoarding with paroxetine in an open trial (Saxena et  al., 2007). Despite problems with the ability to tolerate paroxetine, significant improvement in hoarding was found among the 19 HD patients who completed treatment and hoarding-​specific measures, with a 24% decline in hoarding severity. Twenty-​eight percent of the 32 hoarding patients were considered treatment responders. In the second study, 24 HD patients were treated with 12 weeks of extended release venlafaxine (Saxena et  al., 2014). Among the 23 cases completing treatment, there were substantial declines in symptom severity, 36% on the UCLA Hoarding Severity Scale and 32% on the SI-​ R. Seventy percent were considered treatment responders. Although there are as of yet no randomized control trials on psychopharmacology for HD, these two studies suggest some promise for drug treatment. S UM M A RY Hoarding disorder is a chronic mental disorder present in 2% to 6% of the population. It is characterized by difficulty parting with possessions, regardless of their value. In addition to the volume of possessions, difficulties with organization contribute to buildup of clutter, which makes use of living areas of the home difficult. Extreme clutter can seriously threaten the health and safety of the sufferer and those living nearby. Although these behaviors begin relatively early in life, severe symptoms are often not apparent H oarding D isorder

until decades later. Most HD cases are accompanied by excessive acquisition, particularly compulsive buying and the collection of free things (e.g., trash picking). Insight can vary, though most individuals appear to recognize the negative consequences of the compromised living spaces. Common comorbidities include depression, anxiety disorders, and attention deficit-​hyperactivity disorder. Treatments designed specifically for HD have shown promise in controlled trials, though residual symptoms often persist. Several open trials of pharmacotherapy have shown promising results, but controlled trials are lacking. HD has only recently been recognized as a clinical entity separate from OCD; as a result, much of the early treatment literature was not well focused on this population. With the greater focus that has developed over the past decade, and the formalization of the diagnosis in DSM-​5, it is to be hoped that new and better treatments will emerge in the near future. R E F E R E NC E S Alcon, J., Glazier, K., & Rodriguez, C. From clutter to modern art:  A  Chinese artist’s perspective on hoarding behaviors. Ameican Journal of Psychiatry, 168(12), 1248. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author. Ayers, C., Saxena, S., Espejo, E., Twamley, E., Granholm, E., & Wetherell, J. (2014). Novel treatment for geriatric hoarding disorder:  An open trial of cognitive rehabilitation paired with behavior therapy. American Journal of Geriatric Psychiatry, 22(3), 248–​252. Ayers, C., Wetherell, J., Golshan, S., & Saxena, S. (2011). Cognitive-​ behavioral therapy for geriatric compulsive hoarding. Behaviour Research and Therapy, 49(10), 689–​694. Ayers, C. R., Saxena, S., Golshan, S, & Wetherell, J. L. (2010). Age at onset and clinical features of late life compulsive hoarding. International Journal of Geriatric Psychiatry, 25(2), 142–​149. Beck, J. (2011). Cognitive behavioral therapy:  Basics and beyond (2nd ed.). New York: Guilford Press. Bloch, M., Bartley, C., Leckman, J., et al. (2014). Meta-​analysis: Hoarding symptoms associated with poor treatment outcome in obsessive-​ compulsive disorder. Moecularl Psychiatry, 19(9), 1025–​1030. Brehm, J. W. (1996). A theory of psychological reactance. New York: Academic Press. Bulli, F., Melli, G., Carraresi, C., Stopani, E., Pertusa, A., & Frost, R. O. (2014). Hoarding behaviour in an Italian non-​clinical sample. Behavioural and Cognitive Psychotherapy, 42(3), 297–​311. Chakraborty, V., Cherian, A. V., Math, S. B., et al. (2012). Clinically significant hoarding in obsessive-​compulsive disorder: Results from an Indian study. Comprehensive Psychiatry, 53(8), 1153–​1160. Drury, H., Ajmi, S., Fernández de la Cruz, L., Nordsletten, A. E., & Mataix-​Cols, D. (2014). Caregiver burden, family accommodation, health, and well-​being in relatives of individuals with hoarding disorder. Journal of Affective Disorders, 159(1), 7–​14. Fontenelle, L. F., Mendlowicz, M. V., Soares, I. D., & Versiani, M. (2004). Patients with obsessive-​compulsive disorder and hoarding symptoms: A distinctive clinical subtype? Comparitive Psychiatry, 45(5), 375–​383. Frost, R., & Hartl, T. (1996). A cognitive-​behavioral model of compulsive hoarding. Behaviour Research and Therapy, 34(4), 341–​350. 585

 

Frost, R., Meagher, B., & Riskind, J. (2001). Obsessive-​compulsive features in pathological lottery and scratch-​ticket gamblers. Journal of Gambling Studies, 17(1), 5–​19. Frost, R., Ruby, D., & Shuer, L. (2012). The buried in treasures workshop: Waitlist control trial of facilitated support groups for hoarding. Behaviour Research and Therapy, 50(11), 661–​667. Frost, R. O., & Gross, R. (1993). The hoarding of possessions. Behaviour Research and Therapy, 31(4), 367–​381. Frost, R. O., Rosenfield, E., Steketee, G., & Tolin, D. (2013). An examination of excessive acquisition in hoarding disorder. Journal of Obsessive-​Compulsive and Related Disorders, 3(4), 338–​345. Frost, R. O., & Steketee, G. (2014). The Oxford handbook of hoarding and acquiring. New York: Oxford University Press. Frost, R. O., Steketee, G., & Grisham, J. (2004). Measurement of compulsive hoarding:  saving inventory-​revised. Behaviour Research and Therapy, 42(10), 1163–​1182. Frost, R. O., Steketee, G., & Tolin, D. F. (2011). Comorbidity in hoarding disorder. Depression and Anxiety, 28(10), 76–​884. Frost, R. O., Steketee, G., Tolin, D. F., et al. (2015). Motives for acquiring and saving in hoarding disorder, OCD, and community controls. Journal of Obsessive-​Compulsive and Related Disorders, 1(4), 54–​59. Frost, R. O., Steketee, G., & Williams, L. (2000). Hoarding: A community health problem. Health & Social Care in the Community, 8(4), 229–​234. Frost, R. O., Tolin, D. F., & Maltby, N. (2010). Insight-​related challenges in the treatment of hoarding. Cognitive Behavioral Practice, 17(4), 404–​413. Frost, R. O., Tolin, D. F., Steketee, G., Fitch, K. E., & Selbo-​Bruns, A. (2009). Excessive acquisition in hoarding. Journal of Anxiety Disorders, 23(5), 632–​639. Fullana, M. A., Vilagut, G., Rojas-​Farreras, S., et al. (2010). Obsessive–​ compulsive symptom dimensions in the general population: Results from an epidemiological study in six European countries. Journal of Affective Disorders, 124(3), 291–​299. Grisham, J. R., Frost, R. O., Steketee, G., Kim, H. J., & Hood, S. (2006). Age of onset of compulsive hoarding. Journal of Anxiety Disorders, 20(5), 675–​686. Iervolino, A., Perroud, N., Fullana, M., et al. (2009). Prevalence and heritability of compulsive hoarding: A twin study. American Journal of Psychiatry, 165B(4), 1156–​1161. Kim, H., Steketee, G., Frost, R. O. (2001). Hoarding by elderly people. Health & Social Work, 26(3), 176–​184. Landau, D., Iervolino, A., Pertusa, A., Santo, S., Singh, S., & Mataix-​Cols, D. (2011). Stressful life events and material deprivation in hoarding disorder. Journal of Anxiety Disorders, 25(2), 192–​202. Mataix-​Cols, D., Billotti, D., Fernández de la Cruz, L., & Nordsletten, A. E. (2012). The London field trial for hoarding disorder. Psycholofgical Medicine, 43(4), 837–​847. Mataix-​Cols, D., Frost, R. O., Pertusa, A., et al. (2020). Hoarding disorder: A new diagnosis for DSM-​V ? Depression and Anxiety. 27(6), 556–​572. Matsunaga, H., Hayashida, K., Kiriike, N., Nagata, T., & Stein, D. J. (2010). Clinical features and treatment characteristics of compulsive hoarding in Japanese patients with obsessive-​compulsive disorder. CNS Spectrums, 15(4), 258–​265. Mohammadzadeh, A. (2009). Validation of Saving Inventory-​Revised (SI-​R), Compulsive hoarding measure. Iranian Journal of Psychiatry and Clinical Psychology, 15(1), 33–​41. Mueller, A., Mitchell, J. E., Crosby, R. D., Glaesmer, H., & de Zwaan, M. (2009). The prevalence of compulsive hoarding and its association with compulsive buying in a German population-​based sample. Behaviour Research and Therapy, 47(8), 705–​709. Muroff, J., Steketee, G., Bratiotis, C., & Ross, A. (2012). Group cognitive and behavioral therapy and bibliotherapy for hoarding: A pilot trial. Depression and Anxiety, 29(7), 597–​604. Nordsletten, A., Reichenberg, A., Hatch, S., et al. (2013). Epidemiology of hoarding disorder. British Journal of Psychiary, 203(6), 445–​452.

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Penzel, F. (2014). Hoarding in history. In R. O. Frost, & G. Steketee (Eds.), The Oxford handbook of hoarding and acquiring (pp. 6–​16). New York: Oxford University Press. Pertusa, A., Frost, R., & Mataix-​Cols, D. (2010). When hoarding is a symptom of OCD:  A  case series and implications for DSM-​V. Behaviour Research and Therapy, 48(10), 1012–​1020. Pertusa, A., Fullana, M. A., Singh, S., et al. (2008). Compulsive hoarding: OCD symptom, distinct clinical syndrome, or both? American Jlournal of Psychology, 165(10), 1289–​1298. Przeworski, A., Cain, N., & Dunbeck, K. (2014). Traumatic life events in individuals with hoarding symptoms, obsessive-​compulsive symptoms, and comorbid obsessive-​compulsive and hoarding symptoms. Journal of Obsesibe-​Compulsive and Related Disorders, 3(1), 52–​59. Samuels, J., Bienvenu, O., Nestadt, G., et al. (2002). Hoarding in obsessive compulsive disorder: Results from a case-​control study. Behaviour Research and Therapy, 40(5), 517–​528. San Francisco Hoarding Task Force. (2009). Beyond Overwhelmed: The impact of compulsive hoarding and cluttering in San Francisco and recommendations to reduce negative impacts and improve care. http://​www.mentalhealthsf.org//​documents/​Task%20Force%20 Report%20(FINAL).pdf. Accessed July 4, 2015. Saxena, S., Ayers, C. R., Maidment, K. M., Vapnik T., Wetherell, J. L., & Bystritsky, A. (2011). Quality of life and functional impairment in compulsive hoarding. Journal of Psychiatric Research, 45(4), 475–​480. Saxena, S., Brody, A., Maidment, K., & Baxter, L. (2007). Paroxetine treatment of compulsive hoarding. Journal of Psychiatric Research, 41(6), 481–​487. Saxena, S., & Sumner, J. (2014). Venlafaxine extended-​release treatment of hoarding disorder. International Clinical Psychopharmacoogy, 29(5), 266–​273. Snowdon, J., Pertusa, A., & Mataix-​Cols, D. (2010). On hoarding and squalor:  A  few considerations for DSM-​5. Depression and Anxiety, 29(5), 417–​424. Steketee, G., & Frost, R. (2014). Phenomenology of hoarding. In R. Frost, & G. Steketee (Eds.), The Oxford handbook of hoarding and acquiring (pp. 19–​32). New York: Oxford University Press. Steketee, G, & Frost, R. O. (2013) Treatment for hoarding disorder: Therapist guide (2nd ed.). New York: Oxford University Press. Steketee, G., Frost, R., Tolin, D., Rasmussen, J., & Brown, T. (2010). Waitlist-​controlled trial of cognitive behavior therapy for hoarding disorder. Depression and Anxiety, 27(5), 476–​484. Timpano, K. R., Exner, C., Glaesmer, H., et  al. (2011). The epidemiology of the proposed DSM-​5 hoarding disorder:  Exploration of the acquisition specifier, associated features, and distress. Journal of Clinical Psychiatty, 72(6), 780–​786. Timpano, K. R., Keough, M. E., Traeger, L., & Schmidt, N. B. (2011). General life stress and hoarding:  Examining the role of emotional tolerance. International Journal of Cognitive Therapy, 4(3), 263–​279. Timpano, K. R., Rasmussen, J., Exner, C., Rief, W., Schmidt, N. B., & Wilhelm, S. (2013). Hoarding and the multi-​faceted construct of impulsivity:  A  cross-​cultural investigation. Journal of Psychiatric Research, 47(3), 363–​370. Tolin, D., Frost, R., Steketee, G., & Muroff, J. (2015). Cognitive behavioral therapy for hoarding disorder: A meta-​analysis. Depression and Anxiety, 32(3), 158–​166. Tolin, D., & Villavicencio, A. (2011). An exploration of economic reasoning in hoarding disorder patients. Behaviour Research and Therapy, 49(12), 914–​919. Tolin, D. F., Frost, R. O., & Steketee, G. (2010). A brief interview for assessing compulsive hoarding:  The Hoarding Rating Scale-​ Interview. Psychiatric Research, 178(1), 147–​152. Tolin, D. F., Frost, R. O., Steketee, G., & Fitch, K. E. (2008). Family burden of compulsive hoarding: Results of an internet survey. Behaviour Research and Therapy, 46(3), 334–​344. Tolin, D. F., Frost, R. O., Steketee, G., Gray, K. D., & Fitch, K. E. (2008). The economic and social burden of compulsive hoarding. Psychiatry Research, 160(2), 200–​211. O b sessive - C ompulsive D isorder

 

Tolin, D. F., Meunier, S. A., Frost, R. O., & Steketee, G. (2010). Course of compulsive hoarding and its relationship to life events. Depression and Anxiety, 27(9), 829–​838. Tükel, R., Ertekin, E., Batmaz, S., et al. (2005). Influence of age of onset on clinical features in obsessive-​compulsive disorder. Depression and Anxiety, 21(3), 112–​117. Wheaton, M., Timpano, K. R., Lasalle-​Ricci, V H., & Murphy, D. (2008). Characterizing the hoarding phenotype in individuals with

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OCD: Associations with comorbidity, severity and gender. Journal of Anxiety Disorders, 22(2), 243–​252. Wheaton, M., & Van Meter, A. (2014). Comorbidity in hoarding disorder. In R. O. Frost, G. Steketee (Eds.), The Oxford handbook of hoarding and acquiring (pp. 75–​85). New York: Oxford University Press. Worden, B. L., DiLoreto, J., & Tolin, D. F. (2014). Insight and motivation. In R. O. Frost & G. Steketee (Eds.), The Oxford handbook of hoarding and acquiring (pp. 247–​259). New York: Oxford University Press.

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53. COMORBIDITY IN PEDIATRIC OCD TO URE T T E SYNDROME

Michael H. Bloch, MD, MS

O

bsessive-​compulsive disorder (OCD) is generally considered to have a bimodal distribution in age of onset (see c­ hapter 5). One peak of incidence occurs around the prepubertal years, while the other occurs in early adulthood. Although symptoms of OCD are expressed similarly across the life cycle, there are several important differences between pediatric-​and adult-​ onset OCD. Pediatric-​onset OCD cases are predominantly male, have a stronger family history of OCD, and have higher rates of comorbid ADHD and tic disorders. Understanding the importance of these comorbidities as moderators of treatment effects and being able to properly treat them (and distinguish them from primary OCD psychopathology) is critical to helping children with OCD (Geller et al., 2001; Leckman et al., 1994). Tourette syndrome (TS) and other tic disorders are not included in the category of “OCD and related disorders” in DSM-​5 (see c­ hapter  48); instead, they are categorized as a motor disorder in the chapter on neurodevelopmental disorders (American Psychiatric Association, 2013). Nevertheless, as discussed throughout this chapter, they appear to be related to OCD, so much so that DSM-​5 adds a “tic-​related” specifier to the OCD diagnosis. There is considerable evidence for overlapping pathophysiology and genetics, as discussed later. For these reasons, TS and tic disorders are included in this section on OCD-​related disorders. TS is a tic disorder estimated to affect 0.3% to 1% of school-​aged children (Robertson, Eapen, & Cavanna, 2009; Scharf, Miller, Mathews, & Ben-​Shlomo, 2012). Roughly one third of children with TS will go on to develop OCD during their lifetime. Tics are sudden, repetitive movements, gestures, or phonic productions that typically mimic some aspect of normal behavior. Usually of brief duration,

individual tics rarely last more than 1 second. Many tics occur in bouts with brief inter-​tic intervals of less than 1 second. Individual tics can occur singly, or together in an orchestrated pattern. Motor tics, which can be viewed as disinhibited fragments of normal movement, can vary from simple, abrupt movements, such as eye blinking, nose twitching, head or arm jerks, or shoulder shrugs, to more complex movements that appear to have a purpose, such as facial or hand gestures or sustained looks. These two phenotypic extremes of motor tics are classified as simple and complex motor tics, respectively. Similarly, phonic tics can be classified as simple or complex. Simple phonic tics are sudden, meaningless sounds, such as throat clearing, coughing, sniffing, spitting, or grunting. Complex phonic tics are more protracted, sometimes meaningful utterances. These can vary from prolonged throat clearing, to syllables, words or phrases, to more complex behaviors such as repeating one’s own words (palalalia) or those of others (echolalia), and in rare cases, the utterance of obscenities (coprolalia). According to DSM-​5 criteria (American Psychiatric Association, 2013), TS is characterized by multiple motor and vocal tics that are present for at least 1 year and have an onset prior to age 18. Chronic tic disorder is characterized by motor or vocal tics (but not both) lasting at least one year in duration and is roughly five times more prevalent than TS. DSM-​5 newly established the diagnosis of Provisional Tic Disorder for children who display tics for less than one year (i.e., that do not meet criteria for TS or chronic tics). Figure 53.1 depicts the typical clinical course of tic symptoms in TS. Tics typically (1)  onset around the age of 4 to 6  years; (2)  reach their worst ever severity around 10 to 12  years; and, in roughly two thirds of cases, (3)  decrease in severity during adolescence and

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Relative tic severity (ARRTS)

5

4

3

2

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0

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Age (y) Actual Means Estimates from Model

patients report a fleeting sense of relief after a bout of tics has occurred (Leckman, 2002). With increasing awareness of premonitory urges, TS patients begin to exhibit a variable degree of voluntary control over tic performance. Most individuals are able to suppress their tics for short intervals of time. However, this voluntary control should be likened to that of controlling eye blinking. Eye blinking and tics can both be inhibited voluntarily, but only for a limited period of time and only with mounting discomfort. Thus, some adult TS patients have near complete control over the situation when their tics occur. However, in these cases, resistance to the mounting tension of a premonitory urges can produce mental and physical exhaustion even more impairing and distracting than the tics themselves. C OMOR B IDIT Y IN  T OU R E T T E S YNDROM E

Figure 53.1  THE COURSE OF TIC SEVERITY DURING THE FIRST TWO

Tics are the most prominent feature of TS, but they are often neither the first nor the most impairing psychological disturbance TS patients endure (Hirschtritt et al., 2015). Only ~10% of individuals with TS experience tics without additional comorbidities. The two most common comorbidities in TS are attention-​deficit hyperactivity disorder (ADHD) and OCD. The onset of ADHD symptoms early adulthood. Tics in TS wax and wane in sever- typically precedes the onset of tic symptoms by a couple ity over the course of the disorder. The frequency and of years. In contrast, OCD symptoms typically present number of tics can be highly variable from minute-​to-​ around the age of 12 to 13, after tics have reached their peak minute, hour-​to-​hour, day-​to-​day, week-​to-​week, month-​ severity. Approximately one half of children diagnosed with to-​month, and even year-​to-​year. Tic episodes occur in TS experience comorbid ADHD. Roughly one third of TS bouts, which in turn also tend to cluster. Tic symptoms, patients will experience clinically significant OCD symphowever, can be exacerbated by stress, fatigue, extremes of toms during the course of their lifetime. More details on the temperature, and external stimuli (i.e., in echolalia tics). treatment of comorbid ADHD and OCD in TS are outIntentional movements and intense involvement and lined in later sections of this chapter. concentration in activities tend to dissipate tic symptoms (Leckman, 2002). NE U ROB IOLOGY OF   T IC S Many individuals with tics, especially older ones, are aware of premonitory urges. Premonitory urges involve a feeling of tightness, tension, or itching, accompanied As in the case of OCD, dysfunction of frontostriatal cirby a mounting sense of discomfort or anxiety that can be cuits is hypothesized to be central to the pathogenesis of relieved only by the performance of a tic. These premoni- TS (Marsh, Maia, & Peterson, 2009). Frontostriatal circuits tory urges are similar to an itch, or to the sensation preced- are best known for the execution of planned movements. ing a sneeze. Premonitory urges cause many TS patients to However, these circuits are also crucial for the performance suffer from an endless cycle of rising tension and tic per- of many aspects of goal-​directed behavior, such as those formance, because the relief provided by tic performance that drive action (e.g., cognition, emotion, reward) (Marsh is ephemeral. Thus, soon after tic performance, the tension et al., 2009). Frontostriatal circuits consist of multiple parof the premonitory urge again crescendos. A  majority of allel but interacting neuronal circuits that project information from cortical areas to the striatum (caudate, putamen, DECADES OF LIFE. The solid line connecting the small circles plots the means of the annual rating of relative tic severity scores (ARRTS) recorded by the parents. The dashed line represents a mathematical model designed to best fit the clinical data. Two inflection points are evident that correspond to the age of tic onset and the age at worst-​ever tic severity, respectively.  (Adapted from Leckman et al., 1998 with permission.)

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nucleus accumbens), and back to the cortex via the thalamus (see c­ hapters 20, 21). Frontostriatal circuits are somatotopically and hierarchically organized. Abnormalities in two frontostriatal circuits that initiate from and project back to (1)  premotor and motor cortex and (2)  prefrontal cortex (dorsal prefrontal and orbitofrontal cortex) are central to the pathogenesis of TS (Marsh et al., 2009). Premotor cortex is important for the driving, planning, initiation, and execution of voluntary movements. Electrical stimulation of the supplementary motor area, the component of the premotor cortex that is most consistently implicated in the pathophysiology of TS, can produce (1) synergistic, complex, coordinated movements involving cooperation across multiple joints, analogous to the complex tics seen in TS; and (2) sensations involving the “urge” to move, similar to the premonitory urges experienced by many patients with TS (Fried et al., 1991). Thus, in TS, abnormalities in the frontostriatal circuits initiating in the premotor and motor cortex may underlie both tic generation and the premonitory urges. Supporting this hypothesis, functional magnetic resonance imaging (fMRI) studies have demonstrated activation of the supplementary motor cortex just prior to tic generation (Bohlhalter et al., 2006; Hampson, Tokoglu, King, Constable, & Leckman, 2009). Structural neuroimaging examining 25 children with TS and 35 age-​matched controls demonstrated thinning of the sensorimotor cortex in children with TS compared with healthy controls (Sowell et al., 2008). Among children with TS, tic severity was associated with degree of thinning of the sensorimotor area (especially dorsal regions). Furthermore, severity of facial tic symptoms was associated with degree of thinning in the ventral sensorimotor cortex, which controls the facial, orolingual and laryngeal musculature (Sowell et al., 2008). Prefrontal cortex is important for planning complex cognitive behaviors, personality expression, decision making, and social behavior. Many of these functions are captured under the umbrella of cognitive control, which is the ability to regulate emotional responses and to inhibit temptations or impulses for immediate gratification when waiting for longer-​termed delayed rewards (Mischel, Shoda, & Rodriguez, 1989; see ­chapter 22). Frontostriatal circuits originating in the prefrontal cortex are thought to be particularly important for effective cognitive control, and disruption of these circuits is particularly important for the pathogenesis of TS (Marsh, Zhu, Wang, Skudlarski, & Peterson, 2007), particularly in moderating tic severity and control. Consistent with this hypothesis, an fMRI study of 22 adults with TS revealed that activation of the frontal cortex was associated with tic suppression (Peterson et

T ourette S yndrome

al., 1998). Frontal activation during tic suppression was also associated with increased activity in the caudate and decreased activity in the putamen, globus pallidus, and thalamus (Peterson et al., 1998). The magnitude of activity in the caudate (increased) or putamen, globus pallidus and thalamus (decreased) was significantly associated with severity of tics in the preceding month. Anatomical neuroimaging has consistently demonstrated prefrontal cortex abnormalities in TS subjects, compared with healthy controls. The largest neuroimaging study on TS to date, involving 155 TS subjects and 131 controls, demonstrated larger dorsolateral prefrontal cortex volumes in children with TS and smaller dorsal prefrontal cortex in adults with TS (Peterson et  al., 2001). Larger dorsal prefrontal volumes in children were associated with decreased tic severity. These data suggest that prefrontal cortex hypertrophy may represent a compensatory or adaptive process that attenuates tics. Subsequent structural neuroimaging studies have confirmed the negative association between prefrontal cortex hypertrophy and tic severity in children with TS (Sowell et al., 2008). The most consistent structural neuroimaging finding in TS is a reduction in caudate volume. Large cross-​sectional neuroimaging studies have demonstrated a small but significant 5% reduction in the caudate volume of TS subjects compared to that of controls (Peterson et al., 2003). Studies of monozygotic twins discordant for tic severity have demonstrated reduced caudate volumes in the more severely affected twin (Hyde et  al., 1995). These reductions in caudate volumes in children with TS have been further associated with the persistence of tic symptoms into adulthood (Bloch, Leckman, Zhu, & Peterson, 2005). Postmortem neurostereological studies assessing neuronal density and numbers in adults with severe, intractable TS and five healthy controls suggest a possible mechanism for this caudate volume reduction (Kalanithi et al., 2005., 2010; Lennington et al., 2016). TS subjects demonstrated a reduced overall number of two types of interneurons in the striatum: parvalbumin positive GABAergic and cholinergic interneurons (Kalanithi et al., 2005; Kataoka et al., 2010). The decrease in cholinergic interneurons was greatest in the anterior caudate, the area of prefrontal projections; the reduction was more modest in striatal areas receiving projections from sensorimotor cortex, and density of cholinergic interneurons was normal in limbic areas (Kataoka et al., 2010). Strikingly, the experimental depletion of either of these interneuron types in otherwise normal adult mice produces repetitive behaviors that may represent tics, supporting the causal importance of the pathological changes

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to the development of TS symptomatology (Xu, Kobets, et al., 2015; Xu, Li, & Pittenger, 2016). Together, these recent findings strongly implicate the prefrontal and sensorimotor projection areas of the basal ganglia in the pathogenesis of TS. This focal loss of interneurons may underlie the impairment of cognitive control, and the requirement of increased frontal activation to achieve control during tic suppression, that TS patients experience. This loss of interneurons in sensorimotor projection areas also suggests a possible mechanism for tic generation involving abnormal firing of striatal projection neurons due to impaired inhibition (Albin & Mink, 2006). GENETICS Twin and family studies of TS have demonstrated that it is heritable. Studies have suggested that approximately 60% of the phenotypic variation in TS is explained by genetic factors (Davis et  al., 2013). Evidence suggests that first-​ degree relatives of individuals with TS have a 5-​to 15-​ fold increased risk of developing TS (Schultz et al., 1998). Offspring of a parent with TS have roughly a 10% risk of developing TS. Despite the well established hereditary component of TS, definitively establishing TS-​associated genes has proved to be difficult. In a recently completed genome-​ wide association study (GWAS), no loci achieved genome-​ wide significance (Scharf et al., 2013), although a couple of single nucleotide polymorphisms (SNPs) came close. The SNP rs7868992 on chromosome 9q32 within the gene COL27A1 was strongly associated with a diagnosis of TS (p = 1.9 × 10−6; note that this is considered only a suggestive association, as the generally accepted trend for genome-​wide significance in GWAS is p < 5 × 10–8). This SNP association was replicated in a secondary cohort of 211 TS subjects and 285 controls from two Latin American population isolates from Costa Rica and Colombia (Scharf et al., 2013). COL27A1 is a fibrillar collagen primarily expressed in cartilage, although it is also expressed in the cerebellum during development (Pace, Corrado, Missero, & Byers, 2003). The role of COL27A1 in the development of the nervous system is unknown (Fox, 2008). The SNP rs6539267 on chromosome 12q23, within an intron of POLR3B, was also associated with TS in this GWAS sample, at trend level (p = 7.4 × 10−6; Scharf et al., 2013). POLR3B encodes a subunit of ribonucleic acid (RNA) polymerase III (Dieci, Fiorino, Castelnuovo, Teichmann, & Pagano, 2007). Recessive mutations in POLR3B can cause hypomyelinating leukodystrophy, which typically presents 592

between early childhood to adolescence and is associated with ataxia, motor regression with upper motor neuron signs, and some mild cognitive dysfunction or regression (Daoud et al., 2013). Recent analysis of genome-​wide common variant data from the same TS GWAS estimated that 21% of the hereditability in TS is due to the inheritance of rare variant alleles (genes with a minor allele frequency of less than 5%; Davis et al., 2013). Some of the greatest clues to the underlying pathophysiology and the genetic risk factors for TS have been discovered by investigating rare genes that have a large effect in individual families. Although it is unlikely that the identification of a very rare mutation in a single family will explain a large proportion of the genetics of TS, it may help elucidate the underlying important pathophysiology in the disorder. SLITRK1 is a candidate gene in TS that was initially identified through the discovery of a chromosomal breakpoint in one child with TS, which was judged likely to affect the expression of the gene. Subsequent investigation led to the identification of one frameshift mutation and two identical variants in the 3′ untranscribed region of this gene, among 174 unrelated probands with TS (no anomalies were demonstrated in this gene in over 3,600 controls; Abelson et al, 2005). SLITRK1 encodes a transmembrane protein that is expressed in the fetal brain at 20 weeks gestation in multiple neuroanatomical areas implicated in TS neuropathology, including the cortical plate, striatum, globus pallidus, thalamus, and subthalamic nucleus (Abelson et al., 2005). It is highly expressed in the striatum during early development and is hypothesized to be important in early development of corticostriatal circuits; strikingly, although expression declines dramatically in adulthood, it persists in the cholinergic interneurons of the striatum, which as noted have been implicated in TS by post-​mortem investigations (Stillman et al., 2009). SLITRK1 also interacts with 14-​3-​3 proteins, which are ubiquitously expressed phosphobinding proteins that regulate several important cellular processes, including cell proliferation, neuronal migration, and membrane excitability (Kajiwara, Buxbaum, & Grice, 2009). Another strong candidate gene was established through linkage analysis of a two-​generation pedigree in a densely affected family in which the father and eight children had TS (Ercan-​Sencicek et al., 2010). A rare, functional mutation was identified in the HDC gene, encoding the enzyme L-​histidine decarboxylase, which catalyzes the rate-​limiting step in histamine biosynthesis. HDC knockout mice show decreased brain histamine and increased stereotypies induced by dopamine agonists (Castellan Baldan et al., 2014) and stress (Xu, Li, Ohtsu, & Pittenger, 2015), O b sessive - C ompulsive D isorder

 

supporting the causal relevance of mutations in this gene to TS pathophysiology. ENVIRONMEN TAL RI SK FACTO RS Although genetic studies have identified a large hereditary component of TS, it remains clear that environmental factors are also important in the pathogenesis of the disorder. Several environmental factors, such as stress, fatigue, extremes of temperature, and perhaps some infections make tics worse over the short term. Other factors such as focused concentration may alleviate tics temporarily. The existence of monozygotic twins discordant for tic severity emphasizes the importance of environmental factors (Hyde, Aaronson, Randolph, Rickler, & Weinberger, 1992). In cases of monozygotic twins discordant for tic severity, the twin with more severe tics has been shown to usually possess the lower birth weight and smaller caudate nucleus, as well as to have a greater number of dopamine receptor sites in the caudate nucleus (Hyde et al., 1995; Wolf et  al., 1996). Retrospective case-​control studies examining the birth histories of individuals with TS compared with healthy controls have identified several perinatal risk factors for TS. These risk factors included maternal smoking during pregnancy, low birth weight, reduced gestational age, increased numbers of complications during pregnancy, and low maternal and high paternal age (Burd, Severud, Klug, & Kerbeshian, 1999; Klug, Burd, Kerbeshian, Benz, & Martsolf, 2003; Motlagh et al., 2010; Pasamanick & Kawi, 1956; Whitaker et al., 1997). However, few of these risk factors have been replicated across studies, and the experimental methodology is highly prone to potential recall bias. A prospective longitudinal study that followed 6,090 children born in Avon, UK from before delivery through age 13 to 14  years sought to replicate previous findings regarding perinatal risk factors for TS (Mathews et  al., 2014). This study identified maternal alcohol and cannabis use (but not tobacco) in the third trimester of pregnancy as risk factors for the development of TS. Less than adequate maternal weight gain during pregnancy was also a risk factor. Another recent prospective cohort study examining over 73,000 singleton pregnancies from the Danish National Birth Cohort demonstrated a significant association between maternal smoking during pregnancy and risk of TS (hazard ratio = 1.66); heavier maternal smoking was associated with greater risk (Browne et al., 2016).

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E V IDE NC E - ​B AS E D T R E AT ME NT S F OR T IC DIS OR DE R S Given the waxing and waning course typically seen in tic disorders, any intervention performed in response to symptom exacerbation is likely to be associated with clinical improvement. Thus, it is usually most prudent to treat patients’ overall, long-​term symptom severity rather than chasing individual ebbs and flows in the natural course of the illness. Interventions should be started with the goal of reducing the tics (and the side effects of treatments) to the level that minimizes social and educational impairments, rather than with the goal of completely eliminating the tics—​a goal that is unachievable in the majority of cases. Many cases of TS can be successfully managed without medication. When patients present with coexisting ADHD, OCD, depression, or bipolar illness, it is usually better to treat these “comorbid” conditions first, as successful treatment of these disorders often will diminish tic severity. PSYCHOEDUCATION

Roughly 20% of children with TS demonstrate a significant reduction in tic symptoms over the short term in response to a psychoeducational control condition (Piacentini et  al., 2010). Thus, psychoeducation is a useful intervention that may be sufficient for many younger patients. Psychoeducation should focus on providing relevant and accurate information regarding prognosis and treatment outcomes. Psychoeducation can provide some predictability and structure to families on what initially seem like random fluctuations in tic symptoms. In psychoeducation, it is crucial to stress that tic symptoms, even when they persist to adulthood, are typically compatible with success in academic, occupational and social environments. Additionally, psychoeducation and supportive therapy can minimize impairment associated with tic symptoms. Educational interventions should not only focus on the child and his or her family, but also on areas where the tics may be causing the greatest impairment (e.g., targeting teachers, peers, and relatives). Often psychoeducation and a few simple accommodations in school can make a significant difference in reducing academic impairments in children with TS. Box 53.1 indicates the primary aspects of psychoeducation that can be provided to families of children with TS. The Tourette Syndrome Association (http://​www.tsa-​usa.org/​) and Tourette Syndrome “Plus” (http://​www.tourettesyndrome.net/​) provide additional resources for families. 593

 

PSYCHOEDUCATIONAL POINTS PROVIDED IN CLINICAL EVALUATION OF CHILDREN WITH TS BOX 53.1 

Pearls of wisdom for the treatment of children with TS 1. Tics wax and wane in severity. 2. Focused concentration, especially that involving motor activity, can often improve tics over the short term. 3. Factors that can often make tics temporarily worse include stress, fatigue and physical illness.

(e.g., premonitory urges). Competing response training is based on the hypothesis that tics are encouraged through negative reinforcement; this is similar to the theoretical foundation of ERP therapy in OCD (see ­chapter 37). Performing tics leads to a reduction in premonitory urges, and over time this negative reinforcement cycle encourages repetition of the tic; withholding tics through performance of a competing response breaks this cycle. Effect sizes observed for CBIT in controlled trials (ES ≈ 0.6–​0.7) are similar in magnitude to those observed for the most effective pharmacological treatments for tics (McGuire et al., 2014; Piacentini et al., 2010; Wilhelm et al., 2012).

4. The worst-​ever severity of tics usually occurs between the ages of 10 and 12 years. 5. Tics typically improve throughout adolescence. 6. There is no current evidence that suggests pharmacological treatments alter the long-​term clinical course of TS. 7. The use of pharmacological treatments should be focused at minimizing tics rather than eliminating tics.

PHARMACOTHERAPY

Table 53.1 summarizes evidence-​based treatment recommendations regarding currently available pharmacological and nonpharmacological treatments for tic disorders. Table 53.1 also includes the target dosing range, appraisal of the current evidence-​base by professional organizations, as well as common and significant side effects for pharmacological agents used to treat tic disorders.

8. Comorbid ADHD is common in children with TS and, when present, is usually of greater impairment than the tics themselves. 9. Children with TS are at a high risk of developing OCD during adolescence and early adulthood. 10. The offspring of those with TS have approximately a 10% chance of developing significant tics (assuming their partner has no family history of tics).

BEHAVIORAL TREATMENTS

Comprehensive behavioral intervention for tics (CBIT) is a behavioral treatment for tic disorders that has demonstrated efficacy in reducing tic symptoms in both children and adults with TS, when compared with a psychoeducation and supportive therapy control condition (McGuire et al., 2014; Piacentini et al., 2010; Wilhelm et al., 2012). CBIT is based on habit reversal therapy techniques, consisting of awareness and competing response training. Awareness training involves increasing the patient’s recognition of the occurrence of present tics and the early warning signs of tics, such as premonitory urges. Competing response training involves engaging in a voluntary behavior that is physically incompatible with performing the tic, contingent upon an early warning sign that the tic is going to occur 594

Alpha-​2 Adrenergic Agonists Alpha-​2 adrenergic agonists are currently recommended as the first-​line pharmacological agents in the treatment of tic disorders (Murphy et al., 2013). Alpha-​2 agonists are generally preferred, compared with antipsychotics, in the treatment of children because of their efficacy in treating comorbid ADHD symptoms and their more benign side-​ effect profile. Metaanalysis of randomized, placebo-​ controlled trials has demonstrated that alpha-​ 2 agonists have a small-​ to-​ medium-​ sized treatment effect in improving tic symptoms compared with placebo (standardized mean difference [SMD] = 0.31, 95% confidence interval [CI]: 0.15–​0.48), z = 3.64, p < 0.001; Weisman, Qureshi, Leckman, Scahill, & Bloch, 2013). Comorbid ADHD appears to have a significant moderating effect of the efficacy of alpha-​2 agonists in treating tic symptoms. Trials that only enrolled subjects with comorbid ADHD demonstrated a medium-​ to-​ large effect of alpha-​2 agonists in reducing tics (SMD = 0.68 [95% CI: 0.36–​1.01], z = 4.10, p < 0.001). Trials that excluded subjects with ADHD demonstrated a small, nonsignificant benefit (SMD = 0.15 (95% CI: 0.06–​0.36), z = 1.40, p = 0.16; Weisman et al., 2013). Metaregression similarly demonstrated a strong positive association between proportion of subjects with comorbid ADHD enrolled O b sessive - C ompulsive D isorder

 

TA B L E   5 3 . 1  

PH ARM AC O L O GI C A L AGE N T S US E D TO  TR EAT TI C D I S O R D ER S

Medication

Starting Dose

Titration Schedule

Typical Dosage

Advantages

Side Effects

Haloperidol

0.25 mg per day

0.5 mg every 1–​2 weeks

0.5–​6.0 mg per day

Pimozide

1.0 mg per day

1.0 mg every 1–​2 weeks

1–​10 mg per day

Most effective medications for tics with longest record of use

Tardive dyskinesia, acute dystonic reactions, akathisia, sedation, depression, school and social phobias, and/​or weight gain

Risperidone

0.25–​.5 mg day

0.25–​.5 mg per week divided BID

1–​6 mg per day

Weight gain, sedation, galactorrhea

Olanzapine

2.5–​5 mg per day

2.5–​5 mg every 1–​2 weeks divided BID

5–​20 mg day

Ziprasidone

5 mg per day

5mg every week with BID dosing

20–​40 mg per day

Most effective medications for tics, less side effects than typical neuroleptics, used to treat comorbid aggression and bipolar disorder

Guanfacine

0.5mg QHS

0.5 mg weekly to TID dosing

2–​4 mg divided TID

Helps treat comorbid ADHD

Sedation

Clonidine

.025–​0.05 mcg QD or BID

0.05 mcg added on weekly to TID or QID dosing

0.05–​0.25 mcg/​kg TID or QID

NEUROLEPTICS TYPICAL

ATYPICAL

Weight gain, sedation, galactorrhea Prolonged QT interval, rare heart arrhythmias

ALPHA2-​AGONISTS

in trials of alpha-​2 agonists and their measured efficacy in treating tics (β = 0.0053 (95% CI: 0.0015–​0.0091), z = −2.72, p = 0.006; Weisman et al., 2013).

Antipsychotic Agents Antipsychotic agents are the most effective pharmacological agents for the treatment of tic disorders. Despite this fact, antipsychotic agents are not generally utilized as a first-​line treatment for TS, because of their unfavorable side-​ effect profile. Metaanalysis demonstrated a significant, medium-​to-​large treatment effect of antipsychotic agents in improving tic symptoms compared with placebo (ES = 0.61, 95% CI: 0.36–​0.86, z = 4.80, p = 0.00001; Weisman et al., 2013). Although haloperidol and pimozide are the only medications approved by the Food and Drug Administration (FDA) to treat TS, several other antipsychotic agents, such as risperidone and ziprasidone, also have evidence of efficacy in randomized, placebo-​ controlled trials (Weisman et al., 2013). Both stratified subgroup analysis comparing effect sizes of different antipsychotics (compared with placebo and in head-​to-​head antipsychotic trials) and metaregression found no evidence that T ourette S yndrome

Sedation, hypotension, rebound hypertension on withdrawal

any particular antipsychotic agent was more effective than any other for the treatment of tic disorders (Weisman et al., 2013). Metaregression also suggests that there is no association between maximum dose of antipsychotics used in trials and their measured efficacy (Weisman et al., 2013). Therefore, it is advisable to keep antipsychotic doses lower in TS than those typically used for the treatment of psychotic disorders (Murphy et al., 2013). OTHER TREATMENTS FOR TICS

Botulinum toxin injections are a treatment reserved for adults with severely debilitating tics involving focal muscle groups. Vocal tics (e.g., coprolalia) or motor tics involving the upper face and neck are considered to be the best areas to target with this treatment. Botulinum toxin injections should be performed only by an experienced clinician. A single randomized, controlled trial of 20 adolescents and adults with TS demonstrated that botulinum toxin injections were more effective than placebo in reducing tic symptoms (Marras, Andrews, Sime, & Lang, 2001). However, one possible side effect of this treatment is weakness of the affected muscles, which can cause ptosis, dysphagia, 595

 

hypophonia, and loss of facial expression, depending on the muscles injected. Given the increase in understanding of the neurocircuitry underlying TS, deep brain stimulation (DBS) has been investigated as a possible treatment for adults with severe and debilitating tic symptoms that are refractory to evidence-​based interventions (see c­ hapter 46 for a discussion of DBS in OCD). Randomized, controlled crossover trials have suggested that DBS targeting either the globus pallidus pars interna or the centromedian-​parafascicular nucleus of the thalamus may be effective in the treatment of TS (Ackermans et  al., 2011; Maciunas et  al., 2007; Welter et  al., 2008). However, larger, well-​controlled trials are lacking. Given that a large proportion of children with TS improve during adolescence, these interventions should be reserved only for adult patients with severe and incapacitating tics. Similarly, these treatments should only be performed by an experienced neurosurgeon alongside a psychiatrist/​neurologist experienced in tic disorders and in programming the stimulators after surgery. TR EATM ENT O F CO MO RBI D O CD IN TOURETTE SYN D RO ME Roughly one third of children with TS will experience comorbid OCD symptoms during their lifetime (Bloch, Peterson, et al., 2006). OCD symptoms typically reach their worst-​ever severity a couple of years after tic symptoms, and often persist into adulthood (Bloch, Peterson, et al., 2006). Once they reach adulthood, many children with TS will find their OCD symptoms to be more impairing than the tics themselves. However, it appears that young children with OCD and comorbid tics may be much more likely to experience a remission of their OCD symptoms during adolescence, compared with children with OCD without comorbid tics (i.e., the OCD symptoms may follow a trajectory more similar to the comorbid tics during adolescence; Bloch, Craiglow, et al., 2009). OCD symptoms in patients with comorbid tics are more likely to involve symmetry, ordering, and arranging compulsions as well as “just right” obsessions (Leckman et al., 1994). OCD symptoms in patients with comorbid tics appear just as responsive to cognitive behavioral therapy (CBT) as OCD patients without comorbid tics (March et al., 2007). By contrast, multiple trials have suggested that OCD symptoms in patients with comorbid tics are less responsive to SSRI pharmacotherapy (Geller et al., 2003; March et al., 2007). Metaanalysis suggests that

596

antipsychotic augmentation (adding a low dose of an antipsychotic agent to maximal-​dose SSRI pharmacotherapy for OCD) is more effective in reducing OCD symptoms in adults with comorbid tics (NNT = 2.3) compared with OCD symptoms in adults without comorbid tics (NNT = 5.9; Bloch, Landeros-​Weisenberger, et al., 2006). Given these data, it is currently recommended that all OCD patients with comorbid tic disorders be offered CBT for their OCD symptoms as first-​line treatment (Murphy et al., 2013; Practice parameters for assessment and treatment of children and adolescents with OCD, 1998). SSRIs are still recommended as the initial pharmacological in OCD patients with comorbid tics, given the relatively benign side-​effect profile of SSRIs and the lack of evidence suggesting antipsychotic monotherapy is effective in treating OCD symptoms. T R E AT ME NT OF   C OMOR B ID ADH D IN  C H ILDR E N W IT H   T OU R E T T E S YNDROME AND/​OR   OC D At least one-​half of the children with TS who reach clinical attention experience comorbid ADHD (Khalifa & von Knorring, 2006; Robertson & Eapen, 1992). When ADHD is present in children with tics, these symptoms typically cause greater impairment in academic performance and social relationships than the tics themselves (or an additional OCD comorbidity; Spencer et al., 1998; Sukhodolsky et al., 2003). Psychostimulant medications are currently the first line of treatment for children with ADHD (Dulcan, 1997). In head-​to-​head clinical trials and in metaanalyses, psychostimulant medications have demonstrated superior short-​ term efficacy compared with both non-​psychostimulant medications and psychosocial treatments for ADHD (Faraone, Biederman, Spencer, & Aleardi, 2006). However, concerns regarding the worsening of tics (in children with comorbid TS) or anxiety (in children with comorbid OCD and anxiety) often limit the use of psychostimulant medications. The FDA currently requires package inserts of most psychostimulant medications to list the presence of a tic disorder or a family history of TS as a contraindication to their use. This warning was based on several case reports and case series associating psychostimulant use with the start or exacerbation of tic symptoms in children (Denckla, Bemporad, & MacKay, 1976; Lowe, Cohen, Detlor, Kremenitzer, & Shaywitz, 1982). On the other hand, several lines of evidence suggest that the

O b sessive - C ompulsive D isorder

 

association between psychostimulant medications and tics may be a result of confounding variables. Approximately 20% of children with ADHD develop a chronic tic disorder (Leckman, 2002). When tics and ADHD cooccur, symptoms of ADHD typically precede the onset of tic symptoms by 2 to 3 years; thus, a proportion of children initially diagnosed with ADHD may have undiagnosed tic symptoms (Leckman, 2002). Metaanalysis has demonstrated that psychostimulant medications are effective in treating ADHD symptoms in children with comorbid tic disorders (Bloch, Panza, Landeros-​Weisenberger, & Leckman, 2009). Furthermore, there is no evidence from randomized, controlled trials to suggest that psychostimulant treatment worsens comorbid tic symptoms. Metaanalyses of randomized, controlled trials of stimulants demonstrated new onset tics or worsening of tic symptoms were commonly reported in both the psychostimulant (event rate = 5.7%, 95% CI = 3.7%–​8.6%) and placebo groups (event rate = 6.5%, 95% CI = 4.4%–​9.5%; Cohen et al., 2015). The risk of new onset or worsening of tics associated with psychostimulant treatment was similar to that observed with placebo (risk ratio = 0.99, 95% CI = 0.78–​1.27, z = –0.05, p = .96; Cohen et al., 2015). Alpha-​2 agonists appear to be a wise initial treatment for children with both clinically significant ADHD and tics, as these medications are effective in reducing both ADHD and tic symptoms (Bloch, Panza, et al., 2009). A single randomized, placebo-​controlled trial in children with ADHD and a comorbid tic disorder demonstrated that combination treatment with both methylphenidate (a psychostimulant medication) and clonidine (an alpha-​2 agonist) may be more effective in reducing ADHD symptoms in children with comorbid tics than either treatment alone (Tourette Syndrome Study Group, 2002). Anxiety is listed as a common side effect of psychostimulant medications. Most experienced tertiary OCD providers have recognized OCD as the presenting complaint for a patient with psychostimulant abuse or side-​ effects. Increased anxiety, obsessiveness, depression, and psychosis are possible symptoms of psychostimulant overuse that can produce an OCD-​like syndrome (albeit typically in conjunction with other more common symptoms of psychostimulant abuse such as tachycardia, insomnia, headache, nausea, dizziness, etc.). However, in a metaanalysis that was conducted to analyze anxiety as a side effect in 29 psychostimulant trials involving slightly under 3,000 children with ADHD, the risk of anxiety associated with psychostimulant treatment was significantly lower than that seen with placebo (relative risk [RR] =

T ourette S yndrome

0.86 [95% CI: 0.77, 0.95], z = –2.90, p < 0.05; Coughlin et al., 2015). Higher doses of psychostimulants were associated with a reduced measured risk of anxiety when compared with placebo (β = –0.0039 [95% CI: –0.00718, –0.00064], z = –2.34, p = 0.019; Coughlin et al., 2015). Therefore, it appears that successful treatment of primary ADHD symptoms reduces anxiety to a greater extent than any possible side-​effect of the medication in children with ADHD. C ONC LU S ION Tics cause significant social and academic impairment for many children affected by TS. Several evidence-​based pharmacological and behavioral interventions exist that have demonstrated efficacy in reducing TS symptoms. The majority of children with TS experience a significant decrease in symptoms during adolescence and early adulthood, such that tics are no longer a source of impairment into adulthood. However, the most severe and refractory cases of TS typically persist into adulthood. OCD symptoms are common in children with TS; they often begin around adolescence and remain a substantial source of impairment (often greater than the tics themselves in adulthood). OCD patients with comorbid tics seem equally likely to respond to CBT as those without tics, but exhibit a slightly decreased likelihood of response to SSRIs and an increased likelihood of response to antipsychotic augmentation. When OCD patients with comorbid tics are diagnosed early, effective CBT for OCD is an appropriate first-​line treatment and is often effective in alleviating their symptoms. AC K NOW LE DGE ME NT S Michael Bloch gratefully acknowledges support from the National Institute of Mental Health, the Patterson Foundation, the Brain and Behavior Research Foundation and the Tourette Association of America. The State of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center and UL1 RR024139 from the National Center for Research Resources, a component of the National Institutes of Health, and NIH roadmap for Medical Research. Disclosures:  The author is on the Scientific Advisory Board of Therapix Biosciences.

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S ECT I O N 7. COMORBIDITY

 

 

54. MOOD AND ANXIETY DISORDER COMORBIDITY IN OCD L. Baer, PhD, A. Fang, PhD, N. C. Berman, PhD, and W. E. Minichiello, EdD

common lifetime comorbidities (see Table 54.1). As the base rates of current bipolar I and II illness and dysthymia (as determined by SCID) were relatively low in these studComorbidity among anxiety and mood disorders is the ies, and because research is limited on these comorbidities rule rather than the exception in psychiatric practice and with OCD, this discussion of mood disorder comorbidity research. For example, a large study of 1,127 patients stud- focuses primarily on unipolar depression. ied by structured diagnostic interview found that approxiTwo of the studies summarized in Table 54.1 exammately 50% of patients with a DSM-​IV anxiety disorder also ined the sequence of onset of lifetime OCD and comorbid had one or more currently comorbid anxiety or mood dis- mood and anxiety disorders in these OCD sufferers. In the orders (Brown et al., 2001). The same study found lifetime Netherlands sample, OCD preceded the mood disorder comorbidity exceeding 75% (Brown et al., 2001). Although diagnosis in two thirds of cases, whereas OCD followed obsessive-​compulsive disorder (OCD) has been removed or occurred in the same year as an anxiety disorder diagnofrom the anxiety disorder category in the Diagnostic and sis in two thirds of cases (Hofmeijer-​Sevink et  al., 2013). Statistical Manual of Mental Disorders-​Fifth Edition (DSM-​ Similarly, in the Brazil sample, SCID interview found the 5; see ­chapter 48; this change has been criticized on empirical mean age of separation anxiety disorder was 5.9 years, mean grounds [Abramowitz et al., 2015]), its pattern of comorbid- age of onset of OCD was at 12.6 years, mean age of onset ity with anxiety and mood disorders closely mirrors the gen- of any anxiety disorder was 13.6  years, and mean age of eral pattern seen in anxiety disorders, as described above. As onset of a mood disorder was 24.3 years (de Mathis et al., illustrated in the two left columns of Table 54.1, two recent 2013). Other studies have also found that the onset of the studies of more than 650 patients with primary OCD in first major depressive episode (but not dysthymia [Brown the Netherlands and the United States found that approxi- et al., 2001]) occurs years after OCD onset in the majority mately half of patients met criteria for one or more current of OCD patients (Bellodi et al., 1992; Demal et al., 1993), comorbid DSM-​IV anxiety or mood disorder, diagnosed and some have speculated that may be due to the cumulausing the Structured Clinical Interview for DSM-​IV (SCID; tive effect of functional impairment, disability, and avoidHofmeijer-​Sevink et al., 2013; Pinto et al., 2006). ance associated with OCD symptoms (Brown et al., 2009). High levels of lifetime anxiety and mood comorbidity in OCD mirror the findings with current comorbidity: The right four columns of Table 54.1 summarize the high degree P O S S I B L E R E A S O N S F O R   H I G H L E V E L S of lifetime prevalence of DSM-​IV mood and anxiety dis- O F   C O M O R B I D I T Y   I N   O C D orders among more than 2,000 patients on three contiArtifact of Current DSM-​Based Diagnostic System nents, assessed by SCID interview (de Mathis et al., 2013; Hofmeijer-​Sevink et  al., 2013; LaSalle et  al., 2004; Pinto Some researchers have argued that high psychiatric comoret al., 2006). These four studies found only about 10% to bidity may simply represent an artifact of our current DSM-​ 20% of OCD patients with no lifetime psychiatric comor- based diagnostic system, because the diagnosis of multiple bidity, with lifetime mood and anxiety disorders the most comorbid psychiatric conditions is encouraged by the DSM OVERVIEW O F AN X I ETY AN D A F F ECTIVE CO MO RBI D I TY I N  O CD

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TA B L E   5 4 . 1  

PR E VA L E N C E O F   MO O D A N D A N X IETY C O M O R B I D I TY I N  PATI EN TS WI TH O C D Current Comorbidity by SCID DSM-​IV

Lifetime Comorbidity by SCID DSM-​IV

Netherlands

Brown

Sample

Sample

Any mood disorder

1

2

Netherlands

Brown

Sample

Sample

1

NIMH 2

Sample

Brazil 3

Sample4

24.9%

16.4%

63.9%

74.1%

81.0%

18.3%

15.0%

56.5%

67.2%

65.9%

–​

Dysthymia

5.5%

0%

5.5%

7.8%

24.0%

–

Bipolar disorder I or II

1.0%

0.7%

3.4%

2.7%

12.3%

–​

Any anxiety disorder

36.6%

38.0%

46.1%

52.6%

53.0%

–

–

–

Major depressive disorder

Separation anxiety Social anxiety disorder

–​

–​

70.3%

65.3% 27.6%

19.1%

18.8%

24.1%

27.6%

23.4%

–​

Panic disorder

9.2%

7.2%

19.1%

18.4%

23.1%

–​

Generalized anxiety disorder

9.2%

7.5%

9.2%

7.5%

18.3%

–​

Agoraphobia w/​o panic

1.3%

1.4%

2.6%

1.4%

17.7%

–​

Specific phobia

8.2%

14.7%

10.5%

18.1%

12.0%

–​

Post-​traumatic stress disorder

3.1%

3.4%

4.7%

6.5%

8.4%

19.1%

Somatoform disorders5

5.8%

–​

5.8%

–​

–

7.7%

OCD Only

45.0%

22.3%

9.2%

8.0%

8.0%

58.0%

n = 382 (reference 3 Hofmeijer-​Sevink et al. (2013). Clinical relevance of comorbidity in obsessive compulsive disorder: The Netherlands OCD Association Study. Journal of Affective Disorders, 150, 847–​854.) 1

n = 293 (Pinto et al. [2006]. The Brown Longitudinal Obsessive Compulsive Study: Clinical features and symptoms of the sample at intake. Journal of Clinical Psychiatry, 67[5]‌, 703–​711.) 2

n = 334 (LaSalle et al. [2004]. Diagnostic interview assessed neuropsychiatric disorder comorbidity in 334 individuals with obsessive-​compulsive disorder. Depression and Anxiety, 19, 163–​173.) 3

4

n = 1001 (de Mathis et al. [2013]. Trajectory in obsessive-​compulsive disorder comorbidities. European Neuropsychopharmacology, 23, 594–​601.)

5

Most comparable to DSM-​5 illness anxiety disorder.

(Brown et al., 2009). Indeed, each revision of the DSM has resulted in an increased number of comorbid diagnoses (Brown et  al., 2009).1 Recently, in justifying a reversal of this trend by combining several formerly discrete diagnoses into “autism spectrum disorder,” DSM-​5 developers argued against the practice of attempting to “carve meatloaf at the joints” (WebMD, 2012).

Shared Underlying Personality Trait The various DSM anxiety and mood disorders and OCD diagnoses are all strongly correlated with the well-​studied personality trait of neuroticism, which refers to a stable, 1. Michael First, one of the developers of the SCID for both DSM-​IV and DSM-​ 5, cautions that “comorbidities” based on DSM diagnostic criteria may not be true comorbidities in the traditional medical sense: “It is important to understand that comorbidity in psychiatry does not imply the presence of multiple diseases or dysfunctions but rather reflects our current inability to apply Occam’s razor (i.e., a single diagnosis to account for all symptoms)” (First, M. B., 2005).

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lifelong tendency toward negative affect, including fear, moodiness, and worry (Lahey, 2009). A  recent study estimated that in their sample of 9,270 twins, the genetic correlation of neuroticism (as assessed by the Eysenck Personality Questionnaire) and mood and anxiety disorders were in the range of 0.62 to 0.82, compared with unique environmental correlations in the range of 0.05 to 0.27 (Hettema et al., 2006). Indeed, neuroticism is so important a risk factor for the later development of common mental disorders that it has attracted attention as a significant public health problem (Lahey, 2009). The strongest direct evidence for neuroticism as a mediator of the comorbidity between OCD and mood and anxiety disorders comes from the large Netherlands sample of 382 OCD patients described earlier; these researchers found that the odds ratio for having at least one current comorbid condition was approximately three times greater for OCD patients with high neuroticism than those with lower neuroticism scores (Hofmeijer-​Sevink et al., 2013).

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Shared Underlying Neurobiological and Cognitive Abnormalities

is associated with SAD symptom severity as well as OCD (Boelen et  al., 2009). Thought-​action fusion, a cognitive bias commonly observed in OCD (see ­chapter 18), Some researchers have probed the high correlation of was found to be elevated across anxiety disorder groups, OCD, anxiety, and mood diagnoses by examining gene-​ including GAD, SAD, and panic disorder (Thompson-​ by-​gene and gene-​by-​environment alterations in common Hollands et  al., 2013). Similarly, both individuals with serotonin, glutamate, and other overlapping neurotransOCD and GAD display attentional control deficits mitter systems that may be common pathways for a variety (Armstrong et al., 2011). of DSM disorders (Murphy et al., 2013). Other studies have identified abnormal cognitive processes common to both OCD and related anxiDIF F E R E NT IAL DIAGNOS IS OF   OC D ety disorders. For example, postevent processing (i.e., F ROM  R E LAT E D DIS OR DE R S perseverative review and analysis of a social situation (Mellings et  al., 2000)) has been well studied as a factor in the psychopathology of social anxiety disorder Although OCD, mood, and anxiety diagnoses are over(SAD; Brozovich et al., 2008). Research indicates that it lapping and may not be distinct disorders with different may also be important in OCD, panic disorder with or causes, clinicians and researchers must frequently distinwithout agoraphobia, and generalized anxiety disorder guish among these conditions as best they can. This section (GAD; Laposa et  al., 2014). Similarly, individuals with outlines the most common sources of confusion among OCD and SAD displayed heightened error-​related brain these diagnoses. activity indicative of overactive performance monitoring Table 54.2 presents a summary of the factors differen(Endrass et al., 2014), suggesting that this bias may not tiating OCD from several related disorders (GAD, illness be specific to OCD. Other studies have shown that the anxiety disorder, SAD, and depression) where differential intolerance of uncertainty (the tendency to react nega- diagnosis may be problematic. The most obvious symptom tively to uncertain, ambiguous situations; see c­ hapter 17) that is seen across OCD and mood and anxiety disorders is TA B L E   5 4 . 2  

Defining Features of “Obsessions,” per DSM-​5

D I F F ER E N T I A L D I AGN O S I S O F O C D F RO M  C LO S ELY R ELATED D I S O R D ER S Obsessive-​Compulsive Disorder

Generalized Anxiety Disorder

Illness Anxiety Disorder

Social Anxiety Disorder

Depression

Obsessions are defined by both:(1) Recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted, and that in most individuals cause marked anxiety or distress; (2) The individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e., by performing a compulsion).

Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).The individual finds it difficult to control the worry. The anxiety and worry are associated with three (or more) of the following six symptoms: restlessness or feeling keyed up or on edge; being easily fatigued, difficulty concentrating or mind going blank; irritability; muscle tension; sleep disturbance.

Preoccupation with having or acquiring a serious illness.Somatic symptoms are not present, or, if present, are only mild in intensity. There is a high level of anxiety about health, and the individual is easily alarmed about personal health status. Illness preoccupation has been present for at least 6 months, but the specific illness that is feared may change over that period of time.

Marked fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation, meeting unfamiliar people), being observed (e.g., eating or drinking), and performing in front of others (e.g., giving a speech).The individual fears that he or she will act in a way or show anxiety symptoms that will be negatively evaluated (i.e. will be humiliating or embarrassing; will lead to rejection or offend others)

Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

(continued)

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TA B L E   5 4 . 2  

C O N TI NU E D Obsessive-​Compulsive Disorder

Generalized Anxiety Disorder

Illness Anxiety Disorder

Social Anxiety Disorder

Depression

Most Common “Obsessions”

Fear of being contaminated due to getting sick; fear of accidental harm to oneself or others due to one’s own inaction, or due to not doing rituals properly; need for perfectionism and/​or symmetry to prevent catastrophic consequences or relieve a “just right” feeling; fear of being an immoral, evil, or bad person due to one’s nasty thoughts

Fear of not having enough time to do everything; fear of being overwhelmed by worries forever; fear of having difficulty controlling one’s worry; worry about daily matters such as scheduling, personal relationships, work performance, one’s own health, others’ health, and community affairs

Fear of developing or contracting serious illness due to noticeable signs and symptoms of illness; fear that professional doctors have not been able to detect something wrong

Fear that one is being judged negatively in social situations; fear of being rejected by others; fear of being humiliated or embarrassed; fear of offending others due to something one has said

Nonspecific thoughts about death; thoughts about one’s losses, worthlessness, rejection, and lovability; thoughts about the futility of engaging in activities due to fatigue or predictions regarding the pleasure of an activity

Behavioral Responses

Washing hands compulsively and ritualistically; researching online about disease symptoms/​ contracting disease; self-​examination of bodily signs of disease; avoidance of specific triggers; arranging items in a particular order; counting and checking in a repeated, ritualistic manner

Researching online about disease symptoms/​ contracting disease; hypervigilance to bodily signs of disease; asking others for reassurance

Visiting doctors for reassurance that one does not have a disease; researching online about disease symptoms/​ contracting disease; hypervigilance to bodily signs of disease; self-​ examination of bodily signs of disease

Avoidance of social situations; avoidance of eye contact; avoidance of picking up the phone; avoidance of public presentations; avoidance of being the center of attention; avoidance of stating one’s opinion or being assertive; avoidance of talking to people in authority; avoidance of eating, drinking, writing, or urinating in public; avoiding dating

Avoiding activities of daily living; avoiding and withdrawing from goal-​oriented and previously valued activities

the presence of frequent, upsetting, and seemingly uncontrollable thoughts; these are called ruminations in depression, worries in generalized anxiety disorder, and obsessions in OCD (McLaughlin et al., 2011). Some have suggested the more objective, umbrella term of “unconstructive repetitive thoughts” (Watkins, 2008). Bolded terms in the first row of Table 54.2 reflect the various names the DSM-​ 5 gives to these thoughts across the diagnostic spectrum. Regardless of the name given to these aversive private experiences, they are distinguished by the particular content toward which the repetitive thoughts are directed (these terms are italicized). The second and third rows give examples of the most common distressing thoughts in each disorder, and corresponding behavioral responses, which can all be used to help distinguish one disorder from another. It is important to note that although this table delineates the differences between these disorders, in clinical practice these diagnostic differentials can be exceptionally difficult. 606

Our suggestions are meant to guide clinical decision-​ making, but cannot replace an idiographic functional assessment. Obsessions in OCD share significant overlap with ruminations and worries in depression and anxiety disorders such as SAD, GAD, posttraumatic stress disorder, panic disorder, and specific phobia. Indeed, rumination has been identified as a transdiagnostic factor spanning depression and anxiety disorder categories (McLaughlin et al., 2011). The defining features of OCD-​related obsessions, including their repetitive and unwanted nature, are conceptually overlapping with the core features of rumination, which is also a perseverative and anxiogenic mental behavior. Rumination is defined as “a pattern of responding to distress in which an individual passively and perseveratively thinks about his or her upsetting symptoms and the causes and consequences of those symptoms, while failing to initiate the active problem O b sessive - C ompulsive D isorder

 

solving that might alter the cause of that distress” (Nolen-​ Hoeksema et al., 2008). Obsessions are defined as “recurrent and persistent thoughts, urges, or images that are experienced . . . as intrusive and unwanted.” Despite the clear similarities in these definitions, obsessions have important functional differences from ruminations and worries seen in depression and anxiety disorders (see Table 54.2). This distinction can be important, as it may ultimately affect treatment decisions. For example, misidentifying a patient’s depressive ruminations as clinical obsessions can significantly impact which evidence-​based treatment is delivered (e.g., behavioral activation or exposure and response prevention). Below, we describe ways of differentiating between specific comorbid anxiety and mood disorders. 1. Clinicians should assess whether the ruminative thoughts align with the patient’s values and sense of self (Fineberg et al., 2005). Obsessions in OCD are typically ego-​dystonic (inconsistent with one’s self-​image and values), whereas ruminations in depression and GAD are typically ego-​syntonic (consistent with one’s self-​image and values). Typically, patients with OCD report that their intrusive thoughts are ego-​dystonic, in that they do not align with their character (e.g., a soft-​ spoken veterinarian who loves animals and experiences aggressive obsessions about cutting animals’ throats during an examination). Conversely, a patient in the midst of a depressive episode may report that his ruminations regarding worthlessness fit with his current view of himself (i.e., ego-​syntonic). 2. Clinicians should evaluate the focus or theme of the ruminative thoughts. In OCD, obsessions are typically related to harm, danger, or need for certainty (e.g., OCCWG, 2005); whereas in depression, ruminations focus upon loss, rejection, worthlessness, or lovability (Beck, 1967; Beck et al., 1979; Haeffel et al., 2007; Joiner et al., 1999). Both individuals with SAD and OCD may perseverate on having done something embarrassing, but an individual with SAD may be concerned that this will lead to negative evaluation by others as a result, whereas an individual with OCD is more likely to be concerned that this represents an inability to control actions or impulses, or that they have hurt the other party. 3. Obsessions and depressive or anxious ruminations may be distinguishable based on behavioral responses. For example, individuals with GAD or OCD may both worry about not having locked the door upon leaving M ood and A nxiety D isorder C omor b idity   in   O C D

the house, but an individual with GAD may be more easily reassured by going back and checking on the door once, whereas an individual with OCD may need to return to the house many times because they cannot be certain that the door is really locked. Patients with OCD often actively avoid objects, people, or situations that trigger their obsessions, whereas avoidant behaviors in depression tend to be due to fatigue, lethargy, or assumptions regarding one’s inability to get pleasure from previously valued or enjoyed activities (e.g., “what’s the point of going to the movies, it just isn’t fun anymore”). Like avoidance, reassurance seeking often occurs in both depression and OCD. In OCD, excessive reassurance seeking functions similarly to compulsive checking (Rachman, 2002). Moreover, the patient often demands that the answer be delivered a certain number of times (e.g., “I need my husband to tell me that I  am safe 5 times, no more or less”) or in a specific manner (e.g., “My mom must respond with ‘absolutely not’ to reflect her degree of certainty”). The types of beliefs that trigger this behavior in patients with OCD tend to be related to perceived threats of harm (physical-​or illness-​related), inflated responsibility, or intolerance of uncertainty (OCCWG, 2005; Parrish et  al., 2010). In depression, however, reassurance seeking is more typically associated with perceived social threats, task performance, or competence (Parrish et  al., 2010). Although patients with depression may feel compelled to repeatedly ask whether they are lovable or competent, they tend not to demand that the involved party respond in “just the right way” or a certain number of times. Reassurance-​ seeking behavior may also occur in GAD, illness anxiety disorder, and social anxiety disorder; here, the differential diagnosis may be more difficult. Factors that indicate a likely OCD ritual include rigidity of the request (i.e., the question or answer has to be phrased or received in a specific way or a specific number of times) and the magical nature of the concern (i.e., asking for reassurance about their responsibility over an earthquake). Illness anxiety disorder is a new diagnostic category in DSM-​5 (formerly a diagnosis “hypochondriasis” in the somatoform disorder category in DSM-​IV), in which the patient may or may not have a physical illness, but experiences heightened bodily sensations, feels anxious about possibly having an undiagnosed illness, and often obsessively researches their health concerns and seeks reassurance from doctors and family members, which serves the same function as reassurance seeking and other rituals in OCD 607

 

(Marouf et  al., 2013). In this disorder, the patient’s ruminations/​obsessions typically focus on one particular feared illness, although the feared illness may change over time. In OCD, obsessions about one’s own health generally involve fears of contracting an illness though contamination by germs. 4. Clinicians should determine the emotional consequences of the ruminative thoughts. In OCD, the obsessions primarily provoke fear and anxiety, as well as many other negative affect states, such as sadness, guilt, embarrassment, shame, frustration, and anger. This is also true of comorbid anxiety disorders like GAD, SAD, and illness anxiety disorder. In depression, the ruminations tend not to provoke fear, but rather sadness, guilt, and worthlessness. At times, for patients with depression and suicidal ideation, the ruminations can even comfort the patient and provoke a sense of relief at the prospect of their emotional suffering coming to an end. C L INICA L C ON SI D ERATI O N S I N  TREATING OCD W ITH CO MO RBI D I TY I M PA C T O F   M O O D A N D A N X I E T Y COMORBIDITY ON OCD OUTCOME

Exposure-​based treatment is the first-​line treatment for OCD, and multiple studies have indicated it is robustly effective, with the most common reason for poor outcome being lack of patient adherence (see ­chapter 37). There is little agreement regarding negative impact of diagnostic comorbidity on OCD treatment outcome beyond how it may impact patient adherence to treatment. Research has not identified any consistent negative effect of particular anxiety disorder diagnoses on OCD treatment outcome, although some studies have identified past trauma and associated current dissociation as predictors of poorer outcome (Gershuny et al., 2002; Semiz et al., 2014—whereas others have not; Shavitt et al., 2010). Some studies have concluded that comorbid depression is associated with a poor response to exposure-​based treatments (Abramowitz et al., 2000; Gava et al., 2007; Keeley et al., 2008); others have found no such effect (Boschen et al., 2010; Stewart et al., 2006). Anholt and colleagues (2011) suggest that clinicians should first target OCD symptoms via exposure-​based interventions; however, they argue that some patients may require an adjunctive depression intervention if the depression 608

symptoms are overtly interfering in exposure treatment progress (e.g., minimal motivation, hopeless about the effectiveness of treatment, inability to engage due to fatigue or lethargy). RELATION OF COMORBIDITY TO OCD PRESENTATION

OCD sufferers can present with heterogeneous symptoms (see ­chapter 8). What does research indicate about any relation between anxiety or mood disorder comorbidity and OCD clinical presentation? Regarding comorbid anxiety disorders:  (1)  patients who develop OCD after PTSD may exhibit a more severe clinical presentation, higher rates of aggressive, sexual/​religious, and hoarding symptoms; increased suicidality; and increased rates of comorbid mood, anxiety, somatoform, and impulse control disorders (Fontenelle et al., 2012; Torresan et al., 2013); and (2) patients with OCD and comorbid SAD are more likely to present with sexual/​religious and hoarding obsessions (Assunçao et al., 2012). OCD patients with depression comorbidity report significantly more “forbidden” or “taboo” obsessions (Hasler et  al., 2005; Hong et  al., 2004; Perugi et  al., 1997):  religious (e.g., “I am befriending the devil”; “I want to have sex with Jesus”), aggressive (e.g., “I am going to stab my mother even though I don’t want to”; “I am going to cause my wife to be in a car accident”), and sexual (e.g., “What if I sexually molest my newborn while I am changing her diaper?”; “What if I am gay?”) in nature. Research suggests that such “taboo” obsessions provoke greater embarrassment and shame than other obsessions (Rachman, 1993; Salkovskis, 1999) and are more difficult to resist or dismiss (Besiroglu et al., 2006). Not surprisingly, research suggests that patients with comorbid depression, compared with those without, misinterpret intrusive thoughts such as these to be significantly more dangerous or important, and they report a greater need to control the presence and frequency of these intrusions (Abramowitz et al., 2007). IMPLICATIONS OF RESEARCH FOR TREATING O C D PAT I E N T S W I T H   C O M O R B I D I T Y

General Recommendations 1. Exposure and response prevention (ERP) is the first-​ line nondrug treatment for OCD and this, along with psychoeducation about their OCD symptoms, should be offered to all patients regardless of comorbidity. O b sessive - C ompulsive D isorder

 

Comorbid anxiety and depression symptoms often resolve with adequate OCD response to ERP. 2. Response prevention must include observable rituals such as online “Googling” and asking others for reassurance, and mental rituals, including mental prayer and thought suppression intended to decrease discomfort. 3. If patients are not adherent or not responsive to ERP within a few sessions, cognitive therapy (including instruction in acceptance of uncontrollable repetitive thoughts) is the second-​line treatment and should be offered next. 4. If a patient’s OCD concerns involve religious themes (e.g., religious scrupulosity), then psychoeducation will often require the assistance of an understanding clergyperson (Baer, 2001). 5. If pharmacotherapy is considered, standard pharmacotherapy for OCD (see ­chapter 40) is generally appropriate in the presence of mood or anxiety comorbidity disorders: SSRI antidepressants, which are first-​line agents for OCD, are also first-​line pharmacotherapy for common mood and anxiety disorder comorbidities. (An exception is bipolar disorder, in which pharmacotherapy raises particular challenges.)

Special Considerations in Treating OCD with Anxiety Comorbidity 1. If OCD patients have a chronically high level of baseline anxiety (often with GAD, PTSD, or panic disorder) and ERP is not effective in producing extinction of anxiety within a few sessions, methods to reduce baseline anxiety may be helpful (including relaxation training, cognitive restructuring, or pharmacologic treatment). 2. If a patient with OCD has a comorbid anxiety disorder that involves avoidance of situations required in their exposure treatment for OCD (e.g., social situations for patients with SAD, triggers of taboo thoughts for patients with PTSD, GAD, or panic), they may require a more detailed assessment of avoidance behaviors that may minimize the effectiveness of ERP (e.g., preventing postevent analyzing of events after exposures). 3. For patients with OCD and comorbid GAD, panic or illness anxiety disorder, it may be important to limit focus on bodily sensations in monitoring homework

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since their anxiety symptoms may be worsened by such focus. 4. OCD patients with comorbid GAD may need to learn stimulus control techniques for their GAD worries, such as limiting their worrying to a specific worry time each day. 5. For OCD patients with comorbid panic disorder or PTSD, it may be important to thoroughly assess the internal and external triggers of panic attacks and dissociative episodes to ensure that exposure exercises do not inadvertently trigger them.

Special Considerations in Treating OCD with Depression Comorbidity 1. Because patients who suffer from both OCD and depression misappraise their intrusions as having significantly more importance and danger (Abramowitz et al., 2007), clinicians should consider augmenting their ERP treatment with cognitive therapy (CT) strategies2 (Baer, 2001; Wilhelm et al., 2006; see ­chapter 38). Targeting obsessional beliefs in CT may indirectly alleviate depression, especially for those individuals whose depression symptoms are linked to dysfunctional beliefs regarding control (“something is wrong with me since I cannot stop or control these repugnant thoughts”) and morality (“just thinking about terrible things means I am a terrible person.” Indeed, clinical trials have demonstrated that CT for OCD leads to a significant improvement in depression symptoms (Wilhelm et al., 2006; Yap et al., 2012). 2. Because avoidant behaviors are a prominent feature of both OCD and depression, and patients with OCD who rely upon avoidance as a coping strategy may be more vulnerable to depressive episodes (Ledley et al., 2007), targeting this maladaptive behavior has the potential to reduce the symptom severity of both OCD and depression. To do so, clinicians could incorporate behavioral activation into a cognitive or exposure-​based treatment for OCD in an attempt to improve mood, reintroduce positive reinforcers (e.g., socializing) that were lost due to avoidance, and potentially enhance a patient’s motivation to engage in treatment (Ledley et al., 2007; Lewinsohn, 1975). 2. Cognitive therapy for OCD obsessions involves both cognitive restructuring for intrusive obsessions and instruction in mindful acceptance of intrusive thoughts instead of counterproductive attempts at thought suppression (Baer, L, 2001; Wilhelm et al., 2006).

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C ONCL US ION Comorbidity with other DSM mood and anxiety disorders is the norm in OCD, and thus comorbid symptomatology is likely to arise in the course of any assessment and any treatment. Only 1 patient in 10 has no history of a comorbid disorder, in most studies (see Table 54.1). The striking prominence of comorbidity may reflect the imprecision of our current diagnostic system, shared underlying character traits or other pathophysiological factors, or one disorder emerging as a consequence of another (for example, depression emerging as a consequence of long-​standing OCD symptoms). In most cases mood and anxiety comorbidity need not substantially affect the course of OCD treatment, but careful evaluation of comorbid symptomatology must be a component of any assessment. In some cases comorbidity can interfere with the ability to engage in exposure-​ based therapies, and recognition of this interference must inform individualized treatment if it is to be effective. AC K NOW L ED G EMEN T Preparation of this chapter was supported by an anonymous donation to Dr. Minichiello. R EF ERENCES Abramowitz, J. S., Franklin, M. E., Street, G. P., Kozak, M. J., & Foa, E. B. (2000). Effects of comorbid depression on response to treatment for obsessive-​compulsive disorder. Behavior Therapy, 31(3), 517–​528. Abramowitz, J. S., & Jacoby, R. J. (2015). Obsessive-​compulsive and related disorders:  A  critical review of the new diagnostic class. Annual Review of Clinical Psychology, 11, 165–​186. doi:  10.1146/​ annurev-​clinpsy-​032813-​153713. Abramowitz, J. S., Nelson, C. A., Rygwall, R., & Khandker, M. (2007). The cognitive mediation of obsessive-​compulsive symptoms: A longitudinal study. Journal of Anxiety Disorders, 21(1), 91–​104. Anholt, G. E., Aderka, I. M., van Balkom, A., Smit, J., Hermesh, H., de Haan, E., & van Oppen, P. (2011). The impact of depression on the treatment of obsessive-​compulsive disorder:  Results from a 5-​year follow-​up. Journal of Affective Disorders, 135, 201–​207. Armstrong, T., Zald, D. H., & Olatunji, B. O. (2011). Attentional control in OCD and GAD:  Specificity and associations with core cognitive symptoms. Behaviour Research and Therapy, 49, 756–​762. doi: 10.1016/​j.brat.2011.08.003 Assunçao, M. C., Costa, D. L., de Mathis, M. A., Shavitt, R. G., Ferrao, Y. A., & Torres, A. R. (2012). Social phobia in obsessive-​compulsive disorder:  Prevalence and correlates. Journal of Affective Disorders, 143, 138–​147. doi: 10.1016/​j.jad.2012.05.044 Baer L. (2001). The imp of the mind: Exploring the silent epidemic of obsessive bad thoughts. New York: Plume. Beck, A. T. (1967). Depression:  Clinical, experimental, and theoretical aspects. New York: Harper & Row.

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Obsessive Compulsive Cognitions Working Group (OCCWG). (2005). Psychometric validation of the Obsessive Belief Questionnaire and Interpretation of Intrusions Inventory: Factor analyses and testing of a brief version. Behaviour Research and Therapy, 43(11), 1527–​1542. Parrish, C. L., & Radomsky, A. S. (2010). Why do people seek reassurance and check repeatedly? An investigation of factors involved in compulsive behavior in OCD and depression. Journal of Anxiety Disorders, 24, 211–​222. Perugi, G., Akiskal, H. S., Pfanner, C., Presta, S., Gemignani, A., Milanfranchi, A., . . . Cassano, G. B. (1997). The clinical impact of bipolar and unipolar affective comorbidity on obsessive-​compulsive disorder. Journal of Affective Disorders, 46(1), 15–​23. Pinto, A., Mancebo, M. C., Eisen, J. L., Pagano, M. E., & Rasmussen, S. A. (2006). The Brown Longitudinal Obsessive Compulsive Study:  Clinical features and symptoms of the sample at intake. Journal of Clinical Psychiatry, 67(5), 703–​711. Rachman, S. (1993). Obsessions, responsibility and guilt. Behaviour Research and Therapy, 31(2), 149–​154. Rachman, S. (2002). A cognitive theory of compulsive checking. Behaviour Research and Therapy, 40, 625–​639. Salkovskis, P. M. (1999). Understanding and treating obsessive-​ compulsive disorder. Behaviour Research and Therapy, 37(Suppl 1), S29–​S52. Semiz, U. B., Inanc, L., & Bezgin, C. H. (2014). Are trauma and dissociation related to treatment resistance in patients with obsessive-​ compulsive disorder? Social Psychiatry and Psychiatric Epidemiology, 49, 1287–​1296. Shavitt, R. G., Valerio, C., Fossaluna, V., da Silva, E. M., Cordeiro, Q., Diniz, J. B., Belotti-​Silva, C., Cordioli, A. V., Mari, J., & Miguel, E. C. (2010). The impact of trauma and post-​traumatic stress disorder on the treatment response of patients with obsessive-​compulsive disorder. Euopeanr Archives of Psychiatry and Clinical Neuroscience, 260, 91–​99. Stewart, S. E., Yen, C. H., Stack, D. E., & Jenike, M. A. (2006). Outcome predictors for severe obsessive–​compulsive patients in intensive residential treatment. Journal of Psychiatric Research, 40, 511–​519. Thompson-​Hollands, J., Farchione, T. J., & Barlow, D. H. (2013). Thought-​action fusion across anxiety disorder diagnoses: Specificity and treatment effects. Journal of Nervous and Mental Disease, 201, 407–​413. doi: 10.1097/​NMD.0b013e31828e102c 15. Torresan, R. C., Ramos-​Cergueira, A. T., Shavitt, R. G., do Rosario, M. C., de Mathis, M. A., Miguel, E. C., & Torres, A. R. (2013). Symptom dimensions, clinical course and comorbidity in men and women with obsessive-​compulsive disorder. Psychiatry Research, 209, 186–​195. doi: 10.1016/​j.psychres.2012.12.006 Watkins, E. R. (2008). Constructive and unconstructive repetitive thought. Psychological Bulletin, 134, 163–​206. WebMD website. (2012). http://​blogs.webmd.com/​breaking-​news/​ 2012/​01/​autism-​diagnosis-​change-​what-​does-​it-​mean.html Wilhelm, S., & Steketee, G. S. (2006). Cognitive therapy for obsessive compulsive disorder:  A  guide for professionals. Oakland, CA:  New Harbinger Publications. Yap, K., Mogan, C., & Kyrios, M. (2012). Obsessive-​compulsive disorder and comorbid depression: The role of OCD-​related and non-​specific factors. Journal of Anxiety Disorders, 24, 565–​573.

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55. PSYCHOLOGICAL TRAUMA EXPOSURE AND OBSESSIVE-​C OMPULSIVE SYMPTOMS Dean McKay, PhD, Rachel Ojserkis, BA, and Jon D. Elhai, PhD

TR A UM A A N D O BSESSI VE-​ C OM P UL S I VE SYMPTO MS Obsessive-​compulsive disorder (OCD) is a complex and heterogenous condition, as is reflected in numerous subtypes and dimensions of symptom expression (McKay et al., 2004; see ­chapters 8, 9). Furthermore, epidemiological research shows that comorbid psychiatric disorders are common in individuals with OCD (e.g., Rodgers et al., 2015; see chapter 54). Cooccurring psychiatric symptoms can complicate treatment outcomes and are associated with greater functional impairment as compared with individuals with OCD alone (Markarian et al., 2010). One important cooccurring complicating set of psychiatric symptoms in OCD is trauma. Traumatic event exposure has received specific attention in relation to the associated symptoms of posttraumatic stress disorder (PTSD). The relationship between trauma and OCD has been underexamined. Traumatic events have been temporally associated with the onset of OCD symptoms in the case literature (Pitman, 1993)  as well as more recent empirical work suggesting a potential trauma-​related subtype of OCD (Fontenelle et al., 2012). The concept of traumatic stressors as specific events contributing to the onset of OCD is also in keeping with the classic model postulating that stress either causes or worsens OCD symptoms (de Silva & Marks, 1999). This chapter has three broad aims. First, it outlines research on the shared and unique features of OCD and PTSD. Second, it reviews the extant literature on how trauma exposure, whether as a precipitating factor for OCD or in conjunction with comorbid PTSD, impacts treatment outcome for OCD. Third, it offers recommendations for treatment and future research on the intersection of trauma

and OCD. The chapter focuses on trauma generally and its impact on OCD. However, the literature also refers specifically to PTSD. Accordingly, the research related to PTSD is highlighted, to distinguish it from literature discussing trauma exposure more generally. S H AR E D AND U NIQU E F E AT U R E S OF   OC D AND  PT S D Although syndromally distinct, and separated in the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-​ 5; American Psychiatric Association [APA], 2013), OCD and PTSD share several important symptom features. Both conditions are characterized by intrusive thoughts and imagery that are experienced as frightening and unwanted. To illustrate, obsessions in OCD often involve violent or sexual imagery that the sufferer deems unwanted. In PTSD, intrusive and unwanted images of prior trauma are typical, and sufferers may report these images in language akin to obsessions. Therefore, the experience in these two conditions may be similar, albeit with different content. Avoidance behaviors are prominent in both PTSD and OCD; they function to reduce the anxiety provoked by these intrusive internal experiences. In the case of OCD, avoidance may revolve around situations that evoke obsessional experiences, or people who may prompt the intrusive imagery (such as children, in individuals with obsessions about harming minors). In similar fashion, individuals with PTSD may avoid people or places and activities associated with their trauma. Accordingly, avoidance may be topographically similar yet functionally distinct in OCD and PTSD.

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For both conditions, severe stress also appears to play a critical role in the onset and/​or worsening of symptoms. Although this relation is clearly evident in the diagnostic criteria for PTSD (APA, 2013), evidence supports the impact of stressful life events (e.g., death of a loved one, medical illness, occupational and interpersonal difficulties) on the emergence of OCD (McKeon, Roa, & Mann, 1984; Pollitt, 1957)  and worsening of existing OCD symptoms (Lin et al., 2007), including for traumatic events in particular (Cromer, Schmidt, & Murphy, 2007; Gershuny et  al., 2008; Saunders, Villeponteaux, Lipovsky, Kilpatrick, & Veronen, 1992). Both PTSD and OCD frequently cooccur with anxious and depressive symptoms (e.g., Brown, Campbell, Lehman, Grisham, & Mancill, 2001; Huppert et al., 2005). Both are associated with extensive cognitive errors, such as overestimation of threat, intolerance of uncertainty, beliefs about dangerousness, and concerns about the need to control thoughts (see c­ hapter  17, 18). However, these points of intersection between OCD and PTSD symptoms have been rarely investigated systematically or comparatively. EM P IR IC A L LI TERATURE O N  THE INTER S ECTION O F O CD AN D  TRAUMA To date, research has not identified a pattern of specific learning events associated with the onset of OCD. The DSM-​5 defines trauma exposure (within the PTSD diagnosis) as a particular event or series of events in which an individual encounters “actual or threatened death, serious injury, or sexual violence” either through direct experience, witnessing it in person, learning that it happened to a very close family member or friend, or repeatedly being exposed to such details in the workplace (APA, 2013). In light of the temporally discrete nature of traumatic events, the cooccurrence of OCD and posttraumatic stress symptoms invite an important clinical inquiry:  Is OCD a specific causal consequence of trauma, or merely a simultaneously acquired comorbid condition? And, does trauma worsen premorbid OCD symptoms, thereby leading to specific complications in treatment? Epidemiological work demonstrates generally elevated rates of comorbidity between PTSD and OCD. Large-​scale studies have shown that 30% of individuals with PTSD also meet criteria for a lifetime OCD diagnosis (n = 1,127; Brown et al., 2001), and that 19% of patients with OCD also reported a lifetime diagnosis of PTSD (n  =  1,001;

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Fontenelle et  al., 2012). Individuals who develop PTSD symptoms following traumatic experiences report comorbid lifetime OCD diagnoses at sigificantly higher rates (27%) than those who experience trauma and do not develop PTSD symptoms (3%; Boudreaux, Kilpatrick, Resnick, Best, & Saunders, 1998). Some research has presented the additional claim that the relation between OCD and PTSD may be primarily unidirectional in nature, such that experiencing PTSD symptoms puts individuals at a greater risk for developing OCD as a secondary condition. For example, one study found that individuals with a principal diagnosis of PTSD were significantly more likely to develop OCD (Odds Ratio  =  3.62), but that this same level of elevated risk of developing PTSD was not true of individuals with OCD (Brown et al., 2001). Another large-​scale study of Brazilian individuals with OCD (n = 1001) found that, of the 19% of their sample who met criteria for PTSD within their lifetimes (and for whom data on age of onset of diagnoses were available), 72% of individuals reported that their OCD symptoms developed in conjunction with or shortly after the onset of their PTSD symptoms (Fontenelle et al., 2012). However, the question of temporality and causation in the comorbid presentation of OCD and PTSD is a difficult one to answer definitively, given problems with retrospective memory impacting patients’ abilities to accurately recall details about past symptoms. This is noteworthy particularly in the case of OCD. Recent research suggests that individuals with OCD generally have accurate retrospective memory, but overestimate the degree to which external factors contributed to their symptom expression (Gloster et  al., 2008). On the other hand, individuals with PTSD have inconsistent memory about their traumatic experiences (van Glezen, et  al., 2005). A  clinician’s functional assessment may reveal which condition might respond best to treatment in sequence, but it cannot determine conclusively if the traumatic event resulted in obsessive-​compulsive symptoms. Therefore, this literature only unambiguously supports discussion of these conditions as cooccurring, rather than causally related. Some articles reviewed here do report on “trauma-​induced” OCD. Although we do not challenge these assessments and hypotheses, we offer this caveat for readers’ consideration. CHILDHOOD TRAUMA AND OCD

Several investigations report on childhood trauma and its associated effects on OCD, either in childhood or adulthood. In one study, Lochner et  al. (2002) found

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that individuals with OCD (n  =  74) and trichotillomania (n  =  36) reported significantly higher levels of childhood traumatic experiences (on the Childhood Trauma Questionnaire, CTQ; Bernstein et  al., 1994)  compared with nonpsychiatric controls (n = 31). Lafleur et  al. (2011) examined 130 youth with OCD and also evaluated them for cooccurring psychopathology, including PTSD. They found a small percentage met criteria for PTSD (6%), but that this was a higher incidence compared with another psychiatric group (children with and without attention deficit hyperactivity disorder). This study included assessment of a large sample of adults with OCD (n = 133). These adults also had a small, but significantly greater, incidence of PTSD compared with controls.

possible impact of extremely stressful events on neurobiology and subsequent OCD symptom development (Fostick, Nacasch, & Zohar, 2012; Sasson et al., 2005). In one large-​ scale investigation involving 120 individuals with a diagnosis of OCD, it was found that severity of prior trauma and severity of dissociative symptoms were associated with poorer treatment outcome (using either selective serotonin reuptake inhibitors or cognitive-​behavior therapy; Semiz, Inanc, & Bezgin, 2014). Collectively, these case and uncontrolled treatment studies suggest that trauma exposure is a poor prognostic indicator in OCD. However, it is worth noting that other studies have not shown as clear of a relationship between trauma exposure and OCD severity. In an examination of the relation between childhood trauma and cognitions associated with OCD, Selvi et  al. (2012) evaluated 95 individuals CLINICAL FINDINGS with OCD with a large battery of measures that included As noted earlier, most research on the cooccurrence of the CTQ and several cognitive symptom measures. They trauma and OCD has been in the form of case series, or found that dissociation was associated with OCD cognipost hoc evaluations culled from larger investigations of tions, but that childhood trauma was not. Further, neither OCD generally. The recognition of this presentation in the dissociation nor childhood trauma was associated with clinical literature dates back to 1903, when Pierre Janet dis- symptom severity. cussed such cases in his Lés obsessions et la psychasthénie. The Multiple case series hypothesize the mechanism of case studies outlined discuss the presentation and treatment OCD symptom emergence after trauma as the followof individuals who experienced an assortment of traumatic ing: OCD symptoms initially develop bearing close relation events (e.g., military combat, sexual and physical assault, to the content of the traumatic event and PTSD symptoms, accidents), as well as a wide range of OCD symptoms (e.g., but eventually generalize to unrelated OCD symptoms washing, symmetry, checking, and repetition). and frank presentation of the disorder in its own right (De In one of the earliest clinical illustrations of the cooc- Silva & Marks, 1999, 2001; Fosticket  al., 2012; Freeman currence of trauma and OCD, Pitman (1993) describes & Leonard, 2000; Gershuny et  al., 2003; Pitman, 1993). the case of a Vietnam combat veteran who had persistent For example, de Silva and Marks (1999, 2001) describe the and debilitating OCD and PTSD symptoms follow- case of “Miss M,” who, following a traumatic sexual assault, ing his return to civilian life. Despite extensive treatment developed self-​ washing rituals in response to intrusive efforts involving pharmacologic, behavioral, and psycho- thoughts that she was “filthy” due to being sexually violated. dynamic interventions, his symptoms remained relatively This sense of being “filthy” also then extended to other posunchanged. Pitman discusses negative reinforcement (i.e., sessions in her home. It is worth noting, however, that some relief/​avoidance of anxiety) as a common pathogenic fea- cases reported in the literature present evidence counter to ture between OCD and trauma, and outlines a hypothesis this hypothesized model (i.e., nature of OCD symptoms about how traumatic events are fertile ground for develop- appear to be all-​together unrelated to thematic content of ing compulsive and/​or avoidance behaviors. Specifically, he trauma; de Silva & Marks, 1999, 2001; Sasson et al., 2005). speculates that during times of extreme stress in which one’s Thus, the question of diagnostic precedence and specific life is in danger, it may be initially adaptive to take mea- etiology in this clinical presentation remains unclear. sures of self-​protection and anxiety reduction, but because The work of Gershuny et al. (2003) has sought to demof how strongly these behaviors are reinforced, they can onstrate the difficulties in successfully treating individuals lead to maladaptive behaviors when applied to non–​life-​ presenting with OCD and trauma histories. Gershuny et al. threatening scenarios, or when the traumatic event itself is (2002) compared individuals with treatment refractory over. Two other case series of individuals who developed OCD uncomplicated by trauma (n = 7) to those with sigOCD symptoms in combat settings provide support for nificant trauma histories (n = 8), all of whom received stanPitman’s hypothesized model, and additionally discuss the dard treatment for OCD. The individuals with additional

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trauma histories failed to respond to treatment. A  later series of case studies illustrated four individuals who presented for treatment at a specialty clinic for OCD and also endorsed significant trauma histories. In each of these cases, there was a “hydraulic” effect such that decreases in OCD symptoms led to increases in traumatic stress-​related symptoms, and vice versa, ultimately limiting response to treatment. In a larger chart review study, Gershuny et al. (2008) found that, in a sample of treatment-​resistant individuals with OCD (n = 104), 82% reported a significant trauma history and 39% met criteria for PTSD. CLINICAL CHARACTERISTICS ASSOCIATED WITH TRAUMA IN OCD

Only one study to date has empirically investigated clinical characteristics of patients with cooccurring trauma and OCD. In order to characterize the specific symptom profile of individuals with “trauma-​induced” OCD, Fontenelle et al. (2012) compared the following groups in a large sample of Brazilian individuals with OCD (n = 1,001): individuals with OCD and PTSD that emerged following a traumatic event; those with OCD and PTSD whose OCD reportedly existed prior to the traumatic event; and individuals with OCD and no history of trauma exposure. The results were striking, showing that those with PTSD/​OCD emerging after a traumatic event reported more severe and frequent OCD symptoms, especially aggressive, sexual, and religious obsessions and hoarding. In general, this group also displayed more severe psychopathology than the others, including more comorbid diagnoses, elevated general anxious and depressive symptoms, greater problems with impulsive behaviors (including self-​injurious behavior), and more frequent suicidal ideation. This comparatively severe clinical presentation supports anecdotal observations that individuals with comorbid OCD and trauma symptoms are difficult to treat, and call for additional work improving interventions for this unique clinical population. A FEW CAUTIONARY NOTES ON THE INTERSECTION OF TRAUMA AND OCD

Early in the case literature on the intersection of trauma and OCD, several investigators noted the potentially deleterious effect of attributing the cause of intrusive imagery in OCD to trauma exposure. Lipinski and Pope (1994) illustrated three cases in which the intrusive imagery associated with OCD was conceptualized by prior therapists to be “flashbacks” of repressed childhood trauma. Each of

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the three cases demonstrated classic symptoms of OCD (i.e., washing rituals with intrusive images of contamination; unwanted images of dead animals and other violent images; checking symptoms to ensure family members were not inadvertently poisoned). These experiences were associated with greater resistance to exposure with response prevention for OCD later in these individuals’ courses of treatment. The authors reported that ultimately the three individuals responded well to serotonin-​reuptake inhibitor medications. In another case series, McElroy and Keck (1995) describe three women whose eating disorder and OCD symptoms were attributed to repressed memories of sexual and/​or physical abuse. The effort to uncover these putative repressed memories was unsuccessful, and the three individuals deteriorated clinically. The authors termed this a misattribution of symptom cause, and reported that eventual treatment with serotonin reuptake inhibitor medication was successful for these individuals as well. Finally, although the preponderance of the clinical literature suggests that the presence of trauma and related symptoms is associated with a poorer treatment response in OCD, one report suggests that this relationship is better attributed to complications from depression and overlapping symptoms when evaluated in clinical samples (Huppert et  al., 2005). This evidence for erroneous attribution of OCD symptoms to the effects of past trauma and confounding effects of depression and general negative affectivity is limited, but these cases caution that evidence-​ based assessment is necessary in developing a treatment plans for cases in which trauma is suspected as a complicating feature of OCD. Further complicating the development of treatments for this specific comorbid combination is that PTSD often cooccurs with depression (Elhai, et al., 2008). In addition, it has been long observed that depression complicates treatment for OCD (Keeley, et al., 2008). As a result of this, one can reasonably expect that PTSD, when present with OCD, is also highly likely to be associated with depression. H YPOT H E S IZ E D PS YC H OLOGIC AL ME C H ANIS MS F OR   C OOC C U R R E NC E The case literature reviewed raises several questions about potential mechanisms of comorbidity of traumatic event exposure and related symptoms with OCD. Although empirical literature addressing such questions is currently sparse, existing evidence and theoretical avenues for future investigations are discussed here.

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COGNITIVE MECHANISMS

The case literature has speculated about cognitive mechanisms that may contribute to the cooccurrence of OCD symptoms and trauma, including overestimation of threat, inflated responsibility, and catastrophic misinterpretations of intrusive internal experiences (De Silva & Marks, 2001; Gershuny et  al., 2003). However, these hypotheses have received strikingly little empirical attention. One recent investigation of a sample of undergraduates with traumatic experiences (n = 211) found that posttraumatic cognitions (self-​blame, belief that the world is dangerous, negative ideas about self ) moderated obsessive-​compulsive beliefs (specifically, inflated responsibility and intolerance of uncertainty), which jointly predicted obsessive-​compulsive symptoms (McKay, Ojserkis, & Elhai, 2016). It is worth noting that obsessive-​compulsive beliefs are not specific to OCD (Kim et al., 2016; McKay et al., 2014; Taylor, et al., 2006). Accordingly, the finding that there are numerous cognitive domains that are shared between trauma and OCD should come as little surprise. What is useful, however, is identifying profiles of participants whose cognitive features are particularly predictive of the cooccurrence of trauma and OCD, given evidence that this clinical presentation is associated with greater symptom complexity and poorer treatment outcomes than for either disorder alone.

both generally aversive and OCD-​specific stimuli, compared to healthy control participants. In the case of PTSD, a metaanalysis of 57 studies revealed broad difficulties in emotion regulation (Seligowski et al., 2015). In this metaanalysis, and apropos of the kind of emotion regulation strategy that would be associated with avoidance, research on PTSD showed generally moderate effects for thought suppression (Seligowski et  al., 2015). This means that individuals with PTSD are more likely to engage in thought suppression as an emotion regulation strategy. It has been observed that, in individuals with OCD, thought suppression is a strategy commonly employed to manage emotional experiences (Wenzlaff & Wegner, 2000). However, it is also a strategy that promotes obsessional experiences (Purdon, Rowa, & Antony, 2005). Examined in this light, OCD symptoms may distract from intense negative affect associated with a traumatic experience, whereas PTSD symptoms may provide relief from unrelenting obsessions and compulsions. This model is consistent with emotion-​regulation conceptualizations of worry in generalized anxiety disorder (Borkovec, Ray, & Stober, 1998; Fresco, Mennin, Heimberg, & Ritter, 2013), and may explain the treatment-​resistant “hydraulic” effect observed in the case literature, whereby improvement in one set of symptoms leads to accentuation of the other.

EMOTIONAL MECHANISMS

Disgust and Mental Contamination

Case studies also allude to potential emotional mechanisms for the cooccurrence of OCD and PTSD symptoms, although these questions also have, by and large, yet to be explored in the empirical literature.

Rachman and colleagues describe the phenomena of “mental contamination” to account for how some forms of stressful or traumatic events might lead to contamination responses (Rachman et  al., 2015). In this paradigm, as it specifically relates to trauma, adverse events lead to behaviors designed to alleviate the associated negative emotional state, including washing rituals. These washing rituals are negatively reinforced, and hence maintained. This theory is consistent with examples from the case literature on individuals presenting with OCD and trauma-​related symptoms (e.g, Gershuny et al., 2003; Sasson et al., 2005). Additionally, experimental investigations involving hypothetical stressful events have supported this theoretical premise of the mental contamination literature. One paradigm in particular, the “dirty kiss” experiment, in which individuals imagine being the victim of a nonconsensual kiss, has been shown to produce feelings of contamination in nonclinical participants (Rachman, et al., 2012). Data from clinical samples appears to bolster this finding. One recent study found that, among women who had experienced sexual trauma (n = 50), contamination

Emotion Regulation Gershuny et  al. (2003) suggest that the cooccurrence of OCD and trauma-​related emotional symptoms may be strongly maintained due to the negative reinforcement experienced when each set of symptoms provides relief from distress caused by the other. As with other corresponding topographical aspects of OCD and PTSD (such as the experience of intrusive imagery and avoidance behaviors), both conditions are marked by difficulties in emotion regulation. Stern et al. (2014) found that obsessive-​compulsive symptoms were associated with worse emotion regulation skills and strategies, using a general undergraduate sample and a self-​report questionnaire methodology. Paul et  al. (2016) found that individuals with OCD were less able to manage their emotional responses when presented with T rauma and O b sessive - C ompulsive S ymptoms

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aversion for direct contact with a contaminant (i.e., garbage) as well as indirect contact with possible contaminants (i.e., germs on handrails) were significantly related to mental contamination (i.e., feelings of dirtiness) and posttraumatic stress symptoms (Adams, Badour, Cisler, & Feldner, 2014). Other research has also linked the mental contamination phenomenon to morally (rather than physically) contaminating triggers (Coughtrey, Shafran, & Rachman, 2014; Zhong & Liljenquist, 2006). However, these effects have rarely been replicated (Zuckerman & Siev, 2014). The mental contamination paradigm is a potentially a useful model for explaining the way in which trauma may lead to obsessive-​compulsive symptoms. In a broad sense, negative reinforcement, whereby repetitive behaviors produce a reduction in negative affect, could explain the onset and maintenance of compulsive behavior following trauma. This is consistent with evidence for a propensity toward avoidance learning in OCD generally (Endrass, Kaufmann, & Kathmann, 2011), suggesting that individuals with OCD are at increased risk for developing avoidance behaviors, particularly following trauma. At this time, however, relatively little data or theoretical analyses have addressed how this model could explain OCD symptoms, other than contamination concern. Research efforts may also be directed toward studying disgust dysregulation in the overlap between OCD and traumatic stress symptoms, given evidence that the basic emotion of disgust (see ­chapter 10) may predict mental contamination in individuals with PTSD (Badour, Ojserkis, McKay, & Feldner, 2014). The question of the role of disgust in the intersection of OCD and PTSD symptoms is presently under investigation by some of the current authors (R.O., D.M.). In conclusion, additional experimental data are necessary to clarify the ways in which trauma may lead to obsessive-​compulsive behavior in order to guide the development of improved interventions for this complex and severe clinical population. A P ROP OS ED PRELI MI N ARY M ODEL F OR TREATI N G TRAUMA’S A F TEREFFECTS I N  O CD The literature examined to this point suggests that (a)  trauma exposure may exacerbate symptoms of OCD, (b)  in some instances trauma could serve as the specific learning event that initiates OCD, and (c) that it may not be the trauma per se that leads to difficulties in treatment 618

but ancillary symptoms associated with trauma (i.e., PTSD, dissociation, depression) that interferes with outcome. Although the research on the intersection of trauma and OCD is still preliminary, some broad conclusions may be offered to suggest directions for treatment and additional investigation. Empirically supported treatments for both OCD and trauma involve some degree of exposure-​ based therapy. However, each targets different components of affect and memory structures. For example, in contamination fear associated with OCD, exposure would involve deliberate exposure to contaminants, paced to ensure habituation (Foa & Kozak, 1986). In the case of trauma, exposure typically involves recounting the event in vivid detail, progressing from a strictly descriptive account to a more fully involved personally relevant emotionally detailed rendering (Mørkved, et al., 2014). On the one hand, the similarities in treatment seem encouraging because the modality of therapy is comparable. However, a complication becomes apparent once treatment begins. Namely, which aspect of psychopathology should be targeted first, obsessive thoughts (in OCD) or traumatic reminders (in PTSD)? This conundrum, and the absence of any meaningful method to identify a hierarchical relationship between these two complex syndromes, may account for the poor outcome reported in the literature for individuals with this combination of conditions. One solution to this matter may be culled from the research on differential efficacy of exposure with response prevention for OCD. Specifically, although live (in vivo) exposure is considered most effective for OCD, it has been shown that when exposure is accompanied by therapist-​ guided imagery, outcome is best (reviewed in McKay et al., 2015). The content of this imagery is typically based on assumed concerns associated with the target stimulus for exposure. This is not a requirement, however. Instead, the imagery could be trauma relevant, and would be in line with a putative functional assessment of the presenting condition. On the other hand, it is also possible that in a prolonged exposure session related to PTSD, other narrative accounts could be part of the intervention. As noted in Mørkved et al. (2014), although prolonged exposure is highly efficacious, narrative exposure therapy (NET) is similarly efficacious. The specific difference is that NET emphasizes drawing together disparate fear-​relevant trauma information to form a coherent “story” for the client. In this approach, weaving in OCD-​ relevant information in the narrative could have a palliative effect on symptoms in both conditions. Figure 55.1 illustrates the different perspectives as potentially useful methods for intervention. O b sessive - C ompulsive D isorder

 

Obsessivecompulsive Symptoms

Are trauma symptoms complicating primary OCD?

Exposure with Response Prevention + Trauma-relevant imagery

Traumatic Events (s)

Is OCD a function of traumatic experiences?

Narrative Exposure Therapy with OCDrelevant components of imagery

Figure 55.1  Treatment decision options for cooccurring OCD and trauma.

ASSESSMENT POINTS

In order to execute treatment in this proposed framework, the functional assessment (prior to starting treatment sessions) will serve as a critically important point for determining whether to focus on OCD and incorporate trauma information in imagery, or to target trauma and incorporate OCD-​relevant information in the narrative. One approach to help clarify this is to develop the fear hierarchy for both OCD and trauma. Following completion of hierarchies relevant to OCD and trauma, the therapist determines if any items on one hierarchy would be worsened by stimuli from the other hierarchy. The degree of potentiation of one by the other could help inform which treatment approach to employ. The other critical assessment point is the extent of dissociative experiences the client suffers. This requires careful consideration, as provocation of dissociative experiences could interfere with the emotional processing necessary to produce habituation (as described in Foa & Kozak, 1986). Recent research suggests that dissociation and depersonalization do not moderate outcome of treatment using NET (Halvorsen et al., 2014). However, prior research reviewed noted that dissociation was associated with poorer outcome in OCD (Lipinski & Pope, 1994). C ONCL US IO N S AN D FUTURE DIR ECTION S As the research reviewed here suggests, OCD when accompanied by traumatic stress is more difficult to treat and is associated with worse outcomes compared with OCD without trauma. At this point, there is little systematic research into the cooccurring symptoms that would allow for definitive conclusions regarding treatment. However, based on the treatment research for OCD and trauma’s effects separately, some points of intersection suggest potentially promising options for consideration. T rauma and O b sessive - C ompulsive S ymptoms

There are several possible future directions research that would shed light on how to conceptualize and treat this complex, cooccurring problem. One would necessarily focus on cognitive and behavioral factors, such as those emerging from the mental contamination model of OCD. This would allow for depiction of cognitive factors that might reasonably be included in exposure-​based treatment. This would address a large segment of traumatized individuals, those who have survived sexual trauma, and potentially lead to clear treatment guidelines. Another specific research direction that the extant literature points toward involves specific treatment decisions. This chapter has laid out two possible approaches, based on existing interventions for OCD and traumatic stress separately. It remains to be seen whether there is a desirable specific approach. For example, it is possible that once an individual has this specific combination of symptoms, either approach described here would be comparably efficacious. Another possibility is that, regardless of temporal sequencing of OCD and trauma symptoms, a transdiagnostic model of treatment may be effective (such as the Unified Protocol; Payne et al., 2014). R E F E R E NC E S Adams, T. G., Badour, C. L., Cisler, J. M., & Feldner, M. T. (2014). Contamination aversion and posttraumatic stress symptom severity following sexual trauma. Cognitive Therapy and Research, 38, 449–​457. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, DC: Author. Badour, C. L., Ojserkis, R., McKay, D., & Feldner, M. T. (2014). Disgust as a unique affective predictor of mental contamination following sexual trauma. Journal of Anxiety Disorders, 28, 704–​711. Bernstein, D. P., Fink, L., Handelsman, L., Foote, J., Lovejoy, M., Wenzel, K., Saparetto, E., & Ruggiero, J. (1994). Initial reliability and validity of a new retrospective measure of child abuse and neglect. American Journal of Psychiatry, 151, 1132–​1136. Borkovec, T. D., Ray, W. J., & Stober, J. (1998). Worry:  A  cognitive phenomenon intimately linked to affective, physiological, and interpersonal behavioral processes. Cognitive Therapy and Research, 22, 561–​576. Boudreaux, E., Kilpatrick, D. G., Resnick, H. S., Best, C. L., & Saunders, B. E. (1998). Criminal victimization, posttraumatic stress disorder, and comorbid psychopathology among a community sample of women. Journal of Traumatic Stress, 11, 665–​678. Brown, T. A., Campbell, L. A., Lehman, C. L., Grisham, J. R., & Mancill, R. B. (2001). Current and lifetime comorbidity of the DSM-​IV anxiety and mood disorders in a large clinical sample. Journal of Abnormal Psychology, 110, 585–​599. Coughtrey, A. E., Shafran, R., & Rachman, S. J. (2014). The spontaneous decay and persistence of mental contamination: An experimental analysis. Journal of Behavior Therapy and Experimental Psychiatry, 45, 90–​96. Cromer, K. R., Schmidt, N. B., & Murphy, D. L. (2007). An investigation of traumatic life events and obsessive-​compulsive disorder. Behaviour Research and Therapy, 45, 1683–​1691. 619

 

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56. EATING DISORDER COMORBIDITY WITH OCD Marina Gershkovich, BA, Olivia Pascucci, BA, and Joanna Steinglass, MD

INTRODUC TI O N Eating disorders are defined by abnormal eating behaviors accompanied by excessive concern with body weight or shape (DSM-​5; APA, 2013). Within this broad category, each diagnosis has additional specific criteria. Anorexia nervosa (AN) is defined by maintenance of a significantly low body weight. Bulimia nervosa (BN) is characterized by episodes of binge eating (the consumption of an excessive amount of food in a short period of time) and the use of compensatory behaviors (e.g., vomiting) to avoid weight gain. Binge eating disorder (BED), now recognized in the DSM-​5, is defined by episodes of binge eating without the use of compensatory behaviors. AN affects approximately 0.4% to 0.9% of women and 0.3% of men, BN affects approximately 0.9% to 1.5% of women and 0.1% to 0.5% of men, and BED affects approximately 1.6% to 3.5% of women and 0.8% to 2.0% of men (Hoek & Van Hoeken, 2003; Hudson, Hiripi, Pope, & Kessler, 2007; Preti et al., 2009). Medical complications of eating disorders are common and can affect multiple organ systems (Mitchell & Crow, 2006; Sharp & Freeman, 1993). AN has one of the highest mortality rates of all psychiatric illnesses (approximately 5%; Arcelus, Mitchell, Wales, & Nielsen, 2011; Sullivan, 1995). Eating disorders often co-​occur with anxiety disorders, and one of the most common comorbidities is OCD (Iwasaki, Matsunaga, Kiriike, Tanaka, & Matsui, 2000; Kaye, Bulik, Thornton, Barbarich, & Masters, 2004). Parallels have been drawn between the clinical phenomena seen in OCD and in eating disorders. Individuals with eating disorders experience intrusive thoughts surrounding food and/​or body image, similar to the obsessions described by patients with OCD. Repetitive behaviors related to these preoccupations are also common (Altman & Shankman, 2009; Bartz & Hollander, 2006; Steinglass & Walsh, 2006; Steinglass et al., 2011; Tyagi et al., 2015).

Individuals with eating disorders may avoid eating-​related situations, similar to the avoidance of anxiety-​provoking situations by patients with OCD. The similarities are particularly striking between OCD and AN. A relationship between OCD and eating disorders is also suggested by retrospective studies reporting that an anxiety disorder in childhood often precedes the onset of an eating disorder (e.g., Godart et al., 2003; Kaye et al., 2004; Milos, Spindler, Ruggiero, Klaghofer, & Schnyder, 2002; Speranza et al., 2001; Swinbourne & Touyz, 2007). Understanding the comorbidity between OCD and eating disorders may yield insights into the pathophysiology, assessment, and treatment of each of these disorders. E PIDE MIOLOGY Exact rates of comorbidity between eating disorders and OCD are challenging to estimate. In many community studies, psychopathology is described broadly as “anxiety disorders” and “eating disorders,” without specific delineation of diagnoses. Furthermore, given the low prevalence rates of each disorder, the sample sizes of affected individuals in these studies are often small, which can lead to variability in findings. In studies of clinical samples, the likelihood of comorbidity of any illness is higher than in community samples, which may inflate prevalence estimates (Berkson, 1946). Changes in the diagnostic criteria for AN and BN, and the exclusion of food and eating concerns in the OCD diagnosis starting with DSM-​IV, also contribute to variability in estimates of comorbidity over time. In the largest United States study, the National Comorbidity Survey-​Replication (n  =  1,139), 17.4% of individuals with BN had a lifetime diagnosis of OCD, whereas none of the individuals with AN had OCD (Hudson et  al., 2007). In a community-​based study in 623

 

Switzerland (n = 594), 14.3% of individuals with OCD had a lifetime diagnosis of BN, and 28.6% reported binge-​eating episodes. AN was not detected in this sample (Angst et al., 2004). In other smaller community studies, cooccurrence of an eating disorder with OCD was not found (Grabe et al., 2001; Lewinsohn, Striegel-​Moore, & Seeley, 2000). These studies suggest low overlap between AN and OCD, but data from treatment-​seeking populations suggest otherwise. Among clinical populations of patients with a primary diagnosis of an eating disorder, the prevalence estimates of OCD have ranged from 0% to 69% (Fornari et al., 1992; Godart et al., 2006; Halmi et al., 2003; Iwasaki et al., 2000; Kaye et al., 2004; Lilenfeld et al., 1998; Milos et al., 2002; Swinbourne & Touyz, 2007). Some of the higher prevalence rates come from inpatient samples (Fornari et al., 1992; Lilenfeld et al., 1998). In one eating disorder treatment center (n = 271), Godart and colleagues (2006) found that a current diagnosis of OCD was more common among individuals with AN (17.8%) than with BN (7.1%). In a different study including inpatients and outpatients (n  =  89), 22.4% of individuals with AN and 12.9% of individuals with BN had a lifetime diagnosis of OCD, and 15.4% of the overall sample had a current OCD diagnosis (Speranza et al., 2001). Among patients with a primary diagnosis of OCD, lifetime prevalence rates of an eating disorder have ranged from 10% to 42% (Pinto, Mancebo, Eisen, Pagano, & Rasmussen, 2006; Sallet et  al., 2010; Wu, 2008). Sallet and colleagues (2010) interviewed outpatients with OCD (n  =  815), and found that 6.0% reported a current eating disorder (with BED being the most common, 4.5%) and 2.1% had subthreshold eating disorder symptoms. Lifetime prevalence was higher, at 11.3% (BN = 2.5%, AN = 2.6%, and BED = 7.9%). In another study of patients with OCD (n = 293), the lifetime prevalence of an eating disorder was 10.2% (AN = 3.1%, BN = 3.1%, BED = 1.4%, and Eating Disorder Not Otherwise Specified (ED-​NOS) = 3.1%; Pinto et al., 2006). Individuals with OCD and a comorbid eating disorder (as compared with OCD alone) are more likely to have had previous psychiatric hospitalizations, have made more suicide attempts, and report more symptoms of anxiety and depression (Sallet et al., 2010). When these disorders occur together, OCD symptom severity does not tend to be greater, but eating disorder symptoms tend to be of greater severity and longer duration. (Albert, Venturello, Maina, Ravizza, & Bogetto, 2001; Cumella, Kally, & Wall, 2007; Milos et al., 2002; Sallet et al., 2010). The increased severity and functional impairment when disorders occur together may bring patients into treatment more often (i.e., Berkson’s bias; Berkson, 1946). 624

C LINIC AL F E AT U R E S OCD and eating disorders both manifest intrusive thoughts and repetitive behaviors. In OCD, concerns related to food and eating may be part of a larger dimension of obsessions (e.g., harm-​related fears; contamination from certain food items; fear of choking). These excessive concerns could have an impact on eating habits and nutrition, and may result in unintended weight loss. The underlying concern, however, is not related to weight, shape, or body image. When the individual’s fears center on body shape, an eating disorder diagnosis would be considered. Comorbid diagnoses may be overlooked when patients present to a specialty clinic. In an exploratory study in an anxiety disorders clinic, clinician assessments were compared with patients’ self-​report questionnaires. The clinicians did not identify eating pathology in 80% of the individuals whose self-​report assessments indicated eating disorder symptoms (Becker, DeViva, & Zayfert, 2004). This preliminary finding highlights the importance of inquiring about symptoms related to food, shape, or weight during the initial evaluation and, as necessary, throughout treatment. A complete assessment includes inquiring about daily food intake, episodes of loss of control around eating, episodes of loss of control paired with eating a large amount of food, efforts to limit intake or follow rigid food rules, and use of compensatory behaviors after eating. A careful weight history (including highest and lowest weights) is often informative as well (Walsh & Satir, 2005). ANOREXIA NERVOSA

Anorexia nervosa is characterized by caloric intake that is inadequate to maintain a healthy body weight, accompanied by extreme fear of being fat or gaining weight, and a disturbance in the perception of or valuation of weight and shape. There is no single definition of underweight, though the DSM-​5 refers to the Centers for Disease Control and Prevention definition where the lower limit of normal body weight is a body mass index (BMI) of 18.5 kg/​m2. There are two subtypes of AN: binge-​eating/​purging type (AN-​BP) describes individuals that have had recurrent episodes of binge eating or compensatory behaviors during the last three months; restricting type (AN-​R) describes individuals who lost weight by limiting intake, fasting, and/​or excessively exercising. Individuals with AN may not overtly recognize or endorse an intense fear of weight gain; therefore, in the DSM-​5, the criterion was modified to also include patterns of behavior aimed at preventing weight gain, which allows the clinician to infer the diagnostic fear of weight gain. O bsessi v e - C ompulsi v e D isorder

 

Many psychological symptoms of AN—​ including obsessions and compulsions—​ are more severe in the underweight state. In fact, numerous psychological symptoms have been shown to result from starvation, even among individuals without AN (Keys, Brožek, Henschel, Mickelsen, & Taylor, 1950). In a large sample of patients with AN (n = 324), Halmi and colleagues (2003) analyzed the type and frequency of OCD obsessions and compulsions using the checklist of the Yale-​Brown Obsessive Compulsive Scale (Y-​ B OCS, Goodman et  al., 1989). Excluding food, eating, and calorie-​related concerns and rituals, 74.1% of patients with AN endorsed experiencing obsessions and compulsions at some point in their lifetime. Compared with individuals with OCD, individuals with AN endorsed fewer categories of obsessions and compulsions. Obsessions related to symmetry and somatic concerns and compulsions related to ordering and hoarding were most common among AN patients. Like individuals with OCD, patients with AN show differing degrees of insight surrounding irrational beliefs. Poor insight is associated with poor treatment response in OCD (Catapano et al., 2010; Kishore, Samar, Reddy, Chandrasekhar, & Thennarasu, 2004) and in AN (Saccomani, Savoini, Cirrincione, Vercellino, & Ravera, 1998). In a small study of inpatients with AN (n = 25), the Brown Assessment of Beliefs Scale (Eisen et al., 1998) was administered to assess degree of insight regarding a primary belief associated with weight and eating concerns (Steinglass et al., 2007). Five participants (20% of the sample) expressed no understanding that the belief was irrational, and were categorized as having a “delusional” degree of insight. These findings were replicated in another study that found that 28.8% of individuals with AN (n = 39) endorsed delusional body image beliefs (Konstantakopoulos et al., 2012). These small studies suggest that in some clinical samples, the extreme of “delusional” insight about certain beliefs may occur more commonly in AN than in OCD (e.g., 2%; Eisen et al., 2004; 5%, Foa & Kozak, 1995), and may be more similar to rates in body dysmorphic disorder (e.g., 39%, Eisen et al., 2004; see ­chapter 13). BULIMIA NERVOSA

Bulimia nervosa is characterized by recurrent episodes of binge eating accompanied by the use of compensatory or purging behaviors to prevent weight gain, and overvaluation of and dissatisfaction with body shape and weight. Unlike those with AN, individuals with BN maintain a normal (or overweight) BMI. E ating D isorder C omorbidity with   O C D

Individuals with BN have been found to have mild to moderate scores on the Y-​B OCS, both in acute illness (mean = 13.1, SD = 10.6) and in those who had recovered from BN (mean = 7.9, SD = 7.0; von Ranson, Kaye, Weltzin, Rao, & Matsunaga, 1999). Obsessions related to symmetry and exactness, and compulsions related to ordering and arranging were most common among BN patients. These data suggest that although the clinical overlap between OCD and BN is less striking, OCD-​like symptoms can be present in individuals with BN, and comorbidity does occur. T R E AT ME NT PHARMACOLOGICAL TREATMENTS

Pharmacotherapeutic interventions for AN have been largely disappointing in randomized controlled trials (Claudino et al., 2006; de Vos et al., 2014; Zhu & Walsh, 2002). For example, fluoxetine offered no additional benefit compared with placebo during inpatient weight restoration treatment; weight and associated symptoms improved significantly for both groups (Attia, Haiman, Walsh, & Flater, 1998). Initially, this negative finding was hypothesized to be related to the underweight state (i.e., perhaps there was altered neurotransmitter physiology impairing the action of an antidepressant). Yet even following weight restoration, antidepressants provided no additional benefit (compared with placebo) among patients receiving cognitive-​behavioral therapy (CBT) for relapse prevention (Walsh et al., 2006). Due to a side-​effect profile that includes weight gain, atypical antipsychotics have also been studied in AN, but with mixed results (Kishi, Kafantaris, Sunday, Sheridan, & Correll, 2012; Lebow, Sim, Erwin, & Murad, 2013). The American Psychiatric Association’s guidelines suggest that second-​generation antipsychotics be considered on an individual basis, specifically for patients with severe AN who have delusional beliefs and are resistant to gaining weight (APA, 2006, 2012). Numerous double-​ blind, placebo-​ controlled trials of antidepressant medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), have shown the utility of these medications for individuals with BN (Aigner, Treasure, Kaye, & Kasper, 2011). Pharmacological treatment significantly reduces the frequency of binge eating and purging episodes. A large randomized controlled trial demonstrated that fluoxetine 60 mg was the preferred dose, and that fluoxetine 20 mg 625

 

(the standard dose for major depressive disorder) did not differ from placebo. Fluoxetine is approved by the FDA for the treatment of BN. TCAs and MAOIs are not recommended as first-​line pharmacological treatments for BN due to the unfavorable side effect profiles and the risks associated with drug interactions and overdose (for review, see Flament, Bissada, & Spettigue, 2012).

a randomized controlled pilot study with patients with AN, ERP as an adjunct to inpatient care was associated with increased caloric intake in a laboratory meal (Steinglass et al., 2014). Mirror exposure therapy as an adjunctive outpatient eating disorder treatment has been associated with improvement in body checking, body image dissatisfaction, and eating disorder symptoms (Hildebrandt, Loeb, Troupe, & Delinsky, 2012).

PSYCHOTHERAPY

For individuals with AN, weight restoration is a necessary, though generally not sufficient, first step in treatment (APA, 2006, 2012). Nutritional rehabilitation results in significant improvement in mood, anxiety, and preoccupation with eating and body weight. Effective treatment generally includes structured, behaviorally based treatment with mealtime support, including prescribed meals and observation during and after meals (Attia & Walsh, 2009). No psychotherapy has emerged as the treatment of choice for outpatients with AN, though specialist care, careful monitoring, and CBT are generally recommended (APA, 2006, 2012). CBT is the recommended psychotherapy for BN, according to both the National Institute for Clinical Excellence (NICE, 2004) and APA guidelines (APA, 2006, 2012). CBT for BN (CBT-​BN; Fairburn, Jones, Peveler, Hope, & O’Connor, 1993) has been found to be effective in reducing the frequency of binge eating and purging, and in improving overall eating disorder pathology (Hay, Bacaltchuk, Stefano, & Kashyap, 2009; NICE, 2004). CBT-​BN focuses on normalization of eating patterns via meal plans, and addressing distorted beliefs regarding fear of weight gain after binge episodes, eating, and body image concerns. Interpersonal therapy (IPT) has also been useful for patients with BN and may be recommended for those who do not respond to CBT (Fairburn et al., 1991, 1993; Hay et al., 2009). In a multicenter study directly comparing CBT with IPT, CBT was associated with significantly greater improvement at the end of treatment. At follow-​up, however, the treatment differences between the two groups were no longer significant, due to continued improvement of the IPT group (Agras, Walsh, Fairburn, Wilson, & Kraemer, 2000). Exposure and response prevention (ERP; see ­chapter 37) has been an area of treatment development for eating disorders. When ERP strategies were incorporated into traditional CBT for patients with BN, no additional benefit was observed (e.g., Agras, Schneider, Arnow, Raeburn, & Telch, 1989; Bulik, Sullivan, Carter, McIntosh, & Joyce, 1998). For individuals with AN, exposure therapy has been developed to specifically target eating-​related fears and rituals. In 626

COMORBID OCD AND EATING DISORDERS

To date, no randomized controlled trials have directly addressed the treatment of cooccurring OCD and eating disorders. Two studies have examined the impact of eating disorder treatment on OCD symptoms. In one (n = 508), Olatunji and colleagues (2010) explored the relationship between improvement in eating disorder and OCD symptoms with treatment. They reported that eating disorder treatment reduced OCD symptoms. In a second study of individuals with an eating disorder (n = 2,971), the presence of OCD did not negatively affect inpatient treatment outcome (Cumella et al., 2007). One study examined treatment that directly targeted OCD and eating disorder symptoms simultaneously. Simpson and colleagues (2013) described the treatment course for patients in a residential multimodal program for comorbid OCD and eating disorders (n = 56). All participants had OCD and either AN (41%), BN (25%), or ED-​ NOS (34%). The treatment included exposures focused on OCD-​related fears, and food and body image fears. The meal plan also incorporated the exposure hierarchy. OCD, eating disorder, and depressive symptoms significantly improved with treatment. At discharge, 59% of patients had clinically significant reductions in eating pathology symptoms (