Past, Present and Future of Psychiatry: IX World Congress of Psychiatry [2 vols.] 981021930X, 9810219318, 9810215002

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PAST, PRESENT AND FUTURE OF PSYCHIATRY IA world congress or rsycniatry IX World Congress of Psychiatry Volume I Volume I

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PAST, PRESENT AND FUTURE OF PSYCHIATRY X World Congress of Psvchiati IX World Congress of Psychiatry Volume I Volume I Rio De Janiero, Brazil

6 - 1 2 June 1993

Editors

A Beigel Tucson, Arizona, USA

JJ Lopez Ibor, Jr. Madrid, Spain

JA Costa e Silva Rio deJaneiro, Brazil

(World Scientific Singapore • New Jersey • London • Hong Kong

Published by World Scientific Publishing Co. Pte. Ltd. P O Box 128, Farrer Road, Singapore 9128 USA office: Suite IB, 1060 Main Street, River Edge, NJ 07661 UK office: 73 Lynton Mead, Totteridge, London N20 8DH

PAST, PRESENT AND FUTURE OF PSYCHIATRY IX World Congress of Psychiatry Copyright © 1994 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in anyform or by any means, electronic or mechanical, includingphotocopying, recording orany information storage and retrieval system now known or to be invented, without written permission from the Publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 27 Congress Street, Salem, MA 01970, USA.

ISBN: 981-02-1930-X (Vol. 1) ISBN: 981-02-1931-8 (Vol.2) ISBN: 981-02-1500-2 (Set)

Printed in Singapore.

Printed in Singapore by JBW Printers & Binders Pte. Ltd.

FOREWORD

The IX WORLD CONGRESS OF PSYCHIATRY was a unique event. It represented the first World Congress to be held outside of the Northern Hemisphere. By placing the Congress in Rio de Janeiro, the WPA Executive Committee also wished to affirm its intention to be the organization that officially represents psychiatry throughout the world. The charge to the Scientific Program committee was to develop a program that would truly reflect the advances, impacts, and interests of psychiatry in every corner of the globe. In keeping with this objective, the Editors of this Proceedings have strived to assemble a collection of representative papers from the Congress that will provide to any reader an overview of world psychiatry as conveyed by the presenters at the Congress. From among the more than 2000 presentations that were made in Rio, almost 400 representative authors were selected and contacted. Each was asked to submit at least one paper that had been presented during the Congress. Much to our surprise and delight, almost 75% of those contacted responded affirmatively and have worked with us to prepare the papers contained in this volume. The first authors of the approximately 300 papers contained in these Proceedings represent 40 countries. Thus, this volume not only reflects the multinational presences of psychiatry, but also communicates the diversity of its interests as reflected by the culture and society in which it is being practiced. We have chosen to organize the Proceedings in a manner different from the way the papers were presented at the Congress. This was done in order to enable the reader to proceed immediately to the topical area of greatest interest. However, we invite all readers to examine the richness of the entire volume. It reflects not only the scientific growth of psychiatry, but also the contributions of psychiatry to the understandings of the quality of life and a host of other biopsychosocial issues that affect the way people live within their culture and our world. Because time and space did not permit us to print the volume in all four official languages of the WPA, we selected English because it was the language most commonly used during Congress presentations. To those authors for whom English is not a native tongue, we want to extend our special thanks for the time they spent to prepare their paper in English. As editors, we attempted to provide editorial assistance to all authors whenever possible. Any lack of clarity or the use of an improper editorial style or grammar is a result of our failure to exercise editorial diligence within the time constraints that we faced in order to publish this volume as soon after the Congress as possible. All of the authors have done everything that has been requested. Without their extra effort, this volume would never have become the special reflection of international psychiatry that it hopefully is. A special word of thanks to Dr. Vera Lemgruber, Chair of the Scientific Program Committee. The contents of this Proceedings are a direct result of her efforts in fashioning a truly outstanding scientific program.

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For those who were not able to attend the Congress, we hope that this volume will provide you with the incentive to attend the X World Congress in Madrid in August 1996. For those who were with us in Rio, we hope it serves as a timely reminder of the richness of scientific inquiry that we all experienced and that you will not only join us again in Madrid, but also present again at that Congress. Allan Beigel,M.D. Secretary for Editorial Policy J.A.CostaeSilva,M.D. President of the IX World Congress Immediate Past President J.J. Lopez Ibor, Jr., M.D. Secretary General

PAST, PRESENT AND FUTURE OF PSYCHIATRY J.A. COSTA ESILVA

Mankind's attitude to suffering has always depended on the way he perceives the universe and his own place within it. In early times, prehistoric peoples saw illness in terms of magic, as an ontological entity in its own right. Later the conception that emerged among the Assyrians and Babylonians was religious in the strict sense, with an identification of suffering with sin. It was in post-Homeric Greece that illness finally became a scientific concept. The therapeutic and preventative procedures for controlling or reducing pain in the human body were determined by the logic of these different approaches. The medicine of primitive cultures was an empirical one based on the observation of facts and on rudimentary experience backed up by centuries of practice. In the ancient world there were no doctors with well defined roles. These would only emerge with the rise of Greek civilization. It can be said that since earliest times, there existed three different concepts of pathology: materialist, dynamist and spiritualist. The first sees illness as a sort of external material affliction which attaches itself to the surface of the body and then penetrates into it. In the dynamist conception, illness is the product of a mysterious force, a fluid or current emanating from the gods, which is passed on to the beings, the men and the things with which it comes in contact. Finally, in the spiritualist conception, illness is imbued with a demoniac character: its source is some more or less spiritual entity who attacks at a given moment, and either withdraws or takes up permanent occupation (demoniac possession). If we had to divide psychiatry into periods defining human attitudes in the face of morbid mental states, we could proceed as follows: 1) A period without scientific involvement in psychiatry, when human beings generally perceived mental suffering in terms of magic. Whether it be in the Hellenic era, with basic techniques, or in the Middle Ages with exorcism of the possessed "madman". 2) A stage described by Zilborg as a first psychiatric revolution. This is the era when the ground for psychiatry was just being prepared. It is the Renaissance era, with the notion of separation of religion and science. To the extent that mental illness is no longer seen as demoniac possession, the way is open for an embryonic conception of psychology.

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3) The Age of Reason. At this stage, not only does the previously implanted embryo of a science of psychiatry begin to grow, but with it the exercise of reason, with the result that mental illness is definitively emancipated from superstition, due to inductive reasoning founded on rigorous and objective observation. It is the period of Descartes in philosophy, and of Harvey and Sydenham in medicine, with the description of hysteria. This age of reason and observation begins in the 17th Century and extends into the 18th with the Enlightenment. There is increased confidence in reason to the detriment of tradition and faith. The different aspects of society are more and more founded on rational and mechanistic principles which reinforce man's control over the physical universe. It is also the epoch of systems of classification, where Linnaeus in botany, Cullen and Savage in medicine, and Mendeleev in chemistry undertake the classification of plants, diseases and chemical elements. This movement anticipates Pinel's work at the end of the 18th Century. We can say that he signals the opening of the fourth stage, that of the constitution of psychiatry into a science and branch of medicine. 4) Birth of psychiatry as medicine. Pinel systematises mental illnesses. Others follow in his footsteps, notably Esguirol. In the 19th Century, we can already see psychiatry develop along the lines governing general pathology in medicine, including pathological anatomy. This is the era of descriptive psychiatry with figures such as Kahlbaum and others, who remain more concerned with describing what they see than explaining it. At this period, the previous century's great systematiser, Kraepelin, also comes to the fore, and his influence on modes of diagnosis and classification can be felt to this day. Under the impetus of Darwin's theories, Morel also propounds his ideas on degeneration in psychiatry and Jackson develops his own ideas. Concurrently, the flowering of remanticism dethrones reason and encourages the rediscovery of the irrationality of the human psyche, while instincts and drives take on great importance in the psychiatric field. This is the background against which the work of Charcot, Janer and Freud appears. According to Zilborg, the period from the first to the second psychiatric revolution defines a radical change

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in pathology and opens the way to the construction of an inclusive pathology in our era. It is the rebellion of the dynamic uncounscious, of the importance of history and of the past in the genesis of illnesses. This Freudian mould is also the source of the phenomenological and existentialist schools. In addition, biological psychiatry continues to progress, with the appearance of electro-convulsive therapy, malariotherapy, insulinotherapy, cardiazol, etc. Just after the First World War, the importance of the patient's social dimension begins to emerge. 5) The fifth stage starts in the 1950s with neuroleptics. The use of the first neuroleptic for the treatment of mental illness begins with Delay and Deniker and behavioural science, and with the integration of advances in biochemistry and in central nervious system physiology. It was to lead to a profound redefinition of the role of hospitals and asylums, and to a complete transformation of psychiatry. With the introduction of the idea of the therapeutic community and institutional therapy, movements for the humanisation of the hospital emerged. Psychiatric teams began to change. The patient took on increasing importance to the detriment of the illness. By controlling psychotic symptoms, neuroleptics bring the psychiatrist closer to the patient and correspondingly closer to free expression by the subject. The process which had already occurred in psychosomatic medicine and in the understanding of the neurotic's neurosis, now becomes possible for the psychotic. As a result the mentally ill, rather than the mental illness, become the focus of attention. A period of dilution of diagnosis now began which would culminate in the sixties with the anti-psychiatry movements and their principal trends. At the same time, there arose what is called psychiatric power and the psychiatrisaton of society. Teams came out of the hospitals and turned to peripatetic services, to society and its mental health problems, to community and local psychiatry. In the early 197 0s the crisis deepened. Yet at the same time there were the first stirrings of a psychiatry of synthesis, and anthropological psychiatry, one which would approach man as an indivisible, bio-psycho-social whole, and undertake the task of restructuring the discipline, whether in its theoretical concepts or its

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care and treatment practices. The same period saw a revivial of interest in classificatory diagnosis in psychiatry. It was the era of RDC and DSM-III, which led to today's Tenth Revision of the International Classification of Maladies, ICD-10, as a result of improvements in screening. From the 1980s, the progress of neuroscience led to major developments in the so-called biological dimension of psychiatry with the introduction of new techniques for the study and understanding of the brain's functions. In the sixties, the brain was left out of the teaching of psychiatry in medical courses. Today, it is the mind which is left out. We know more and more about the functions of the brain, but as yet very little about the link between the bain and thought. The challenge that faces us in the century to come will be to integrate the growing mass of information we possess on cerebral function and mental illness, with the psychological, social and cultural factors which also affect human behaviour. In the 21st Century, psychiatry will have access to very sophisticated data and complex technologies. However, despite of the progress, we are aware of a disaffection with psychiatry, with its human dimension, a disaffection with humanism. It is in this area that psychiatry needs to take a stand as we approach the 21st Century. All this mass of knowledge about man's biological dimension needs to be brought to bear on a better understanding of the human being.

THE WORLD OF PSYCHIATRY -1993 A SUMMARY KEYNOTE ADDRESS WORLD CONGRESS OF PSYCHIATRY YVES PELICIER, M.D. Professor of Psychiatry Faculty of Medicine Necker Paris 70015, France

The list of advancements achieved by modern psychiatry, and the disciplines and sciences which have aided it is so considerable that we have the choice, be it of devoting all of this conference to it, or of limiting ourselves to a report, which will give some indication of the probable evolution of the discipline and the profession. Particularly since the '80s, the uses of new knowledge, acquired thanks to molecular biology, have been transforming genetics, the physiology of the brain, and immunology. The evolution of medical imagery has led to a better knowledge of cerebral illnesses, of hemodynamics, and of the condition of marked molecules. Psychotherapies are also the object of very active research; interpersonal, cognitive and behavioral therapies occupy an important place next to the treatments inspired by psychoanalysis. In fact, what seems to be the characteristic of the progress of knowledge in psychiatry is its extreme diversity. It would be unfair and inaccurate to favor exclusively the role of the neurosciences. We anticipate great things from them, but for the moment, there is no reason to underestimate the other sciences. We need all available therapeutic information. Even after being successfully treated with a neuroleptic, a schizophrenic is an individual marked by the illness, the suffering and the deficiency. How to help him manage his daily affairs; how to facilitate his relationships; how to sustain his effort to remain in the social group? Where mental illness is concerned, I believe there is a consensus today to adopt a biopsychosocial model. In other words, everyone knows that no human, whether healthy or ill, can escape the triple determination of biological, psychological and sociological needs. The image of psychiatry in society is universally bad. Yet, the questions which arise concerning the quality of the image of psychiatry are not a rhetorical exercise. There are one of the major obstacles to the development of an alliance between psychiatrists, illnesses and society, and they negatively condition the politics of mental health. With some qualification, the negative perception is universal, which does not signify that the causes are simple. On the contrary, there are several factors involved. Most often, the mental illnesses which medicine describes are regrouped under the same term of madness, that is to say, of insanity. Thus, mental illness pertains to that negative region of existence, alongside pain, informity, and death. It's a life apart, which others perceive

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with that stigmatization which we often denounce without really being able to reduce it, thus causing us feelings of shame, culpabihty, exclusion, fear or derision. In 1993, one is again obliged to recall that mental illness exists, that it does not result from a feebleness of personality, or from a lack of courage orfroma vice. In spite of all this, we continue to confound the difficulties of life, the unhappiness of the human condition, with pathology. But, to this moral conception curiously responds that which could seem altogether contradictory, the fatalism founded in an erroneous conception of heredity. Thus, stigmatization is not limited to the sick individual but to all his descendants. With regard to the mentally ill, it must be said that our societies are stigmatizing, informist and racist. This needs to stop. No scientific advances can completely succeed in such an atmosphere. In this review of the misunderstandings and obstacles which prevent the image of psychiatry from being better conformed to the reality of the discipline, it is necessary to raise the sensitive question of the power of psychiatrists, so often discussed by the public and the media. This theme of the abuse of power by psychiatrists has been much discussed. It experienced a considerable development, in the 70s, with the anti-psychiatiy movement. All was not false, but the view was warped. Perhaps we should hold the terrible state of a large number of psychiatric hospitals, the overcharging, and the precariousness of the hygiene responsible for this image. But in truth, every psychiatric institution is always suspected of being an asylum. Still, every doctor has two tasks: to diagnose and to treat. Each epoch attempts its syntheses. Ours is largely dominated by two classifications; the one North American, DSM III R (soon DSM IV), the other presented by WHO (O.M.S.), ICD10 (CIM10). With respect to this, I shall make the following observations: 1. Psychiatrists, as well as promoters of these classifications, know that they are not perfect; they are but proposals, subject to revision. These classifications involve an enormous amount of work for which we must give their designers credit. 2. It would no doubt be useful to internationalize the discussion. For example, the DSM i n or IV cannot be considered as uniquely relevant to psychiatrists in the United States. It is an instrument for all psychiatrists and we must give more consideration to cultural diversities and national traditions. The entire community would profit from this. 3. In short, we must exorcise all dogmatism while maintaining within our classifications the open character of provisional instruments, forcibly reduced but furnishing the basis for a common language. Other signs of rupture in the psychiatric fabric are visible: the disparity in the structure and the means of care between rich and poor countries is evident. Undoubtedly, we must not look for a uniformity which would erase cultural and traditional differences. But the existence, in the world, of hospitals where the mentally ill are packed together without proper sanitation or in a condition of promiscuity, is intolerable. The fact that certain of the mentally ill are not treated, even though the remedies exist, because there is no money to pay for medical attention is scandalous. It needs to be said, it needs to be shouted out; medical progress is not the same for all, and we must not tolerate it, no more than we would starvation or the violation of human rights. Another domain in which difficulties are evident and progress necessary, is that of the education of the public.

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Mental health is a phenomena of society. Now, these ways of speaking and this exchange of ideas are badly done, or done in an irregular fashion. All too often, the information is only media hype. One could wish for the creation of a real partnership for mental health. Certain countries are already successfully doing so. I am thinking of Australia and Canada. Some others make an effort to introduce some notions of health education into the school curriculum. We must not forget also the education of parents. Too often, in the less fortunate areas, but also equally in others, children are left to fend for themselves, and even when they are not abandoned in the streets, they find in the family, neither guidance nor emotional security, nor role models to help them to develop their own personality. The characteristic of a living discipline is to evolve, to change. From that point of view, who could deny that in this latter half of the century, psychiatry has known enormous upheavals which have sometimes taken on the aspect of crises or revolutions, with some negative aspects, but also with great advances. For too long the psychiatrist has been a solitary man. Perhaps it is time to break this isolation which is at the same time spatial and ideologic. In a large number of countries, psychiatry is put in the general hospital. This attracts some people and frightens others. There is no miracle solution; in fact, we confuse two different problems. What is known as the psychiatry of linkage is indispensable to the smooth functioning of medicine. Epidemiology shows us the importance of disorders and mental illnesses in the general population, and even more so in the hospital population. To neglect these aspects costs dearly; in sufferance and in budget. One of the solutions is to bring psychiatry closer to the services of medicine, surgery, and specialists so that they can all share their diagnostic systems and its therapeutic support. Besides, the presence of a psychiatrist, employed in an organization, a participant on the team, in its difficulties and in its failures, as well as in its successes, is very effective. What distinguishes a modern practice from one which is not is precisely the suppleness and flexibility of its standards; going from conventional hospitalization to liberal forms of patient care in their homes. Deinstitutionalization is on the whole a transinstitutionalization which would allow us to give to the mentally ill the institution which best suits his needs at a given moment of his evolution. To put the mentally ill out in the street is not realistic even if the idea has a generous side. One cannot deny the existence of mental illness by eliminating the places where it may seek refuge. There is here a profound social injustice. The sick individual never ceases to be a person. This principle is indispensable especially in a situation where mental retardation has caused the insane to be in a deeply lost state. I am absolutely in disagreement with a theory which would distinguish human beings as persons based on their ability to think clearly, hence they're respectable; and those who can't as non-persons, to whom only charity would be due. In fact, these deeply lost souls are people in the eyes of doctors and care givers or those who love them. What constitutes a person is reciprocity. If this demented soul is not a person to me, then what am I, myself? The honor of psychiatry, its ultimate professional value, is the respect of the unique being which is in every man, regardless of his condition. We are linked to him in a situation of justice where one gives and the other receives. After a long practice of psychiatry, spanning many decades, I know that our sick sometimes give more than they receive.

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CONTENTS Part I Advances in Neuroscience Chapter I: Genetic Aspects 1. New Markers of Alcohol Consumption: CDT and 5HTOL Borg S., Helander A., Beck O., Carlsson A. V., and Stibler H. (Sweden)

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2. Psychosis and the Problem of Human Brain Evolution Crow T. J. (UK)

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3. Territory and Hierarchy in the Evolution of Psychoses KellettJ. M. (UK)

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4. Molecular Genetics in Psychiatry Research Mendlewicz J. (Belgium)

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5. Mediating Variables in Familial Schizophrenia Mezaros K, Willinger U., Lang M., Beran H, Fischer G., Lenzinger E., Reiter E., Resinger E., Strobl R., and Aschauer H. N. (Austria)

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6. The Molecular Genetics of Early Onset Familial Alzheimer's Disease Mullan M. (USA)

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Chapter II: Neurochemistry 1. The Role of CCK in Panic: Clinical Research Bradwejn J. (Canada)

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2. Tardive Dyskinesia Mechanisms and Abnormal Glucose Metabolism Casey D. E. (USA)

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3. Methylated Indoles in Obsessive-Compulsive and Phobic Disorders Ciprian-Oliver J. and Cetkovich-Bakmas M. G. (Argentina)

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4. ELISA Quantification of the Amyloid A4 Precursor Protein in Cerebrospinal Fluid of Patients with Alzheimer's Disease Muller-Spahn F.f Naser W., Klages U, Modell S., Bartke /., and Hock C. (Germany)

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5. CCK, Schizophrenia, and Anxiety: CKK-B Antagonists Inhibit Dopamine Neurons Rasmussan K. (USA) 6. Modulation of Natural Killer (NK) Cell Activity by Hormones of the Hypothalamic-Pituitary-Adrenal Axis in Anorexia Nervosa Ravizza L., Masera R. G, Prolo P., Saurenghi A. K, Zanalda E„ Sartori M. L, and Angeli A. (Italy)

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7. Neurochemical Correlates of Cerebral Asymmetry in Schizophrenia Reynolds G. P., and Cutts A. J. (USA)

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8. Anti Sm Antibodies in Schizophrenia Sirota P., Schild K., Firer M, Zurgil N., Barak Y., Elizur A., and Slor H. (Israel)

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9. Neuroleptics Affect Dopamine Uptake by Platelets from Schizophrenic Subjects Sundram S., Dean B., Hill C, Copolov D. (Australia) 10. Behavioral Pharmacology of Self-Injury (Netherlands) Tuinier S. and Verhoeven W. M. A. (Netherlands) 11. Evidence for the Major Role of Monoaminooxidase Hyperactivity in the Pathogenesis of ADHD (Attention Deficity Hyperactivity Disorder) Wirth S., Trott G. K, Nissen T.t and Nissen G. (Germany)

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Chapter III: Neurophysiology 1. Alzheimer's Disease: A Lysosomal Disorder Bernstein H. G, Kirschke H.t Wiederanders B. (Germany), Rinner R. and Rinne A. (Norway)

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2. 5-HT ID Autoreceptors in the Action of Antidepressant Drugs Briley M. and Moret C. (France)

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3. Cognitive Impairment in Physiological and Pathological Aging Cazzullo C. L (Italy)

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4. Pituitary DA-D2 Receptors Are Not Increased in Treated Schizophrenics Dean B., Pavey G., Copolov D. (Australia), and Kleinman 7. (USA)

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5. The Interaction of Dopamine and Serotonin in Developing Psychopharmacological Models De Smedt G. (Belgium) 6. Serotonin Receptor Subsets in Obsessive-Compulsive Disorder Dolberg O. T., Sasson Y., Kindler S., Cohen R., Kotler M., and Tjohar J. (Israel) 7. Limbic Assymetry Confirmed by lomazenial SPECT in Patients with Panic Disorders Kaschka W. P., Feistel K, and Ebert D, (Germany) 8. Effect of Acute Anxiety on Cranial Blood Flow Matthew R. J. and Wilson W. H. (USA) 9. Human 5-HT ID Receptors: Cloning Discoveries and Their Impact on Human Drug Design Pauwels P. J. (France) 10. Microstructural Analysis of Motor Control in Schizophrenia Rosen A. J. and Westergaard C. K. (USA) 11. New Light on the Process of Neuronal Destruction in Alzheimer's Disease Roth M. and Wischik C. (UK)

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Part II Diagnostic Classification, Assessment, and Testing Chapter IV: Nosology and Classification 1. Psychiatric Nosology on the Way from Symptomatology to Semiology Berner P. (Austria) 2. International Classification of Impairments, Disabilities, and Handicaps (ICIDH-1980): Suggestions for Revision Cooper J. E. (UK) 3. Ensuring Equivalence of ICD-10 Versions in Different Languages Dilling H. (Germany), Nakane Y. (Japan), Freyberger H. J., and Mombour W. (Germany)

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4. Culture and Psychopathology Foulks E. F. (USA) 5. Evaluating Differing Rates of Alcohol Use Disorders Among the General Population Grant B. F. (USA)

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6. The Impact of Diagnostic Systems on Treatment Helmchen H. (Germany)

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7. Typology and Course of Endogenous Psychoses Lazarescu M. and Ienciu M. (Romania)

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8. The Search for New Models in Psychiatry Pichot P. (France)

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9. The ICD-10 Multiaxial System: Preliminary Results of Field Trials 157 Lopez Ibor J. J. (Spain), Sartorius N., Janca A. (Switzerland), Kastrup M. (Denmark), Katsching H. (Austria), and Mezzich J. (USA) 10. Psychiatric Pathology: Genome and Personality Llavero F. (Spain)

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11. Development of the Classification of Mental Disorders Incorporated in the International Classification of Disease Sartorius N., Ustun T. B., and van Drimmelen J. (Switzerland)

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12. ICD-10 Primary Care Version for Recognition and Management of Mental Disorders Ustun T. B. and Sartorius N. (Switzerland)

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Chapter V: Assessment 1. Issues on Forensic Psychiatry Epidemiology Arboleda-Florez J. A. and Love E. 7. (Canada)

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2. Psychiatric Screening Instruments for Children and Adolescents Berganza C. E., Gaitan L, Cazali L (Guatemala), and Mezzich 7. E. (USA)

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3. Cultural Meaning in Self-Mutilation Favazza A. R. (USA)

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4. Behavioral Assessment in Psychiatry: Concepts, Measurement, and Meaning Gaebel W., Ellgring H., and Wolwer W. (Germany) 5. Assessing Quality of Life in Health Care Herrman H. (Australia) 6. Gender Difference in the Presentation of Mental Illness and in Reaction to Life Events Maud C. M. (South Africa) 7. Psychiatric Diagnosis in Primary Care and the Personal Health Scale Mezzich J. E. (USA), Caldera J. T. (Nicaragua), and Berganza C. E. (Guatemala)

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Chapter VI: Testing 1. An Introduction to Recent Trends in Neuroimaging Relevant to Psychiatry Copolov D. (Australia) 2. Laboratory Testing in Psychiatry Da Costa D. A. (Brazil) 3. Schizophrenic Patients are Impaired in Performing a Visual Pars-Pro-Toto Test of Object Recognition Grusser O. J., Ott B., and Von Cranach M. (Germany)

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4. Assessment of PTSD with Self-Rating Scales Hovens J. E. (Netherlands)

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5. Brain Imaging in Psychiatry Kishimoto H., Fujita H., and Kosaka K. (Japan)

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6. Rating of Depressive Symptoms: Objective vs. Subjective Rating Korner A., Bent-Hansen J., Lauritzen L., and Bech P. (Denmark)

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7. Adaptation of the Expert System ADINFER in the Assessment of Dangerousness Ohayon M., Caulet M., and Fournier L. (Canada)

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8. Psychometric Properties of the Beck Depression Inventory Richter P. (Germany), Heerlein A. (Chile), Kick K, and Biczo P. (Germany)

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9. The Composite International Diagnostic Interview (CIDI) Robins U N. (USA)

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10. The Functional Topography of Psychiatric Illness as Shown with SPECT Rubin R. T. (USA)

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11. Explorations of Differences Between DSM m-R and IGD-10 Using the WHO-CIDI As A Diagnostic Tool in Clinical Practice Smeets R. M. W. and Ter Smitten M. H. (Netherlands)

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12. Magnetic Resonance Imaging Findings in Schizophrenia: Relationships with Language and Thought Disorders, Symptomatology and Cognitive Performance Vita A., Died M., Giobbio G. M, Comazzi M., Caputo A., and Invernizzi G. (Italy)

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Part III Advances in the Understanding of Mental Disorders Chapter VII: Affective Disorders A: Definition, Etiology and Phenomenology 1. Bipolar II: Prevalence and Clinical Significance of the Soft Bipolar Spectrum Akiskal H. S. (USA)

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2. Recurrent Brief Depression Angst J. and Hochstrasser (Switzerland)

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3. The Causes of Puerperal Psychosis Brockington I. F. (UK)

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4. Thyroid Function in Depressed Patients: Maprotiline vs. Fluvoxamine De Mendonca Lima C. A. and Carron R. (Switwerland), Vandel S. and Bechtel P. (France)

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5. What is Subsyndromal Symptomatic Depression (SSD)? Judd L. L., Rapaport M. K, Paulus M. P., and Brown J. L. (USA) 6. Epidemiology of Seasonal Affective Disorders (SAD) and Its Subsyndromal Form (S-SAD) Kasper S. and Neumeister A. (Austria)

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7. Do Melancholies and Manic-Depressives Have a Personality Disorder Kraus A. (Germany)

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8. Seasonality and Recurrence in Affective Disorders Lopez-Almaraz R. (Mexico)

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9. Contingent Negative Variation in Depressive Disorders: State or Trait Marker? Papart P., Ansseau M., and Timsit-Berthier M. (Belgium)

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10. Memory, Anticipation, and Depression Perez-Rincon G. H. (Mexico)

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11. New Subtypes of Depression: Implications for Research Rapaport M. H. and Judd L. L. (USA)

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12. Mood Disorders and Season of Presentation: A Preliminary South African Study Szabo C. P. (South Africa)

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B: Treatment 1. Modern Views on the Treatment of Therapy-Resistant Depression Achte K., Kuoppasalmi, and Naukkarinen H. (Finland)

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2. Psychosocial Vulnerability Factors and Long-Term Treatment of Depression: Perspectives for Future Studies Bauwens F., Mendlewicz J., Staner L., and Pardoen D. (Belgium)

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3. Fluvoxamine and Lithium or Carbamazepine in Bipolar Patients: Clinical and Biological Findings Marazitti D., Presta S., Rotondo A., and Conti L. (Italy)

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4. A 10 Years Follow-up Study of Suicide Attempters Nordentoft M. and Breum L. (Denmark)

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5. Paradigm for the Management of Resistant Depression Okasha A. (Egypt) 6. Inadequate Treatment for Depression: Frequent Cause of Therapeutic Failure Ortiz Fragola E. and Fahrer R. (Argentina)

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7. Therapeutic Innovation in Depressive Disorders Pande A. (USA)

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8. Maintenance Electroconvulsive Therapy in Affective Disorders Papadimitriou G. N., Papakostas Y. G, Zervas I. M.t and Stefanis C. N. (Greece)

364

9. Sleep Deprivation in Acute and Maintenance Treatment of die Affective Disorders 368 Papadimitrious G. N., Chistodoulou G. N., and Stefanis C. N. (Greece) 10. The Family of the Depressive Patient: From Melancholic Type of Melancholic Family Peters U. H. (Germany)

372

11. Targeted Pharmacotherapy in Depression Management: Comparative Pharmacokinetics of Fluoxetine, Paroxetine, and Sertraline Preskorn S. (USA)

378

12. Seasonal Affective Disorder, Light Therapy, and the Serotonin System Rosenthal N. E, Garcia-Borreguero D., Schwartz P. /., Jacobsen F. M., Joseph-Vanderpool J. R., Oren £>. A., and Murphy D. L. (USA.)

386

13. Treatment of Severe Depression with Cognitive Behavior Therapy Those M. E. (USA)

392

14. Management of Depression in Real-Life Settings: Knowledge Grained from Large-Scale Clinical Trials Thompson C (UK)

402

XXIII

Chapter VIII: Schizophrenia and Related Psychotic Disorders A: Definition, Etiology and Phenomenology 1. Positive and Negative Symptoms: Concepts, Definitions, and Significance Andreasen N. C, Arndt S., Flaum M., Millere D., and Swayze V. W. (USA)

411

2. Schizophrenia: 100 Years is Enough Brockington L (UK)

418

3. Delusional Misidentification Syndromes: Recent Developments Christodoulou G. (Greece)

424

4. Relationship Between Positive and Negative Symptoms: Response to Antipsychotic Drugs and Structural Brain Abnormalities Elkis K, Friedman L., Lys C, Meltzer H. Y, and Bond D. D. (USA) 5. Facial Expression in Schizophrenic Patients Ellgring H. and Gaebel W. (Germany) 6. Clinical Correlates of Immune Dysfunctions in a Subgroup of Schizophrenic Patients Ganguli, R., Brar J. S., Damaraju C. V., Gubbi A. V., Yang Z.-W., Chengappa K. N. R., and Rabin B. S. (USA)

430

435

440

I. Long Term Follow Up Studies of Schizophrenia in Different Cultures Harrison G. (UK), Gulbinat W. and Sartorius N. (Switzerland)

445

8. Communicative Stress and Coping in Schizophrenic and Healthy Persons Kasermann M. L. and Altorfer A. (Switzerland)

451

9. The Dimensional Complexity of the EEG in Untreated Acute Schizophrenics Koukkou M., Lehmann D. (Switzerland), Wackermann J., and Dvorak I. (Czech Republic) 10. Multiaxial Diagnosis of Schizophrenic Patients Mezzich J. E. (USA) and Zapata-Vega M. I. (Peru) II. Gender Differences of the Dexamethasone Suppression Test in Schizophrenia Rybakowski J. K. and Plocka M. (Poland)

456

460

466

xxiv 12. Schizophrenia: A Human Disease — Clinical, Research, and Human Rehabilitation Aspects Sarwer-Foner G. J. (USA)

470

13. Comorbidity and Multiformity in Schizophrenia Stefanis C. N., Dikeos D. G, and Papadimitriou G. N. (Greece)

477

14. Gestures and Speech Activity in Schizophrenia and Depression Wolwer W. and Gaebel W. (Germany)

482

B: Treatment 1. The Effect of a Full Support Model of Team Case Management on the Rehabilitation Goals of Patients with Schizophrenia Aberg-Wistedt A. and Cressel T. (Sweden)

487

2. Intermittent Neuroleptic Long-Term Treatment in Schizophrenia: State of the Art Gaebel W. (Germany)

493

3. Quick/Slow Neuroleptic Response in Schizophrenia: A Validity Study Hai-Gwo H. and Ta-Jen C. (China, Taiwan)

497

4. Intermittent Medication in Schizophrenia: Predictors of Outcome Herz M. I. (USA)

502

5. Teaching Coping Skills to Prevent Relapse in Schizophrenia Herz M. I., Lamberti J. S., and Brown S. (USA)

505

6. Application of Clinical Pharmacokinetics in the Management of Schizophrenia: Cross-Cultural Differences Javaid J. L. (USA), Marcolin M, A. (Brazil), Janicak P. G, Sharma R. P., Davis J. M. (USA), and Motta Z (Brazil)

508

7. Family Intervention in Schizophrenia: New Approaches and Outcome in Single- and Multi-Family Group Formats McFarlane W. R. (USA)

513

8. The Schizophrenic Patient's Transition from Hospital to Extramural Facilities: Problems and Possible Solutions Mundt Ch., Erbacher H., and Lauter R. (Germany)

519

XXV

9. Some Aspects of the Rehabilitative Efforts for Long Term Schizophrenic Patients Sarwer-Foner G. J. (USA)

525

Chapter IX: Organic Mental Disorders A: Definition, Etiology and Phenomenology 1. Auto-Aggressive Behavior in Mentally Retarded Persons: A Developmental Psychiatric Approach Dosen a. (Netherlands) 2. Assessment of Depression with Psychometric Scales in Alzheimer's Disease Geroldi C, Frizoni G. B., Zanetti O., Blanchetti A., and Trabucchi M. (Italy) 3. Cultural Factors Influencing Prevalence and Prognosis of Epilepsy in East Africa Jilek-Aall L. and Jilek W. G. (Canada)

531

538

543

4. Clinical, Diagnostic Issues and Therapy in Psychogeriatry Montenegro R. (Argentina)

548

5. Assessment and Classification of Mental Retardation in ICD-10 Mulcahy M. (Ireland)

551

6. Neuropsychology of Dementia and Depression in Old Age Reisches F. M. and Geiselmann B. (Germany)

554

7. A Case Control Study of Risk Factors on Alzheimer's Disease: Multicenter Collaboration Study in China Shen Y.-C, Li G, Li Y-T., Chen C.-K, and Li S.-R. (China)

559

Chapter X: Substance Use Disorders A: Definition, Etiology and Phenomenology 1. Structured and Semi-Structured Instruments for Assessing Substance Use Disorders: The WHO CIDI-SAM vs. The WHO Scan Comptom W. M. and Cottier L. B. (USA)

563

XXVI

2. Drinking Situations, Mood and Depression As Predictors of Alcohol Relapse El-Guebaly N. and Hodgins D. C. (Canada) 3. Biological Mechanisms Underlying the Development and Maintenance of Addictive Behavior Helmchen K, Schmidt L. G. (Germany), Schuckit M. A. (USA), Almeida O. F. X., Shippenberg T. S., Holsboer F. (Germany), Borg S., Beck O., Helander A., Stibler H., Voltaire A. (Sweden), and Rommelspacher H. (Germany) 4. A Two Component Theory for the Development of Alcohol Withdrawal Syndrome: Experimental and Clinical Evidence Hemmingsen R. (Denmark) 5. Role of Premorbid Type of Character in Alcoholism Ivanets N. (Russia) 6. Assessment of Alcohol- and Drug-Related Problems in Different Cultures Janca A. (Switzerland), Gureje O. (Nigeria), and Bennett L. A. (USA)

568

573

577

581

584

B: Treatment 1. Follow-Up of Heroin Addicts Under Treatment with Naltrexone Correia M. M., Padua J., and Da Costa N. F. (Portugal) 2. Prescribing of Non-Addictive Drugs to Drug Addicts: Attitudes of Drug Users and Ex-Users Liappas J., Malliori M., Kokkevi A., Koundi P., Papavasiliou N., and Stefanis C. (Greece) 3. Psychopharmacological Management of Substance Abuse Singh A. N. (Canada) 4. Clinical and Polysomnographic Results after Withdrawal from Long-Term High Dose BZD (Benzodiazepine) Addiction Steinberg R., Weess H. G., Vogg J., Meyer J., Schneider C, Birzele H. J., and Pritzel M. (Germany) 5. Treatment of Alcohol Withdrawl Symptoms in Hospitalized Patients Trixler M., Kovacs Z. S., and Szabo I. (Hungary)

589

594

599

604

608

XXVII

Chapter XI: Panic, Obsessive Compulsive and Other Anxiety Related Disorders A: Definition, Etiology and Phenomenology 1. PTSD in Children and War: A Phenomenological Study and a Follow-Up in a Refugee Camp in Zagreb Grappe M. (France)

613

2. Suicidal Intents in Panic Disorder Griez E., Verburg C, Pols H., and Meijer J. (Netherlands)

618

3. Student's Stress in China, Japan, and Korea: A Transcultural Study Kim K. I. and Won H. (Korea), Liu X. and Liu P. (China), and Kitanishi K. (Japan)

623

4. Alexithymia and Restraint Theory: A Preliminary Analysis Lolas F. and Sanfuentes M. T. (Chile)

629

5. Obsessive Compulsive Disorder: A New Perspective in Diagnosis and Treatment Lydiard R. B. (USA)

631

6. Unified Theory of Obsessive-Compulsive Disorder Yaryura-Tobias J. A. (USA)

638

7. Quantitative EEG in Panic Disorder Patients and Normal Controls Zacharakis C. and Tagaris G. (Greece)

643

B: Treatment 1. Long-Term Management of Panic Disorder De La Fuente J. R. (Mexico)

648

2. Panic Disorder with Agoraphobia and Depression Djurdjic S. and Kunovac J. (Yugoslavia)

651

3. Anxiety Center at Laennec Hospital: First Epidemiological Results Granger B., Alberque C, and Debray Q. (France)

655

4. Efficacy and Safety of Alpidem versus Aprazolan and Placebo in Generalized Anxiety Disorders in the Elderly Laakmann G., Eich F. X., Baghai T., Boval P., Garreau M., Heritier C. L., and Kuhn K. (Germany)

658

XXVIII

5. Behavioral and Psychopharmacological Treatment of Obsessive Compulsive Disorder Neziroglu F. A. (USA)

663

6. On the Treatment of Panic Disorder Nishizono M. (Japan)

670

7. Standardized Outcome Assessment in Panic Disorder Treatment Shear M. K and Maser J. D. (USA)

673

8. Anxiety Disorders: A Diminished Role for Psychoanalysis Wolpe J., Craske M, Reyna L, and Pascotta V. (USA)

678

Chapter XII: Eating Disorders A: Definition, Etiology and Phenomenology 1. The Sexology Approach in Anorexia Bellussi G. (Italy) 2. Dieting Severity and Its Relationship to Alcohol and Drug Use in Young Women Drenowski A., Krahn D. D., Kurth C L., Gomberg E., and Demitrack M. (USA) 3. Risk Factors for an Unfavorable Course of Bulimia Nervosa: What Future Should Patients Expect Fichter M. M., Quaflieg N., Rief W., Liebl C. (Germany) 4. Bulimia Nervosa in a Community Sample: Prevalence, Co-Morbidity and Psychosocial Functioning Garfinkel P. E., Lin E, Goering P., Spegg C, Goldbloom D. S., Kennedy S., Kaplan A. S., and Woodside D. B. (Canada)

685

687

691

695

5. Personality Disorders in Anorexia Nervosa: Relation to Outcome Kennedy S. H. and Ralevski E. (Canada)

696

6. The Rise of Bulimia Nervosa Lucas A. R. and Soundy T. J. (USA)

701

7. Mental and Personality Disorders in a Sample of Subjects Suffering from Eating Disorders Manara F. and Caruso R. (Italy)

704

XXIX

8. Binge Eating Disorder and Obesity Nutzinger D. O. and De Zwaan M. (Austria)

709

B: Treatment 1. Psychobiological Mechanisms of Macronutrient Intake in Eating Disorders Halmi K. and Sunday S. (USA)

714

2. Anorexia Bulimia: Treatment of Network Rovera G. G., Balzola F., and Rovera G. (Italy)

717

3. Controlled Trials of Psychological Treatments in Eating Disorders Russell G. F. M. (UK)

721

4. Treating Eating Disorders with Cognitive-Behavioral Psychotherapy Samuel-Lajeunesse B. and Divac S. M. (France)

725

Chapter XIII: Disorders of Childhood and Adolescence A: Definition, Etiology, Phenomenology 1. An Epidemiological Study of Childhood Hyperkinetic in Hong Kong: A Preliminary Report Ho T. P., Lieh-Mak F., Leung P. W. L. (Hong Kong), and Luk E. S. L. (Australia) 2. Adolescent Psychiatry Today Knobel M. (Brazil) 3. Comparing Health Profiles for Children with Psychiatric and Other Medical Conditions Landgraf J. M., Ware J. E., Jr., Schor E., Ross Davies A., and Rossi-Roh K (USA) 4. Pre-School Psychopathology and Early Mother-Child Interaction: Results of a Longitudinal Study Schmidt M. H. and Esser G. (Germany)

729

733

737

748

XXX

B: Treatment 1. Psychopharmacology in Aggressive Children: Methodology and Efficacy Campbell M., Small A. M., and Anderson L. T. (USA)

753

2. Follow-Up of Children on Ritalin from Childhood to Adolescence Hamadani H. G. (USA)

757

3. Children's Partial Hospital at Summer Camp Hamadani H. G. (USA)

760

4. New Contributions for Psychotherapy Mother-Baby Helou H. (Argentina)

763

5. The Role of Oligoantigenic Diet in Hyperkinetic Children Schmidt M. H., Mocks, P., Lay B., Eisert H. G, Fojkar R., Fritz-Sigmund D., Marcus A., Musaeus B. (Germany)

768

Chapter XIV: Disorders Associated with Physical Conditions A: Definition, Etiology and Phenomenology 1. Suicidal Behavior in HIV Disease: A Case-Control Study of Deliberate Self-Harm in People with HIV Infection Catalan J., Per garni A., Seijas D., Lief T., and Burgess A. (UK)

773

2. Psychosocial Aspects of Cancer: Implications for Quality of Life (QL) Measurement and Intervention Cella D. F. (USA)

778

3. Psoriasis: Psychosis of the Skin De Federicis M. and Lanari S. (Italy)

784

4. Anxiety Pre- and Post-Surgery: An Evaluation in Laparoscopic Surgery 789 Fahrer R., Taraciuk M., Ortega B., Diez J., and Sakamoto N. (Argentina) 5. Vulnerability to Psychiatric Distress in Individuals with HIV Disease Gala C, Pergami A., Catalan J., Burgess A., and Invernizzi G. (Italy) 6. Psychological Disorders in General Medical Settings: Results of the WHO study Goldberg D. (UK), Costa E Silva J. (Brazil), Le Crubier Y. (France),

793

798

XXXI

Ormel H., Sartorius N., Ustun B. (Switzerland), Von Korff M., and Wittchen U (Germany) 7. Prevalence of Psychosocial Morbidity in Spinal Cord Injured Patients Lobera M., Saz P., and Lobo A. (Spain)

799

8. The WHO Neuropsychiatric AIDS Study: Results of Neuropsychological Evaluation Maj M., Star ace F., and Sartorius N. (Switzerland)

804

9. Psychosocial Adjustment and the Relationship Between Cancer-Organ Loss and Psychopathology in Mastectomy Ozkan S. and Turgay M. (Turkey)

808

10. Contraception and Aborton: Personality and Psychological Suffering Rizzardo R., Novarin S., and Forza G (Italy)

813

11. Karoshi — Death from Overwork in Japan Shimomitsu T, Iwane H., Katsumura T, Ohya Y., Sakamoto A., Odagiri Y, and Fujinami J. (Japan)

817

12. An International Study of Primary Care Mental Disorders: WHO Collaborative Project on "Psychological Problems in General Health Care" Ustun T B. and Sartorius N. (Switzerland)

822

13. The Psychiatric Symptoms in Patients with Chronic Pain Verimli A., Turkcan A., and Erdine S. (Turkey)

827

14. Long-Term Efficacy of Uvulopalatopharyngoplasty for Sleep Apnea Vgontzas A. N., Manders E., Bixler E. O., Manfredi R. L., Vela-Bueno A., and Kales A. (USA)

832

15. Cross-Cultural Aspects of Psychopathology in General Health Care: Neurasthenia Yan H. Q. and Xiao S. F. (China)

837

B: Treatment 1. Intervention by Means of Suggestive Measures in Patients Suffering from AIDS Bengesser G. and Walli J. (Austria)

844

XXXII

2. Psychodermatology Clinic: Structure and Patient Population Garnis-Jones S., Ravindran A. V., Ripley C, and Jones B. D. (Canada)

847

3. Doctor/Patient Relationship In Psycho-Oncology: An Update Penna T. L. M. (Brazil)

850

4. Cardiac Transplanation: The Necessity of Psychiatric Consultation Sakkas P., Hatjistavrakis /., Nanas J., Margari Z, Koundi K., Moulopoulos S., and Stefanis C. N. (Greece)

853

PartlV Treatment Approaches Chapter XV: Psychotherapy and Psychoanalysis 1. Newer Trends in Psychoanalysis Battegay R. (Switzerland)

861

2. Acute Psychological Crisis and Short-Term Psychotherapy Bressi C. and Invernizzi G. (Italy)

866

3. A Brief Therapy Approach to Borderline Patients de Fahreh M. J. (Argentina)

871

4. Counter-transference: An Instrument for Understanding Eizirik C. L. (Brazil)

874

5. The Swedish Umea Model of Cognitive Psychotherapy Hagglof H. (Argentina)

878

6. Psychotherapy of Limited Time and Delimited Objective Knobel M. (Brazil)

881

7. The Future of Psychoanalysis Knobloch F. (Canada)

885

8. Borderline Patients: Guidelines for Short-Term Psychotherapeutic Approaches Leibovich M. A. (USA)

890

XXXIII

9. Psychotherapy for the Twenty-First Century Lemgruber V. (Brazil)

896

10. Short-Term Integrated Psychotherapy, Focal Psychotherapy, and Pharmacotherapy Lemgruber V. (Brazil)

897

11. Integration Between Cognitive-Structural and Humanistic Psychotherapies Linares F. (Argentina)

900

12. Psychoanalysis and Psychotherapy: Present and Future Differences and Integration Macias R. (Mexico)

903

13. Cognitive Psychotherapy with the Difficult Patient Ferris C. and Skagerlind L. (Sweden)

907

14. The Clinical Approach in Psychiatry Pichot P. (France)

910

15. Outcome and Followup Results in Severely Disturbed Patients Treated with Cognitive-Behavior therapy Skagerlind L (Sweden)

912

Chapter XVI: Pharmacotherapy 1. Symposium on Expert Opinion About the Use of Psychotherapeutic Medications Baiter M. B., Ban T. A. and Uhlenhuth E. H. (USA)

917

1A. Interchangeability of Medications in the Treatment of Some Common Psychiatric Conditions Baiter M. B., Ban T. A., and Uhlenhuth E. H. (USA)

918

IB. Indications for Psychopharmacologic Treatment Across a Broad Spectrum of Psychiatric Disorders Ban T. A., Baiter M. B., and Uhlenhuth E. H. (USA)

922

1C. Treatment Choices and Strategies for Some Common Psychiatric Conditions Uhlenhuth E. H., Baiter M. B.f and Ban T. A. (USA)

926

XXXIV

2. Striking A Balance Between Safety and Efficacy: Experience with the SSRI Sertraline Casey D. E. (USA) 3. Alpidem, A New Anxiolytic for Treating and Preventing Benzodiazepine Withdrawal Syndrome: A Double-Blind Placebo Controlled Study Cassano G. B., Borghi C, Petracca A. (Italy), Morselli P. L. and Garreau M. (France) 4. Not All Benzodiazepines Are Alike: Update 1993 Kales, A., Vgontzas A. N., and Bixler E. O. (USA) 5. Japanese Phase I Study of Olanzepine (LY170053): A New Antipsychotic Drug Kudo Y. and Nishimura T. (Japan) 6. Strategies for Prescribing Benzodiazepines Hirschfeld R. M. A. (USA) 7. Drop-Outs and Feasibility of Maintenance versus Intermittent Neuroleptic Treatment Linden M., Gaebel W., Koepke W., Muller P., Muller-Spahn F.f Pietzcker A., and Tegeler J. (Germany) 8. Clinical Efficacy of Reversible and Selective MAOIs in Major Depression: Placebo-Controlled Trials of Moclebemide Paykel E. S. (UK) 9. Recent Developments in Antidepressants Paykel E. S. (UK) 10. Reversible and Selective MAOIs in Psychiatric and NonPsychiatric Disorders Priest R. G. and Roberts M. (UK) 11. Benzodiazepines-Long Term Use, Side Effects and Dependency Rydberg U. (Sweden) 12. Tianeptine in the Treatment of Depression: A Multicenter Long-Term Study Sarteschi P., Bertolino A., Ciani N., Corsini G U, DeMaio D., Del Signore S., Guazzelli M., and Nicoletti F. (Italy)

929

937

942

947

950

960

963

966

969

974

978

XXXV

13. Citalopram in Major Depression: A Comparative Study with Fluvoxamine, Preliminary Results Timmerman L., Huffman P. M. J., Hoogdiun C. A. L. (Netherlands) 14. Quality of Life: Experience with Sertraline Turner R. (UK) 15. New Antipsychotic Drugs in Schizophrenia: French Experience and Perspectives Vanelle J. M., Poirier M. F., Galinowski A., and Loo H. (France)

982

987

997

Chapter XVII: Psychosocial Approaches 1. Psychoanalytic Milieutherapy Ammon G. (Germany)

1003

2. The Therapeutic Concept of the Dynamic-Psychiatric Hospital Menterschwaige Ammon G. (Germany)

1007

3. Crisis Intervention and Psychiatric Emergencies at the Emergency Room of General Hospitals: Which Minimal Model? De Clercq (Belgium)

1009

4. The Impact of Hospitalization: Relatives Feelings' and Needs in Hospitalization in the Italia Model of Psychiatry Furlan P. M., Ramello D., Cristina E., Girardo S., Pessot M., and D'Onofrio M. R. (Italy) 5. The Therapeutic Community Method in Psychiatric and Geriatric Care: An Overview Isohanni M. (Finland) 6. Psychiatric Services for the World's Deaf Population Robinson L. D. (USA) 7. Healthy Work Organization in Preventive Psychiatry: Towards A New Definition of Health Sandberg C. G. and Nerell G. (Sweden)

1014

1022

1027

1030

XXXVI

Chapter XVIII: Other Therapeutic Approaches 1. ECT: A Modern Perspective Abrams R. (USA)

1033

2. The Art Therapy in Psychiatric Alternatives Treatment Ba G. and Facco F. (Italy)

1036

3. A Cooperative ECT Study: Elevating the Treatment to International Standards Chardhry H. R., Pfersmann D., Hoffman P., Loimer N., and Chaudhry M. R. (Pakistan)

1040

4. The Psychiatric Unit at a General Hospital as Core Part of a Detailed Community Mental Health Care System Goop U. and Bauer M. (Germany)

1043

5. Mobile Units: A New Community-Oriented Mental Health Strategy For Rural Areas Ierodiakonou C. S. (Greece)

1046

6. Emergency Psychiatry: New Models, New Treatment Strategies Invernizzi G. (Italy)

1050

7. The Influence of Induction Agents on the Efficacy of ECT Neumann R.t Huber C, Lieder F., Oberbauer K, Cunther V., and Schwitzer J. (Austria)

1052

8. Psychiatric Emergency in a General Hospital: Epidemiological Survey Tawil S. P., Illel K„ Tran /., Mirable V., Ferreri M.f and Alby J. M.

1055

Part V National Perspectives on mental Disorders, The Treatment of the Mentally 111 and the Practice of Psychiatry Chapter XIX: Americas 1. A new Beginning (Women in Psychiatiy in the United States) Benedek E. (USA)

1061

xxx vii

2. The Present State and Task of Child and Adolescent Psychiatry in the United States Campbell M. and Jensen P. S. (USA) 3. Mental Illness and Life Conditions in Prostitutes in Rio de Janeiro de Meis C. and Da Silva Filho J. F. (Brazil) 4. Epidemiology of Alcoholism in Brazil: Distribution of Rates of Prevalence by Social Classes Dunningham W. A. (Brazil)

1065 1070

1073

5. Alcohol Use in American Indians Foulks E. F. (USA)

1077

6. Why USA Students Do Not Enter Psychiatry Freedman A. M. (USA)

1082

7. Psychiatric Education in Brazil Gentil V. (Brazil)

1084

8. Overview of Practice Issues in Canada at the Turn of the Century Gosselin J. Y. (Canada)

1087

9. Justice Thomas Views Psychiatry: An Ominous Omen for the 21st Century Halpern A. L. (USA)

1093

10. Working Process and Mental Suffering: The Case of Subway Train Drivers Jardim S. and Silva Filho J. F. (Brazil)

1099

11. Migration and Mental Illness in Mexican Americans Leon R. L. (USA)

1106

12. Modern and Traditional Psychiatric Care Systems in Peru Lopez Hartmann R. G. (Bolivia), Llanos R. (Peru), and Wolpert E. M. (Germany)

1109

13. Psychiatric Assistance in Bolivia Lopez Hartmann R. G. (Bolivia) and Wolpert E. M. (Germany)

1114

xxxviii

14. The Chilean Psychiatric Care System Rojas G, Varas Y., Olivos P., Lolas F. (Chile), and Wolpert E. M. (Germany)

1118

15. Comorbidity in Drug Abuse: The U.S. Experience Salloum I. M., Mezzich J. E., Cornelius J. R., and Daley D. C (USA)

1120

16. Screening and Measuring Degree of Psychological Stress in Antarctica Sharma S. and Deshpande S. (India)

1125

17. United States Medical Student Education in Psychotherapy Tasman A. (USA)

1131

18. Overview of Psychiatric Residency Education in the United States Tasman A. (USA)

1134

19. Ethnicity and Alcoholism in the United States Wintrob R. M. (USA)

1137

20. Reforms in Western Eruopean Psychiatry, with Special Reference to Germany, and in Countries of the "Third World", with Special Reference to Bolivia, Chile, and Peru: What Can They Learn from Each Other? Wolpert E. M. (Germany) and Lolas F. (Chile)

1142

Chapter XX: Europe 1. The Fifteenth Century as a Golden Age of Spanish Psychiatry Alonso-Fernandez F. (Spain)

1145

2. Mafia Violence and Mental Illness in Italy Alroe C. J. (Australia)

1150

3. Epidemiology of Mental Disorders in French Primary School Pupils Bailly D., Duquenne P., and Parquet P. J. (France)

1157

4. Psychiatric Thought and Practice in Greece Christodoulou G. N. (Greece)

1161

5. Vocational Rehabilitation in German Psychiatry: A Prospective Study I 1165 Elkelmann B., Wethkamp B., Inhester M., and Reker T. H. (Germany)

XXXIX

6. Challenges in Developing Models for Psychiatric Education in Eastern Europe Hoschl C. (Czech Republic) 7. Trends That Shape the Psychiatric Thought in Practice in Spain Lopez-Ibor J. J. (Spain)

1170

1174

8. Easting Disorders: An Epidemiological Study on a Sample of 12,460 Students from the High-Schools in an Area of Northern Italy Manara F. and Caruso R. (Italy)

1177

9. Psychological and Social Problems Among Immigrants in the Province of Ancona, Italy Marchesi G. F., Santone G., Giordano A., and Baldoni A. (Italy)

1182

10. Psychiatric Education in Argentina Musacchio A. (Argentina)

1187

11. Personality Disorders in the Conditions of War Mandic N. and Delalle-Zebic M. (Croatia)

1191

12. Child and Adolescent Psychiatry in Germany Today Nissen G. (Germany)

1194

13. Psychiatric Thought and Practice in Germany Peters U. H. (Germany)

1198

14. Epidemiology of Mental Diseases in Russia: Prediction Attempt Rotstein V. (Russia)

1206

15. Social Conditions and Mental Illness Among Homeless People in Copenhagen Wandall-Holm N. and Nordentoft M. (Denmark) 16. The Programs of the German Government from 1973 and 1981 for Reforming German Psychiatry: What has Happened in German Psychiatry Since Then? Wolpert E. M. and Peters U. H. (Germany) 17. The Situation of the German Psychiatry Before and After The German Reunion Wopert E. M. and Kohler G. K. (Germany)

1209

1213

1217

xl

Chapter XXI: Africa, The Middle East, Asia and Australia 1. Diagnostic and Therapeutic issues of Atypical Depression in Japan Asai M., Nakane Y, and Kanba S. (Japan) 2. Familial History of Opium Use and Reported Problems Among Addicts in Pakistan Chaudhry H. R. (Pakistan), Arria A. and Tarter R. (USA), Chaudhry S. and Chaudhry N. (Pakistan) 3. Cultural Aspects of Morbid Fears in Qatari Women Fahkr-El Islam M. (Qatar) 4. Problems of Clinical Typology and Prognosis of PTSD in Afghan Veterans Morozov P. V., Krasniansky A. N., and Zverkova I. V. (Russia)

1221

1225

1233

1236

5. History of Mental Health and Psychiatry in Japan Oda 5. (Japan)

1239

6. Postgraduate Psychiatric Education in the Middle East Okasha A. (Egypt)

1241

7. Changing Scene of Urban Violence in India Sharma S. (India)

1246

8. National Epidemiological Survey on Mental Disorders in China Shen Y-C, Than W.-X., and Chen C-H. (China)

1251

9. Office Refusal in Japan Shibayama M. and Seki N. (Japan)

1253

10. The Present State of Mental Services in Japan Terashima S. (Japan)

1257

Part VI Psychiatric Perspectives on Issues Affecting the Practice, Role, and Future of Psychiatry Chapter XXII: Education Issues 1. Health Care Programs in the Training of General Practitioners Andreozzi G. and Fahrer R. (Argentina)

1261

xli

2. Training and Teaching Psychotherapy to Medical Students Eizirik C. L. (Brazil)

1263

3. Teaching Psychotherapy in the Medical School Fahrer R. and Peretti M. C. (Argentina)

1267

4. Lack of Sexual Education in Medical Studies Franco Ramini J. A. (Argentina)

1271

5. Education in Addiction Medicine for Psychiatry Galanter M. (USA)

1275

6. The Forming of a Psychotherapist: Different Perspectives Macias R. (Mexico)

1278

7. Medicine and Leadership Role Musacchio A. (Argentina)

1284

8. New Program: Study of Substance Abuse in Medicine Musacchio A. (Argentina)

1289

9 A Proposal on Undergraduate Psychiatric Education Based on a Questionnaire Survey on Psychiatric Education Nishizono M. (Japan)

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10. Postgraduate Psychiatric Education in Japan Nishizono M. (Japan)

1297

11. Education of a Psychiatrist: What is Needed? A World Perspective Sarwer-Foner G. J. (USA)

1320

12. The New Post-Graduate Program in German Psychiatry - What is New on It? Wolpert E. M., Berger M., Buchremer G. (Germany)

1307

Chapter XXIII: Public Policy Issues 1. Touristic Psychiatry: Attempt of Analysis and Proposal of Solution Aviles-Aceves E. A. (Mexico)

1313

xlii

2. The Participation of American Psychiatry in Addressing Today's and Tomorrow's World Issues Beigel A. (USA) 3. Trends that Shape Psychiatric Thought and Practice in Europe Christodoulou G. N. (Greece) 4. Toward the Prevention of Psychiatric Disorders in the Military Establishment Collazo C. R. (Argentina) 5. Exploring the Relationship Between Homelessness and Mental Disorders Forunier L., Ohayon M., Caulet M., and Gaudreau J. (Canada) 6. Mental health Ecology: A Contribution to an Interdisciplinary Scientific Approach Infante R. G. G. (Brazil)

1320

1323

1326

1329

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7. Unemployment and Mental Health: A Review Kalimo R. and Vuori J. (Finland)

1336

8. The Future Perspective of Japanese Psychiatric Policy Kim Y. and Fujinawa A. (Japan)

1342

9. Interregional and Professional Uncertainties in Transcultural Psychiatry Kortmann F. (Netherlands)

1346

10. New Urban Violence in Germany Peters U. H. (Germany)

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11. The Relational Net in the Phenomenon of Mafia Petiziol A. and Rullo S. (Italy)

1356

\2. The Psychopathology of Hatred and Collective Violence Rogers R. R. (USA)

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13. Society's Influence on Mental Health: Particularly on Psychiatry Sarwer-Foner G. J. (USA)

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14. Urban Violence in the United States Sorel E. (USA)

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15. Third World Perspectives on Social Psychiatry Varma V. K. (India)

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16. Job Satisfaction among Mentally 111 Employees 1383 Wethkamp B., Eikelmann B., Inhester M., and Reger T. H. (Germany) 17. Quality Assurance in German Psychiatry Wolpert E. M. and Gaebel W. (Germany) 18. Productive Person Years: A New Method for Understanding Medical Costs Wyatt R. J. and De Saint Ghislain I. (USA)

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Chapter XXIV: Legal and Ethical Issues 1. New Mental Health Law in Japan Asai K. (Japan)

1399

2. Preventing Self-Injurious Behavior in Young Offenders Chapman A. J., Livingston M. S.} and Feldman M. P. (UK)

1403

3. The Burnout Syndrome in Helping Professions: The "Stressing" Care in Psychiatric Services Di Giannantonio M., Mencacci C, Bassi M., Favetta S., Leonetti D. (Italy)

1407

4. Have I Been Corrupted? Furedi J. (Hungary)

1412

5. Ethics and Conceptualization and Use of Psychiatric Diagnosis Kastrup M. C. (Denmark)

1416

6. The New Finnish Law on the Status and Rights of a Patient Kokkonen P. (Finland)

1421

7. Psychiatric Perspectives of Political Coercion: The William Sargant Hypothesis Revisited Kotsopoulos S. (Canada) 8. Research on Human Subjects: A Challenge in Psychiatry Lolas F. (Chile)

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xliv 9. Corruption and Mental Health Musacchio A. (Argentina) 10. Psychiatric Lessons to be Learnt from Persecution: The Persecuted and Persecutors Peters U. H.

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11. Violence in the Family: Aspects, Issues, and Ethical Considerations Rae-Grant Q. (Canada)

1447

12. Ethics and New Technologies in Psychiatry Steenfeldt-Foss Ow (Norway)

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PART I

Advances in Neuroscience

NEW MARKERS OF ALCOHOL CONSUMPTION: CDT AND 5HTOL STEFAN BORG1, ANDERS HELANDER1, OLOF BECK2, ANNETTE VOLTAIRE CARLSSON1 and HELENA STIBLER3 Department of Clinical Neuroscience, Karolinska Institute, x Psychiatry Section, St. Goran's Hospital, and 3Neurology Section, Karolinska Hospital, and 2 Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden ABSTRACT Carbohydrate-deficient transferrin (CDT) in serum and 5-hydroxytryptophol (5HTOL) in urine are new markers of alcohol consumption with inherent high sensitivity and specificity. An elevated level of CDT indicates high exposure to alcohol due to overconsumption, whereas an increased 5HTOL level reflects each single intake of alcohol. The two markers have different characteristics and can be used in combination to monitor patients undergoing treatment in an outpatient program.

1. INTRODUCTION A number of laboratory tests have been proposed as markers to diagnose excessive alcohol consumption and alcoholism. Their application in the clinical situation has often been restricted due to lacks in sensitivity and/or specificity. In the present paper, two new markers of alcohol consumption are presented: carbohydrate-deficient transferrin (CDT) in serum, which is used for detection of regular high alcohol consumption, and 5-hydroxytryptophol (5HTOL) in urine, for detection of recent alcohol intake. The biochemical background, clinical characteristics, and recent method developments to enable their use, alone or in combination, in routine clinical work are discussed.

2. CDT The microheterogeneity of the iron transport protein transferrin of the predominant phenotype C in serum is dependent upon the number of negatively charged terminal sialic acid residues in the carbohydrate chains. The main component with an isoelectric point (pi) of 5.4 contains 4 molecules of sialic acid per molecule of transferrin (tetrasialotransferrin).1 Normal serum also contains small amounts of transferrin with higher pi values, representing tri- and disialotransferrin (pi 5.6 and 5.7, respectively), as well as components with lower pis corresponding to penta- and hexasialotransferrin.1 In alcohol-abusing patients, elevated amounts of disialotransferrin and, to a lesser degree, mono- and asialotransferrin, are found, and the levels are normalized during abstention.2'3 Studies have shown that transferrin from

3

4 alcoholic patients contains significantly lower concentrations of sialic acid than healthy persons and the contents of neutral galactose and JV-acetylglucosamine are also reduced.4 Those findings resulted in the denomination carbohydrate-deficient transferrin, or CDT. The isoelectric focusing technique originally used for assay of CDT was regarded too complex for routine work and replaced by a method based on isocratic anion-exchange chromatography in disposable microcolumns followed by a transferrin radioimmunoassay (RIA).5 This technique measured all transferrin components isoelectric at above pH 5.65 as CDT. To increase the technical stability, a modification was later introduced so that separation was based on ionic strength rather than pH. Thereby, mainly the isotransferrins with a pi greater than 5.7 are measured.6 Elevated CDT levels were noted in healthy subjects after daily intake of 60 g of ethanol for 10 days. Clinical evaluation of 251 individuals showed a sensitivity for alcohol abuse of 93% and a specificity of 98%. The correlation between reported current alcohol consumption and CDT was 0.38 (p < 0.001). During abstinence, the mean half-life of elevated CDT values was 17 days.5'7 Evaluation of the transferrin pattern in patients with various nonalcohol-related diseases, including liver diseases, failed to show the abnormality unless there was a history of excessive alcohol consumption. Treatment with a number of commonly used drugs was not associated with an elevation of CDT. However, slightly elevated levels were seen in single cases of primary biliary cirrhosis, chronic active hepatitis, and drug-induced liver injury. False-positive results have also been found in individuals with rare, genetic D-variants of transferrin.8 In patients with an inborn error of glycoprotein metabolism (CDG syndrome), extremely high CDT levels are constantly present.9 These original findings have been confirmed by several other independent groups employing various methods.10'17 In one study, alcoholics were followed as outpatients for up to 6 months during long-term, abstinence-oriented treatment. In some cases (10%), elevated levels of CDT were reported despite the patients denied consumption of alcohol, and the possibility of other reasons behind the rise in CDT in alcoholic patients was discussed.18 Therefore, we decided to study the CDT levels in alcoholic patients trying to remain abstinent for 6 months by using the 5HTOL level in urine to expose any intake of alcohol.

3. 5HTOL 5-Hydroxytryptophol (5HTOL) is a metabolite of the biogenic amine serotonin (5-hydroxytryptamine; 5HT) and occurs as a normal trace constituent in human urine. 5HT is initially catabolized via oxidative deamination into an intermediate aldehyde which can be oxidized further into 5-hydroxyindole-3-acetic acid (5HIAA) or reduced into 5HTOL. Normally, 5HIAA is the predominant urinary end-product of 5HT catabolism with only a small fraction (< 1 %) transformed to 5HTOL. However, the formation of 5HTOL is increased dramatically after the ingestion of ethanol while the 5HIAA formation is concomitantly decreased. This metabolic shift is manifested in urine, and the 5HTOL excretion will not return to normal until several hours after the blood and urinary ethanol levels have reached zero.19,20 Based on this observation, an increased urinary level of 5HTOL has been used as a biochemical marker to indicate recent alcohol consumption.21 To increase the specificity of the marker, 5HTOL is expressed as a ratio to 5HIAA instead of relative to creatinine, since dietary 5HT (e.g., banana, pineapple, nuts) can otherwise cause false-positive results.22 5HTOL and 5HIAA levels in urine are analyzed using methods

5

based on gas chromatography-mass spectrometry (GC/MS) and high-performance liquid chromatography (HPLC).19,23 Both 5HTOL and 5HIAA are relatively stable in urine samples upon storage.23'24 A limit to discriminate between normal and elevated levels of the 5HTOL to 5HIAA ratio has been set (20 pmol 5HTOL/nmol 5HIAA) after studying abstinent Caucasian and Oriental subjects. The within-day and day-to-day stability during periods of abstinence are very high. After ingestion of 0.8 g ethanol/kg over 30 min in the fasted state, or 0.8-2.3 g/kg over 3 h together with food, the urinary 5HTOL/5HIAA ratio increased 60- to 260-fold and peaked 2-5 hours after urinary ethanol, and did not return to baseline until about 10 hours after ethanol was no longer detectable.20 The sensitivity of 5HTOL as a marker of recent alcohol consumption is superior to that of ethanol, as shown in an experiment where healthy subjects drank moderate amounts of alcohol (3-98 g/day, mean 25 g). Out of 77 drinking occasions, 52 were detected in the next morning by an elevated 5HTOL level, but only 5 by the presence of ethanol. Hitherto, the only known factor other than alcohol consumption that may lead to an elevated 5HTOL/5HIAA ratio is treatment with drugs inhibiting the enzyme aldehyde dehydrogenase (disulfiram and calcium cyanamide).

4. COMBINED USE OF CDT AND 5HTOL CDT and 5HTOL have been used in combination to monitor alcohol dependent patients in an outpatient treatment program.25 The patients were trying to abstain from alcohol for 6 months and visited the clinic 3 times a week. Serum samples for determination of CDT were collected once a week and urine samples for determination of 5HTOL/5HIAA and ethanol were sent to the laboratory daily. Besides, relapses were reported in interviews. All patients were found to be drinking without spontaneously admitting to. In all patients with elevated CDT levels, a high regular alcohol consumption was confirmed by elevated urinary 5HTOL/5HIAA ratios (Fig. la). Other patients had normal CDT levels throughout the entire period, although several drinking occasions were detected by an elevated 5HTOL (Fig. lb). In most cases, an elevated urinary 5HTOL/5HIAA was the only indicator to reveal alcohol consumption. In one patient, the detection of drinking by elevated urinary 5HTOL/5HIAA helped to reach total abstention from alcohol. Significantly lower baseline levels of CDT were noted among abstaining alcohol patients compared to teetotalers. Thus, to increase the sensitivity of the marker, it was suggested that individual cut-off levels could be used during monitoring instead of reference levels calculated from healthy subjects. An increase of 20% or more from the individual baseline was chosen, based on the coefficient of variation among 23 male patients. Altogether, 70 episodes with CDT elevations of 20% or more were observed, of which 63 were verified by elevations in 5HTOL/5HIAA and/or by self-report. Only 19 episodes were detected when the ordinary reference value was used. Thus, individual reference values may be recommended whenever possible. To conclude, CDT and 5HTOL have complementary properties for reliable early detection of alcohol misuse and treatment monitoring.

6

Fig. 1. Detection of alcohol consumption in two male alcohol dependent outpatients by CDT in serum and 5HTOL/5HIAA in urine. The dotted and dashed lines represent the cut-off levels used for CDT and 5HTOL/5HIAA, respectively.

5. REFERENCES 1. Hamann, A. "Microheterogeneity of serum glycoproteins as revealed by flat-bed isoelectric focusing", in Electrofocusing and Isotachophoresis. Radfola, B. J. and Graesslin, B. (eds), pp. 329-335, W. de Gruyter, New York (1977). 2. Stibler, H., Borg, S. and Allgulander, C. "Clinical significance of abnormal heterogeneity of transferrin in relation to alcohol consumption", Ada Med. Scand. 206,275-281 (1979). 3. Stibler, H., Sydow, O. and Borg, S. "Quantitative estimation of abnormal microheterogeneity of serum transferrin in alcoholics", Pharmacol. Biochem. Behav. 13, 47-51 (1980). 4. Stibler, H. and Borg, S. "Evidence of a reduced sialic acid content in serum transferrin in male alcoholic patients", Alcohol Clin. Exp Res. 5, 545-549 (1981).

7 5. Stibler, H., Borg, S. and Joustra, M. "Micro anion exchange chromatography of carbohydrate-deficient transferrin in serum in relation to alcohol consumption", Alcohol. Gin. Exp. Res. 10, 535-544 (1986). 6. Stibler, H., Borg, S. and Joustra, M. "A modified method for the assay of carbohydrate-deficient transferrh (CDT) in serum", Alcohol Alcoholism suppl. 1, 451-454 (1991). 7. Stibler, H. arid Borg, S. "The value of carbohydrate-deficient transferrin as a marker of high alcohol consumption", in Biomedical and Social Aspects of Alcohol and Alcoholism. Kuriyama, K., Takada, A. and Ishii, H. (eds), pp. 503-506, Elsevier, Amsterdam, (1988). 8. Stibler, H., Borg, S. and Beckman, G. "Transferrin phenotype and level of carbohydrate-deficient transferrin in serum in healthy individuals", Alcohol Clin. Exp. Res. 12,450-453 (1988). 9. Stibler, H. and Jaeken, J. "Carbohydrate-deficient serum transferrin in a new hereditary systemic syndrome", Arch. Dis. Child. 65, 107-111 (1990). 10. Vesterberg, O., Petren, S. and Schmidt, D. "Increased concentrations of a transferrin variant after alcohol abuse", Clin. Chim. Ada. 141, 33-39 (1984). 11. Storey, E., Mack, U., Powell, L. and Halliday, J. "Use of chromatofocusing to detect a transferrin variant in serum of alcoholic subjects", Clin. Chem. 31, 1543-1545 (1985). 12. Schellenberg, F. and Weill, J. "Serum desialotransferrin in the detection of alcohol abuse", Drug Alcohol Depend. 19,181-191(1987). 13. Gjerde, H., Johnsen, J., Bjorneboe, A., Bjorneboe, G.-E. and Merland, J. "A comparison of serum carbohydrate-deficient transferrin with other biological markers of excessive drinking",,Sc6 months

marked decrease in aggressive incidences and injurious assaults

open

eltoprazine up to 60 mg 12 months

transient reduction of self-injurious behavior in 4 patients

double blind placebocontrolled

eltoprazine 20 mg 6 weeks

no improvement

(n=D

Verhoeven et al. , self-destructive behavior 1992 (n=9)

Kohen, 1993

aggressive and selfinjurious behavior (n=8)

decrease in aggression in 5 patients

75 References 1. Reid, A.H., "Psychiatry of mental handicap: A review", Journal of Royal Society of Medicine 76, 587-592 (1983). 2. Aman, M.G., "Assessing psychopathology and behavior problems in persons with mental retardation: A review of available instruments", Rockville MD: U.S. Department of Health and Human Services (1991). 3. Van Praag, H.M., "Two-tier diagnosis in psychiatry", Psychiatry Res. 34, 1-11 (1990). 4. Kraemer, G.W. and Clarke, A.S., "The behavioral neurobiology of self-injurious behavior in rhesus monkeys", Prog. Neuropsychopharmacol. Biol. Psychiatry 14, 141-168 (1990). 5. Depue, R.A. and Spoont, M.R., "Conceptualizing a serotonin trait. A behavioral dimension of Constraint", Ann. N Y Acad. Sci. 47-62 (1986). 6. Bohus, B., Koolhaas, J.M., Korte S.M., Bouws, G.A., Eisenge, W. and Smit, J., "Behavioral pysiology of serotonergic and steroid-like anxiolytics as antistress drugs", Neurosci. Biobehav. Rev. 14, 529-534 (1990). 7. Verhoeven, W.M.A., Tuinier, S., Sijben, A.E.S., "Biological and pharmacological aspects of selfinjurious behavior". In: Fletcher, R.J. and Dosen A. (Eds.) Mental Health Aspects of Mental Retardation, Lexington Books, Free McMillan Inc. 291-324 (1993). 8. Verhoeven, W.M.A. and Tuinier, S., "Dimensional Classification and behavioral pharmacology of personality disorders", submitted (1994).

EVIDENCE FOR THE MAJOR ROLE OF MONOAMINOOXIDASE HYPERACnVTTY IN THE PATHOGENESIS OF ADHD SIGRUN WIRTH, M.D., GOTZ-ERIK TROTT PROFESSOR M.D., THOMAS NISSEN, GERHARDT NISSEN PROFESSOR M.D. Department for Child and Adolescent Psychiatry University ofWurzburg Fuchsleinstrafie 15, 97080 WUrzburg, FRG

The discovery of the effect of psychostimulants in the treatment of the hyperkinetic syndrome by Charles Bradley in 1937 represents a considerable milestone in the history of child and adolescent psychiatry. On the one hand the development of the specific child and adolescent psychiatric pharmacology began with this, and this treatment is still scientifically relevant 55 years after its introduction. On the other hand the systematic investigation of the hyperkinetic syndrome only started after the introduction of an effective possibility of treatment. In the last decades Methylphenidate and D-L-Amphetamine are used in the treatment of attention deficit hyperactivity disorder. In the diversity of their pharmacological effects it is interesting to isolate the effective part that can be made most responsible for the therapeutic effectiveness in the hyperkinetic syndrome. The Dopamine-lackhypothesis is based on the observation that the dose of Neurotoxin 6-Hydroxy-Dopamine destroys selectively dopaminergic neurons which might cause hyperkinetic behavior in experiments on animals. As a contradictory factor it can be said that Dopamine-agonists such as Piribidel, Levodopa and Amantadine provided to be ineffective in the treatment of hyperkinetic syndrome. For some time the Norepinephrine-hypothesis has been discussed. On the one hand it has been assumed that the stimulants are competitively found to the post synaptic Norepinephrine receptors and in this way block the noradrenergic transmission. This, however, could not be proved. Noradrenergic sympathomimetica showed no effect in the treatment of ADHD. The Serotonin hypothesis is based on the observation that the destruction of serotonergic neurons in animals leads to increased activity and aggression. On the other hand substances like L-tryptophan and Fenfluramine have shown no therapeutic effect in ADHD. Besides Dextroamphetamine and Methylphenidate some antidepressants such as Desipramine have showed positive effects in the treatment of ADHD. Zametkin et al. showed in 195 that the selective MAO-A-blocker Clorgyline and Tranylcypromine but not the MAO-B-blocker Deprenyl proved to be effective in the treatment of ADHD. For this reason we determined in the 24-hour urine of hyperkinetic children the changes in the excretion of the biogenic amines Norepinephrine, Serotonin and Dopamine.

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1. METHODS 20 children aged 5, 9-13,4 years, average age 9,1 years, were recorded that fulfilled the diagnostic criteria according to DSM-III-R for the hyperkinetic syndrome. The children were not allowed to suffer from epilepsia or to have any considerable cerebral organic disorders or dominant conduct disorders or an intelligence quota under 80 in the WISC-R. The test-persons were given apediatric, internal and neurological examination, an EEG was performed, blood test, urine status as well as a survey on the most important blood chemical parameters in an 18 channel analyzer were carried out. Children with indication of an additional illness were taken out of the examination group. The first collection of the 24-hour urine took place at the earliest after 7 days to be able to considerably reduce the effects of getting accustomed as situative factors independent of the illness can change the concentration in the biogenic amines and their metabolites. Nurses as well as the children had their attention drawn to the importance of a very careful collection of urine. Afterwards the children were treated with Methylphenidate, we started with a morning dose of 5 mg. The dose was increased each time by 5 mg, until a sufficient clinical effect was noticed. With a daily dosage of 10 mg the medication was divided into 2 doses, with a dosage of over 20 mg to 3 doses per day. The dose was a minimum of 10 mg, a maximum of 30 mg Methylphenidate per day (average dose 23, 75 mg per day). At the earliest after 10 and at the latest after 20 days in the individually reached end dose, under the same conditions 24-hour urine was collected again. HVA and 5-HIAA were determined by means of a HPLC process. MPHG was gaschromatographically determined. 2. RESULTS The exact collection of the test-persons must be considered as very reliable. There were no differences between the volume of the first and second collection that were below the expected measure. In the Wilcoxon test there was no significant difference (p < 0.2627). The main resulting product of Serotonin, the 5-HIAA was not significantly changed under Methylphenidate medication (p< 0.7938). The Dopamine-metabolite HVA did not show any significant changes either in the Methylphenidate therapy (p < 0.3637). The excretion of MHPG varied extremely significantly in both measuring points (p< 0.0001). The observation of the trends that missed the statistical significance level was also interesting. Thus there was no correlation between the MHPG-excretion before medication and the age. There was no connection between the age and the therapeutic effective dose or the decrease in MHPG-concentration either nor in correlation with the Methylphenidate dose. A trend was remarkable that was shown between age and the MHPGdecrease. The older the patients were the less the tendency was towards the decrease in MHPG-concentration. The changes in the HVA-concentration under medication showed the tendency that with a lower Methylphenidate-dose there was more of a decrease and with higher doses more of an increase in the HVA-excretion. On the whole, our findings correspond to the recognized theses at the moment on ADHD and support the hypothesis that the activity of the monoaminooxidase can be given considerable significance in the pathogenesis of this illness.

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ALZHEIMER DISEASE: A LYSOSOMAL DISORDER? Hans-Gert Bernstein Institute forNeurobiofogy, P.O. Box J860, B-3900S Magdeburg, Germany Heidrun Kirschke Institute of Biochemistry Martin LutJier University ,B-061 14 BaBe, Germany Bernd Wiederanders Insltute of Biochemistry FrledrleJ] ScM/er University D-07743 Jena, Germany Riitta Rinne and Ari Rinne Institute of Patiiofogy, University of Tromso, Norway

ABSTRACT Beta-amyloid formation is a characteristic neuropathologic hallmark of Alzheimer disease (AD). It requires abnormal proteolytic cleavage of amyloid precursor protein (APP). Two cellular pathways are known to exist for the processing of APP: the secretory way delivering both normally and aberrantly processed fragments and the endosomal/lysosomal way possibly clearing overexpressed APP to prevent amyloid formation. This immunocytochemical study shows that lysosomal proteases (cathepsin B, D, L, and S) and endogenous proteinase inhibitors (cystatins A and C, and to a lesser extent B) occur co-localized in extracellular senile plaques. We conclude that inhibition by cystatins of this lysosome-associated proteolytic "clearance way" may be a reason for the formation and/or further growth of neuritic plaques. Besides, the putative role of lysosomal mechanisms in other AD-associated phenomena is discussed.

1. Introduction Alzheimer disease (AD) is the fourth leading cause of death in the developed world. This form of dementia is neuropathologically characterized by massive loss of neurons in discrete brain areas, intracellular neurofibrillary tangles and extracellular deposition of amyloid (mainly complexes of the insoluble B-amyloid protein, AB) in neuritic plaques and within the wall of cerebral microvessels (1). The formation of AB is thought to involve an altered proteolytic processing of the amyloid precursor protein (APP), an 105-120 kDA transmembrane protein expressed in neuronal and non-neuronal cells (2,3). Two cellular pathways have been identified to manage proteolytic processing of APP - the secretory (trans-Golgi) and the endosomal/lysosomal ones (4-7). It is at present not clear, whether both pathways work interdependent^ or not. Recent evidence from several laboratories has shown that the secretory pathway that involves membrane-associated proteases, is capable of delivering both normally (non-amyloidogenic) and aberrantly (potentially amyloidogenic)

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cleaved fragments of APP, whereas the endosomal/lysosomal way is thought to generate in a first step transiently existing COOH-terminal, AB-bearing fragments (i.e. putative candidates for amyloid formation), which are in a second step completely degraded by lysosomal proteases (most probably cysteine proteinases), thus precluding the liberation and intracellular persistence of AB (8-10). Due to the "beneficial" action of these enzymes the intracellular route of APP processing the intracellular route of APP processing should be regarded as non-amyloidogenic. Indeed, no intracellular AB has yet been found. However, application of artificial inhibitors of cysteine proteinases leads to an accumulation of COOH-terminal fragments (10,11). We herein show that neurons contain at least two of the known natural inhibitors of cysteine proteinases, which accumulate together with the enzymes in senile plaques of Alzheimer patients. 2. Material and Methods Postmortem human brains (several neocortical areas, hippocampus, hypothalamus and Nuc. basalis of Meynert) from 12 individuals with a clinical diagnosis of probable AD and 8 agematched neurologically normal controls were studied. Neuropathologic diagnosis of AD and tissue handling were as described earlier (12). The immunocytochemical protocol involved the use of monospecific, polyclonal antisera against the following cysteine proteinases cathepsins B, L, H and S (12-14). The proteinase inhibitors cystatin A, B and C were detected using both monoclonal antibodies (15,16) and polyclonal antisera. Sternberger's unlabeled immuno-enzyme technique was applied (17). Controls involved substitution of primary antibodies by buffer, replacement by preimmune sera and immunoabsorption tests. 3. Results Cathepsins B, L, and S (but not H) were immunolocalized in multiple neurons and a few glial cells of normal brains. The granular nature of the reaction product indicates the lysosomal origin of the immunoreactions. Cystatin A was also found to be widely distributed throughout normal human brain. Its cellular localization was confined to neurons and - to a lesser extent- to pericytes. Cystatin C was immunodetected in some neocortical and hypothalamic nerve cells. Cystatin B occurred in microglial cells only. In AD brains the cellular appearance of the enzymes and inhibitors was essentially the same as in unaffected brains. However, cathepsin-positive material showed a tendency to form clusters within the neuronal cytoplasm. Additionally, all antigens (except cystatin B) were detected in multiple senile plaques (Figs. 1 and 2), where cathepsins and cystatins were found to be co-localized. Cystatin B decorated only a minority of plaques. Sometimes, cathepsin-immunoreactive microglia was found to be closely associated with plaques. A subpopulation of microglial cells was moderately immunoreactive for cathepsin H.

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4. Discussion We and others (12,18-22) have repeatedly shown the appearance of lysosomal proteinases in senile plaques. The signifance of this observation is yet not fully clear, however. The endosomal/lysosomal route of APP processing is now believed to preclude the generation of amyloidogenic fragments from the precursor under normal conditions (10.23). Inhibition of certain cysteine proteinases (cathepsins) was shown to give rise to A3-bearing splitting products (10,11). It is currently not known, whether or not such a process may really take place. This study demonstrates the existence of at least two inhibitor candidates of those proteases in the human CNS. Moreover, our results show the common appearance of both cathepsins and cystatins in senile plaques of AD patients. In AD brains, a scenario is imaginable that involves leakage of cathepsins from fragile (21,22) neuronal lysosomes into cytoplasm, and/or release of lysosomal proteinases into the extracellular space, where the enzymes persist in plaque-associated, lipofuscin-containing vesicles (20,21). In either case they may come into contact with cystatins and form enzymatically inactive enzymeinhibitor complexes. Although such complexes have yet not been isolated from AD brains, it is reasonable to suppose that such an interaction would block cathepsins, thereby giving rise to amyloigogenic peptides through the "lysosomal" route. This hypothetic pathway would be even more dangerous than the production of A3 via the secretory way, since A3 has an increased tendency to form insoluble conglomerates under conditions of an acidic pH (24). Remarkably, the role of lysosomal mechanisms in AD is not restricted to amyloid formation. Enzymatically active lysosomes accumulate in a typical manner in neocortical neurons of AD patients long before other degenerative changes can be detected, indicating that altered lysosome function is an early event in AD (21, this study). Moreover, various cathepsins have been shown to degrade neurocytoskeleton proteins, whereby profound shifts in the spectrum of degraded proteins occur during brain aging and as a result of changes of intraneuronal pH (25). It has therefore been speculated that lysosomal proteinases are also involved in pathologic processes finally leading to the manifestation of another hallmark of AD - the neurofibrillary tangles (18). Undouptedly, AD is a mulifactorial disease involving environmental, genetic, social and other components. However, there is increasing evidence in favor of a pivotal role of lysosomes in many molecular events leading to AD. In this respect AD is also a "lysosomal disorder".

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5. References 1: Muller-Hill, B. and Beyreuther, K.. Annu. Bev. BiocJiem. 58, 287 (1989). 2. Kang, J., Lemaise, H.-G.. Unterbeck. A., Salbaum. J. M., Masters. Grzeschik, K. H.. Mulhaup, G.. Beyreuther. K. and Muller-Hill, B., Nature^ 733 (1987). 3. Estus, S., Golde, T. E. and Younkin. S. G.. Ann. NY Acad Sci. 674, 102 (1992). 4. Selkoe. D. J.. ScienceZAb 1058 (1990). 5. Haass. C. Koo. E. H.. Helton. A.. Hung. A. Y. and Selkoe. D. J., Nature^

6075 (1992).

6. Cole. G. M.. Bell. L. Tuong, Q. B. and Saitoh. T., A.nn. NY Acad Sci 674. 138 (1992). 7. Kuentzel. S. L. Ali. S. M.. Altman. R. A.. Greenberg.B. D. and Raub. T. J.. BiocJiem. / 2 9 5 , 367 (1993). 8. Busiglio. J.. Gabuzda. D. H.. Matsudaira. P. and Yankner. B. A.. Proc. NatJ Acad. Sci l/SA%, 2092 (1993). 9. Shoji. M., Golde. T. E.. Ghiso, J.. Cheung. T. T.. Estus. S.. Shaffer. L M.. Cai. X.-D.. Mc Kay, D. M., Tintner, R., Frangione. B. and Younkin. S. G., Science?®. 126 (1992). 10. Siman, R., Mistretta.S.. Durkin, J. T., Savage. M.. Trusko, S. and Scott. R. W., / Biol CJiem. 268, 16602 (1993). 11. Ivy, G. 0.. Ann. NY Acad. Jfc/674, 89 (1992). 12. Bernstein. H.-G.. Kirschke. H.. Wiederanders. B., Schmidt. D. and Rinne, A., Brain Bes. BuB. 24, 543 (1990). 13. Bernstein, H.-G., Kirschke, H., Wiederanders, B.. Khudoerkov. R. M., Hinz, W. and Rinne, A., Ada JiistocBem. SuppJ.m, 19 (1992). 14. Kirschke, H., Wiederanders, B.. Bromme, D. and Rinne. A.. Biochem. / 2 6 4 . 467 (1989). 15. Bernstein. H.-G., Jarvinen, M., Pollanen, R., Schirpke, H., Knofel, B. and Rinne, R., Neurosci 131 (1988).

Letters^

16. Bernstein, H.-G., Rinne, R., Kirschke, H., Jarvinen, M., Knofel, B. and Rinne, A., Brain Bes. BuJJ.'m the press 1993. 17. Sternberger, L. A., Jmmunocytocnemistry{

2nd Edition) John Wiley New York 1979.

18. Bernstein. H.-G., Bruszis, S., Schmidt, D., Wiederanders, B. and Dorn, A., J. HirnforscLZ^

613 (1989).

19. Cataldo, A.M., Thayer, C. Y., Bird, E. D.. Wheelock, T. R. and Nixon, R. A., Brain Bes. 513, 181 (1990). 20. Cataldo, A. M., Paskevich, P. A., Kominami, E. and Nixon, R. A., Proc. NatJ. Acad Sci. l/SAM, 10998 (1991).

83 21. Nixon. R. A.. Cataldo. A. M.. Paskevich. P. A.. Hamilton. D. J.. Wheelock, T. R. and Kanaley-Andrews, L, Ann. NY Acad Sci 674, 65 (1992). 22. Nakamura, Y., Takeda, M., Suzuki. H.. Hattori, H., Tada, S., Hashimoto, S. and Nishimura, T., Neurosci. Letters^, 195 (1991). 23. Selkoe, D. J., WSM, 403 (1993). 24. Knauer, M. F.. Soreghan. B., Burdick, D., Kosmoki, J. and Glabe, C. G., Proc. natl Acad Sci USA 3d, 7437 (1992). 25. Matus. A. and Green, G. D. L, BiocnemistryZ^

8083 (1987).

Fig 1. Large neocortical pyramids and senile plaques contain cystatin A in an AD patient. Fig. 2. Cathepsin S immunopositive senile plaque in the neocortex of an AD patient at a higher magnification.

5-HTID

AUTORECEPTORS IN THE ACTION OF ANTIDEPRESSANT DRUGS.

Mike BRILEY and Chantal MORET Centre de Recherche Pierre Fabre, 17 Ave Jean Moulin, 81100 Castres, France ABSTRACT Recent evidence suggests that desensitisation of serotonin (5-HT) autoreceptors may play a key role in the action of antidepressants acting on the serotonergic system. Selective 5-HT reuptake inhibitors (SSRI's), when administered acutely to animals, have little effect by themselves, suggesting the existence of powerful regulatory mechanisms controlling 5-HT neurotransmission. Indeed it has been shown that the release of 5-HT from nerve terminals is under the control of 5-HT autoreceptors (5-HTIB subtype in rodents, 5-HT ID in other species including man). During prolonged administration with a SSRI the regulatory systems become desensitised allowing the level of synaptic 5-HT to rise with a consequent increase in the stimulation of one or more types of postsynaptic 5-HT receptor. Thus it is only after prolonged administration that the pharmacological activity of an SSRI is fully expressed which may explain the latency of therapeutic action seen with these drugs in man. Total or partial inhibition of one or more of the various 5-HT feedback systems may be expected to lead to a sharp increase in 5-HT neurotransmission and consequently a rapid antidepressant action as predicted by the 5-HT deficit hypothesis of depression. Antagonists of 5-HT ID autoreceptors situated on serotonergic terminals thus represent an exciting new therapeutic target for antidepressant therapy. A significant clinical improvement in depressive symptoms is only seen after an antidepressant has been administered for 10 to 15 days. When antidepressants are administered acutely to animals they have little effect on serotonin neurotransmission as determined by in vivo microdialysis1. This is true both for tricyclic antidepressant drugs which tend to inhibit the uptake of both noradrenaline and serotonin and the newer more selective serotonin reuptake inhibitors (SSRI). This suggests the existence of powerful regulatory mechanisms controlling serotonergic neurotransmission. Studies from our group and elsewhere have shown that the release of serotonin from neuron terminals is under the control of 5-HT autoreceptors2. The autoreceptors controlling the release of 3H-5-HT from slices in vitro have been shown to be of the 5-HT^ receptor subtype in rodents2 and the species analogue, the 5-HT 1D receptor subtype, in other species3, including man4. The firing rate of raphe neurons is also under the control of somatodendritic 5-HT 1A autoreceptors located on the 5-HT cell bodies situated in the raphe nucleus5, while

84

85 the control of the activity of tryptophan hydroxylase, the rate limiting enzyme of serotonin synthesis, is complex involving both 5-HT 1A and 5-HT 1D receptors6. During prolonged administration with a SSRI these systems become desensitised5*7*8 and their regulatory effects on serotonergic neurotransmission are weakened or lost. Administration of the SSRI, citalopram (10 mg/kg/day ip), to rats for 21 days followed by a washout of 24 h results in an increased stimulation-induced release of serotonin from hypothalamic slices preloaded with

H-5-HT. The increase was even greater when 50

mg/kg/day ip citalopram was used7. In addition the concentration-effect curve of the autoreceptor agonist, LSD, was shifted to the right compared to control animals indicating a desensitisation of the autoreceptor. The desensitisation of the terminal release controlling autoreceptor has also been deduced from indirect electrophysiological measurements5. Neurons in CA3 region of the hippocampus possess postsynaptic 5-HTj A receptors which when stimulated by the serotonergic innervation from the raphe induce a hyperpolarisation of these cells. Thus by electrically stimulating the raphe neurons and measuring the hyperpolarization of cells in the hippocampus it is possible to measure the overall efficiency of this serotonergic pathway. The administration of the autoreceptor antagonist, methiothepin, produces an increased hyperpolarization through blockade of the feedback inhibition of release. The extent of the effect of methiothepin can thus be used to deduce the sensitivity of the terminal autoreceptor. After two weeks administration of citalopram (20 mg/kg/day ip for 14 days)5 the efficiency of serotonergic neurotransmission was increased by desensitisation of the terminal autoreceptor. Furthermore the increased efficacy of the stimulation of the raphe on the hyperpolarisation of the CA3 hippocampal cells induced by injection of the autoreceptor antagonist, methiothepin, was lost in SSRI-treated rats. Acute administration of a SSRI, such as citalopram, results in a large decrease in the activity of tryptophan hydroxylase, the rate limiting enzyme in the synthesis of serotonin6. Since agonists at 5-HT 1A and 5-HT1B, but not at 5-HT2, receptors reduce the activity of tryptophan hydroxylase in a similar manner6, it is probable that 5-HT 1A and 5-HT 1B receptors are involved in this effect. The involvement of other non-5-HT2 receptors cannot, however, be ruled out. Repeated administration of citalopram (50 mg/day for 21 days followed by 24 h washout) results in an increased basal activity of tryptophan hydroxylase8. The inhibitory effect of acutely administered citalopram is, however, still present8. Following chronic administration of a SSRI both terminal 5-HT1B autoreceptors7 and somatodendritic 5-HT 1A autoreceptors5 are desensitised. Since the effect of acutely administered citalopram is not modified, the involvement of a receptor other than 5-HT 1A or 5-HT 1B seems likely. Desensitisation of the somatodendritic 5-HT 1A autoreceptor, responsible for the modulation of raphe firing, is also observed after chronic exposure to a SSRI. Administration

86 of citalopram (20 mg/kg/day ip) for 2 days resulted in a decreased firing of dorsal raphe serotonergic neurons through stimulation of somatodendritic 5-HT 1A receptors in the raphe nucleus. After 7 days administration of citalopram, however, this effect is attenuated and after 14 days it had completely disappeared5. The desensitisation of these feedback mechanisms has the effect of allowing the level of synaptic serotonin to rise with a consequently increased stimulation of one or more types of postsynaptic 5-HT receptor. Acutely the stimulatory effcts of an SSRI are held in check by the feeback mechanisms and it is only after prolonged administration that the pharmacological activity of an SSRI is fully expressed. This may explain the latency of therapeutic action seen with these drugs in man. An obvious consequence of this hypothesis is that total or partial inhibition of one or more of these serotonergic feedback systems should lead to a rapid increase in serotonergic neurotransmission and consequently an alleviation of the symptoms of depression. In chosing the target autoreceptor, however, the postsynaptic effects must be borne in mind. 5-HT 1A receptors exist both pre- and postsynaptically9 and the stimulation of postsynaptic 5-HT 1A receptors seems to be involved in the antidepressant process10. Although blockade of the presynaptic 5-HT 1A receptors will block the feedback mechanism which reduces the firing of the raphe nucleus, simultaneous antagonism of the postsynaptic 5-HT 1A receptors will tend to block the effects of the increased synaptic levels of 5-HT. Thus the non-specific blockade of pre- and postsynaptic 5-HT 1A receptors (which appear to be pharmacologically identical) may be self-defeating. 5-HTjrj) receptors are localised presynaptically, serotonergic terminals2'11,

either as autoreceptors

where they modulate the release of serotonin,

on

or as

heteroreceptors on the terminals of other transmitters such as GABA 12 or acetylcholine13> where they regulate (stimulation inhibits release) the release of these neurotransmitters. Stimulation of postsynaptic 5-HTJB in rodents (and thus presumably 5-HTu) receptors in other species including man) produces mainly an increase in anxiety and agitation14. Thus a selective 5-HT 1D antagonist, through its blockade of 5-HT terminal autoreceptors, would be expected to increase 5-HT release leading to an antidepressant effect. The antagonism of the postsynaptic 5-HT 1D receptors may lead to a reduction of the anxiety that so often accompanies depressive states. Specific 5-HT 1D antagonists may thus represent interesting new therapeutic agents for the therapy of depression as well as other hyposerotonergic conditions such as OCD. The possible additional benefit of an anxiolytic effect make them even more attractive. There are, as yet, no selective 5-HT 1D antagonists available but experiments using the non-selective 5-HT autoreceptor antagonist, methiothepin, have given encouraging results. Indeed, local perfiision, through the microdialysis probe, of the guinea-pig substantia nigra, a

87

region rich in 5-HT terminals and 5-HT 1D receptors, with methiothepin results in a large (as much as 10 fold) increase in the level of extracellular serotonin15. Similarly intraperitoneal administration of methiothepin also results in a smaller but significant increase in 5-HT release in this region15. The extent to which autoreceptor dysfunction may play a role in the physiopathology of depression remains to be clarified but at present the pharmacological tools are very poor. The discovery of selective 5-HTjp autoreceptor antagonists will thus provide not only new potential therapeutic agents but also valuable tools to investigate the biochemical basis of depression,

anxiety,

OCD

and

other

psychiatric

disorders

involving

serotonergic

neurotransmission.

References 1. Adell, A. and Artigas, F. Naunyn-Schmiedeberg's Arch. Pharmacol 343, 237-244 (1991). 2. Moret, C. In "Neuropharmacology of serotonin" (ed Green A.R.) Oxford University Press, Oxford 21-49 (1985). 3. Hoyer, D. and Middlemiss D.N. Trends Pharmacol. Sci. 10,130-132 (1989). 4. Galzin, A.M., Poirier, M.F., Lista, A., Chodkiewicz, J.P., Blier, P., Ramdine, R., Loo, H., Roux, F.X., Redondo,A. andLanger, S.Z.J. Neurochem. 59, 1293-1301 (1992). 5. Chaput,Y., De Montigny, C. and Blier, P. Naunyn-Schmiedeberg's Arch. Pharmacol. 333, 342-351 (1986). 6. Moret, C. and Briley, M. Brit. J. Pharmacol. 108, 96p (1993) 7. Moret, C. and Briley, M. Europ. J. Pharmacol. 180, 351-356 (1990). 8. Moret, C. and Briley, M. Neuropharmacology 31,679-684 (1992). 9. Miquel, M.C., Doucet, E., Boni, C , El Mestikawy, S., Matthiessen, L., Daval, G., Verge, D. and Hamon, M. Neurochem. Int. 19,453-465 (1991). 10. Briley, M. and Moret, C. Clin. Neuropharmacol. 16, 387-400 11. Engel, G., Gothert, M., Hoyer, D., Schlicker, E. and Hillenbrand, K. Naunyn-Schmiedeberg's Arch. Pharmacol. 332, 1-7 (1986). 12. Hen, R. Trends Pharmacol. Sci. 13, 160-165 (1992). 13. Maura, G., Fedele, E. and Raiteri, M. Europ. J. Pharmacol. 165,173-179 (1989). 14. Chopin, P., Moret, C. and Briley, M. Pharmacology and Therapeutics (in press) (1994). 15. Moret, C. and Briley, M. Neuropsychopharmacology 9, 79s (1993)

COGNITIVE IMPAIRMENT IN PHYSIOLOGICAL AND PATHOLOGICAL AGING CARLO LORENZO CAZZULLO Milano President Association Research in Schizophrenia Hon. President Italian Society of Psychiatry

Cognitive impairment can be regarded as a "physiological" or a pathological process. In the former case in the elderly the diagnostic term of age associated memory impairment (AAMI) (Crook, 1989: Crook et al., 1986) or "benign forgetfulness" is used. In the latter case, it is a core symptomatology of different dementia processes. However, cognitive impairment is not restricted to the area of aging, Alzheimer disease or other forms of "classical dementias"; it is also observed in neurological disorders like M.S. or AIDS Dementia Complex and in long-lasting psychopathological disorders (e.g. deficit versus non deficit schizophrenias (Carpenter 1987). The common denominator of all these so heterogeneous situations is represented by the deficit in one or more neurotransmitter pathways differently impaired in all these conditions. For instance, in schizophrenia cognitive impairment seems to be more linked to the dopaminergic system, particularly in negative and deficit forms, while in Alzheimer' Disease it is the cholinergic system to be basically involved. However, it should be stressed that the cognitive impairment usually stems from the combination of alterations of various neurotransmitter systems (i.e. Ach, 5HT, NE DA). Actually an important role seems to be played by the exitatory aminoacid (EAA) pathways deeply involved in cognitive hippocampal activities concerning memory and learning. The involvement of glutaminergic brain contents and NMDA receptors sensibility can be envisaged both in neurological (epilepsy, S.L.A.) and psychotic disorders (i.e. the glutaminergic hypothesis of schizophrenia) with different dimensions. This premise is relevant to introduce the concept of treatment of cognitive impairment in general; in the following I will trace the main strategies: 1) Direct increase in the brain content of neurotransmitters (for instance blocking neuronal reuptake mechanisms or enzyme metabolizing neurotransmitters; 2) stimulation of brain receptors (using compounds against each receptor or blocking presynaptic receptors). 3) compounds increasing metabolism in the C.N.S. and/or increasing protein synthesis. Clinical trials of potential therapeutic agents in Alzheimer disease have become a mainstream concern of the pharmaceutical industry in the last decade, paying too little attention to other neurological and psychological conditions, which have different pathogenetic patterns, but sharing some common clinical features. Some brain phospholipids like phosphodytilserine endogenously occurring have been proposed acting on cellular metabolic functioning and neurotransmitters.

88

89 Particularly promising, at least in Alzheimer disease, are the components blocking metabolism of Ach metabolizing enzyme acetylcholine esterase (like eptastigmine or other cholinomimetic agents). Some A2 agonists like clonidine or guanfacine have been proved to be effective in physiological cognitive impairment (AAMI). Piracetam is another compound of the first so-called "nootropic" drugs, a unique class of drugs which seems to affect mental functioning. These drugs in animals improved higher telencephalic functioning such as learning and memory. Drugs like oxyracetam or amiracetam activate cerebral metabolism and are devoid of sedative or other psychotropic activity other than on cognitive stimulation, they increase arousal or slight anxiety are sometimes reported. Trials with these components in human senile cognitive disorders have shown equivocal results. These drugs seem to have some beneficial effect on cognitive impairment in the elderly, both pathological and physiological, but very poor in deficit situations of psychotic patients. In the latter the use of drugs acting on dopamine or NA or 5HT seems more important. Particularly 5HT and dopamine: the use of dopamine agonists or 5HT reuptake in negative schizophrenia and in deficit schizophrenias in our experience is encouraging. Equally promising seems for the future also the use of drugs acting on NMDA receptors. If pharmacologic interventions are to be successful in ameliorating cognitive impairments, we should first be careful in selecting patients, then in assessing their problems before treatment, and finally to produce evidence that the latter have improved their mental efficiency without damaging them. Of course, we can tackle these problems at different levels and in different ways. We may wish to tailor our intervention according to the clinical diagnosis - hence to the presumed pathophysiology of the deficits - or to the clinical prognosis if we have one, or on the basis of our previous experience with a certain class of nootropics, but in any case we will certainly need details of the neuropsychological and behavioral profiles of our patients and require the data to be as objective as possible. And this, I want to emphasize, is a priority for any of us, for we do not want to treat just a "feeble memory" - as the patients commonly report -, nor we want to produce enormous efforts in trying to improve a devastating cognitive deterioration or to pass over subtle initial deficits which may become significant over time. Hence, we must rely primarily on the clinical tools developed by the cognitive sciences - neuropsychology, cognitive and behavioral psychology - which can assist us in the diagnostic process and in the assessments of treatment effects; my contention is that clinical scales, though a useful complement, are not enough to the purpose, nor are the briefer assessment instruments such as MMSE (Mini Mental State Examination) for they miss important details or they lack sensitivity. A comprehensive neuropsychological evaluation - at least at the beginning - is mandatory and a worthwhile accomplishment since it sets the reference point for any future reassessment. Data obtained by means of the Luria-Nebraska Neuropsychological Battery (LNNB), a broad-scope instrument show the relevance of several important issues, such as the deficits as a function of some broad nosological classes, the average cognitive profile of each class and its distinctive features. Is this information important for the management of single patients on a daily base?

90

May we conceal of treating any patient without knowing anything less than how severe is his impairment as compared to that of other patients with the same CNS pathology of different CNS pathologies, or how selective his deficits are? It is common place in the neuropsychological literature to read of significant analogies between apparently different CNS diseases as far as cognitive deficits are concerned. But in spite of this, too often no account is given of the global cognitive status of patients who are said to suffer from deficits of "memory", or "planning abilities" or who lack attention as if these deficits were completely isolated ones, without touching other abilities. For example, discussing memory deficits has become popular also as a target for putative nootropic agents, but we must recall that under such rubric a number of different entities exist, and that we also lack a definitive understanding of why and how the brain memorizes and recalls in different situations. And since life is an ever changing and complex situation, many have already realized that the experimental approach of Ebbinghaus cannot be readily transposed to the problem of assessing everyday cognition. An Neisser wrote in 1976, "...A satisfactory theory of human cognition can hardly be established by experiments that provide inexperienced subject with brief opportunities to perform novel and meaningless tasks". His implicit call for new instruments of assessment and approaches has been rather neglected for quite a long time. Nowadays, we are witnessing the birth of "ecologic" approaches both in the research and in the clinical fields of psychology, neurology, geriatrics and psychiatry. Most of these efforts are driven by rehabilitation purpose. Why should pharmacological treatment not be regarded as trailing purpose too? I think this is an interesting problem which should be considered.

REFERENCES 1. Crook T.H., Bartus R.T., Ferris S.H. et al.: Age associated memory impairment. Proposed diagnostic criteria and measures of clinical change. Report of a National Institute of Mental Health work group. Dev. Neuropsychol. 2:261-276,1986. 2. Crook T.H.: Diagnosis and treatment of normal and pathologic memory impairment in later life. Seminary in neurology 9: 20-30,1989. 3. Crook T.H., Petrie W., Wells C, Casadei MassarrD.: Effects of Phosphatidylserine in Alzheimer's disease. Psychopharmacol. Bull. 28(1) 61-66,1992. 4. Mc Entese W., Crook T.H., Jenkin L.R. et al: Treatment of age-associated memory impairment with guanfacine. Psychopharmacol. Bull. 27(1) 41-46,1991.

PITUITARY DA-D2 RECEPTORS ARE NOT INCREASED IN TREATED SCHIZOPHRENICS. Brian Dean, Geoffrey Pavey and David Copolov.

The Rebecca L. Cooper Schizophrenia Research Laboratories, The Mental Health Research Institute of Victoria, Parkville, Victoria, 3052, Australia and

Joel Kleinman NIMH Neurosciences Center, Saint Elizabeth's Hospital, Washington D.C., USA.

ABSTRACT Dopamine-D2 receptors have been shown to be increased in the caudate-putamen of brain tissue obtained at autopsy from subjects with schizophrenia. This change in dopamine-D2 receptors was thought to be due to an effect of neuroleptic drug treatment rather than being pathophysiological in nature. In this study dopamine-D2 receptor density has been shown not to differ on the anterior pituitary from subjects with schizophrenia compared to those on the anterior pituitary from subjects who have committed suicide and subjects with no history of mental illness who did not commit suicide. Thus, changes in dopamine-D2 receptor density in response to neuroleptic treatment appears to be tissue specific. Furthermore, as the pituitary only contains dopamine-D2L receptors, the increase in dopamine-D2 receptors in the caudate-putamen in response to neuroleptic drug treatment may only involve certain forms of the dopamine receptor which display affinity for these drugs.

INTRODUCTION The dopamine hypothesis of schizophrenia proposes that over-active dopaminergic neurons are the cause of some of the symptoms of schizophrenia (7). A number of studies, using brain tissue obtained at autopsy from subjects with schizophrenia, have been carried out in an attempt to confirm this hypothesis. Initial studies demonstrated increased densities of dopamine-D2 receptors in caudate putamen of brain tissue from subjects with schizophrenia (9). Logically this increase in dopamine-D2 receptors, in the absence of decreased levels of dopamine (7), would produce an increase in dopaminergic activity in the brain and was taken as supporting the dopamine hypothesis of schizophrenia. The early studies measuring dopamine-D2 receptor density were carried out using tissue obtained from schizophrenic subjects who had been treated with neuroleptic drugs (9). Such drugs are thought to act therapeutically by antagonising the dopamine-D2 receptor (11). When these studies were repeated using tissue from schizophrenic subject who had never been treated with neuroleptic drugs, the increase in dopamine-D2 receptor densities were either much lower or absent (6). Following these findings and the demonstration of increased dopamine-D2 receptors in dopamine-rich areas of brains from rats treated with neuroleptic drugs (13), it became accepted that the change in dopamine-D2 receptor densities in the brain tissue from subjects with schizophrenia was a drug effect rather than a pathophysiological change. Significantly, plasma prolactin levels in subjects with schizophrenia have been shown to increase on commencement with treatment with neuroleptic drugs (1). This increase was thought to be due to neuroleptic drugs antagonising the ability of dopamine to inhibit the secretion of prolactin, an effect mediated by the dopamine-D2 receptor on the pituitary (2). Moreover, the observation that a standardised dose of neuroleptic drug produced a lower

91

92 rise in plasma prolactin levels in male schizophrenic subjects who had not been treated with neuroleptic drugs for at least one month (5) suggested that the effects of neuroleptic treatment was long lasting. Thus, it seemed possible the density of dopamine-D2 receptors on the pituitary of schizophrenic subjects, like those in the caudate-putamen, had been changed by treatment with neuroleptic drugs. To determine if increased dopamine-D2 receptors were present on pituitaries from schizophrenic subjects treated with neuroleptic drugs we measured dopamine-D2 receptors on anterior pituitary obtained at autopsy from subjects who had a history of schizophrenia, subjects who had committed suicide and subjects who had no history of schizophrenia and had not committed suicide.

METHOD Tissue Collection Anterior pituitaries were obtained at autopsy from 7 subjects with chronic paranoid schizophrenia, 7 subjects who did not have schizophrenia but who had committed suicide (suicide) and 7 subjects with no history of mental illness who had not committed suicide (control)(Table 1). All of the schizophrenic donors had been treated with neuroleptic drugs. Urine screens revealed trace levels of neuroleptic drugs in one subject with schizophrenia and one subject who had committed suicide but did not have schizophrenia. In addition, trace levels of tricycle antidepressants were detected in the urine of 3 donors who had committed suicide.

Measurement of [125I]Iodosulpride Binding After collection, tissue wasrapidlyfrozen in iso-pentane in dry ice. When required the tissue was thawed, cleaned and frozen in iso-pentane over dry ice prior to being cut in 20fxm sections, thaw-mounted onto gelatin coated slides and stored at 4°C for 30 minutes. The sections were then incubated with InM [125I]Iodosulpride, KHM ketanserin and a range of concentrations of haloperidol (0 to lO^M) in lOOjil 50mM Tris buffer containing 120mM NaCl, 5mM KC1, 2mM CaCl, ImM MgCl and 0.1% bovine serum albumin for 45 minutes at room temperature and then washed four times for five minutes in ice cold buffer. The washed sections were dried and then apposed to Amersham Hyperfilm betamax for 1-3 weeks prior to development in Kodak D-19 developer. Quantitative analysis was carried out using an MCID image analysis system comparing the density of the exposed hyperfilm to Amersham micro-calibration scales. The ability of haloperidol to reduce [125I]Iodosulpride binding by 50% (IC50) and maximal drug binding (BmaX) values were calculated using the Ligand computer program. Statistical analysis of the data was carried out using the Anova test in the Minitab computer software.

RESULTS The IC50 values for haloperidol displaceable [I125]Iodosulpride binding to pituitaries from subjects with schizophreniarangedfrom 1.2 to 16.6 nM compared to 1.7 to 33.5 for the suicide group and 3.2 to 27.5 control group (Table 1). The maximal number of binding sites, Bmax, on the pituitaries from subjects with schizophreniarangedfrom 4.2 to 32.0 fmol/mg protein compared to arangeof 6.1 to 34.2 on the tissue from the suicide group and 5.7 to 50.2 on the tissue from the control group. There were no significant differences between the ages, the post-mortem interval (PMI) or the IC50 and Bmax values for [I,25]Iodosulpride binding between the three groups (Table 1). Furthermore, there was no relationship between the IC50 or BmaX vales and PMI or

93 between the IC50 values and the age of the donor. By contrast, there was a significant correlation (r=0.5; p=0.011) between the Bmax values and the age of the donor. Table 1: The mean _+ SD of the age, post-mortem interval IC50 and BmSiX values of [I125]Iodosulpride binding to pituitaries from subjects with schizophrenia, subjects who had committed suicide and subjects with no history of mental illness who had not committed suicide. The data for [I125Jiodosulpride binding was obtained from an experiment on each pituitary in which the effect of each dose of displacing agent (haloperidol) was measure in triplicate.

Diagnoses

Chronic Paranoid Schizophrenia Suicide Control

Sex (M/F)

6/1 5/2 4/3

Age (yrs)

35.4± 9.9 33.7±15.14 48.0±22.8

PMI (hrs)

15.9±10.1 22.7±17.0 20.0±12.6

(nM)

8.7± 6.3 13.5±12.5 13.2± 7.8

Bmax (fmol/mg protein)

17.5±11.6 16.7± 8.9 17.0±15.0

DISCUSSION The number of dopamine-D2 receptors on the pituitaries obtained at autopsy from subjects with schizophrenia has been measured and been shown not to differ from the number of receptors on pituitaries from non-schizophrenic subjects who had or had not committed suicide. Furthermore, the ability of haloperidol to occupy dopamine-D2 receptors on pituitaries from the three groups of individuals did not differ. There was a significant correlation between Bmax values for the binding of [125I]Iodosulpride to anterior pituitary and the age of the tissue donor. However, as there was no significant difference between the mean ages of the three groups it seems this finding would not prevent comparison of results between the schizophrenic and other individuals. As the number of subjects in this study are low, the findings reported must be regarded as preliminary. However, these data contrast with the studies of dopamine-D2 receptors in the caudate-putamen where the number of dopamine-D2 receptors have been shown to be increased (9). Furthermore, as some studies demonstrating elevated number of dopamineD2 receptor had equally low numbers of donors (4,8,14) it would seem unlikely these differing findings could simply be due to the low number of subjects in this study. When the studies of striatal dopamine-D2 receptors in schizophrenia were carried out it was thought that these receptors represented a homogenous binding site at which neuroleptic drugs acted (9). More recently, three dopamine receptors have been cloned that show a high affinity for neuroleptic drugs (12). However, only one of these receptors, the dopamine-D2L receptor, seems to be present in the pituitary (3). Hence it would seem possible that the density of this receptor is not altered by neuroleptic drugs whilst other forms of dopamine-D2 receptor in the caudate-putamen are up-regulated. This question could be addressed by in situ hybridisation studies examining the messenger RNA in brain tissue from subjects with schizophrenia. Significantly, treatment with neuroleptics has been shown not to cause an increase in the number of dopamine-D2 receptors in subjects with Huntington's chorea and Alzheimer's disease (10). This differing effect may be due to different doses of drugs used to treat individuals with different illnesses. On the other hand, the demonstration of unaltered dopamine-D2 receptors on pituitaries from subjects with schizophrenia may suggest that the changes in dopamine-D2 receptor density in response to neuroleptics may not only be tissue but also disease specific. Whether the changes in dopamine-D2 receptor density in the caudate-putamen of schizophrenic subjects in response to neuroleptic treatment is in any way related to the therapeutic effects of neuroleptic drugs remains to be elucidated.

94 Unfortunately, the status of dopamine-D2 receptors in the caudate-putamen of the subjects on whom measures of pituitary dopamine-D2 receptors were made is unknown. However, our data suggests that the significance of the demonstration of elevated dopamine-D2 receptors in the caudate-putaman made from subjects with schizophrenia made need to be re-addressed. In particular, a study of dopamine-D2 receptors in pituitary and caudateputamen from the same donors would be warranted to clarify the issue of tissue specific effects of neuroleptic drugs. Such a study should also include an assessment of messenger RNA levels of the five distinct forms of the dopamine receptor now known to exist (12) to address that possibility that the effect of neuroleptic treatment on receptor density is restricted to particular dopamine receptors.

ACKNOWLEDGMENTS This work was funded by the NH&MRC Schizophrenia Research Unit, the State Government of Victoria and the Rebecca L. Cooper Medical Research Foundation Ltd.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12. 13. 14.

Beumont, P.J.V. (1986): Endocrinology and schizophrenia. In: Handbook of studies on schizophrenia. Part 1, edited by G. Burrows, et al, pp. 105-116. Elsevier, Amsterdam. Borgundvaag, B. and George, S.R. (1985): Dopamine inhibition of anterior pituitary adenylate cyclase is mediated through the high-affinity state of the D2 receptor. Life ScL, 37:379-386. Bunzow, J.R., Van Tol, H.H.M., Grandy, D.K., Albert, P., Salon, J., Christie, M., Machida, C.A., Neve, K.A., and Civelli, O. (1988): Cloning and expression of a rat D2 dopamine receptor cDNA. Nature, 336:783-787. Hess, E.J., Bracha, S., Klein man, J.E., and Creese, I. (1987): Dopamine receptor subtype imbalance in schizophrenia. Life ScL, 40:1487-1497. Keks, N.A., Copolov, D.L., and Singh, B.S. (1987): Abnormal prolactin response to haloperidol challenge in men with schizophrenia. Am. J.Psychiatry, 144:1335-1337. Mackay, A.V.P., Bird, E.D., Spokes, E.G., Rossor, M., Iversen, L.L., Creese, I., and Snyder, . S.H. (1980): Dopamine receptors and schizophrenia: Drug effect or illness? Lancet, i:915-916. Meltzer, H.Y. (1987): Biological studies in schizophrenia. Schizophr.Buli, 13:77-107. Reynolds, G.P. and Czudek, C. (1988): Status of the dopaminergic system in post-mortem brain in schizophrenia. Psychopharmacol.Bull., 3:345-347. See man, P. (1987): Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse, 1:133-152. Seeman, P., Bzowej, N.H., Guan, H.C., Bergeron, C , Reynolds, G.P., Bird, E.D., Riederer, P., Jellinger, K., and Toutellotte, W.W. (1987): Human brain Dl and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's Disease's. Neuropsychopharmacology, 1:5-15. Seeman, P., Lee, T., Chau-Wong, M., and Wong, K. (1976): Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature, 261:717-719. Sibley, D.R. and Monsma, F.J. (1992): Molecular biology of dopamine receptors. TIPS, 13:61-69. Stefanini, E., Frau, M., and Gessa, G.L. (1991): Increase in D2 dopamine receptors in the substantia nigra after chronic (-)-sulpiride treatment. Brain Res., 555:340-342. Toru, M., Watanabe, S., Shibuya, H., Nishkawa, T., Noda, K., Mitsushio, H., Ichikawa, H., Kurumali, A., Takashima, M., Mataga, N., and Ogawa, A. (1988): Neurotransmitter, receptors and neuropeptides in post-mortem brains of chronic schizophrenic patients. Acta Psychiatr.Scand., 78:121-137.

THE INTERACTION OF DOPAMINE AND SEROTONIN IN DEVELOPING PSYCHOPHARMACOLOGICAL MODELS G.DESMEDT Janssen Research Foundation Beerse, Belgium

The introduction of neuroleptics represented a major advance in the treatment of schizophrenia. It is widely accepted that their antipsychotic effect is pharmacologically based on central dopamine antagonism and that D2 receptor occupation is the primary action of these drugs. However, a significant proportion of patients do not respond to any currently available agent. Even among responders, negative or "deficit" symptoms respond less well than positive or "productive"ones; and undesirable extrapyramidal symptoms (EPS) limit the usefulness of a particular drug and the patient's compliance. The search for better drugs is ongoing and has resulted in the synthesis of selective Di or D2 receptor antagonism, partial D2-receptor agonists, non-dopaminergic and drugs which block D2-receptors and other receptors. Of the non-dopamine pathways in the brain, there is now little doubt that the one most closely related to schizophrenia is that involving serotonin. Studies with both typical and the so-called atypical neuroleptics, such as clozapine, suggest that the number of both dopamine and serotonin receptors is altered in schizophrenia. And it>lso seems very likely that these two substances interact. This idea of an interaction between serotonin and dopamine has extremely important implications for treatment. There is evidence that the negative symptoms of schizophrenia are associated with overactivity of the serotonin system (most probably with a hypersensitivity of 5-HT post-synaptic neurones). If so, then combined administration of drugs with specific dopamine-and serotonin-blocking activity might be beneficial in treating both types of symptom pattern. In addition, it is widely accepted that the extrapyramidal symptoms seen with neuroleptic treatment are (at least partly) due to inhibition of striatal dopamine pathways. Co-administration with a 5-HT receptor blocker should therefore disinhibit the striatal dopamine system and reduce the severity of these EPS side-effects. Clinical studies with the selective serotonin 5-HT2 antagonist have confirmed this model. When ritanserin was added to conventional neuroleptic treatment, negative symptoms improved and the severity of existing EPS decreased, whilst the control of the positive symptomatology was maintained Compounds potently blocking serotonin and dopamine which can be used in monotherapy do now exist. The most recent development in this respect is the synthesis of risperidone. Risperidone has been found to reduce both positive and negative symptoms of schizophrenia and to be associated with a low incidence of EPS. These bindings, which argue in favor of a more elaborate model of a balanced association of serotonin and dopamine antagonism, fit the facts more closely, and drugs developed on this basis will serve the patient better than those generated in accordance with the older and more restricted ideas involving dopamine alone.

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SEROTONIN RECEPTOR SUBSETS IN OBSESSIVE-COMPULSIVE DISORDER O.T. DOLBERG, Y. SASSON, S. KINDLER, R. COHEN, M. KOTLER and J. ZOHAR Psychiatric Division Sheeba Medical Center Tel Hashomer, Ramat Gan 52621, ISRAEL

ABSTRACT Obsessive Compulsive Disorder (OCD), is characterized by a drug specific response, not observable in other affective or anxiety disorders. It is clearly evident that only compounds with serotoninergic profiles have anti-obsessional effects. Thesefindingshave led to several studies examining the relevance of the serotonin in OCD, using probes with alternating affinities for the receptors of the serotoninergic system. One way to interpret the results of these challenge studies is to exclude the 5HT1A receptor subsystem from the focus of attention and to point to the involvement of the 5HT1D and 5HT2C receptors as possible candidates for the mediation of OC symptoms.

1. INTRODUCTION Among the various affective and anxiety disorders, obsessive compulsive disorder (OCD) is unique in that the only drugs effective in this disorder are those that possess a serotoninergic profile. This finding has been substantiated repeatedly in studies that have documented the anti-obsessional effects of clomipramine (CMI), and the selective serotonin reuptake inhibitors (SSRFs), such as fluoxetine, fluvoxamine, sertraline and paroxetine. Other drugs, such as desipramine (DMI), a non-serotoninergic tricyclic, which is an effective antidepressant and antipanic agent, does not display anti-obsessional effects1,2.

2.

SEROTONINERGIC HYPOTHESIS OF OCD

These studies support the hypothesis that the anti-obsessional effects of these drugs are mediated through the serotoninergic system. However, whether or not serotonin is implicated in the pathophysiology of OCD is an entirely different question. To examine the involvement of the serotoninergic system in OCD, pharmacological challenges have been performed, using selective serotoninergic agonists and antagonists and noting the behavioral as well as the neuroendocrine response of OCD patients to these challenges. The probes employed in the challenge studies have varying affinities for serotoninergic receptors, among them mCPP, MK212, ipsapirone and metergoline. MCPP is a serotoninergic agonist with comparable affinities for 5HT1A, 5HT1D, and with greater affinity for 5HT2C. In a double blind, placebo controlled study, mCPP was administered to 12 OCD patients and 20 normal controls. Following mCPP, but not after placebo, patients with OCD experienced a transient but marked exacerbation of obsessive compulsive symptoms. Administration of mCPP reliably increased prolactin levels in normal controls, while in OCD patients, prolactin response was blunted. The

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results of this study , and other studies ' suggest that OCD patients show a hypersensitivity of the receptor subtypes that mediate OC symptoms, and a diminished response of the serotoninergic receptor subsystem that mediate the neuroendocrine response. To verify the serotoninergic role mediating the mCPP response, OCD patients were treated with metergoline, a non-selective serotoninergic antagonist, which blocks 5HT1 A, 5HT1D and 5HT2C receptors, one hour prior to the administration of mCPP. Pre-treatment with metergoline, abolished the behavioral response of OCD patients to mCPP. This study suggests a role of the 5HT1 and 5HT2 receptor subsystems in OCD. Another serotoninergic probe, MK212, a 5HT agonist with affinity for 5HT1A and 5HT2C, was studied in OCD patients. Administration of MK212 was associated with diminished cortisol and prolactin response in OCD patients compared to normal controls, but with no behavioral alterations . In another study, a 5HT1A ligand, ipsapirone, was administered to 12 OCD patients and 22 normal controls. There was no behavioral response regarding OC symptoms, neither was there any change in thermal or neuroendocrine response between the OCD patients and the controls. The lack of behavioral, thermal and endocrine differences between the two groups, suggests that the 5HT1A receptor subsystem does not play a pivotal role in OCD. Taken together, the results of the mCPP, the MK212 and the ipsapirone studies might suggest which serotoninergic receptor subsystem is involved in OCD. The main difference between the probe that was associated with a behavioral exacerbation (mCPP) versus the probe that was not associated with any noticeable changes (MK212), is their affinity for the 5HT1D receptor subsystem. Therefore, is appears that the 5HT1D receptor subsystem, which is densely located in the basal ganglia and the caudate nucleus, merits further investigation as a possible candidate for the mediation of OC symptoms. 3. SUMMARY In conclusion, concentrating on a single neurotransmitter or a single receptor subsystem is undoubtedly an over simplification. Increasingly, our understanding of brain serotoninergic pathways indicate a highly differential family of circuits with receptors that are regulated heterogeneously, are indicated to clarify the importance of the balance of the various receptor subtypes, as well as the possible influence of another type of receptor. The serotoninergic hypothesis of OCD is essential for our understanding of this disorder, but is not sufficient to explain the pathophysiological basis of this disorder. 4. REFERENCES 1. Zohar, J., Kindler, S., "Update on the Serotoninergic Hypothesis of Obsessive Compulsive Disorder", Proceedings 18th CINP Congress, 5-6 (1992). 2. Zohar, J., "Up-date on the Serotoninergic Hypothesis of Obsessive-Compulsive Disorder", Biol. Psychiatry 29,105s (1991). 3. Zohar, J., Mueller, E.A., Insel, T.R., Zohar-Kadouch, R.C., Murphy, D.L., "Serotoninergic Responsivity in Obsessive-Compulsive Disorder", Arch. Gen. Psychiatry 44, 946-950 (1987). 4. Zohar, J., Insel, T.R., Zohar-Kadouch, R.C., Mueller, E.A., Murphy, D.L., "Serotoninergic Role in Obsessive-Compulsive Disorder", in Progress in Catecholamine Research, Part C: Clinical Aspects, 385-391 (1988). 5. Zohar, J., Insel, T.R., "Obsessive-Compulsive Disorder: Psychobiological Approaches to Diagnosis, Treatment and Pathophysiology", Biol. Psychiatry 22,677-687 (1987).

98 6. Zohar, J., Kindler, S., "Serotoninergic Probes in OCD", Int. Clin, Psychopharmacology 7,39-40 (1992). 7. Lesch, K.P., Hoh, A., Disselkamp, T.J., Wiesmann, M., Osterheider, M., Schulte, H.M., "5Hyd^oxytryptamine 1A Receptor Responsivity in Obsessive-Compulsive Disorder. Comparison of Patients and Controls", Arch. Gen. Psychiatry 48,540-547 (1991).

Limbic Asymmetry Confirmed by lomazenil SPECT in Patients with Panic Disorder

Wolfgang P. Kaschka1, Herbert Feistel2, and Dieter Ebert1

Departments of Psychiatry1 and Nuclear Medicine2, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany

ABSTRACT Benzodiazepines are therapeutically effective in different types of anxiety disorders. Using iomazenil SPECT, a method which enables us to label cerebral GABA A/benzodiazepine receptors, we investigated the question if there are differences between patients suffering from anxiety disorders and control persons with regard to the quantitative cerebral distribution of these receptors, which might play a role in the pathogenesis of anxiety states or disorders. As of yet, seven patients and six control persons have been investigated, in whom no structural cerebral anomalies were revealed by CCT and/or NMR and who had been without any benzodiazepines for at least four weeks. Quantitative evaluation of cerebral perfusion and receptor binding showed relative hypoperfusion and decreased receptor binding in parts of the temporal lobes of the patients, but not the controls.

1. Introduction Benzodiazepines are therapeutically effective in different psychiatric disorders dominated by, or associated with, anxiety. They bind to the GABA A^enzodiazepine receptor which controls a chloride channel (for review see 1). Single photon emission computed tomography (SPECT) using J1 ^-iomazenil is a suitable method to demonstrate receptor ligand binding in this system (2, 3). Iomazenil, a derivative of flumazenil, acts as a partial inverse agonist at the GABA Afaenzodiazepine receptor. In the concentration range used for SPECT it does not show any measurable pharmacodynamic or clinical effects. The present investigation was designed to elucidate the question if anxiety disorders are associated with alterations of the cerebral distribution of GABA A/ benzodiazepine receptors possibly supporting a pathogenetic role of this system as proposed by Insel et al. (4). In a preliminary study (5), we were able to demonstrate relative hypoperfusion and decreased receptor binding in parts of the left temporal lobes of five patients with panic disorder as compared with four control persons. Our findings confirm and extend earlier observations by Reiman et al. (6) who had reported on an abnormal asymmetry of cerebral blood flow (CBF) in a region of the parahippocampal gyrus of patients with panic disorder in the absence of a panic attack, using a positron emission tomography (PET) technique.

99

100

2. Patients and Methods As of yet, 13 patients (7 men and 6 women) between 21 and 51 years of age (median: 35 years) were included in the study. All of them had complete legal competency and had given their written informed consent to participate. The study had been approved by the ethics committee of the Medical Faculty of the University of Erlangen-Nuremberg. The relevant clinical and demographic data of the patients are shown in table 1. Diagnoses were made according to DSM-III-R criteria (7). The control group was constituted of subjects with dysthymic or delusional (paranoid) disorders who had reported on low levels of anxiety and had reached scores below 14 on the Hamilton Anxiety Scale (HAMA; 8,9,10), respectively, when rated on three days during the week before SPECT examination. At inclusion into the study all patients had been off benzodiazepines for at least four weeks. Urine tests for benzodiazepines were negative. Organic brain diseases had been excluded by neurological and endocrinological examination, EEG, CCT, and/or NMR. After 15 min of adaptation under resting conditions (lying position, eyes closed, darkened and quiet room) 150 MBq Jl23iomazenil were injected intravenously. Two SPECT examinations were performed 10 min and 120 min p.i., respectively, using an Orbiter camera with a neurofocal collimator (64 x 64 matrix, 64 angle increments, recording time 30 sec/angle). The data obtained during the perfusional phase (10 min p.i.) and during the receptor binding phase (120 min p.i.) were evaluated according to an algorithm developed by Podreka et al. (11). Brain data between the parietal and the lower cerebellar poles were condensed into four slices, parietal, ventricular, thalamic, and cerebellar (see Figure 1). Using a regions of interest (ROI) technique, 36 anatomically significant areas were depicted (Figure 1) and regional perfusion indices (RPI) were calculated for each region (RPI = cts/voxel of one region divided by the mean cts/voxel of all regions x 100 [%]).

3. Results RPI of the perfusional phase (10 min p.i.) and of the receptor binding phase (120 min p.i.) were evaluated separately (Table 1). In the hippocampal (HI), inferior temporal (IT), and inferior frontal (IF) regions most of the patients, but not the controls, showed a higher activity in the right hemisphere as compared with the left one during the perfusional phase. In the receptor binding phase (120 min p.i.) the patients showed either aright> left or a left > right asymmetry in the ROIs mentioned above (Table 1).

4. Discussion Investigating cerebral blood flow (CBF) in panic disorder patients by means of a positron emission tomography (PET) technique, Reiman et al. (6) have detected an asymmetry (right > left) in parts of the parahippocampal gyrus (for review see 12). These findings are confirmed by our present study. Together with the work of Reiman's group, the data presented in table 1 suggest that there is some sort of primary asymmetry in temporal (and frontal) parts of the limbic system of patients with panic disorder. As of yet, it is not clear if this asymmetry is a merely functional or possibly a structural one. As the asymmetry can already be detected during the perfusional phase in our study, GABA A/benzodiazepine receptors, though therapeutically relevant, appear to be essentially unrelated to these findings. SPECT

Figure 1: Regions of interest (ROIs) used for the analysis of SPECT data. Parietal slice: SF1 superior frontal 1, Cl central 1, SP superior parietal; ventricular slice: SF2 superior frontal 2, MF medial frontal, C2 central 2, IP inferior parietal, SO superior occipital; thalamic slice: SF3 superior frontal 3, IF inferior frontal, BG basal ganglia, TH thalamic, IP inferior parietal, 10 inferior occipital; cerebellar slice: FBfrontobasal,IT inferior temporal, HI hippocampal, CB cerebellar o

s Table 1:: Clinical and demographic data and selected regional perfusion indices (RPI) of the patients investigated (HI hippocampus, IT inferior temporal, IF inferior frontal, MF medialfrontal;1: left, r: right)

Pat.No.

Gender

Age

Diagnosis (DSM-III-R)

RPI lOmin .p.i. HI 1

1

m.

47

300.21

IT r

1

120 min p.i.

IF r

"47" 57

62 65

1 84

ffl

MF r 94

1

r

116 108

1

IT r

40 60

—

MF

IF r

1

r

1

r

1

53

65

91

106 ~Tl2

108

2

m.

37

300.21

59 62

67 67

90

88

103 110

56 49

68

53

91

80

103

111

3

m.

23

300.01

66

71

62 75

90

106

101 106

54 63

63

72

82

99

102

110

4

m.

47

300.01

61

53

69 66

99

94

106 102

46 42

60 57

93

97

101

107

5

f.

21

300.23

62

57

67 65

87

89

103 101

55 47

66 66

81

92

98

106

6

m.

35

300.23

60

55

69 61

92

88

105 106

55 43

64 49

87

87

104

110

7

f.

21

300.23

49

49

51

87

88

102 105

52

59

55

56

89

98

102

109

8

m.

35

300.29

64

61

69 65

104 101

106 101

50 48

62

57

91

97

98

103

9

m.

47

300.4

57 60

57 66

91

92

HI 113

62 62

67 72

98

105

109

113

10

f.

25

297.10

65

65

69 70

97

101

100 100

63 64

70 71

86

98

103

105

11

f.

26

300.4

71

63

69 71

98

100

109 109

61

56

86 80

98

99

105

116

12

f.

51

300.4

66

70

62 64

104 105

101 107

60

58

62 65

96

100

102

101

13

f.

45

300.4

61

62

72 74

95

104 102

53 45

71 62

99

108

97

105

59

101

103

investigations of panic disorder patients using other imaging agents will shed more light on this question. Likewise, possible influences of age, gender, and handedness (dominant hemisphere) remain to be elucidated. With regard to "subject anxiety" as a possible interfering variable, Mountz et al. (13) have elegantly demonstrated that this type of anxiety does probably not confound CBF measurements during routine PET scanning.

5. Literature 1. 2. 3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Mohler, H., "GABA ergic synaptic transmission. Regulation by drugs", Arzneimittelforschmg/Drug Res 42 (I), 211-214 (1992). Holl, K., Deisenhammer, E., Dauth, J., Carmann, H., and Schubiger, P.A., "Imaging benzodiazepine receptors in the human brain by single photon emission computed tomography (SPECT)", NuclMedBiol 16, 759-763 (1989). Beer, H.-F., Blauenstein, P.A., Hasler, P.H., Delaloye, B., Riccabona, G., Bangerl, J., Hunkeler, W., Bonetti, E.P., Pieri, L., Richards, J.G. and Schubiger, P.A., "In vitro and in vivo evaluation of iodine-123-Ro 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors", JNuclMedZl, 1007-1014 (1990). Insel, T.R., Ninan, P.T., Aloi, J., Jimerson, D.C., Skolnick, P., and Paul, S.M., "A benzodiazepine receptor-mediated model of anxiety. Studies in nonhuman primates and clinical implications", Arch Gen Psychiatry 41, 741-750 (1984). Kaschka, W.P., Feistel, H., Ebert, D., Joraschky, P., and Marienhagen, J., "Cerebral GABA A^enzodiazepine receptor distribution in anxiety disorders", Clinical Neuropharmacology 15 (Suppl. 1, Pt. B), 27 (1992). Reiman, E.M., Raichle, M.E., Butler, F.K., Herscovitch, P., and Robins, E., "A focal brain abnormality in panic disorder, a severe form of anxiety", Nature 310, 683-685 (1984). American Psychiatric Association "DSM-III-R: diagnostic and statistical manual of mental disorders", 3rd ed, revised. APA, Washington, DC, 1987. Hamilton, M., "The assessment of anxiety states by rating", Br J Med Psychol 32, 50-55 (1959). Hamilton, M., "Diagnosis and rating of anxiety", In: Lader, M.H. (ed) "Studies of anxiety", Br J Psychiatry [Spec Pub] 3, 76-79 (1969). Hamilton, M., "048 HAMA. Hamilton anxiety scale", In: Guy, W. (ed) "ECDEU assessment manual for psychopharmacology", revised ed., Rockville, Maryland, (1976) pp 193-198. Podreka, J., Suess, E., and Goldenberger, G., "Initial experience with Tc-99mHMPAO brain SPECT", JNuclMedll, 1657-1666 (1987). Wu, J.C., Buchsbaum, M.S., Hershey, T.G., Hazlett. E., Sicotte, N., and Johnson, J.C., "PET in generalized anxiety disorder", Biol Psychiatry 29, 11811199(1991). Mountz, J.M., Modell, J.G., Wilson, M.W., Curtis, G.C., Lee, M.A., Schmaltz, S., and Kuhl, D.E., "Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia", Arch Gen Psychiatry 46, 501-504 (1989).

EFFECT OF ACUTE ANXIETY ON CRANIAL BLOOD FLOW ROY J. MATTHEW, M.D. and WILLIAM H. WILSON, PH.D. Department of Psychiatry Duke University Medical Center Durham, North Carolina, USA

ABSTRACT 133 Intracranial blood flow was measured with the Xenon inhalation technique and extracranal flow (forehead skin perfusion) with laser Doppler flowmetry during anxiety induction with epinephrine/saline infusions during 5% C02 inhalation in physically healthy generalized anxiety disorder patients and normal volunteers. Measurements of cerebral blood flow (CBF), forehead skin perfusion, blood pressure, pulse rate, respiratory rate, end tidal C02 and ratings of anxiety were made under resting conditions and during epinephrine or saline infusions given under double blind conditions while subjects inhaled room and 5% C02. Subjects who reported severe anxiety showed lease hypercarbic CBF increase and most forehead skin perfusion. Hypercarbic cerebral vasodilation correlated inversely with anxiety levels during C02 inhalation while forehead skin flow correlated positively with it. 1.

INTRODUCTION

The relationship between anxiety and cerebral blood flow (CBF) is influenced by a number of factors (1) . In the normal brain, CBF and brain function are closely related. The other anxiety related factors which influence CBF are sympathetic stimulation (2), hypocapnia and increased blood viscosity. Previous investigators found both anxiety related increase and decrease in CBF. In general, mild anxiety was found to increase CBF while more severe anxiety seemed to decrease it (1). While increased CBF during mild anxiety may be due to brain activation, the mechanisms responsible for cerebral vasoconstriction associated with severe anxiety are unclear. It did not seem to be related to increased blood viscosity or hypocapnia. In animals, vasoconstriction induced by carbon dioxide was used to buy several investigators to demonstrate the cerebral vasoconstrictive effect of sympathetic activation (2,3-7) . We hypothesized that CO2 inhalation can be used to demonstrate the cerebral vasoconstriction associated with severe anxiety in human subjects. Although CO2 itself induced anxiety, we combined it with epinephrine infusions to maximize the possibility of an anxiety response. Epinephrine does not cross the blood brain barrier (8) and it does not directly influence CBF (9). 2. METHOD Twenty four patients with generalized anxiety disorder (GAD-Age 38.9, SD2 9.2 years, 11 males/13 females) and 26 normal controls (Age 34.9, SD 9.9 years, 15 males/11 males)

104

105 participated in this study. All participants were physically healthy and free of medication for a minimum of 4 weeks before this study. During a single visit to the laboratory, CBF was measured thrice for each participate with the ^Xenon inhalation technique (10). Laser Doppler flowmetery (11) was used to record skin forehead blood flow (LDBF) during the entire experiment. A laser imaging probe was attached to the forehead approximately over the glabella. Other measurements made during the experiment included end-tidal levels of C02 (PEC02) , blood pressure, pulse, respiratory rate and anxiety levels measured with STAI (12) and POMS (13). All subjects had CBF and 36 had forehead skin flow measurements. The first CBF measurement was under resting conditions. Thirty minutes later, the second measurement and another thirty minutes the third measurement were conducted. During the first measurement, subjects inhaled room air. During either the second or third measurement, they inhaled a mixture of 5% C02 in room air. During the other measurement, they once again breathed room air. Sequencing of C02 versus room air breathing during the second and third measurements was done on a random basis. Patients and controls were also randomly assigned to receive either intravenous infusions of epinephrine (0.2 microgram/Kg over 3 min) or saline before the second and third CBF measurements. The epinephrine group received epinephrine and the saline group, saline before both the second and third CBF measurements. In other words, saline versus epinephrine was a between group factor in the design. 3. RESULTS We ordered the patients and controls on the basis of change in the combined State anxiety (STAI) and POMS Tension (sum of standardized scores) during C02 inhalation into approximate thirds with the lower third having a decrease in anxiety, the middle having no change or minimal increase, and the top third having a more severe increase in anxiety. Chisquared analyses indicated no difference in the number of patients and controls, or males and females assigned to these three anxiety groups, and ANOVA indicated no difference in the ages of the three groups. CBF/PEC02 ratio were ranked across all subjects (31) . Analysis of these ranked data indicated a highly significant group difference (F=8.07, p< .001). The largest ratio was in the decreased anxiety group and the smallest ratio in the high anxiety group (Figure 1). We compared the three anxiety groups on forehead skin flow in a Group by Time model (Figure 2) and found a significant interaction (MANOVA F=3.07, p< .001). Those in the high anxiety group had a greater increase in LDBF.

106 We computed multiple Pearson r correlations between each time point on the LDBF after 5% C02 with each of the single values of State Anxiety , POMS Tension, respiration rate, pulse rate and CBF/C02. These correlations (r values) were plotted over time (Figure 3 ) . The objective of this analysis was to determine if the pattern of correlations observed across the multiple time points of LDBF would be different among the various dependent measures. We set an alpha level at p< .01 as an index to compare the correlations. There were significant positive correlations between change in anxiety and tension with LDBF, significant negative correlations between CBF/C02 and LDBF, but no significant correlations with respiration rate or pulse rate. The most compelling aspect of Figure 4 is that the positive correlations between LDBF and the anxiety ratings come at the point that the maximum differences between anxiety groups in LDBF are present, and this is the point that the correlations with CBF become significantly negative. 4. DISCUSSION COz inhalation combined with epinephrine infusion induced a maximum degree of anxiety. Subjects who became severely anxious showed a decrease in hypercarbic cerebral vasodilation; C02 is a very well known cerebral vasodilator (14). The severe anxiety group also showed increased forehead skin blood flow. Hypercarbic cerebral vasodilation correlated inversely with anxiety levels during C02 inhalation while forehead skin blood flow correlated positively with it. Neither the changes in hypercarbic cerebral vasodilation nor forehead cutaneous flow could be accounted by epinephrine infusion. Large numbers of experiments conducted in animals clearly support reduction of hypercarbic cerebral vasodilation by sympathetic stimulation. Sympathetic stimulation has been reported to produce dilation in forehead skin flow (15-19). Thus it would seem highly likely that the reduction in hypercarbic vasodilation and increased forehead skin perfusion were both mediated cervical sympathetic stimulation. Unlike other animals, in man and higher primates, there is near complete separation of intra and extracranial flow. One of the few exceptions to this rule is the supraorbital branch of the ophthalmic which originates from the internal carotid artery and supplies the forehead. It also forms anastomoses with facial artery which originates from the external carotid (20,21). Anxiety related increase in forehead skin flow may repress a shunting of blood from the intracranial to the extracranial via the supraorbital artery. This may explain the red face which accompanies anxiety. Increase in extracranial flow may be a vestigial remnant of the mechanism present in lower species to protect the brain against excessive decrease in intracranial flow during fear. It should be noted that sympathetic control of CBF is more potent in nonprimate species.

107 5. ACKNOWLEDGEMENT This research was supported by a grant from NIMH (MH42232) to the first author. 6. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Mathew, R.J.and Wilson, W.H., Am J Psychiatry 147:838849, (1990). Edvinsson, L. Trends Neurosci 5:425-428 (1982). Busija, D.W.and Heistad, D.D., (1984) J Phvsiol 347:35-45 (1984) . D'Alecy, L.G., Rose, C.J.and Sellars, S.A., Circ Res 45:771-785 (1979). Harper, A.M., Deshmukh, V.D., Rowan, J.O. and Jennett, W.B., Arch Neurol 27:1-6 (1972). James, I.M., Millar, R.A.and Purves, M.J. Cir Res 25:77-93 (1969) . Wei, E.P., Kontos, H.A.and Patterson Jr., J.L., Am J Phvsiol 7:H697-H703 (1980). Axelrod, J., Weil-Malherbe, H.and Tomchick, R. J Pharmacol Exp Ther 127:251-256 (1959). Olesen, J. Neurology 22:978-987 (1972). Obrist, W.D., Thompson, H.K., Wang, H.S. and Wilkinson, W.E. Stroke 6:245-256 (1975). Fagrell, B. (1985) J Cardiovasc Pharmacol 7(suppl 3):S53S58, (1985). Spielberger, C D . , Gorsuch, R.L.and Lushene, R.D. STAI Manual. Consulting Psychologist Press, Palo Alto California (1970). McNair, D.and Lorr, M. Profile of mood states-bipolar form. Educational and industrial testing service. San Diego, California (1986). Kety, S.S., Schmidt, C.F. (1948) J Clin Invest 27:484492 (1948). Drummond, P.D., Lance, J.W., Brain 1110:793-803 (1987). Drummond, P.D., Finch, P.M., Brain 112:1351-1358 (1989). Drummond, P.D., Psvchophysiolocrv 28:172-176 (1991). Nordin, M., Thomander, L., Wallin, U.and Hagbarth, K-E., Electroencephaloqr Clin Neurophysiol 66:S73 (1987). Nordin, M. J Phvsiol 423:241-255 (1990). Baptista, A.G. Aspects of cerebral circulation, in Brain Metabolism and Cerebral Disorders. Edited by Himwich, H.E., New York, Spectrum Publications (1976). Fisher, C M . The anatomy and pathology of the cerebral vaculature in Modern Concepts of Cerebrovascular Disease. Edited by Meyer, J.S., New York, Spectrum Publications (1975).

108

FIGURE

FIGURE 2

FIGURE 3

HUMAN 5-HT 1D RECEPTORS : CLONING DISCOVERIES AND THEIR IMPACT ON HUMAN DRUG DESIGN Petrus J. PAUWELS Laboratory of Cellular Neurobiology, Centre de Recherche Pierre Fabre 81106 Castres Cedex, FRANCE ABSTRACT With exception of the 5-HT4 receptor, all members of the 5-HT receptor family have now been cloned, expressed and characterized in cell lines. The 5-HT1D receptor subfamily seems to be complex. Two separate human 5-HT1D receptor genes (5-HT1Da and 5-HT1Dp (or 5-HT1B)) have been isolated. A single amino acid underlies the major pharmacological differences between rat 5-HT1B and human 5HT1Dp receptors. Hence, human receptor clones provide the preferredfirst-levelscreening for human drug design. Receptor-mediated functional activity in transfected cell lines is dependent on the downstream cascade of receptors in the host cell. Evaluation of intrinsic activity of compounds in various receptor expression systems that functionality correlate to that of the target tissue in vivo will allow a better definition of agonist, partial agonist and antagonist activity of compounds. Within the 5-HT receptor family, 5-HT

binding sites were first found in bovine brain

membranes by Heuring and Peroutka (1987) . The pharmacological binding characteristics of these sites did not correlate with any previously defined 5-HT receptor subtype. Subsequently, 5-HT

binding sites were respectively found in the central nervous system of dog, guinea-pig, 2

3

rabbit, pig, hamster, sheep, monkey and human (Waeber et al., 1988 ; Peroutka et al., 1989 ; Beer et al., 19924 ; Bruynvels et al., 1992 5 ; Lowther et al., 19926 ; Pauwels et al., 19937). 5HT

receptors are like 5-HT

function as autoreceptors.

receptors negatively coupled to adenylate cyclase and may

Their anatomical distribution in human, bovine, guinea-pig and

porcine brain is similar to that of 5-HT

receptors in mouse and rat brain. These receptors

are mainly concentrated in the caudate and substantia nigra. regarding the clinical significance of 5-HT

Relatively little is known

receptors; they may be involved in cardiovascular

function, perhaps in depression and anxiety and may be of value for the treatment of movement 8

disorders (Glennon and Westkaemper, 1993 ). The 5-HT receptor family seems to be complex. Two separate human 5-HT receptor genes (5-HT and 5-HT (or 5-HT )) have been isolated (Hamblin and Metcali, 19919, Weinshank et al., 199210). The binding properties of both human receptor clones resemble the properties of human, bovine and guinea-pig 5-HT binding sites. The 5-HT receptor differs fairly substantially from the 5-HT receptor in transmembrane regions, yet is essentially indistinguishable from the 5-HT

receptor in turns of its pharmacological binding l Da

109

110 properties. In this situation a modified proportion of amino acid alterations can apparently have very little effect on the binding properties of a receptor. However, the pharmacological binding properties of the rat 5-HT

receptor are dramatically different from those of the

human 5-HT1TM> receptor although the rat 5-HT1D receptor differs from its human counterpart (5-HT

) at only 4 % of its transmembrane amino acids. Mutation of Thr355 located in the

seventh transmembrane region of the human 5-HT

receptor to the equivalent amino acid in

the rat receptor (Asn) yields a protein with an almost identical binding pharmacology to the rat 5-HT 10 receptor (Metcalf et al, 199211). This illustrates that a single amino acid underlies the ID

major pharmacological differences between rat 5-HT

and human 5-HT

receptors.

Therefore, human receptor clones appear to provide the preferred first-level screening for human drug design. Less emphasis has been placed on the examination of the properties of functional responses of human 5-HT

receptor systems. Both cloned human 5-HT

receptors were

found to couple to adenylate cyclase inhibition. The EC -values obtained for sumatriptan at each receptor subtype match well or just not with the affinity constants for binding (Miller et al., 1992 12 ; Van Sande et al., 1993 13 ; Zgombick et al., 199314). The over-expression of receptors or signalling mechanisms may indicate that a drug has full agonist activity. However, in whole tissue studies the drug may be a partial agonist or antagonist, as a result of a lower functional reserve. MetergolineT and 6-adrenergic receptor antagonists, such as pindolol and propranolol, have been shown to be antagonists, partial agonists or even agonists at 5-HT receptors (Schoeffier and Hoyer, 198915 ; Murphy and Bylund, 1989 16 ; Pauwels et al, 17

1994 ). Similarly, for 5-HT

receptors transfected into Hela cells the intrinsic activity of

drugs such as ipsapirone, buspirone, spiroxatrine and MDL 73005 changed from full agonist 18

to silent antagonist in a lower expression system (Boddeke et al., 1992 ). Using 5-HT receptors transfected into NIH-3T3 cells, the maximum response to full and partial agonists were found to change with receptor density but the EC -values of both full and partial agonists were almost independent of receptor density (Varrault et al., 199219). Several reasons may account for these differences in agonist sensitivity. number does not appear to be the sole determinant of intrinsic activity.

Receptor

The efficiency of

coupling is also dependent on ligand efficacy, the guanine nucleotide-binding protein and effector. This explains substantial differences in the degree of amplification at the level of the receptor-guanine nucleotide-binding protein-effector complex among different systems. Therefore, the importance of the host cell in the downstream cascade coupling of a receptor and/or limitations that the host cell may excert on the activity of a receptor has to be taken into account for evaluation of receptor activity (Van Sande et al., 1993 ). It further strenghtens that compounds may yield agonist, weak agonist or antagonist activity depending on the target cell. Hence, results obtained with receptors expressed in transfected cell lines have to be

111 interpreted with caution.

It is important to evaluate intrinsic activity of compounds

preferentially in various receptor expression sytems that functionally correlate to that of the target tissue in vivo. In conclusion, the use of cloned receptor genes and the possibility for expression in eukaryotic cells and reconstitution with G-proteins offer new means for studying the drugreceptor interactions and the role of G-proteins. The availability of uniform populations of appropriate coupled receptors prepared by heterologous expression will play an important role in the design and evaluation of subtype-specific compounds. Moreover, it will allow to define in a very precise way the agonist/antagonist properties of compounds. receptors will hopefully allow the distinction between 5-HT

Access to cloned

receptors that have been

pharmacologically characterized in both the central nervous and cardiovascular systems. Anyhow, special care has to be taken for an understanding of the physiological roles of the different 5-HT,^ receptor sites since this is coming much more slowly than the progress in 5HT molecular biology. In this respect the recent results obtained by means of gene-targeting techniques to produce mouse-mutants and to analyse the consequences of these mutations on 20

the physiology of the animal are very promising (Hen et al., 1993 ).

References 1) Heuring, R. E. and Peroutka, S. I , "Characterization of a Novel H-5-HT Binding Site Subtype in Bovine Brain Membranes", J. Neurosci. 7, 894-903 (1987). 2) Waeber, C , Schoefifter, P., Palacios, J. M. and Hoyer, D., "Molecular Pharmacology of 5-HT

Recognition

Sites : Radioligand Binding Studies in Human, Pig and Calf Brain Membranes, Naunyn Schmiedebergs Arch. Pharmacol 337, 595-601 (1988). 3) Peroutka, S. J., Switzer, J. A. and Hamik, "Identification of 5-Hydroxytryptamine

Binding Sites in Human

Brain Membranes, Synapse 3, 61-66 (1989). 4) Beer, M. S., Stanton, J. A., Bevan, Y., Chauhan, N. S. and Middlemiss, D. N., "An Investigation of the 5HT

Receptor Binding Affinity of 5-Hydroxytryptamine, 5-Carboxamidotryptamine and Sumatriptan in the

Central Nervous System of Seven Species", Eur. J. Pharmacol 213, 193-197 (1992). 5) Bruinvels, A. T., Lery, H., Nozulak, J., Palacios, J. M. and Hoyer, D., "5-HT

Binding Sites in Various

Species : Similar Pharmacological Profile in Dog, Monkey, Calf, Guinea-Pig and Human Membranes", Arch. Pharmacol. 346, 243-248 (1992). 6) Lowther, S., De Parmentier, F., Crompton, M. R. and Horton, R. W., "The Distribution of 5-HT 1D and 5HT

IE

Binding Sites in Human Brain", Eur. J. Pharmacol 111, 137-142 (1992).

7) Pauwels, P. J., Palmier, C. and Briley, M., "Identification of 5-Hydroxytryptamine

Binding Sites in Sheep

Caudate Nucleus Membranes", Biochem. Pharmacol 46, 535-538 (1993). 8) Glennon, R. A. and Westkaemper, R. B., "5-HT 1990s", Drug News and Perspectives 6, 390-405 (1993).

Receptors : a Serotonin Receptor Population for the

112 9) Hamblin, M. W. and Metcalf, M. A., "Primary Structure and Functional Characterization of a Human 5HT

-Type Serotonin Receptor", Mol Pharmacol 40, 143-148 (1991).

10) Weinshank, R. L., Zgombick, J. M., Macchi, M. J., Branchek, T. A. and Hartig, P. R., "Human Serotonin ID Receptor is Encoded by a Subfamily of Two Distinct Genes : 5-HT and 5-HT " Proc. Natl. Acad. Set 89, 3630-3634 (1992). 11) Metcalf, M. A., McGuffin, R. W. and Hamblin, M. W., "Conversion of the Human 5-HT™ Serotonin Receptor to the Rat 5-HT

Ligand-Binding Phenotype by THR

ASN Site Directed Mutagenesis", Biochem.

Pharmacol. 44, 1917-1920 (1992). 12) Miller, K. J., King, A., Demchyschyn, L., Niznik, H. and Teitler, M., "Agonist Activity of Sumatriptan and Metergoline at the Human 5-HT Receptor : Futher Evidence for a Role of the 5-HT Receptor in the Action of Sumatriptan", Eur. J. Pharmacol. Mol. Pharmacol. 227, 99-102 (1992). 13) Van Sande, J., Allgeier, A., Massart, C. Czernilofsky, A., Vassart, G., Dumont, J. E. and Maenhaut, C , "The Human and Dog 5-HTHT

Receptors Can Both Activate and Inhibit Adenylate Cyclase in Transfected

Cells", Eur. J. Pharmacol. Mol. Pharmacol. 247, 177-184 (1993). 14) Zgombick, J. M. Borden, L. A., Cochran, T. L., Kucharewicz, S. A., Weinshank, R. L. and Branchek, T. A., "Dual Coupling of Cloned Human 5-Hydroxytryptamine and 5-Hydroxytryptamine -Receptors Stably Expressed in Murine Fibroblasts : Inhibition of Adenylate Cyclase and Elevation of Intracellular Calcium Concentrations Via Pertussis Toxinsensitive G Protein(s), Mol. Pharmacol. 44, 575-582 (1993). 15) Schoeffter, P. and Hoyer, D., "5-Hydroxytryptamine 5-HT1D and 5-HT.- Receptors Mediating Inhibition 1J3

ID

of Adenylate Cyclase Activity. Pharmacological Comparison with Special Reference to the Effects of Yohimbine, Rauwolscine and some p-Adrenergic Antagonists", Naunyn-Schmiedeberg's Arch. Pharmacol. 340, 285-292 (1989). 16) Murphy, T. J. and Bylund, D. B., "Characterization of Serotonin-

Receptors Negatively Coupled to ID

Adenylate Cyclase in OK Cells, a Renal Epithelial Cell Line from the Opossum", J. Biol. Chem. 249, 535-543 (1989). 'auwels, P. J. and Palmier, C, "Inhibition by 5-HT of Forskolin-induced cAMP Formation in the Renal 17) Pauwels, P. J. and Palmier, C , "Inhibition by 5-HT of Forskolin-induced cAMP Formation in the Renal Opossum Epithelial Cell Line OK : Mediation by a 5-HT,_ like Receptor and Antagonism by Methiothepin", lr>

Neuropharmacology in press (1994).

Raymond, J. R., Schoefiler, P. and Hoyer, D., "Agonist/Antagc

18) Boddeke, H. W. G. M., Fargin, A., Raymond, J. R., Schoeffter, P. and Hoyer, D., "Agonist/Antagonist Interactions with CLoned Human 5-HT

Receptors : Variations in Intrinsic Activity Studied in Transfected

HeLa Cells", Naunyn-Schmiedeberg's Archs Pharmac. 345, 257-263 (1992). 19) Varrault, A., Journot, L., Audigier, Y. and Bockaert, J., "Transfection of Human 5-Hydroxytryptamine Receptors in NIH3T3 Fibroblasts : Effects of Increasing Receptor Density on the Coupling of Hydroxytryptamine

Receptors to Adenylyl Cyclase", Molec. Pharmacol. 41, 999-1007 (1992).

20) Hen, R., Boschert, U., Lemeur, M., Dierich, A., Ait Amara, D., Buhot, M. C , Segn, L., Misslin, R. and Sandou, F., "5-HT

Receptor "Knock Out : Pharmacological and Behavioral Consequences", Society for

Neuroscience 23rd Annual Meeting, Abstract 265.6 (1993).

MICROSTRUCTURAL ANALYSIS OF MOTOR CONTROL IN SCHIZOPHRENIA ALEXANDER J. ROSEN and CINDY K. WESTERGAARD Psychology Department University of Illinois at Chicago Chicago IL 60680

ABSTRACT Schizophrenic and affective (unipolar and bipolar) patients, their first degree relatives, and normal controls participated in a series of investigations that focused on motor control. Subjects were required to maintain prescribed levels of grip tension (within .5-1.5 kg of 15, 30, and 40% MVC) on a hand dynamometer for 156 sec trials. Dependent measures included peak force, mean force, peak deviations, number of oscillations, number of times and amount of time outside the target window, direction errors, and responsivity to and recovery from auditory feedback. Movement within the target window was also examined. Data analyses revealed that the grip task is both sensitive to psychopathology and specific to schizophrenia. Schizophrenic patients could be discriminated from all other subjects on some measures whereas affectives and schizophrenics could be separated from normals on others. First degree relatives of schizophrenics were discriminable from the patients but not when screened for any signs of psychopathology. The results are discussed in terms of a potential vulnerability marker that may index motor dysfunction. This dysfunction might lead to idiosyncratic motor strategies that can be measured by simple laboratory tasks and used to reduce diagnostic heterogeneity.

The use of motor abnormalities to describe schizophrenic pathology has a history that goes back to Kraepelin and Bleuler, a history that clearly predates the advent of neuroleptic drugs. More recent research suggests that motor dysfunction related to neurological impairment clearly characterizes schizophrenic patients, specifically in the coordination of motor activity and the sequencing of motor patterns (Heinrichs and Buchanan, 1988). Studies of regional cerebral blood flow in schizophrenic patients during a motor task reveal a diffuse organization and lack of laterality in motor control (Guenther, 1986). Motor readiness and motor cortex potentials are reduced in schizophrenics (Chiarenza et.al., 1985; Singh et.al., 1992). There are also reports of biochemical abnormalities and morphological changes in muscle fibers, together with Hoffman-reflex abnormalities, some of which appear in healthy relatives (Meltzer, 1976; Crayton, 1977). The most complete clinical investigations of motor abnormalities in adult schizophrenics have been done by Manschreck (1986) and his colleagues. These investigators found that disturbances in voluntary motor behavior were present in nearly all cases of conservatively diagnosed schizophrenia but only in very few cases of affective disorder, and that neuroleptic drugs tended to reduce both the number and severity of the disturbances. These results are consistent with a review of admissions to a British asylum in the 19th century which, using RDC criteria to

113

114

examine detailed case histories, concluded that movement disorders equivalent to tardive dyskinesia were noted in nearly one-third of the schizophrenic patients (Turner, 1989). There is also a large literature that implicates motor abnormalities as potential vulnerability markers. Fish (1975) observed motor symptoms in children who later developed psychopathology and described them in terms of neurointegrative deficits which were related to a genetic history of schizophrenia but not to obstetrical complications. The most comprehensive studies of neurological and motor abnormalities in high-risk populations have been the Israeli and Danish longitudinal studies (e.g., Marcus et. al., 1987). These studies found that children of schizophrenic parents had neurological impairments that included right-left orientation, motor coordination, and fine motor performance. Recent research by Walker et.al. (1991) provides additional support for the use of motor abnormalities in childhood as predictors of later psychopathology. Research by ErlenmeyerKimling et.al. (1989) also showed that neuromotor measures added significant sensitivity to the detection of high-risk children, and were particularly effective for the prediction of affective flattening (Dworkin et.al., 1993). Rosen et.al., (1991) demonstrated that motor abnormalities could be assessed in a quantitative and systematic way as a source of behavioral markers for schizophrenia. Four experiments were run in which subjects were required to maintain prescribed levels of grip tension (15, 30, and 40% of maximum voluntary contraction) for 156 second trials. At each tension level a target window was created by adding 1kg of force (+ and - .5kg on each side) to the correct force. When a subject strayed above or below the target window, a tone (64db at 1315 Hz) came on. In some experiments a second task (discrimination between squares of various sizes) was presented simultaneously with the grip task. The groups that we studied included both inpatients and outpatients, medicated and unmedicated, schizophrenics and unipolar/bipolar subjects. In all of the studies, schizophrenic patients could be discriminated from all other groups by the increased amount of time they spent outside the target window. The feedback tone did not seem to account for group differences inasmuch as the schizophrenic deficit occurred regardless of its presence, contingency status, or intensity. The grip deficit was present whether or not subjects were paid for good performance; it was present whether or not subjects were concentrating solely on gripping as opposed to seeing the gripper embedded in a dual task design; and it was present whether schizophrenics were medicated or not. There were no discemable effects of any clinical variables (chronicity, BPRS symptom status, medication amounts), or demographic variables (age, gender, SES). Schizophrenic patients could be discriminated from both unipolar and bipolar patients, neither of whom were themselves significantly different from normal controls. These results did not appear to be a function of task difficulty nor divided attention. The deficit appeared to be traitlike in that performance did not covary with

115 clinical symptoms and there was a .82 internal consistency and .78 retest reliability for grip performance. Moreover, when first degree relatives were selected by exclusion of psychiatric diagnosis, and hospitalization/medication history but not family history of neurological disease nor presence of any psychological symptoms, they too showed the grip deficit. Taken together, these early results suggested that the grip task seemed to be a promising candidate for a vulnerability marker of schizophrenia. The question for our most recent studies has to do with the mechanisms underlying the marker. The model with which we are working hypothesizes, in keeping with the literature already described, that schizophrenics have a differential data limitation on the motor aspects of the grip task. This led us to a microstructural analysis that focuses on motor programs, conceptualized as a set of commands that guide skilled movements through the automated control of muscle and joint coordination. Such programs insure that appropriate force acts upon the right joint at the right time. Motor programs may be construed as plans of action that involve motor memories which simplify sensory interpretations and minimize neural decision making. We conceptualize the grip task as a motor program with two components, a pulse (P1) and a step (P2). The pulse consists of an isotonic contraction of the muscles of the fingers, wrist, elbow, and arm in an attempt to locate the target tension. The pulse requires a fast ballistic contraction of the agonist muscle followed by a contraction of the antagonist. The step is a sustained isometric contraction of these same muscles for the purpose of staying on target. It requires a continuous fixed tension with periodic adjustments to correct for under- and over-gripping, a process that is feedback dependent. Using this model, we then analyzed grip performance with a wider variety of dependent measures and with a bigger target window (+ or - 1.5kg). In addition to time off the target tension, we examined: time to execute a successful P1; number of times off target in P2; percent and mean peak force in P2; responsivity to the feedback tone (defined as the time taken to initiate a correct movement); recovery time (defined as the time taken to return to the target window); number of drops to zero force; number of over-or under-shoots through the window; number of occurrences of constant (at least three seconds) force above or below the window; number of direction errors (incorrect movements to the tone, i.e., away from the window); and movements within the target window. The results, in general, replicated previous studies. P1 differences did occur, but with great variability. Significant differences between schizophrenic and other groups occurred in the P2 phase of the task. Moreover, by analyzing different measures it was possible to separate schizophrenics from all other groups as well as both patient groups from the rest of the subjects. And, when first-degree relatives were carefully screened to exclude any signs of psychopathology, no differences between patients and relatives could be discerned. In fact, when differences

116 occurred between the carefully screened first-degree relatives of schizophrenics and normals, they were generally shared with the screened relatives of the bipolars. Only one measure (peaks) clearly identified the schizophrenic's relatives. The grip task, therefore, appears to be both specific to schizophrenia and sensitive to psychopathology in general. The former is anchored to a set of variables that include mean percent force, movements inside the window, drops to zero force, direction errors, and constant force in the face of auditory feedback. The latter include over- and under-shoots through the window, number of oscillations at low tension; and number of peaks above and below the target window. The measures that are related to sensitivity may reflect the sharing of deviations common to schizophrenia and affective disorder, perhaps as a consequence of experiential variables that produce attentional fluctuations. The specificity to schizophrenia may be more related to motor deviations that have, since Kraepelin and Bleuler, distinguished this group from all others. Negativity, moving in the wrong direction when the feedback tone comes on, and letting go of the gripper completely suggest an inability to maintain a constant motor output in the face of unyielding task demands. Pressure variations within the target window suggest a deficit in fine motor control that may involve kinesthetic feedback. The superordinate (Heinrichs, 1993) problem that remains, however, is to explain the marked variability within the schizophrenic group. One way to do this is to focus on schizophrenia as a neurodevelopmental disorder. Thelen (1990) has argued that the timing and sequencing of developmental changes are not represented in the brain's hardware, nor in any dedicated software, but emerge from the interaction of the infant and the environment to produce adaptive behavior patterns. Thelen's research shows quite clearly that infant movements exhibit selforganizing properties that are characteristic of dynamic systems. Because sequence and timing of motor acts are discovered within the natural dynamics of the body and the demands of the task, the possibility for considerable individual variation is great. We believe that this variability is the key to understanding the maladaptive patterns of motor development that come to characterize schizophrenia. The next important question is how this motor variability is related to cognitive dysfunction. We hypothesize that a motor output deficit limits or distorts a child's ability to construct an adaptive set of perceptual categories or maps of reality. Faulty selections, based on subtle motoric defects, create maladaptive percepts that can not endure long term environmental stressors. The tremendous degree of individual variation in this developmental process allows for the evolution of idiosyncratic motor patterns. This not only sets the stage for differentiating schizophrenics from all other groups but provides the beginnings of an analysis designed to reduce the heterogeneity within. It is our hope that microstructural analyses of motor control will help segregate out patients with different etiologies, courses, and responses to treatment so that individualized interventive and preventive strategies can ultimately be developed.

117

ACKNOWLEDGMENTS We would like to thank the ISPI staff for their assistance with patient selection and care, Lumumbe Mbekeani for designing the software, Ralph Haber for suggesting some of the dependent measures, and Mark Coward for assistance with data analysis. These investigations were supported, in part, by grants to the senior author from the University of Illinois at Chicago Campus Research Board, the Scottish Rite Foundation, and the NIMH. Some of the data described in the text were collected as part of the doctoral dissertation of the junior author.

REFERENCES 1. Heinrichs, D. and Buchanan, R.W., "Significance and meaning of neurological signs in schizophrenia", American Journal of Psychiatry 145, 11-18 (1988). 2. Guenther, W., "EEG mapping of left hemisphere dysfunction during motor performance in schizophrenia", Biological Psychiatry 21, 249-262 (1986). 3. Chiarenza, G.A., Papkostopoulos, D., Dini, M., and Cazzuclo, C.C., "Neurophysiological correlates of psychomotor activity in chronic schizophrenics", Electroencephalography and Clinical NeurophysiologySI, 218-228 (1985). 4. Singh, J., Knight, R.T., Rosenlicht, N., Kotun, J.M., Beckley, D.J., and Woods, D.L.,"Abnormal premovement brain potentials in schizophrenia", Schizophrenia Research 8, 31-41 (1992). 5. Meltzer, H.Y., "Neuromuscular dysfunction in schizophrenia", Schizophrenia Bulletin 2, 106-135(1976). 6.Crayton, J., "Neuromuscular pathophysiology in psychiatric patients", Psychiatrica Fennica 50, 145-153 (1977). 7. Manschreck, T.C., "Motor abnormalities in schizophrenia", in H.A. Nasrallah and D.R. Weinberger (Eds.), Handbook of Schizophrenia 1, ElsevienNew York (1986). 8. Turner, T., "Rich and mad in Victorian England", Psychological Medicine 19,29-44 (1989). 9. Fish, B., "Biological antecedents of psychosis in children", in D.S. Freedman (Ed.), Biology of the Major Psychoses, Raven Press:New York (1975). 10. Marcus, J., Hans, S.L., Nagler, S., Auerbach, J.G., Mirsky, A.F., and Aubrey, A., "Review of the NIMH Israeli kibbutz-city study and the Jerusalem infant development study", Schizophrenia Bulletin 13, 425-438 (1987). 11. Walker, E.F., Davis, D.M., Gottlieb, L.A., and Weinstein, J.A., "Developmental trajectories in schizophrenia: Elucidating the divergent pathways", in E.F. Walker (Ed.), Schizophrenia: A life course developmental approach, Academic Press:New York (1991). 12. Erlenmeyer-Kimling, L, Golden, R.R., and Cornblatt, B.A., "A taxometric analysis of cognitive and neuromotor variables in children at risk for schizophrenia", Journal of Abnormal Psychology 98, 203-208 (1989). 13. Dworkin, R.H., Cornblatt, B.A., Friedmann, R., Kaplansky, L.M., Lewis, J.A., Rinaldi, A., Shilliday, C , and Erlenmeyer-Kimling, "Childhood precursors of affective vs. social deficits in adolescents at risk for schizophrenia", Schizophrenia Bulletin 19, 563-577 (1993). 14. Rosen, A.J., Lockhart, J.J., Gants, E.S., and Westergaard, C.K., "Maintenance of gripinduced muscle tension: A behavioral marker of schizophrenia", Journal of Abnormal Psychology A00, 583-593 (1991). 15. Heinrichs, R.W., "Schizophrenia and the brain: Conditions for a neuropsychology of madness", American Psychologist 48, 221-233 (1993). 16. Thelen, E., "Dynamical systems and the generation of individual differences", in Individual Differences in Infancy: Reliability, Stability, and Prediction, J. Colombo and J.W.Fagen (Eds.), Erlbaum:Hillsdale, New Jersey (1990).

NEW LIGHT ON THE PROCESS OF NEURONAL DESTRUCTION IN ALZHEIMER'S DISEASE SIR MARTIN ROTH and CLAUDE WISCHIK University of Cambridge Cambridge, England

Enquiries into Alzheimer's disease in Cambridge have concentrated during the past decade on the neurofibrillary tangle. This was the only cerebral lesion first described by Alzheimer in the disease that bears his name. The 'tangle' is made up of paired helical filaments (PHF). The molecular architecture of phf was defined for thefirsttime in 1985 (Wischik et al) when thesefilamentswere shown to be made up of an assembly of sub-units heaped into aribbonwhich is folded into a left handed double helix. This structure cannot arise by any simple rearrangement of the normal architectural constituents of neurons. It can only be a de novo polymer made up of constituents not found in the normal brain. This has proved to be the case. It has been demonstrated that the main constituent of the phf is the protein tau which is required for the assembly and the maintenance of microtubules thereby permitting transport of materials required for the integrity of synapses in higher association pathways in the brain. It is present in an altered form and redistributed in the brains of those with AD. As the phf in AD undergo proteolysis the cell expands, the cell membrane ruptures and extracellular tangles are extruded into the neuropil where they form 'ghost' tangles. The neuron is destroyed in the process; each 'ghost' tangle is the tombstone of a neuron which has been destroyed. It has been shown that the greater the number of 'ghost' tangles the smaller the number of neurons. The processes described above have been followed with the aid of antibodies prepared against different segments of tau protein. Phf has been found to contain the middle repeat segment of tau protein; this is a truncated and highly insoluble fraction of the protein. The process of neuronal destruction and the progress of dementia are paralleled by the growing accumulation of insoluble tau at the expenses of normal soluble tau protein which predominates in the brain of well preserved elderly (and young) control subjects. Immuno-assays have been developed to measure the concentration of both insoluble and soluble tau protein in the brains of patients with Alzheimer's disease and controls. Insoluble phf tau has been shown present in twenty-fold excess in Alzheimer's disease as compared with cognitively intact controls. In the temporal cortex the difference is forty-fold (Mukaetova-Ladinska 1993). Therefore AD is characterized by an almost complete redistribution of the normal pool of tau protein from the soluble form into an insoluble fraction of it. Moreover the amount of soluble polymerized tau has also been shown in Cambridge to correlate highly with the extent of neurofibrillary pathology (Mukaetova-Ladinska 1993) and the loss of nerve cells (Bondareff et al 1993).

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As immuno-assays have not shown any significant increase in beta amyloid protein in patients with AD as compared with controls it would seem that redistribution (into the body of nerve cells from their axons) and a manifold increase truncated and insoluble tau is a better predictor of the extent of cognitive impairment in Alzheimer's disease than other molecular changes which have been described. The findings provide a basis for investigating the possibility of blocking the pathological accumulation of soluble tau protein in the pyramidal cells in the cerebral cortex. Apath has been created for investigating the truncation, redistribution and polymerization of tau protein in tangle bearing cells which are doomed to destruction.

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PART II

Diagnostic Classification, Assessment, and Testing

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PSYCHIATRIC NOSOLOGY ON THE WAY FROM SYMPTOMATOLOGY TO SEMIOLOGY PETER BERNER UniversitatsklinikfiirPsychiatrie Wahringer Gurtel 18-20 1090 Vienna, Austria

The probability, stressed by A. Frances et al., that a number of the descriptive categories contained in our current classifications result from heterogenous causes requires the development of research diagnostic criteria appropriate to seize distinct underlying etiologies. The way to accomplish this task has already been traced by I.P. Falzet's observation that the "foreground - symptomatology" frequently has different origins which may eventually be discovered by a careful screening of the "background symptomatology". In this perspective French psychiatry makes the distinction between symptomatology and semiology: The first describes, defines and names abnormal phenomena without reference to their origin; the second, on the other hand, aims to identify "signs" which allude to specific etiologies. Hoche called these signs "axial symptoms", or, if some particular symptom combinations would turn out to have this semiological value, "axial syndromes". The aim to identify signs was already attempted before Hoche by E. Bleuler who made the distinction between primary and secondary schizophrenic symptoms, claiming that the latter were mere coping mechanisms. This approach is the one mainly pursued at present by the Bonn School of Huber which tries to single out characteristic basic symptoms for schizophrenia. In the field of mood disorders the search of signs pointing to a specific etiology generally has to be based on the identification of "endogenous" features such as those contained in the melancholic subtype of major depressive episodes in the DSMIII-R. In the same perspective Sheehan proposed to distinguish endogenous from exogenous anxiety. Many researchers claim today that a pure semiological approach focussing on symptoms hypothetically supposed to be linked with specific basic disturbances is a more promising strategy to improve psychiatric nosology than the reference to symptomatological categories which may be of heterogenous origin. The application of the "polydiagnostic approach", which is being pursued by several groups of investigators, may contribute to enhance this shift from descriptive to etiologically based classifications. This technique utilizes the simultaneous application of various diagnostic systems on one and the same sample of patients in order to test their construct validity with regard to a defined validation criterion such as, for instance, course, outcome, response specific treatments, biological findings or genetic data. This strategy requires the fulfillment of certain prerequisites and a strict methodology which can be schematically presented by taking as an example the testing of the hypothesis that endogenous depressions response favorably to a certain antidepressant whereas non-endogenous depressions are not influenced by this compound.

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Polydiagnostic studies are to be based on the following prerequisites: 1. The baseline data must contain all features required by the diagnostic systems the study intends to compare (Mc Glashan). 2. The patient sample should be broadly defined in order not to lose possible positive cases through a primarily too exclusive selection. 3. In addition to the main validation criterion the study should provide supplementary information for testing the underlying hypothesis. For instance if a study focuses on treatment response, course criteria, genetic data, etc., should also be collected in order to evaluate the results obtained. Based on these premised the following stepwise screening of the results are to be undertaken: Step 1: Identification of successful and unsuccessful systems. If none of the compound classifications gathers a significant number of cases meeting the prediction, two possibilities must be envisaged: Either the chosen validation criterion has no discriminating capacity (for instance, the prescribed drug does not act selectively on endogenous depressions) or the sample does not comprise different etiological entities. The answer to this question must be searched for by referring to other validating criteria. Step 2: Extraction of features which determine the attribution to "effective" systems. If there are single pertinent features common to all cases that meet the prediction, the different degrees of effectiveness of the compound systems can be explained by the fact that "ineffective" classifications tolerate the features but do not consider them as decisive, whereas the "effective systems incorporate them as obligatory for the diagnostic attribution. If several single features turnout to be decisive for the identification of cases meeting the prediction, the success of the different "effective" systems may be based on different features which in the future should be included in a polythetic criterion. Step 3: Analysis of the weak points of the "effective" systems. This step must search for the answer to two questions: a) Are the cases included in the "effective" systems but not meeting the predictions really false positive ones? Or are there other reasons for their failure, for instance, in the case of treatment response studies, poor compliance or resorption problems? b) Are the patients which could not be attributed to the "effective" systems but meet the expectations really false negative cases? This would imply, for instance, in regard to our example, that there are endogenous depressions which we are unable to diagnose by means of our actual knowledge. Or were the assumptions wrong, for instance, the supposition that the applied antidepressant acts only on endogenous depressions? Step 4: Analysis of the "ineffective" systems. Why do these systems include the majority of cases not meeting the predictions and exclude many meeting them? Frequently such failures occur because ineffective systems do not consider truly decisive features as obligatory and / or require often a certain degree of severity which exclude milder forms of the disorder. Step 5: Analysis of the results obtained by mean of other validating criteria such as further illness-course and genetic data. This must be completed by a careful

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assessment of the symptomatological, neuropsychological and neurophysiological particularities of the "false negative" or "false positive" cases as well as of the real "positive" ones in order to obtain new clinical or laboratory data enabling us to refine our diagnostic attributions. Step 6: Conceptualization of more effectively structured diagnostic instruments. The described methodology paves the way for an improvement of our diagnostic systems through the identification of the pertinent features of the different classifications. The extraction of these "signs" may lead to the establishment of semiological diagnoses which will facilitate the etiological research. The detailed analyses of false negative cases may, in addition, enhance the discovery of significant attribution criteria which up to now have escaped attention. The pursuit of the polydiagnostic approach will enable us to reduce the number of symptoms which have to be checked in psychiatric examinations, since many of them appear in various entities of heterogeneous etiology. This will lead to a simplification of the diagnostic instruments with which researchers lose time and which are strainuous for the patients. It will also enable us to discover those symptom combinations and course particularities that are a endoved with a real semiological value because they are linked to distinct nosological entities or - what is perhaps more likely - to certain particular vulnerabilities. REFERENCES 1. Berner, P., Methodological Aspects of Follow-up Studies on Psychotic Patients in a Polydiagnostic Perspective, Psychopathology 24,5,297-303 (1991). 2. Bleuler, E., Dementia praecox oder Gruppe der Schizophrenien. In G. Aschaffenburg (ed.). Handbuch der Psychiatrie, Leipzig, Deuticke (1911). 3. Falzet, IP., Desmaladiesmentaleset desasyles desalienes,Paris (1864). 4. Frances, A., Pincus, H., First, M., Widiges, Th., The Future of Psychatric Classification Communication on the IX World Congress of Psychiatry, Rio (1993). 5. Hoche, A., Die Bedeutung der Symptomkomplexe in der Psychiatrie, Z. Ges. Neurol. Psychiatr. 12,540-551 (1912). 6. Huber, G., Das Konzept substratualer Basissymptome und seine Bedeutung fur Theorie und Therapie schizophrener Erkrankungen, Nervenarzt 54, 23-32 (1983). 7. Mc Glashan, T.H., Capenter, W.T. Jr., Bartko, J., Dissues of design on methodology in long-term followup studies, Schizophr. Bull. 14, 4, 569-574 (1988). 8. Sheehan, D.V., Sheehan, K.H., The classification of phobic disorders. Int. J. Psychiat Med. 12, 243-265 (1983).

INTERNATIONAL CLASSIFICATION OF IMPAIRMENTS, DISABILITIES AND HANDICAPS: (ICIDH-1980): SUGGESTIONS FOR REVISION JOHN E. COOPER Emeritus Professor of Psychiatry University of Nottingham NG72UH, U.K.

ABSTRACT

Suggestions are made for r e v i s i o n of the I n t e r n a t i o n a l C l a s s i f i c a t i o n of Impairments, D i s a b i l i t i e s and Handicaps, published by WHO Geneva in 1980. The d e f i n i t i o n s of the t h r e e concepts have been simplified, and t h a t of handicap r e s t r i c t e d t o i n t e r f e r e n c e with the performance of s o c i a l r o l e s . The content of /the t h r e e c l a s s i f i c a t i o n s has been kept s t r i c t l y in l i n e with £he d e f i n i t i o n s , and a s e t of interviewing and r a t i n g schedules /is also in p r e p a r a t i o n . The needs of mental health workers have be/en kept in mind, but most of the suggested changes are of equal i n t e r e s t t o workers in physical medicine.

/ INTRODUCTION The I n t e r n a t i o n a l C l a s s i f i c a t i o n of Impairments, D i s a b i l i t i e s and Handicaps (ICIDH-80) has had a mixed r e c e p t i o n s i n c e i t was p u b l i s h e d 13 y e a r s a g o . The i d e a of d i v i d i n g t h e consequences of d i s e a s e s and i l l n e s s e s i n t o t h r e e s e c t i o n s h a s been found u s e f u l , and t h e d e f i n i t i o n s of t h e t h r e e c o n c e p t s have g e n e r a l l y found f a v o r . But t h e c o n t e n t of t h e d e t a i l e d c l a s s i f i c a t i o n s t h a t were developed from t h e c o n c e p t s h a s caused problems i n t h e p r a c t i c a l a p p l i c a t i o n of t h e scheme i n c l i n i c a l p r a c t i c e . The main problems o v e r l a p between t h e t h r e e c l a s s i f i c a t i o n s , and c o m p a r a t i v e l y l i t t l e space d e v o t e d t o t h e a s s e s s m e n t of t h e performance of s o c i a l roles. With t h e need f o r a v e r s i o n of ICIDH t o go a l o n g s i d e t h e r e c e n t l y produced ICD-10 i n mind, a r e v i s e d v e r s i o n of ICIDH has been produced, c a l l e d f o r t h e moment IDH-93. I t has no o f f i c i a l s t a t u s , but w i l l contribute t o the o f f i c i a l r e v i s i o n p r o c e s s about t o b e g i n . D e f i n i t i o n s i n IDH-93 The d e f i n i t i o n s have been s i m p l i f i e d and made more uniform. Impairment i s l i m i t e d t o i n t e r f e r e n c e w i t h p h y s i c a l and p s y c h o l o g i c a l f u n c t i o n s , l e a v i n g out l o s s e s and abnorm a l i t i e s of a n a t o m i c a l s t r u c t u r e . (These need t o be described, but in a separate statement.) 126

127 Disability is renamed "personal disability", but otherwise remains the same. Handicap is limited to interference with the performance of social roles, and is renamed "role handicap". The definitions are as follows:IMPAIRMENT is any interference with the performance of a normal psychological or physical function, including appearance. PERSONAL DISABILITY is any interference with the performance of a normal personal activity in relation to the immediate environment. ROLE HANDICAP is any interference with the performance of a normal social role, expressed as interaction with others in the performance of their own social roles. Points Common to all Three Concepts. Judgement of what is normal depends upon age, sex, and a variety of personal, social and cultural influences and expectations. These influences are usually obvious for role handicap, but are also often present to lesser degrees for personal disability and for impairments. They are all disadvantages for the person concerned, but expressed in the context of the type of performance that is being assessed. The loss of performance may be intrinsic or imposed. Intrinsic here means that the loss of performance is due to a disease or disorder. Imposed means that outside agencies, persons or events impose the reduction in performance on the person concerned. Use of IDH-93 as a Linked System. Each section can be used separately if required, but IDH93 is designed to be used as linked system, in which an entry for an individual in one part is not repeated in another part. This allows the relationships between the three concepts to be examined, and possible causal links examined. Schedules for Interviewing and Rating. The experience gained in several large scale international collaborative studies organised by WHO Geneva, using schedules covering many types of psychological impairments (PIRS) and selected disabilities and handicaps (WHO-DAS) has shown that there is a demand for interviewing and rating schedules that give guidance about how assessments can be made. This is particularly important for research studies. Accordingly, interviewing and rating schedules are being prepared which are derived directly from the classifications of IDH-93 (already partly prepared in outline). It is important that the items in the new schedules should be compatible with existing items in the WHO schedules, so that comparisons can be made with the extensive data from the WHO studies.

ENSURING EQUIVALENCE OF ICD-10 VERSIONS IN DIFFERENT LANGUAGES Horst Dilling Department of Psychiatry, Medical University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, FRG and Y. Nakane Department of Neuropsychiatry, Nagasaki University, School of Medicine 7-1 Sakanato-Machi, Nagasaki 852, Japan and Harald J. Freyberger Department of Psychiatry, Medical University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, FRG and Werner Mombour Max-Planck-Institute for Psychiatry, Kraepelinstr. 10, 80804 Munich, FRG ABSTRACT The primary goal of translating psychiatric texts like ICD-10, Chapter V (F) of the World Health Organization (WHO) from the original English into other languages is to achieve equivalence of content. The aim of the present study was to evaluate the procedures and special problems of the different versions of ICD-10 from the English original into other languages. With help and permission of WHO a questionnaire was developed and sent out to the official WHO-translators in 17 different languages. The results refer to 13 replies. It could be shown that different centres used differnt procedures ensuring equivalence between the core versions of ICD-10 and the related instruments. Principal problems of equivalence with terms and expressions used in ICD-10 were discussed with regard to these procedures. 1.

Introduction The primary goal of translating psychiatric texts from the original English into other languages is to achieve equivalence of content. It is not sufficient to translate the text literally word by word; it is necessary to know the exact equivalence of the technical terms in the two languages, and also the theoretical concepts contained within a word, a technical term, or a standard phrase, along with all their connotations, which may even differ for the same word in both languages [1]. The World Health Organization (WHO) has a long tradition of translations, but in transforming ICD-9 to ICD-10 the work has been multiplied especially with regard to Chapter V (F), the classification of mental and behavioural disorders [2, 3, 4]. ICD-10 is much more

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129 extensive than its predecessors. Besides a greater number of diagnoses the explicatory texts are now longer compared to these in earlier editions. Because of the high demand, psychiatrists with training and professional experience in both languages are better qualified to make such a translation than are professional translators, even if the latter are more fluent in the foreign language and have a better knowledge of vocabulary and grammar. The aim of the present study was to evaluate the procedures and special problems of the translations of the different version of ICD-10, Chapter V from the English original into different other languages. 2.

Methods With help and permission of WHO we developed a questionnaire containing 14 items concerning (i) the sort and content of the translation of different documents related to ICD-10, Chapter V (Clinical Descriptions and Diagnostic Guidelines [2]; Short version [3], Diagnostic Criteria for Research (DCR) [4]; Composite International Diagnostic Interview [5]; Schedules for Clinical Assessments in Neuropsychiatry (SCAN) [6]; (ii) the procedures ensuring compatibility or equivalence between the different version resp. documents of ICD-10 and the original texts; (iii) specific problems in the translation of single diagnostic terms and psychopathological features in the different sections of ICD-10. In February, 1993 the questionnaire was sent out to the official WHO-translators in 17 different languages. Until June, 1993 we got 13 replies (Arabic, Czech, Danish, French, German, Greek, Italian, Japanese, Korean, Persian, Serbian, Spanish and Turkish).

3. Results 3.1. Translation of the "family of documents" Table 1 shows an overview concerning the translations of the most important documents of ICD-10. In some countries there are different groups translating the guidelines, some of the other texts and the structured (SCAN) or standardized (CIDI) diagnostic interviews. For instance in German, CIDI and SCAN are translated by different working groups which are also responsible for the official WHO-training courses. This created problems in translation since the diagnostic and psychopathological terms in the translations have to be uniform. It was agreed upon by the groups that the standard of translation are the guidelines or the DCR respectively; the other translations have to be adapted to that standard. Therefore certain differences have to be corrected according to the central text. The next question concerned the procedures, ensuring equivalence between the core version and all the other translations (cf. table 2). If different groups were translating, the central group was revising in most cases the text of the others, in some cases the additional groups participated in this revision. Only in a few cases like Arabic and Serbian was this revision done by a professional translator. The guidelines in about half the cases were translated within the responsible centre itself (cf. table 3), some doing so in cooperation with other centres. For the German language we had three centres: one for child and adolescent psychiatry and two for adult psychiatry, all of whom were interchanging their texts. Only one centre - that in Prague - was assisted by a professional translator. The translation done by psychiatrists or psychologists of the different centres was controlled by the own centre, by other groups, by professional translators and in one case by a person whose mother tongue was English.

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Table 1.

Translation of the "family of documents" in different languages

Language

Guidelines

Short version

DCR

CIDI

SCAN

Arabic Czech Danish French German Greek Italian Japanese Korean Persian Serbian Spanish Turkish

yes yes no yes yes yes yes yes yes yes yes yes yes

no yes yes yes yes no yes yes no yes no yes no

no no F60 yes yes no yes yes no no no yes no

no no no yes yes no no yes no no yes no yes

no no yes yes yes yes no yes no no no no yes

Table 2.

Procedures ensuring equivalence between the core versions and the instruments C one group consisting of three subgroups in Luxembourg, Paris, Strasbourg and several other coworkers)

Language

number of groups

revision by the own group

revision by another group

revision by a translator

Arabic Czech Danish French German Greek Italian Japanese Persian Serbian Spanish Turkish

two one one one five one one two one one no no

yes yes yes (F60) yes yes yes no yes yes yes yes no

yes no no no yes yes no yes no yes yes no

yes no no no no no no no no yes no no

3.2. Special problems with single diagnostic terms Different problem areas concerning the translation were mentioned (cf. table 4). First, there may be no exact synonym or paraphrase available like for example in German when we try to translate "disorder" and "disturbance" differently. We found only one word

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Table 3.

Evaluation of the translation of the clinical diagnostic guidelines (Danmark: no translation)

only within the centre

by other groups

professional translator

Czech Greek Italian Persian Serbian Turkish

Arabic French German Japanese Spanish

Arabic French

Table 4.

Principal problems of equivalence with terms and expressions used in ICD-10, Chapter V (F)

Language

Terms

Arabic

persistent delusional disorders (F22), reaction to severe stress (F43), pica (F50.8, F98.3), conduct disorders (F91) flashbacks (Flx.70), schizotypal disorder (F21), persistent delusional disorder (F22), (depressive) episode (F32), dissoziative disorders (F44), somatoform disorders (F45) harmful use (Flx.l), dependence syndrome (Flx.2), schizotypal disorder (F21), persistent delusional disorder (F22), bipolar affective disorder (F31), persistent affective disorders (F34), adjustment disorders (F43.2), dissociative disorders (F44), somatoform disorders (F45), Bulimia nervosa (F50.2), specific personality disorders (F60), factitious disease (F68.1) no major problems delirium (F05, Flx.4), maor depression (F32, F33), somatic syndrome (F32), borderline-personality (F60.31), disorder possession disorders (F44.3) disorder psychoactive substances (F10-F19),uncomplicatedacute intoxication (Flx.00), undifferenciated schizophrenia (F20.3), course of schizophrenia (F20.xl-3), polymorphic (F22.3), somatic syndrome (F32), somatoform disorders (F45), sexual preference (F65), sexual orientation (F66) flashbacks (Flx.70), dissocial personality disorder (F60.2) factitious disorder (F68.1) delirium (F05, Flx.4), affective disorders (F3), somatoform disorders (F45), specific personality disorders (F60), conduct disorders (F91) bad trip (F16), sensitiver Beziehungswahn (F22), haltlose Personlichkeit (F60.8), feeble mindedness (F70)

Czech Danish

French German Greek Italian Japanese

Persian Serbian Spanish Turkish

by a person with English mother tongue

translation/ backtranslation

Italian Serbian

Spanish

Spanish (partly)

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which is to be accepted as translation for both English expressions. Second, certain terms in other languages have a different meaning for example in translating the word "stress". Another problem comes up with the change in the meaning of different psychopathological terms such as "delirium", which in French and German psychiatry is used in a contrasting way and which now according to WHO, covers a rather wide range compared to our earlier understan-ding of this term. The Spanish word "delirio" means not only "delirium" as in "delirium tremens", but also "delusions". Therefore in the Spanish translation only "delirium" and "ideas delirantes" are used, avoiding the term "delirio". The third problem concerns the different use of certain terms in a wider or in a more restricted sense, like the term "affective" which now is used in a wider sense than before and which psychopathologically is difficult to define. Therefore table 4 shows an overview of diagnostic terms which gave rise to difficulties for the translators. For instance "flashbacks", "persistent delusional disorder", "bulimia nervosa" and some German expressions like 'sensitiver Beziehungswahn4 or 'haltlose Personlichkeit' created problems. This may sometimes be only a problem of translation like in "flashback" or "pica" but often as well a problem of adjustment for the psychiatrists of the respective language like in "schizotypical disorder". - The terms printed in boldface type are mentioned more than once. 4. Conclusion We want to finish by stating that in most of the ICD-10 versions in different languages the editors or the translators tell the reader that this is a translation and not an adaptation. While this is true, a good translation still has to be an adaptation to the language as well, one for the psychiatrists working in that language. In summarising, most of the translators seem to have had few problems in transforming the English text into their own language. By means of the procedures described in comparing between different groups, and with the help of international studies we are approaching the equivalence of translations to a very high degree. Some distance between the different texts will remain, but this will not limit international cooperation and understanding in regard to different diagnoses. References [1] Mombour W, Spitzner S, Reger KH, von Cranach M, Dilling H, Helmchen H, "Summary of the qualitative criticism during the ICD-10 field trial and remarks on the German translation of ICD-10", Pharmacopsychiatry 23, 197-201 (1990). [2] World Health Organization, "The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines", WHO, Geneva, 1992a. [3] World Health Organization, "The ICD-10 classification of mental and behavioural disorders. Short Glossary", WHO, Geneva, 1992b. [4] World Health Organization, "The ICD-10 classification of mental and behavioural disorders. Diagnostic Criteria for Research (DCR)", WHO, Geneva, 1993a. [5] World Health Organization, "Composite International Diagnostic Interview (CIDI)", WHO, Geneva, 1991. [6] World Health Organization, "Schedules for Clinical Assessments in Neuropsychiatry (SCAN)", WHO, Geneva, 1993b.

CULTURE AND PSYCHOPATHOLOGY EDWARD F. FOULKS, M.D, PH.D. Psychiatry Tulane Medical Center 1430 Tulane Avenue New Orleans, Louisiana 70112, USA

ABSTRACT This paper discusses a number of caveats which psychiatrists should employ when applying the diagnostic criteria of the DSM-III-R or the ICD-10 to patients in diverse ethnic settings. Many traits which are included as diagnostic criteria for various disorders in Euro-American societies maybe considered normal in other cultures. In these cases, traits may be perceived as both ego-syntonic by the patient and sociallysyntonic by the patient's reference group. Issues of whether a trait is maladaptive or causes functional impairment or subjective distress are related to the cultural context. It is, therefore, important to consider cultural context in order to differentiate normal role-behavior from the extremes that might indicate a disorder.

Psychiatrists need to be sensitive to potential cultural variations in behavior and perceptions of behavior when applying the descriptions contained in the DSM-III-R to individuals from ethnic or social class groups other than their own. All people, diagnosticians included, are implicitly, unconsciously, and perhaps inevitably guided in their discriminations by categories acquired from the sub-culture of their origin. Many anthropologists, in fact, question whether it is even possible to actually transcend cultural barriers and gain true understanding of the subtle meanings, values and emotions contained in the personality of someone from a different ethnic group. Psychiatrists often assume that disorders described in the DSM-III-R as well as their required diagnostic criteria are "real entities" rather than culturally relative behaviors, and that they are potentially discoverable in certain proportions in all human groups worldwide. This position essentially ignores the importance of culture on behavior, and instead focuses on those universal behaviors which all human groups have in common. Such universalist assumptions are supported by increasing evidence that some psychiatric disorders have a genetic predisposition, and by large scale surveys that

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134 have reported that similar symptom clusters are found in patients from widely divergent cultural and societal areas ( 1 , 2 ) . Giving additional impetus to this perspective are the many recent discoveries of the biological basis of behavior and emotion. These discoveries have provided the expectation that ultimately psychiatric disorders will not only be defined with phenomenological precision, but by measurable deviations from normal neurophysioiogy as well. Questions remain, however, as to whether these deviations are marked by definable boundaries from the normal, as seen from example in such genetic disorders as trisomy-21, or whether psychopathoiogy represents the extreme ends of gaussian distributions of normal human traits, or are shaped in most part by cultural factors. Issues of whether a behavioral or personality trait is maladaptive, causes functional impairment, or subjective distress are usually related to the cultural context. Defining or labeling deviances from "normal" is a culturally relative exercise, and its boundaries are determined by the values, ideals, and social-structures of the society. What may be adaptive in the traditional cultural context - may be maladaptive in the encounter with a different and dominant culture system. Raybeck (3) has also recently pointed out that labeling a person who doesn't conform to the normal is less likely to occur in small societies, and that this factor may account for better rates of remission for severe mental disorders in these societies compared to larger scale societies. Indeed, the labeling of deviants in large scale societies may actually enhance social integration of others by scapegoating the misfits, and thereby reaffirming the acceptable norms of behavior. It should be noted, however, that while smaller societies may tend to use deviant labels in public less frequently, they nevertheless recognize severe mental disorders, attempt to different iate them categorical ly from mystical status and other normal culturally patterned behaviors, and have developed nomenclatures of behavioral and mental aberrations (*, 5). Another factor complicating the development of a universal standard for diagnosing the psychiatric patient across ethnic groups is the observation that different cultures have tended to emphasize different traits of personality as ideal. The traits of novelty seeking, quick-temperedness, and extravagance may be ideals of behavior for males in certain society, where childrearing patterns, sanctions, rituals, and institutions are also seen to educate and reinforce these vales. Furthermore, given evidence that there are genetic

135 factors involved in the expression of these traits (6) a society valuing such traits may promote marital and mating patterns which would select for them. Therefore, because of cultural learning factors as well as perhaps the more controversial, genetic selective breeding factors, it might be expected that each society would not only idealize but actually realize unique patterns of personality and deviations defining pathology. Studies of personality development across cultures also indicate that rearing patterns and socialization practices vary considerably in experiences during important periods of development in childhood. Parenting in any society is mostly determined by learned beliefs, values, and practices that are for the most part historically derived. The uniqueness of childhood experiences across cultures may play an important role in shaping certain traits of personality, emphasizing some while suppressing others. In this process ideal versus deviant traits would be implicitly or explicitly defined within any cultural context. Another culturally relative consideration in making diagnosis is the fact that certain atypical individuals may be found in the ranks of mystics, priests, ministers, artists, and others who transcend typical and ideal social roles, and are considered to make major overall contributions to their societies. In these cases, the definitions of personality disorder resting on determinations of functionality relative to the culture of origin may assume a different dimension when such an individual is displaced to the context of another culture. The Vietnamese refugee, who is a highly developed Buddhist may exhibit traits which are a religious inspiration to others in his home country, but which may lead to a diagnosis of Schizoid Personality Disorder in the European or American clinic. Impairments in the cross-cultural context may also be the result of maladjustment to a majority or new cultural perspective which is dominant, or related to dysfunction of the reference group itself. Traits which do not result in impairment, and are not considered to be undesirable by the patient of his/her reference group, usually should not be included on the list of traits essential to meeting diagnostic criteria. Such cautions may avoid mislabeling and unnecessarily stigmatizing people from foreign ethnic groups or social classes. Cultural psychiatry research has revealed that we must proceed with exceptional caution, theoretically and practically, in applying the scientific categories developed in western societies to those of the rest of the world.

136 References 1. 2. 3. 4.

5. 6.

World Health Organization, The International Pilot Study of Schizophrenia. Geneva (1993). Epidemiologicai Catchment Area Program (ECAP), Archives of General Psychiatry - entire issue 41, 931-1005 (1984). Raybeck, D., "Anthropology and Labeling Theory: A Constructive Critique", Ethos. 16, 371-397 (1988). Westermeyer, J. and Wintrob, R., "Folk Criterion for Diagnosis of Mental Illness in Rural Laos; on being insane in sane places", Am. J. of Psychopathology, 136, 755-761 (1979). Murphy, J., "Psychiatric Labeling in Crosscultural perspectives", Science. 19, 1019-1028 (1976). Cloninger, C., "A systematic method for clinical description and classification of personality variants", Arch. Gen. Psychiatry - 44, 573, 544 (1987).

EVALUATING DIFFERING RATES OF ALCOHOL USE DISORDERS AMONG THE GENERAL POPULATION BRIDGET F. GRANT Division of Biometry and Epidemiology National Institute on Alcohol Abuse and Alcoholism 5600 Fishers Lane Rockville, Maryland 20857 USA

ABSTRACT The purpose of this study was to compare DSM-III-R and Draft DSM-IV formulations of alcohol was disorders in terms of prevalence and overlap in a representative sample of the United States general population. The prevalence of DSM-III-R and DSM-IV alcohol abuse and dependence combined were strikingly similar, despite discrepancies in the separate component diagnosis of abuse and dependence. The major finding of this study showed a reversal of the abuse-to-dependence ratio associated with the DSM-IV classification. Unlike previous surveys using DSM-III-R definitions, the prevalence of DSM-IV abuse exceeded that of dependence in this general population sample. Reasons for this discrepancy were discussed in terms of the differences in the number and content of abuse and dependence criteria and the relationship between abuse and dependence categories.

1. INTRODUCTION Similar to any classification system for alcohol use disorders, one major purpose of the Diagnostic and Statistic Manual on Mental Disorders-Fourth Edition Draft Criteria (DSM-IV)1 is their applicability to the wide diversity of contexts in which they would be used. As such, the criteria must be applicable across settings, including inpatient, outpatient, partial patient, private practice, primary care, and community populations. The focus of this study is on the Draft DSM-IV criteria's role as a tool for the communication of accurate public health statistics expressing the magnitude of the alcohol problem in general population settings. The impact of proposed changes in the DSM-IV criteria sets on the prevalence of the preceding DSM-III-R alcohol use disorders2 in the United States would have broad implications concerning the utility and credibility of the DSM-IV definitions for the purpose of alcohol epidemiologic research.

2. METHODOLOGY 2.1 Sample This study is based on a nationally representative survey on alcohol use and alcohol-related problems sponsored by the National Institute on alcohol Abuse and alcoholism (NIAAA). The data were collected as part of the 1988 National Health Interview Survey (NHIS), conducted by the National Center for Health Statistics. A total of 43,809 individuals responded. Including nonresponse to the basic health and demographic component of the NHIS, the overall response rate for the Alcohol Supplement was 85.5%.

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2.2 DSM-m-R and DSM-IV Diagnosis Current diagnoses of DSM-III-R and DSM-IV alcohol abuse and dependence were derived by matching each of the diagnostic criteria of these disorders with symptom items (those experienced during the year preceding the interview) appearing on the NHIS survey questionnaire. As a result of this process, all DSM-III-R and DSM-IV abuse and dependence criteria were operationalized and have been presented in detail elsewhere.3,4 23

Data Analysis

Variance estimates were generated using SUDAAN,5 a software package that uses Taylor Series linearization techniques to adjust for sample design characteristics. SUDAAN was used to estimate the standard errors for all prevalences of DSM-III-R and DSM-IV alcohol use disorders appearing in this study. Kappa coefficients were used to measure chance-corrected agreement between DSM-III-R and DSM-IV diagnoses.6 3. FINDINGS Table 1 presents the 1-year prevalence rates, standard errors, and population estimates of DSM-III-R and DSM-IV alcohol abuse and dependence by age, sex, and race. The 1-year prevalence rates of alcohol abuse and dependence combined for each classification were remarkably similar. Prevalence rates of overall DSM-III-R and DSM-IV alcohol abuse and dependence were 8.63% and 8.56%, respectively each representing approximately 15 million Americans. However, the concordance between diagnostic categories was far from perfect as expressed in terms of Kappa value of only 0.76. The reason for the apparent discrepancy between the two classification systems was readily seen when the component rates of abuse and dependence were examined. For DSM-III-R, the prevalence of alcohol abuse (2.38%) was much lower than the prevalence of dependence (6.25%). The reverse was true for the DSM-IV classification: the prevalence of alcohol abuse (4.72%) exceeded that of alcohol dependence (3.84%). Although the percentage of respondents classified as dependent without abuse was less than the percentage of respondents classified as dependent with abuse in both classifications, the corresponding percentage of those respondents meeting dependence without an abuse diagnosis was much smaller using the DSM-IV (0.77%) compared with the DSM-III-R (1.75%) definitions. The Kappa values for the abuse and dependence categories were consistent with the pattern of observed prevalence. The Kappa value for dependence vs. no dependence diagnosis between DSM-III-R and DSM-IV classifications was 0.73, while the corresponding Kappa value was only 0.60 for abuse vs. no abuse diagnoses. Despite the striking reversal in the abuse-to-dependence ration associated with the DSM-IV diagnosis, there seemed to be very little discrepancy between the sociodemographic differentials observed for the two diagnostic systems. One-year prevalences of alcohol abuse and dependence combined were greater for males (DSMHI-R, 13.35%; DSM-IV, 13.27%) compared with females (DSM-ffl-R, 4.36%; DSM-IV, 4.31%). Prevalences were also greater among whites than among nonwhites. Rates for

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white males and white females exceeded the rates for their nonwhite counterparts by approximately 34.0% and 46.0%, respectively, in both classifications. Prevalence rates of alcohol abuse and dependence combined were much higher among males and females under the age of 45 years than among those 45 years and older, for both classifications. In general, rates for DSM-III-R and DSM-IV abuse and dependence decreased as a function of increasing age.

4. DISCUSSION The prevalence of DSM-III-R and DSM-IV alcohol abuse and dependence combined were nearly identical in this population sample, despite the fact that the concordance between the systems was moderate. When the rates of alcohol abuse and dependence were desegregated, the reasons for the discrepancy between the classification systems were revealed. Dependence diagnoses were more prevalent than abuse diagnosis using DSM-III-R formulations, while the reverse was true for the DSM-IV definitions. This reversal in the abuse-to-dependence ration represents a radical departure from the results of all epidemiologic surveys using psychiatric measures of alcohol use disorders conducted in the US general population to date.3'7"8 Several reasons can be identified for the reversal. The number of DSM-IV dependence criteria was fewer than for DSM-III-R resulting in fewer ways to achieve a diagnosis of dependence. In fact, the most prevalent abuse or dependence criterion in this general population sample was drinking in situations that might be physically hazardous (20.0%). When this criterion was exclusively used to define DSM-IV abuse, and not also dependence, as was the case in the DSM-III-R abuse, one could predict a reduction in the prevalence of DSM-IV diagnoses. Perhaps the most important reason for the shift in the DSM-IV abuse-to-dependence ratio was the change from overlapping criteria for abuse and dependence in DSM-III-R to non-overlapping criteria in DSM-IV. Epidemiologic research projects using the new DSM-IV definitions of alcohol abuse and dependence will be markedly affected. Changes in the DSM-III-R criteria, now appearing in the DSM-IV formulation, will alter the magnitude of alcohol abuse in relation to dependence reported in public health statistics and render trend analysis of alcohol use disorders difficult. Although the sociodemographic differential associated with DSM-IV abuse and dependence did not differ from that of DSM-III-R, it is not clear how gradients of risk for alcohol use disorders will be affected. Perhaps an explicit statement of the rationale and empirical support for changes introduced into the DSMIV formulations will provide the impetus to the acceptance of such changes, despite their cost.

5. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Revision, Draft Criteria, Washington, DC: the Association (1993). 2. American Psychiatric Association. Diagnostic and Statistical Manual ofMental Disorders-Third EditionRevised, Washington, DC: the Association (1987). 3. Grant, B.F., Harford, T.C. Pickering, R., Dawson, D.A. Stinson, F.S. and Noble, J. "Prevalence of DSM-III-R Alcohol Abuse and Dependence, United States, 1988", Alcohol, Health & Research World 15 91-96, (1992). 4. Grant, B.F. "Prevalence of the Proposed DSM-IV Alcohol Use Disorders: United States, 1988, British J. Addict. 87,309-316 (1993).

140 5. Research Triangle Institute. Software for Survey Data Analysis (SUDAAN) Version 6.0, Research Triangle Park, NC: the Institute (1991). 6. Shorten, H J A . "Measuring Pairwise Agreement Among Many Observers", Biometrics 6,497-504 (1980). 7. Grant, B.F. and Harford, T.C. "The Relationship Between Ethanol Intake and DSM-III-R Alcohol Dependence", /. Stud. Alcohol 51,448-456 (1990). 8. Helzer, J.E. and Canino, G J. Alcoholism in North America, Europe and Asia, New York: Oxford University Press (1992). 9. American Psychiatric Association. Diagnostic and Statistical Manual ofMental Disorders, 4th Ed. Options Book: Work in Progress, Washington, DC: the Association (1991).

Table 1.

Prevalence of DSM-III-R and DSM-IV Alcohol Abuse and Dependence by Sex, Age, and Race: United States, 1988 DSM-IV

DSM-m-R

Characteristic Abuse

Dependence

Abuse

Dependence

Sex Male Female

3.77 1.12

9.58 3.24

7.49 222

5.78 2.09

Age 18-29 30-44 45-64 65 +

4.00 2.67 1.55 0.46

12.65 6.41 2.81 0.90

8.85 5.18 2.43 0.69

7.93 3.82 1.74 0.55

Sex x Race White Male White Female Non-white Male Non-white Female

4.00 123 233 0.49

10.00 3.45 6.96 2.01

7.91 2.44 4.85 0.94

6.02 2.18 4.27 159

Total

2.38

625

4.72

3.84

THE IMPACT OF DIAGNOSTIC SYSTEMS ON TREATMENT H. HELMCHEN Direktor der Psychiatrischen JQinik und Poliklinik derFreien Universitdt Berlin Eschenallee 3, 1000 Berlin 19, FRG

1. FACTS AND IMPLICATIONS The ultimate purpose of diagnosis is prognostic information and successful treatment of the individual patient. However, current diagnostic systems in psychiatry are far from serving this purpose. The APATask Force Report on treatments of psychiatric disorders (KARASU1989) makes this very clear, although or even because it is specifically related to DSM-III-R disorders, the currently most developed psychiatric diagnostic system in terms of operationalization, comprehensiveness and acceptance. Caution and warnings in the use of the described treatments as obligatory standards for specific psychiatric disorders can be found running like a red thread throughout the whole report. In almost all chapters such statements can be found as, "there can be no correct treatment for an individual who suffers from one variant or another of a heterogeneous disorder" as schizophrenia is assumed to be (p. 1485), or, "the concept of therapeutically and prognostically valid patient subtypes within the general class of individuals with alcoholism remains an area in need of further study" (p. 1071). Or, "in discussion of treatment of a condition...a clinician must be able to consider each clinical problem at several conceptual levels in designing the most appropriate treatment program." (p. xli). These warnings are not only justified to combat the misuse of today's preliminary knowledge as though it were definitive, but also by the fact that in principle a class in a diagnostic system can, at best, serve only to indicate more or less specifically a therapeutic principle but not a specific application in the individual case. Nevertheless, nowadays even such global therapeutic impact of diagnostic classes seems to be rather low. An example for less specification is the currently predominant conviction that the KRAEPELINIAN triadic system, or -- at most ~ rough three-digit diagnoses as in DSM-III-R or ICD-10 may serve as a framework for the focal point of treatment: so-called minor psychiatric disorders, reactive or maladaptive or adjustment disorders, and personality disorders primarily for psychotherapeutic or social treatments; endogenous psychoses basically for drug treatments; and, organic mental syndromes for treatment of the causes ~ if known. Somewhat greater specification may be exemplified by drug treatment in psychotic disorders, e.g. antidepressant drugs in depressive disorders, and MAO-inhibitors in atypical depression. However, although these examples refer to established indications of treatment principles, even their specificity to certain diagnostic classes remains to be validated. This implies the risk of neglecting other indications, e.g. the relevance of social treatments in schizophrenic disorders, especially in residual states with negative symptoms, or the

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efficacy of antidepressant drugs in some anxiety disorders, particularly in panic disorders. The latter example may also illustrate the impact of treatments on the classification of psychiatric disorders. In general, the specificity of relationship between diagnostic classes and distinct treatments is fairly limited. In other words: the more individual the treatment goal, the less useful psychiatric diagnosis is, or, vice versa. And, it should be added: the less severe the condition the more individually responsive it is to both personality and environment.

2. FUNCTIONS OF PSYCHIATRIC DIAGNOSIS WITH REGARD TO TREATMENT a) Psychiatric diagnosis serves as an instrument for organizing epidemiologic data for administrative use, especially for both quantity of service planning, e.g. the rapid increase of dementias, and improvement in quality of service settings, e.g. for schizophrenic patients, as a framework for specific treatments (HELMCHEN 1981). b) Psychiatric diagnosis in some cases regulates financing of care and service use, e.g. the 1984financingrecommendation of a Task Force Report of the United States Department of Health and Human Services to remove limitations of Medicare coverage on services of Alzheimer's disease and related disorders (KARASU1989, p. 802). c) In the individual case, the impact of any timely diagnosis on treatment is the challenge to treat, e.g. to diagnose a beginning dementive process against so-called normal aging, or to differentiate a sluggish schizophrenic process from a non-psychotic personality disorder. d) But does the diagnosis of schizophrenia in an individual case really help to indicate whether and which drug treatment, alone or in which combination and sequence with which other psychosocial treatment, should be given? I think it does, but only in the following sense: psychiatric diagnosis as schizophrenia or hypochondriasis and body dysmorphophobic disorder or any other specific diagnosis can be used as a: • key to more or less adequately organized knowledge, conceptual as well as empirical, and as an • instrument to organize and reflect the individual evaluation data. However, again, this knowledge is less well organized with regard to specific treatments: in general it can be found either for each psychiatric diagnosis multimodal and vastly overlapping treatments (e.g. KARASU 1989, REID1983), or each treatment is indicated for a bulk of diverse psychiatric diagnoses ~ as the most textbooks on psychiatric treatments show (e.g. APA 1984, BENKERT et al. 1986, MELTZERetall987). The last observation points to principal restrictions of using psychiatric diagnosis for individual treatment planning.

3. LIMITATIONS AND SOLUTIONS Psychiatric diagnoses are not specifically designed or even empirically proven as instruments for treatment planning, and psychiatric treatments are mainly symptomatic

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and unspecific to the existing psychiatric diagnoses. If treatment planning means the selection of the treatment with the most specific efficacy in a given special psychiatric condition, then specificity of both psychiatric diagnoses and treatments must be elaborated much more in order to improve treatment planning. This will be discussed for psychiatric diagnoses and for psychiatric treatments in the following: a) Psychiatric diagnoses: Treatment specific disadvantages of psychiatric diagnoses and systems are as follows: • Heterogeneity: This means first the fact that psychiatric diagnoses and their classification are a non-systematic mixture of different aspects of psychiatric disorders, e.g. phenomenology, etiology, or course, and furthermore, of different concepts, e.g. in the case of schizophrenia that of course-related entity by KRAEPELIN, or that of a group of disorders by BLEULER. Thus, the problem of heterogeneity of nosological groups arises due to the polythetic approach of many diagnostic categories. Heterogeneity sensu strictu means a class of several genetically different psychiatric disorders under the same diagnostic term. Diversity, in contrast, means the fact that different aspects, e.g. stages or sections of the course, of one disease can be found under different diagnoses; diversity also results from concepts as that of vulnerability insofar as it differentiates under a longitudinal perspective more or less time-invariant trait factors for disposition from time-dependent state factors for precipitation or persistence of a current disorder: a consequence may be the need for multiple diagnosis in the same patient. But does a multiple diagnosis help to overcome a simple addition of single treatments for each partial diagnosis into an integrated treatment based on scientifically proven knowledge on interactions and sequences of single treatments? • Arbitrariness: Changing and unregulated predominance of such aspects in the definition of psychiatric diagnoses and their classification from author to author or from one panel of experts to another revealed their arbitrariness and their nature as conventions, i.e. frequently there is no theoretical substantiation and/or no empirical basis. Examples are the change of time criteria or the grading of severity of depression (MOLLER 1990). The existing diagnostic systems are tentative systems, which have to be modified or extended only on the grounds of cumulative knowledge based on empirical findings. • Inflation of diagnostic systems: Therefore, the challenge (by ROBINS et al. 1970, KENDELL1975,1985, and others) was convincing in proving the quality of psychiatric diagnoses in terms of reliability, validity, specificity and sensitivity by empirical research. Such proof of the quality of psychiatric diagnoses, particularly as instruments for treatment planning, has not yet been brought forward. This is due perhaps to the fact that more time is needed to produce respective scientifically sound and representative results rather than to attenuate by conventions the disadvantages of existing diagnostic systems. Thus, the last 15 years have brought an inflation of diagnostic systems - n o w at least ten major systems exist (BERNER et al. 1983, PHILIPP et al. 1987, STIEGLITZ et al. 1990) ~ related to special purposes, e.g. research or care and treatment, or care in different regions: developing vs. developed, eastern vs. western, rural vs. urban, etc., and, in order primarily to improve the reliability of diagnoses and

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systems by more operationalization. Various reviews were able to confirm this (e.g. GROVE, 1987). An improvement in reliability does not, however, necessarily mean an increase in validity. This is to be demonstrated by extensive validity studies, especially in regard to predictive validity. • Lack of predictive validity: One way how this multiplicity, heterogeneity and rapid change of systems impacts negatively on acting habits and behavior of the treating psychiatrist may be the loss of his confidence in any classification system without the gain of insight into the instrumental nature of psychiatric diagnoses. Another negative consequence is an increasing difficulty in comparing the results of empirical research, including therapy research, based on different diagnostic systems. It is necessary to demand longer intervals of time between the revisions of individual systems, because it is difficult to compare results and also because the continued development of systems is not necessarily linked to an increase in validity (e.g. CORYELL et al. 1987). For example it is necessary to evaluate the relevance of the individual criteria (e.g. sensitivity, specificity) which constitute the diagnostic categories. It remains to be proven whether relevant results for treatment planning can be provided by the polydiagnostic approach ~ a trial to apply various diagnostic systems to the same disorder in order to find homogeneous groups of patients as the common overlap of all systems (BERNER et al. 1983). In any case, the predictive validity of psychiatric diagnoses remains to be proven. • Further difficulties which restrict the usefulness of the currently accepted psychiatric diagnoses for individual treatment planning: • Psychiatric diagnoses do not contain the severity of the disorder although it may justify different treatments (KLEIN 1980); • Psychiatric diagnoses say almost nothing about the developmental stage of the disorder. However, in front of the theoretical background of the differentiation of the development of the disorder into states and time invariant traits and the further differentiation of the latter into dispositional and residual traits it can be assumed that a differential therapy response will also be influenced by the dynamic of the disease process. POST et al. (1986) tried to explain the development of affective psychosis up to and including rapid cycling by models of kindling and sensitization and concluded that different developmental stages of an apparently unitary phenomenon such as kindling are differentially responsive to treatment. •

Psychiatric diagnoses give no hint as to neuronal systems or receptor types by which biological treatments, for example with psychotrophic drugs, become effective, quite apart from the fact that these drug therapy-relevant neuronal systems must not necessarily be the same neuronal system which are decisive for the pathogenesis of the disorder and therefore relevant to the diagnosis. Thus, the dopaminergic mechanism of the anti-psychotic efficacy of neuroleptics is no evidence for the so-called dopamine hypothesis of schizophrenia (CARLSSON 1987). This is because the primary disturbance may be in other systems, for example the glutamatergic systems (KORNHUBER et al. 1989), the psychopathogenic effects of which will be mediated exclusively ~ but even only mediated ~ by the dopaminergic system.

Therefore, treatment specific improvement of psychiatric diagnoses and systems will be expected from realization of the following considerations:

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Most psychiatric diagnoses contain at most only a small segment of the plethora of indicators which a treating psychiatrist must observe in making his choice as to treatment ~ its timing, intensity/dosage, duration, combination, sequence, etc. Major indicators are (FRANCES et al. 1984): • Psychopathological syndromes or symptoms, specifically known as target symptoms. A second dimension for treatment indication is the severity of symptoms/syndromes. • Course of the disorder: age at onset, duration, stage, etc. or, in a broader sense: morbid developments, e.g. premorbid traits (transient or persistent insufficient coping capacity due to transient or persistent stress and/or personality disorder or psychiatric disorder) leads via the maladaptive state of alcohol abuse to the morbid state of alcohol dependence and (directly or consequentially) to secondary morbid states as organic mental disorders. • Causal factors, e.g. in somatogenic psychic disorders or organic mental disorders respectively. • Risk or conditional factors for a disposition, e.g. antisocial personality disorder in male alcoholics or pre- and perinatal brain lesions in schizophrenics, or for precipitation and persistence, e.g. somatic diseases and handicaps in depression of the aged, or lowered capacity of coping and compliance. Furthermore, the pathoplastic factor of age, e.g. multimodal long-term treatment for developmental disorders of infancy, childhood and adolescence, or multiple treatments of the often multimorbid states of the aged, or gender. Last, but not least, unknown factors, related to the openness of individual human development, e.g. peculiarities of life style. • Responses to therapeutic interventions: by anamnestic experiences of the individual (and first-degree relatives), and/or by standardized short-term treatments as probes of dynamic capabilities of defined systems. All these treatment indicators could be comprehensively and best accomplished in a multiaxial diagnostic system (MEZZICH 1988, STIEGLITZ et al. 1988). This, of course, does not mean that each individual case should comprise of a class in a system, since this would constitute a nonsystem. However, such a multiaxial diagnostic system organizes knowledge for the treatment relevant function of psychiatric diagnoses. Since the introduction of DSM-III the concept of a multiaxial diagnostic system, as conceptualized in the 20's by KRETSCHMER (1919) and BIRNBAUM (1919) and developed after 1947 (ESSEN-MOLLER et al.), has been a goal in the major diagnostic systems. However, a number of unsolved problems still exist (STIEGLITZ et al. 1990), e.g. there are no rules for making decisions about establishing the necessary number of axes for a comprehensive description, furthermore no software for easy handling the data with practically useful results, and most axes have not been sufficiently elaborated by systematic empirical research, and in practice only the first axis of DSM-III-R is used primarily. Therefore, for example, Axis I should not be used as a system of nosological diagnoses named as syndromes, but actually as treatment relevant psychopathological syndromes or psychopathological basic disturbances, e.g. the dynamic basic disturbances by JANZARIK (1959) or the positive/negative distinction by CROW (1985). Furthermore, the diagnostics of

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Axis II - personality as a real dimensional axis and not as a group of categories of personality disorders -- should be developed in the psychological (v. ZERSSEN et al. 1990) as well as in the biological direction. Not least of all, major emphasis should be laid on aspects as in Axes III and IV, especially with regard to the development of standardized short-term treatment interventions and systematic evaluation of treatment responses, b) Psychiatric treatments: Diagnosis specific efficacy of psychiatric treatments does not exist by the following reasons: • Main indicators are either psychopathological syndromes or (target-)symptoms, both for biological, treatments (drugs, ECT, sleep deprivation) and for behavioral psychotherapy, or supposed causal factors, for somatic treatment as well as for psychodynamic therapy. These indicators are not, or at least, not unanimously linked to psychiatric diagnoses. Therefore, the capacity of the latter to serve for treatment planning is rather limited. • There is no evidence of nosological specificity of treatments. This may be due to the fact that available psychiatric treatments have more than one effect and that their efficacy may be related to their effects on more than one psychological or biological system. The same psyehotherapeutic treatments will be applied in diverse minor and some major psychiatric disorders with different psychiatric diagnoses, neuroleptics are effective in acute schizophrenias as well as in mania or in delirious states, curative efficacy of carbamazepine was validated in epilepsies, neuralgies, both manic and depressive states and prophylactic efficacy in manic-depressive and schizaffective disorders, etc. This, among other reasons, led to the postulates of denosologization of (biological) psychiatry (v. PRAAG et al. 1987) and of cross-diagnostic or transnosological comparisons of treatments (HELMCHEN 1984, 1990, BENKERT 1990, KLEIN 1989, KLIESER 1990). First steps in this direction are findings that defined drug treatments have specific efficacy against defined biological disturbances as those of the serotonin-system, which are related to different psychopathological syndromes or diagnoses such as depression, suicidality, aggressiveness and lack of impulse control, or even obsessive-compulsiveness and lack of impulse control, or even obsessive-compulsive disorder (INSEL et al. 1990, ZOHAR et al. 1987) - "Serotonin-System Related Syndromes: SRS" (CASSANO et al. 1990). Other examples are the recent proposal of HUDSON and POPE (1990), who identified by response to antidepressant treatment a family of "affective spectrum disorders". BENKERT (1990) proposed as "minor psychiatric disorder" a similar concept of a group of mainly the same disorders (panic disorder, generalized anxiety, phobic disorders, dysthymia, hyposomnia, pain (migraine), and various psychosomatic disorders), defined by the same criterion of a common response to antidepressant treatment. Therefore, they may share a pathophysiological anomality. However, treatment response may not only identify comparable pathophysiological mechanisms in morbid states with different diagnoses, but also different pathophysiological mechanisms under the same diagnosis, e.g. the early observation of the efficacy of the antidepressant drug imipramine against a distinct type of anxiety disorder, later termed as panic disorder (KLEIN 1964), but possibly not against generalized anxiety, or neuroleptic response to type I schizophrenia against prevailing neuroleptic nonresponse of type II

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schizophrenia (CROW 1985, BROWN et al. 1990). (For further examples see HELMCHEN 1990,1991). The apparent discrepancy between these concepts with regard to anxiety disorders may remind the reader that KLEIN (1989) emphasized the possibility that differences in drug response may be due not to different underlying disorders but to different states of severity of the same disorder ("severity gradient"), e.g. MAO-I responsiveness predominantly in generalized (severe) social phobias but rarely in discrete (mild) social phobias. Therefore, distinct treatments should be comprehensively compared with each other and in different psychiatric states or diagnoses in order to establish whether they have a differential predictive validity (KLEIN 1989). In that case, treatment response may indicate a specific disturbance of biological or psychological mechanisms and their specific relationship to psychopathological basic disturbances. Thus, efforts seem promising to develop treatment response as one dimension of diagnostic systems in psychiatry that is more valid for treatment planning than the existing systems.

4. CONCLUSIONS AND SUMMARY 1. If the ultimate purpose of diagnosis is prognostic information and successful treatment of the individual patient, then the current diagnostic systems in psychiatry are far from this goal. At best, currently they may a. serve to organize epidemiological data for administrative use in service planning as a framework for specific treatments, b. regulate in some cases financing of treatment, care and service use, e.g. in Alzheimer's disease, c. be used for each specific diagnosis as • a key to knowledge, • an instrument to organize and reflect the individual evaluation, • a challenge to decide something. 2. Thus, the impact of existing diagnostic systems in psychiatry on treatment planning is fairly small. Reasons are with regard to a. psychiatric diagnoses: • heterogeneity and diversity, • predominance of their conventional nature, and • therefore, arbitrariness and lack of empirical scientific proof of their quality, particularly differential predictive validity, • inflation of diagnostic systems and revisions; b. psychiatric treatments: • indication mainly by target symptoms with equivocal or no relationship to psychiatric diagnosis, • lack of comparative evaluation with regard to both other treatments and other diagnoses: nosology-independent or "transnosological" evaluation. 3. Future developments and solutions will be seen in:

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a. a moratorium for further diagnostic systems and revisions until sufficient empirical results of the following measures exist: b. empirical and systematic elaboration of the multiaxial DMS-III-R, especially of axes III and IV with regard to a c. comprehensive and comparative evaluation of treatment responses.

5. REFERENCES 1. American Psychiatric Association Commission on Psychiatric Therapies: The Psychiatric Therapies, APA, Washington DC 1984. 2. BENKERT, O., H. HIPPIUS: Psychiatrische Pharmakotherapie, Springer, Berlin-Heidelberg-New York 1986. 3. BENKERT, O: Functional Classification and Response to Psychotropic Drugs. In: BENKERT, O., MAIER, W., RICKELS, K. (eds.): Methodology of the Evaluation of Psychotropic Drugs. Springer, Berlin-Heidelberg-New York 1990, pp. 155-163. 4.BERNER, P., GABRIEL, E., KATSCHNIG, H., KIEFFER, W., KOEHLER, K., LENZ, G. & SIMHANDL, CH.: Diagnosekriterien fiir schizophrene und affektive Psychosen. Weltverband fur Psychiatrie, Wien 1983. 5. BIRNBAUM, K.: Der Aufbau der Psychose. Ein klinischer Versuch. Allg.Z.Psychiatr.75,455-502 (1919). 6. BROWN, W., HERZ, L.: Response to Neuroleptic Drugs as a Device for Classifying Schizophrenia. In: Schizophrenia Bull 15,123-129 (1989). 7. CARLSSON, A.: Overview of Dopamine Mechanisms: Neurochemical and Pharmacological Evidence. In: HELMCHEN, H., F. A. HENN (eds.): Biological Perspectives of Schizophrenia. J. Wiley, Chichester, New York 1987, pp. 283-298. 8. CASSANO, G.B., H.A. AKISKAL (eds.): Serotonin-System-Related Syndromes (SRS). Psychopathological and therapeutic links. Symposium in Venice 29-31 March 1990. 9. CORYELL, W., ZIMMERMAN, M.: Progress in the classification of functional psychoses. Am J Psychiatry 144,1471-1474 (1987). 10. CROW, T.J.: The Two-Syndrome Concept: Origins and Current Status. Schizophrenia Bull 11, 471-486 (1985). ll.ESSEN-MOLLER, E., WOHLFAHRT, S.: Suggestions for the amendment of the official Swedish classification of mental disorders. Acta psychiatscand., suppl.47,551-555 (1947). 12. FRANCES, A., CLARKIN, J., PERRY, S.: Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection, Brunner/Mazel, New York 1984. 13. GROVE, W.M.: The reliability of psychiatric diagnosis, in C.G. LAST & H. HERSEN (eds.), Issues in Diagnostic Research, Plenum Press, New York 1987, pp. 99-119. 14. HELMCHEN, H.: Functions and consequences of psychiatric diagnoses. In: AGASSI, J. (ed.): Psychiatric diagnoses. Proceedings of an International Interdisciplinary Interschool Symposium, Bielefeld University 1978. Balaban International Sciences Services, Philadelphia 1981, pp. 99-105. 15.HELMCHEN, H.: Zur Problematik diagnostischer Kriterien fiir biologisch-psychiatrische Untersuchungen. In: HOPF, A., H. BECKMANN (eds.): Forschungen zur biologischen Psychiatrie, Springer, Berlin-Heidelberg-New York-Tokyo 1984, pp. 50-53. 16.HELMCHEN, H.: Psychiatrische Diagnostik ex juvantibus? Nervenarzt 61,148-152 (1990). 17.HELMCHEN, H.: Psychopharmakotherapie und Atiologie. In: SCHNEIDER, F., M. BARTELS, K. FOERSTER, HJ. GAERTNER (eds.): Perspektiven der Psychiatrie, G. Fischer, Stuttgart-Jena-New York 1991, pp. 57-66. 18. HUDSON, J., POPE, H. JR.: Affective Spectrum Disorder: Does Antidepressant Response Identify a Family of Disorders With a Common Pathophysiology? Am J Psychiatry 147,552-564 (1990).

149 19. INSEL, T.R., WINSLOW, J.T.: Neurobiology of OCD. In: JENIKE, M., BAER, L , MINICHIELLO, M. (eds.): Obsessive-Compulsive Disorders: Theory and Management. Yearbook Medical Publishers, Lit­ tleton, Mass. USA 1990. 20.JANZARIK, W.: Dynamische Grundkonstellationen in endogenen Psychosen. Springer, BerlinGottingen-Heidelberg 1959. 21.KARASU, B. (ed.): Treatments of Psychiatric Disorders. A Task Force Report of the American Psychiatric Association. APA, Washington, DC 1989.

22. KENDELL, R.E.: The Role of Diagnosis in Psychiatry. Blackwell, Oxford 1975. 23.KENDELL, R.E.: Which schizophrenia? In: Huber, G. (ed.): Basisstadien endogener Psychosen und das Borderline-Problem. Schattauer Verlag, Stuttgart-New York 1985, pp. 145-156. 24.KLEIN, D.F.: Delineation of two drug-responsive anxiety syndromes. Psychopharmacology 5, 397-408 (1964). 25.KLEIN, D.F.: The pharmacological validation of psychiatric diagnosis. In: ROBINS, L.N., BARRETT, J.E. (ed.): The Validity of Psychiatric Diagnosis. New York, Raven Press 1989, pp. 203-214. 26.KLIESER, E.: Psychopharmakologische Differentialtherapie endogener Psychosen. Thieme, StuttgartNew York (1990). 27.KORNHUBER, J., S. MACK-BURKHARDT, P. RIEDERER, G.S. HEBENSTREITZ, G. P. REYN­ OLDS, H. B. ANDREWS, H. BECKMANN: (3H)MK-801 Binding Sites in Postmortem Brain Regions of Schizophrenic Patients. J Neural Transm 77, 231-235 (1989). 28.KRETSCHMER, E.: Gedanken iiber die Fortentwicklung der psychiatrischen Systematik. Z.Neurol. 48, 370-377 (1919). 29.MELTZER, H. (ed.): Psychopharmacology. The Third Generation of Progress, Raven Press, New York 1987. 30.MEYENDORF, R.: Klinische Psychopathologie, psychiatrische Diagnose und Therapie in der Psychiatrie. Psychiatr, Neurol med Psychol 42,193-200 (1990). 31.MEZZICH, J.E., Structural methodology for designing diagnostic systems. In: MEZZICH, J.E., M. v. CRANACH (eds.) International Classification in Psychiatry. Unity and Diversity. Cambridge University Press, Cambridge-New York-Sydney (1988), pp. 298-305. 32.MOLLER, H.-J.: Personal Communication, 1990. 33.PHILIPP, M., MAIER, W.: Diagnosesysteme endogener Depressionen, Springer, Berlin-HeidelbergNew York 1987. 34. POST, R.M., D.R. RUBINOW, J. C. BALLENGER: Conditioning and sensitation in the longitudinal course of affective illness. Br J Psychiatry 149,191-201 (1986). 35.PRAAG, H.M. v., KAHN, R.S., ASNIS, G.M., WETZLER, S., BROWN, S.L., KORN, M.L.: Denosologization of Biological Psychiatry or the Specificity of 5-HT Disturbances in Psychiatric Disorders. J Aff Disord 13 (1987), pp. 1-8. 36.REID, W.H.: Treatment of the DSM-III Psychiatric Disorders. Brunner/Mazel, New York 19&3. 37. ROBINS, E., GUZE, S.B.: Establishment of Diagnostic Validity in Psychiatric Illness: Its Apphcation to schizophrenia. Amer. J. Psychiat. 126,983-987 (1970). 38.STIEGLITZ, R.-D., HELMCHEN, H.: Recent inquiries on standardized assessment and comprehensive diagnosis. (1990) (in press) 39.STIEGLITZ, R.-D., FAHNDRICH, E., HELMCHEN, H.: AMDP in multiaxial classification. In: MEZZICH, J.E., M. v. CRANACH (eds.). International Classification in Psychiatry. Unity and Diversity. Cambridge University Press, Cambridge-New York-Sydney (1988), pp. 180-204. 40.ZERSSEN, D. v., POSSEL, J.: A Case History Analysis of the "Manic Type" and the "Melancholic Type" of Premorbid Personality in Affectively 111 Patients. Eur Arch Psychiatr Neurol Sci 239,347-355 (1990). 41.ZOHAR, J. INSEL, T.R.: Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment and pathophysiology. Biol Psychiatry 22,667-687 (1987).

TYPOLOGY AND COURSE OF ENDOGENOUS PSYCHOSES MIRCEA LAZARESCU Psychiatry Dept. Timisoara University of Medicine and Pharmacology Str. I. Vacarescu 21 Timisoara, R-1900, Romania and MONICA IENCIU Psychiatric Clinic Str. I. Vacarescu 21 Timisoara, R-1900, Romania

ABSTRACT The paper presents some results of a research project started in 1985, consisting in the recording of all cases of endogenous psychoses in a certain area, and their evolutive survey. We have found to be present some atypical evolutive patterns. Defined schizophrenia clarifies within 2 year since first hospitalization. This fact must be taken into consideration in the epidemiological studies. Schizo affective psychoses as well as the affective-delusional ones, have a nosological uncertain statute.

The paper present some results of a research project started in 1985, some of them being already presented on the International Congresses in Athens 1989, Budapest and Geneva in 1991, Timisoara and Koln in 1992, Paris and Lisboa in 1993.

1. THE AIM OF THE RESEARCH Consists in semistandardized recording (in a Case Register) of all new cases of mental disorders that approach standard definition of "endogenous psychoses", characterized by hospitalization, and appear in a certain area (Timis county, with approx. 700,000 inhabi­ tants and since 19 the recordings were restrained to Timisoara city, which has approx. 350,000 inhabitants). The course of these cases is watched by recording their clinical episodes and making 2 and 5 years surveys regarding their nosological statute and demographic parameters. 1.2 Theoretical Assumptions of the Research: a). The elimination of the hierarchic principle of Jaspers in the cases of endogenous psychoses. b). It accepts three main types of psychotic episodes: schizophrenic, delusional, affective (and mixed). c). It accepts a difference between episode and illness: the last consisting in many episodes with certain features regarding specific genetic charge, premorbid personality, clinical defects and therapeutic response, separated by at least six months periods. d). It accepts for every illness any course pattern, Also, is accepted the possibility of

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151 occurence of some "non-typical" episodes, the illness being defined by the proeminence of a certain kind of episodes and of other factors from the ones mentioned above. From this course's point of view, can be accepted "typical" cases as well as the ones with various levels of deviance. Have been recorded only the cases with a clear clinical picture, excluding the mild and even medium depressions and the schizo-typal personalities. For diagnoses we have used ICD-9; since 1987, the ICD-10 was also taken into consideration, Timisoara Centre taking part in the International Field Trial. Have been considered the following kinds of episodes: a).Schizophrenia :sure and probable (less than 6 months) b). Delusional psychoses: persistent; brief (less than 3 months) c). Manic : manic; mania with congruent delusion; mania with incongruent delusion; schizo-manic d). Depressive: severe depression; depression with congruent delusion; depression with incongruent delusion; schizo-depressive e). Bipolar: alternative; synchronic.

2. RESULTS: The assessment of all endogenous psychoses cases in Timisoara, defined as stated above, has been made at the beginning of the year 1993. The number of cases first recroded and the ones present on assessment is shown in Tab. 1. The years 1985 - 1988, were first recorded with a total amount of 273 cases. The distribution of nosological groups as they first appeared and on catamnesis, is shown in Tab.2 (in the final state having less 27 cases). The less stable nosological group from the evolutive perspective appeared to be the Brief Delusional Episodes group; from the first 78 cases, 41 had a single episode, 3 had a recurrent course, and the others proved to be the onset of another disease. From the cases that had another diagnoses on their first episode and later changed course to clear schizophrenia, 26 clarified in less than 2 years since first hospitalization, and only 5 of the cases in the following period. For the years 1985 and 1986, on the catamnesis date, from 131 cases, 18 presented schizo-affective episodes (from a total amount of 74 episodes), 14 being schizo-manic and 21 schizo-depressive. From the evolutive point of view, 5 of this cases can be considered as being bipolar, 3 manic mono-polar, 5 depressive mono-polar and 4 schizofrenic. Only 2 cases progressed only with a schizo-affective recurrent episode. The nosological statute of these episodes is still uncertain for us. In the same group we have encountered 12 cases of depressive episodes with incongruent delusions. Only 2 cases had reccurent episodes of the same kind; 5 had defined as being predominantly monopolar depression and 5 as persistent delusion.

3. CONCLUSIONS: The examination of some epidemological samples from an evolutive point of view, can clarify some nosological problems. It is considered as useful the apprehensive research of the "atypical" cases, by multicentres studies.

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Tab.l No. of cases of endogenous psychoses pssassssssa

I Year

1985

1986

1987

1988

1989

1990

1991

1992

No.of cases I at the I begining of | the research

78

68

66

61

74

48

64

69

!

I No. of cases at the I assesment 1 moment

72

59

60

55

72

47

62

-6

-9

-6

-6

from which: 9 changed in persistent depressions and 23 in paranoid depressions

I

Tab.2 The distribution of nosological groups. At the recording moment

At the assesment moment

II Various manic 1 episodes and bipolar 1 episodes

32

28

Various depressive episodes

49

53

Delusional (paranoid) persistent episodes

26

23

Brief delusional episodes

78

71

Clear or possible | schizophrenic I psychoses

88

103

W

i

n

—

—

—

i

i

n

i

—

—

1 1 1

from 27 cases: 4 changed into bipolar psychoses, 4 in paranoid depressions, 9 in 1 persistent delusions and 10 in schizophrenia. |

THE SEARCH FOR NEW MODELS IN PSYCHIATRY P. PICHOT Academie Nationale de MHecine 24 rue des Fosse's-Saint-Jacques F-75005 Paris, France

ABSTRACT The new psychiatric classifications, DSM-III and ICD 10, are both nosologies - definitions of the different mental disorders - and nosographies - hierarchical distributions of those entities into broader classes. Their characteristics are the use of diagnostic criteria, the multi-axiality, the use of a categorical model and the emphasis on the use of objectively observable facts for the definitions. The categories correspond generally to syndromes. The increase of reliability of diagnosis has been a positive result. They are however negative consequences: the continuous increase of the number of categories, the artificiality of the nosological structure and, despite the expected homogeneity of the categories, the existence of an abnormally high level of co-morbidity and the lack of congruence between categories and psychopharmacological activity. Among the new possible directions for new classification models are discussed the use of a dimensional model and, in order to build a meaningful hierarchical nosography, the use of the results of epidemiology (co-morbidity), psychopharmacology and genetic correlations.

The last decades have witnessed a rebirth of the interest in psychiatric classifications, as testified by the number of papers published in scientific journals whose purpose is to confirm or disprove the validity of newly proposed categories. In this respect, and although it was the result of an evolution which began several years before, the publication by the American Psychiatric Association of the third edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-III) was a milestone. Presented initially as an instru­ ment specifically elaborated to answer the particular needs of the American psychiatrists, it was adopted the world over, because it evidently responded to some unformulated expectations of a majority of specialists irrespective of the school to which they belonged. The ICD 10 published recently by the World Health Organization has practically taken over the basic rules on which the DSM-III rested and, with only some minor differences, its categories. The DSM-IV already in an advanced state of preparation represents a further development in the same direction. We have also been confronted in the last ten years with a change of such a scope that it can only be compared with the introduction, at the end of the XlXth century, of the Kraepelinian system. The term "Neokraepelinianism" proposed by some American authors to quality the new trends is appropriate in so far as it illustrates the reappearance of a domain of the psychiatric thought which had known for many decades an evident decline and whose necessity had even been contested. However it is evident that the basic principles on which the new classifications rest are fundamen­ tally different from those embodies in the older ones, of which Krapelein's is the model. The purpose of this presentation is to review critically the nature and value of some of those principles in the light of the results of their applications and to suggest alternative

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possibilities. Before beginning our discussion, a point of importance has to be remem­ bered. DSMs and ICD 10 classifications refer to mental disorders: the word is part of the title of ICD 10 and of DSM and both emphasize that their purpose is classification. In medicine one distinguishes two complementary aspects of the science of classification and, even if the vocabulary is not always respected, they emphasize two important steps in the process, respectively nosology and nosography. In the classical use of the words, the purpose of thefirstis to define entities - diseases or, according to the presently preferred psychiatric usage, disorders - and nosography which is the hierarchical distribution of the entities into broader categories such as classes, etc. Old and new classifications are both nosologies and nosographies. DSM-III defines the criteria allowing the diagnosis of Panic Disorder - the nosological part - but Panic Disorder belongs together with other entities to the class of Anxiety Disorders, defined by the presence of "anxiety and avoidant behavior" - the nosographic part. We shall disregard here the mental disorders of proven organic cause. The difficul­ ties of their classification are not basically different from those encountered in all fields of medicine, as already pointed out by Georget in 1820 who made a fundamental distinction between the organic disorders whose psychological and behavioral manifesta­ tions were but symptoms of somatic diseases, and "essential madness", that is mental disorders of yet unknown origin. The classification of the forms of "essential madness" remains the central issue of psychiatric classification. The four main characteristics of the new classifications are 1) each entity is defined by diagnostic criteria, 2) the classification is multi-axial, 3) it is categorical, 4) the diagnostic criteria derive from objectively observable facts. The introduction of diagnostic criteria, a reaction against the demonstrated low reliability of psychiatric diagnosis, derives directly from the use by statistical psychology of rating scales and indirectly from the impetus given to the construction of diagnostic algorithms by the development of com­ puters. The multi-axial structure is less fundamental - it is specific in the ICD 10 to the research version. Its purpose is to record in Axes III to V informations not included in the diagnosis, which is attributed to Axes I and II, according roughly to the transient or permanent character of the disorder. Whatever the theoretical precautions of the authors of DSM-III, the new classifications are categorical, an automatic consequence of the way diagnostic criteria are used. The categories are usually not exclusive. Use of diagnostic criteria, multi-axiality and categorical structure are technical aspects. The a-theoretical character of the classification is of a more basic nature. It implies in principle the rejection of any classificatory criterion based on a 'non proved' etio-pathogenic hypothesis and relies in practice on the symptomatology and eventually on the evolution. The categories are syndromes. Although the authors do not always adhere as strictly as they claim to this basic principle, the syndromal nature is a central feature and the major theoretical break with the tradition. What are the consequences? One is positive: the use of diagnostic criteria has greatly improved the reliability of the diagnosis. But others are less favorable. To rely exclusively on symptomatic criteria raises problems, one being the optimal size of the categories. Because one tends to favor extremely homogenous ones in the hope that symptomatic homogeneity will be the expression of intrinsic specificity, their number has been progres­ sively increased. If a patient presents a depressive syndrome, no less than 28 diagnoses are available according to ICD 10, even if one excludes the depressions of organic cause. In another perspective, the 'non proved theories' now rejected allowed to bring together in a meaningful way several categories and to define broader ensembles: the concepts of

155

endogenous psychoses, of neuroses or of hysteria can be mentioned among others. With the present system, the hierarchical arrangement of entities, which constitutes the nosography, has taken a largely formal character. Modern classifications tend to become a juxtaposition of an increasing number of symptomatic independent categories. Among the practical reasons leading to the adoption of a system in which each category is expected to be extremely homogenous, were the necessities of drug trials and of epidemiology. It was expected that a correspondence could be found between category and response to a drug, and that each 'case' in an epidemiological survey would be clearly identified by a single diagnosis. Those hopes have not been fulfilled. Drugs of a given biochemical category are not effective in all patients with a given diagnosis and are active in disorders which do not even belong to the same class: the serotonine reuptake inhibitors are an often quoted example. This has led to the theory of the 'transnosological action' of drugs. In epidemiology one had to introduce the concept of cormorbidity to describe, but not to explain, the fact that a large proportion of 'cases' receive simulta­ neously two or more diagnoses. It is true that comorbidity exists also in somatic medicine, but the levels observed in psychiatry leave no doubt about the fact that it does not correspond to the coexistence of two diseases in the same individual, but to the lack of independence between the entities. One is confronted with the basic question: should we continue to use the same principles and to improve, or should we try radically new perspectives? Two main points will be briefly discussed: the adequacy of the categorical model, the basis of the selection of criteria in the building of a nosography. Several models of classification have been described by the logicians and formalized mathematically. The categorical model, derived from the natural sciences, has been used in medicine and, for that reason, adopted for the classification of mental disorders. The DSM-IV Draft has briefly discussed the problem. It evoques the possibility of substituting a numerical dimensional model to the present one, while admitting that such a step would be difficult because of the lack of agreement on the dimensions and of the absence of familiarity of the psychiatrists with this type of model. The choice of appropriate models has to be based on empirical statistical research, for the time being insufficient in scope. It offers the only possibility to demonstrate the adequacy of a model to the observed facts. A categorical model is only applicable if the existence of discontinuous clusters of individuals defined by relevant characteristics can be proved. It is possible that some models are applicable in some areas, but not in others. Thus the dimensional model appears to have special promises in the field of personality disorders. The substitution of more appropriate classification models to the present simple categorical one, a legacy of botany, is a prerequisite for future progress. Modern classifications remain extremely conservative in some aspects: many entities have remained practically unchanged in their general limits, their subdivision in homog­ enous sub-entities being the main difference. The emphasis on the analytic trend together with the absence of new synthetic concepts is reflected in the weakness of the nosographic part. The classes which regroup subordinate entities are either traditional ones, such as schizophrenia, or, if new, based on superficial criteria. To have dissociated anxiety neurosis into Panic Disorder and Generalized Anxiety Disorder, to have attributed various manifestations formerly subsumed under the concept of hysteria to several unre­ lated classes has not the same conceptual importance as Kraepelin's synthesis of Dementia praecos. The rejection of non-proved theories has to be accepted. But the purely symptomatic approach is not a sufficient substitute especially when it comes to build a

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nosographic hierarchy. Modern systems recognize it implicitly when they use, against their proclaimed principles, an hypothetical psychological mechanism, the alternation of integrative functions, to bring together under the heading 'Dissociative Disorders' several distinct entities. One can of course entertain the hope that biological methods of investi­ gation will provide new and decisive elements. But, in their absence, we have already at our disposal suggestive observed factors on which we can rely. The transnosological action of drugs, the cormorbidity, the genetic correlations between symptomatologically distinct categories expressed by the concept of 'spectrum' are available data on which we must try to build new broader entities.

THE ICD-10 MULTIAXIAL SYSTEM: PRELIMINARY RESULTS OF FIELD TRIALS PROF. JUAN J. LOPEZ-IBOR JR. Psychiatric Unit San Carlos Hospital Complutense University Madrid, Spain DR. NORMAN SARTORIUS Director Division of Mental Health W.HO. Geneva, Switzerland A.JANCA Division of Mental Health W.HO. Geneva, Switzerland DR.M.KASTRUP Hvidovre Hospital Kopenhaguen, Denmark PROF. H. KATSCHNIG Department of Psychiatry University of Vienna Vienna, Austria PROF.J.MEZZICH Department of Psychiatry University of Pittsburgh Medical Center Pittsburgh, USA. ABSTRACT A multiaxial classification is today unavoidable in psychiatry and also perhaps in other fields of health care. The ICD-10 multiaxial formulation provides three axis which represent a solid rational approach to consider separatelly clinical disorders, disablement and enviromental factors. The definition and diagnosis of clinical disorders without considering disablement or enviromental factors is the cornerstone of a system which will allow better decissions according to the different task and goals of health care professionals. Preliminary results of world wide field trials show that significant aspects of problems of patients are excluded when using a single axis diagnosis and that the ICD-10 proposal is an easy instrument to use.

INTRODUCTION. The draft of the ICD-10 multiaxial system has three axes. The first one includes general psychiatric syndromes, the developmental conditions (including personality disorders and mental retardation) and physical diseases. In the following it is called axis I (Clinical Disorders). The second deals with levels of disablement associated with the pathological phenomena included in axis I. The third one includes factors in the environment of the patient that might be relevant to the presentation and course of the clinical disorders. Several multiaxial systems have been proposed to better describe the condition of patients and to consider aspects that looked distinct. The main types or themes of the different proposals identified by Mezzich (1979) are:

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158

1.

Phenomenology (symptomatology, personality disorder and intellectual level/mental subnormality).

2.

Etiological or associated factors (biological and psychosocial factors conceptualized and organized in various ways).

3.

Time frame (onset, duration and course of the symptomatology).

4.

Social functioning (work performance, interpersonal relations, and other aspects of adaptive functioning).

5.

Other (psychopathological severity, certainty and "illness" and "caseness" contrast proposed by Kato, 1977), defense mechanisms.

ICD-10 is a classification to be used in a great variety of situations, including primary care, and in developing countries. Although there is not a consensus, much less a theory, of which is the most adequate number of axises, the reason mentioned supports a simpler multiaxial system. Furthermore, there is not a clear definition of what an axis is or should be. Of course, multiple axises can describe clinical reality in a better way, but they can be seen also as (partially) independent decision lines, which would even represent the activities of different health professionals (i.e., in DSM-III axis I, psychiatric disorders: psychiatrists; axis n, personality: psychologists; axis DI, somatic disorders: other physicians; axis IV, social adaptation: social workers). They can also be seen as a way to integrate psychiatric care with rehabilitation and prevention interventions, that is to say, between psychiatric and mental health activities. In any case, five axises may be too many to be used in situations apart from those present in developed countries. The relationship between the different axis of multiaxial systems is seldom clarified. In the following the relationships between the axes dealing with psychiatric disorders and those dealing with the personality as well with the organic/somatic disorders will be considered. The relationship between personality disorders and somatic illness is an almost forgotten research topic. Psychiatric classifications have been guided in the past by Jasper's hierarchical principle (Jaspers, 1963), which is a principle widely used in clinical diagnosis in medicine in general. Today there is a tendency to move away from this principle, which can be easily done by withdrawing the exclusion criteria from a classification. This approach leads to multiple diagnosis, something that is important in the description of patients and in the gathering of information. In a hierarchical system, a patient with major depression, who suffers also from panic attacks, will be unrecognizable from one who never had such symptoms of anxiety. This multiple diagnosis approach does not mean that a co-morbidity of several disorders has to be accepted (Frances, 1989). It is just a better way describing reality. ICD-10 axis I (Clinical Disorders). The contens of axis I, roughly, equivalent to axis I, n and m of DSM-III and later versions of the American Psychiatric Association Classification.

159

Axis I (Clinical Disorders) includes: Psychiatric disorders of chapter F of ICD-10. Personality disorders of chapter F of ICD-10. Other disorders of chapters A-E and G-Y of ICD-10. There are several reasons to justify what seems to be a step backwards from DSM-III independence of axis II (Personality) and axis III (Organic conditions), whose purposes are to remind clinicians the importance of the personality of their patients and of the physical diseases that they may be suffering too. One reason has to to with the expansion of Axis I (Psychiatric Disorders) which is the expression of an historical trend consisting in the incorporation to axis I (Psychiatric Disorders), of disorders that were previously included in other axis affecting those personality disorders that can be identified as clinically relevant because of its etiology, severity or psychopathology or the organic disorders. Ever since Bingley (1958) described epileptic traits of the personality of patients with temporal lobe tumors without epileptic fits, the epileptic personality disorder is not a variant of the personality but an organic disorder. Similarly, according to DSM-EQ, many patients who previously would have been diagnosed as suffering from some kind of affective personality disorder, will receive the diagnosis of an affective disorder (i.e., cyclothymia or dysthymia). In ICD-10, what was used to be called schizotypal personality disorder is named schizQtypal disorder and it is to be found in the section of schizophrenia and delusional disorders. Finally, there are reasons to sustain that anxious-avoidant personality disorder would be more correctly classified with categories belonging to the section on Neurotic, Stress Related and Somatoform disorders. A second reason is the difficulties in definig personality and personality disorders. The main reason for having axis II in DSM-III separate from I was to ensure that personality aspects were not been overlooked in the presence of more florid I disorder (Frances, 1980). Prior personality traits may be relevant for the clinical picture (Widiger and Hyler, 1987, have discussed many possibilities). Nevertheless several aspects have to be considered: 1.

Psychiatry has always had difficulties in the definition and classification of personality disorders, although it has recognized them since early times. This difficulty may even be related with a certain dislike for patients suffering from personality disorders (Lewis and Appleby, 1988) The classification of the abnormal personality variants is problematic. Two main principles have been applied, both very different from the categorical classification of the rest of psychiatric syndromes. One is prototypical (i.e., Schneider's approach, 1950), another one is dimensional (i.e., as based on MMPI). Very often personality disorders have been considered as minor forms of psychosis (psychosis mitis) or at least they have been described using with words that suggested a strong relationship between them. Personality is an ill-defined concept and different authors have used different notions. For Schneider (1950), personality does only include tendencies and will, specifically excluding the instinctive and somato-vital layers of psychological life as well as the intelligence (that was also excluded by Jaspers (1963), who considered

160

intelligence an instrument of the personality) which are those whose biological factors could be more directly investigated. 2.

Personality disorders as included in DSM-III and even more so in ICD-10 do not include all the aspects of personality relevant for psychiatry or medicine (type A behavior, Friedman and Rosenman, 1964 and other are excluded).

3.

The axis I-fl distinction in DSM-m has been criticized because the differences between I and n are often difficult or arbitrary (Gunderson and Pollack, 1985), because the interaction between axis I and II is sometimes confusing and sometimes becomes a diagnostic redundancy. The association of specific personality disorders and psychiatric disorders has received considerable attention in the attempt to clarify if there are etiological relationships, or if it is an artifact or the expression of a comorbidity. A multiple diagnostic approach, without prejudging the nature of the association may clarify this area. The most commonly described associations have been: alcohol and substance abuse and antisocial personality disorder or other personality disorders, although a personality disorder may be preexisting, but not necessarily be predisposing (Blume, 1989) or borderline personality disorder (Alnaes and Torgersen, 1988b); schizophrenia and schizoid and schizotypal personality disorder; mood and substance abuse disorders and borderline personality disorder (Akiskal et al, 1885; Gunderson et al, 1985, Alnaes and Torgersen, 1988b), or with other personality disorders such as "eccentric" or "dramatic" or a combination of several of them (Alnaes and Torgersen, 1988a, 1988b, 1990). The association of mood disorders and borderline personality disorder has even been found when studying biological markers (Lahmeyer et al., 1988, 1989); obsessive-compulsive disorder and anankastic personality disorder (Alnaes and Torgersen, 1988b) and anxiety disorders and dependent, avoidant and histrionic personality disorder (Mavissakalian and Hamann, 1988). The contrary is also frequent, the association of personality disorders with anxiety and depressive disorders (Klass et al., 1989) or other disorders. Nevertheless, these associations are difficult to interpret as, for instance, some mood disorders may increase the relevance of pre-existing personality traits (Joffe and Regan, 1988). In the case of the association of eating disorders with borderline personality disorders (Johnson et al., 1989; Yager et al., 1989)) the question of what is first may be raised.

4.

ICD-10 chapter F includes only disorders (which ever they are, they are symptoms or syndromes clinically relevant).

The strategy of ICD-10 multiaxial approach allows to have the personality disorders in Axis I (Clinical Disorders) and the normal or abnormal personality variants as described in Chapter Z, in ICD-10 axis n. Therefore, there is a clear distinction between personality disorders and personality variants, the latter may be considered as a representation of individual defense systems against external psychological stresses (Millon, 1981) and internal, which can manifest themselves in many aspects of the life of the individual. Therefore, the diagnosis of a personality disorder (axis I, Clinical Disorders) several diagnostic criteria, that is to say, symptoms, have to be present, while the personality of the patient is defined by the presence of specific traits or defense or coping styles. This

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means that the concept of personality disorder relies on clinical diagnosis while the evaluation of the personality of a patient may need a different approach and the use of more specific methods for the evaluation, such as psychological tests. The methodology of the evaluation of the personality relies on particular principles (Huber, 1988) which do not fully overlap with clinical methodology. This approach will probably allow that personality disorders be more clearly defined, and simultaneously displaces in ICD-10 axis n the problem of the assessment of the personality, the dimensions to be considered in a classification and the evaluation of the degree of abnormality of the personality traits present. A third reason to expand axis I is to include somatic disorders. The somatic axis disorder axis in DSM-III and other nosological systems bears in it unsolved problems. The main one is that its relationship to general psychiatric syndromes is not always clear. A somatic disorder can be the cause or result of a psychiatric disorder, or both be secondary to another disorder or just a concomitant clinical phenomena. To have psychiatric disorders and other disorders in a single axis could also help in preventing the separation of psychiatry from general medicine (Sartorius, personal communication). Organic psychiatric disorders, as described in ICD-10, are disorders and not mere secondary symptoms of brain affections. Some of them are to be found also in other chapters of ICD-10, mainly in the neurological chapter. The strategy adopted by ICD-10 prevents the splitting of a single disorder, i.e., Alzheimer's dementia, into a psychopathological syndrome (chronic organic brain syndrome) and a neurological disease. Axis II on Disablement. Axis II on Disablement follows the principles of the International Classification of Impairment, Disabilities and Handicaps (ICIDH), also provided by WHO which is presented in this volume. It has a simple structure and uses thje term disablement in a general meaning which included the three levels of the ICIDH, impairment, disability and handicap. For the field trials a short version of the WHO Disability Assesment Scale was used, which evaluates the disablement present in 5 different areas: 1)

2) 3) 4) 5)

Global rating, which represents the best estimate of the degree of dysfunction in relation to the maximum level of expected functioning in the socio-cultural context of the patient. The main reason for dysfunction should also be indicated, i.e. mainly psychiatric, mainly somatic, both somatic and psychiatric. Personal care and survival. Occupational functioning: performance of expected role as remunerated worker, student or homemaker. Functionig with family: interaction with spouse, parents, children and other relatives. Broader social behaviour (functioning in other roles and activities): interaction with other individuals and the community-at-large, leisure activities.

The disablement is rated using any of the values from 00-99, including intermediate values. The following anchor values and definitions are provided to facilitate rating: 00

No dysfunction:

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The patient's functioning conforms to the norms of his/her reference group or sociocultural context. 20

Minimum dysfunction: Deviation from the norm in one or more activities/roles is present. The disturbances are minor but persist over the greater part of the time period. More conspicuous dysfunctions may appear for very short periods, e.g. one or two days.

40

Obvious dysfunction: The deviation from the nrom is conspicuous and dysfunctions interfere with social adjustment. Dysfunction in at least one activity/role persists nearly all the time. More severe dysfunction may appear only for a few days.

60

Serious dysfunction: Deviations from the norm are marked in most activities/roles and persist more than half of the time.

80

Very serious: Deviations in all areas aree very severe and persist nearly all the time. Action by others to remedy or control the dysfunction might be required (according to the rater's judgement), but it does not need to have taken place in order to make this rating.

99

Maximum dysfunction: Deviation from the norm has reached a crisis point. A clear element of danger to the patient's own existence or social life and/or to the lives of others may be present. Some form of action or social intervention is necessary. Axis II on environmental factors.

Axis n on environmental factors basically includes the ICD-10 Z codes (Factors influencing health status and contact with ehalth services (Z00-Z99), which are relevant for psychiatry and Mental health. They are grouped in the following categories: Environmental/circumstantial factors: 1. Problems related to negative life events in childhood and upbringing 2. Problems related to education and literacy 3. Problems related to primary support group, including family circumstances 4. Problmes related to the social environment 5. Problems related to housing or economic circumstances 6. Problems related to (un) employment 7. Problems related to physical environment 8. Problems related to psychosocial or legal circumstances 9. Problems related to family history of diseases or disabilities Life-style/life-management problems: 10. Problems related to lifestyle (in the absence of a respective Axis I disorder) 11. Problems related to life-management difficulty

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METHODOLOGY. As past ICD-10 field trials WHO Mental Health Division provided the Coordinating Centers with a description of the methodology, samples of the forms and a diskette with the computer program to collect the data. The stuy consisted of a familiarization phase, followed by the rating of 12 psychiatric case histories provided by the WHO. by two clinicians and the evaluation of 10 general psychiatric patients by two clinicians conducting a joint interview of each patient. RESULTS. Following preliminary data of the two first types of research is presented. Forteen Field Trials Coordinating Centers (table I), guided the research in almost one hundred centers, in over 31 countries and in 15 languages.

Table I: Field Trials Coordinating Centers Bangalore (India) Nagasaki (Japan) Cairo (Egypt) Naples (Italy) Campinas (Brasil) Oxford (UK) Liibeck (Germany) Risskov (Denmark) Luxembourg Rookville (USA) Madrid (Spain) Shanghai (China) Moscow (Russia) Wellington (Australia) Following we present a preliminary analysis of the data of 9 centers (table II), which included 586 patients (61.1% male and 38.4% female), most of them evaluated as inpatients (78%).

Table II: Field Trials: Preliminary data of 9 Centers Lucknow (India) Udaipur (India) Bangalore (India) (2 Centers) Cairo (Egypt) Yangon (Myanmar) Rosanna (Australia) Wellington South (New Zealand) (2 Centers) Axis I (Clinical disorders) diagnosis. 99.5% of the patients had an axis I diagnosis, 36.7% had two diagnosis and 18.7% had 3 or more diagnosis (figure 1). The most frecuent diagnosis was an F3, Mood (affective) disorders (43.3%), followed by F2, Schizophrenia, schizotypal and delusional disorders (29.8%), F4, Neurotic, somatoform and stress related disorders 28.4%) and Fl, Substance abuse disorders (23.4%). This represents a wide range of psychiatric conditions, mostly severe ones and reflects a positive tend towards multiple diagnosis.

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Figure 1: Axis I (Clinical Disorder) Diagnosis (Ordinals indicate diagnosis choice).

Figure 2: Axis n (Disablement)

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Axis II (Disablement) evaluation. Axis II diagnosis showed an significant amount of disabelment present. 329 records (56.7%) had nofcntryin the disablement codes. Even considering that as an abscence of disablement 26.9% were rated as severe to maximal in the Global assessment. Similar ratings for the rest of the categories were: Personal: 18.5 %; Occupational: 31.4%; Family: 27.4% and Broader social: 34.6% (figure 2). Therefore, an abscence of an axis II evaluation would carry out the loss of an important information for a high number of of patients, and an axis on disablement is fully justified. Axis IQ (Environmental factors). Axis III shows a wide range distribution of enviromental factors, with an over representation of those related to the primary support group cathegory (figure 3). If all family factors items are added up, not taking into account to which cathegory, they belong (figure 4), the image emerges of the high importance of family problems in the circumstances of psychiatric patients. Nevertheless, it should also be noted that the different social and cultural backgrounds of the patients studied may lead to the loss of specific broader social factors when calculating the figures for the whole of the sample and therefore to an overn-representation of the family factors. Applicability. Researchers were asked to rate the aplicability of the multiaxial version. 4 out of 5 found the three axis very easy or rather easy to apply (figure 5).

Figure 3: Axis III (Environmental factors)

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Figure 4: Axis HI (Environmental factors)

Figure 5: Applicability

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FUTURE DEVELOPMENTS. The final analysis of the data for all the centers will lead to a modification of the ICD-10 multiaxial formulation in order to: a) Clarify Axis II leading to a better understanding of the importance and rating system of disablement. b) A redefinition of Axis III items to consider some missing and to eliminate those of very small frecuency. c) Reach a clearer definition of the whole system to make it appropiate for psychiatric and none psychiatric use. REFERENCES Akiskal, H., Yerevanian, B., Davies, G. et al. (1985) The nosological status of borderline personality: Clinical and polisomnographic study. Amer. J. Psychiatry. 142: 192Alnaes, R. and Torgersen, S. (1988) The relationship between DSM-III symptom disorders (Axis I) and personality disorders (Axis II) in an outpatient population. Acta Psychiatrica Scandinavica 78: 485-492. Alnaes, R. and Torgersen, S. (1988) DSM-III symptom disorders (Axis I) and personality disorders (Axis II) in an outpatient population. Acta Psychiatrica Scandinavica 78: 348-355. Alnaes R. and Torgensen S. (1989) Personality and personality disorders among patients with major depression in combination with dysthymic or cyclothymic disorders. Acta Psychiatrica Scandinavica 79: 363-369. Bingley, I. (1958) Mental symptoms in temporal lobe epilepsy and temporal lobe glioms. Acta Psychia. et Neurol. suppl. 123 33, Blume S.B. (1989) Dual diagnosis: psychoactive substance dependence and the personality disorders. J. Psychoactive Drugs 21; 139-44. Cloninger, C.R. (1987) A systematic method for clinical description and classification of personality variants. Arch. Gen. Psychiatry 44: 573-588. Essen-Moller, E. and Wohlfahrt, S. (1947) Suggestions for the amendment of the official Swedish classification of mental disorders. Acta Psychiatrica Scandinavica 47 (suppl.): 551555. Frances, A. (1980) The DSM-III personality disorders section. A commentary. Am. J. Psychiatry 137, 1050Friedman, M. and Rosenman, R.H. (1960) Overt behavior in coronary disease. J. Amer. Med Ass. 173: 1320-1325. Gunderson, J and Pollack, W. (1984) Conceptual risks of the Axis I-II division in: Biologic responses styles. Clinical implications (eds. H. Klar and L. Siever). Page 82. American Psychiatric Association, Washington D.C. Gunderson J. and Elliot G. (1985) The interface between borderline personality disorder and affective disorder. Amer. J. Psychiatry 142: 277Huber, W. (1988) Methodology of the evaluation of the personality. Acta Neurochir Suppl (Wien) 44: 48-53. Jaspers, K. (1963) General Psychopathology. University of Chicago Press, Chicago. R.T. and Regan, J J . (1988) Personality and depression. J. Psychiatric Res. 22: 279-286. Johnson, C , Tobin, D. and Enright, A. (1989) Prevalence and clinical characteristics of borderline patients in an eating-disordered population. J. Clin. Psychiatry 50: 9-15. Kato, M. (1977) Multiaxial diagnosis in adult psychiatry. Paper presented at the VI World

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Congress of Psychiatry, Honolulu, Hawaii. Klass, E.T. DiNardo, P.A. and Barlow, D.H. (1989) DSM-IH-R personality diagnoses in anxiety disorder patients. Compr Psychiatry 2Q: 251-258. Lahmeyer, H.W., Val, E., Gaviria, F.M., Prasad, R.B., Pandey, G.N. Rodgers, P., Weiler, M.A. and Altman, E.G. (1988) EEG sleep, lithium transport, dexamethasone suppression, and monoamine oxidase activity in borderline personality disorder. Psychiatry Res. 25: 19-30. Lahmeyer, H.W., Reynolds, C.F, 3d., Kupfer, DJ. and King, R. (1989) Biologic markers in borderline personality disorder: a review. J. Clin. Psychiatry 5Q: 217-225. Lewis, G. and Appleby, L. (1988) Personality disorder: the patients psychiatrists dislike. Brit. J. Psychiatry 152: 44-49. Mavissakalian, M. and Hamann, M.S. (1988) Correlates of DSM-IH personality disorder in panic disorder and agoraphobia. Compr Psychiatry 2£: 535-544. Mezzich, J.E. (1979) Patterns and issues in multiaxial psychiatric diagnosis. Psychological Medicine 2: 125-137. Millon, T. (1981) Disorders of personality: DSM-HI axis H. Wiley, New York. Reich, J.H. (1988) A family history method for DSM-m anxiety and personality disorders. Psychiatry Res. 2£: 131-139. Reich, J. and Troughton, E. (1988) Frequency of DSM-IH personality disorders in patients with panic disorder: comparison with psychiatric and normal control subjects. Psychiatry Res. 2& 89-100. Schneider, K. (1950) Psychopathic personalities. Grune & Stratton, New York (9th. ed.). Tellenbach, H. (1980) Melancholy. Duquesne Univ. Press, Pittsburgh. Widiger, T.A. and Hyler, S.E. (1988) Axis I and H interactions, In: Psychiatry (eds. R. Michelis, J.O. Cavenar et al.) Vol 1. Chapter 29. J.B. Lippincott, Philadelphia. World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. Geneva, Switzerland. Yager J., Landsverk J., Edelstein C.K. and Hyler SE. (1989) Screening for Axis II personality disorders in women with bulimic eating disorders. Psychosomatics 2Q: 255-62.

PSYCHIATRIC PATHOLOGY: GENOME AND PERSONALITY PROF. F. LLAVERO Professor of Psychiatry University of Salamanca Salamanca, Spain

Some years ago at the foundation of the GROUP FOR THE ADVANCEMENT OF PSYCHIATRY by the Journal "Actas-Luso-Espanolas de Neurologia, Psiquiatria y Ciencias Afines", founded by Lopez Ibor, I proposed the figure of the mythological centaurs as the most emblematic and true symbol of the object of psychiatry. My wish was that the bidimensional constitutive and heterological singularity of the psychiatric body doctrine should not be forgotten. In other words, the researcher has to be always in the direction of the Natural Sciences and also in the direction of the Sciences of the Spirit although the accents do change with age and culture. In this sense already Kant postulated: "Man is always himself but never the same". Facing the complex bidimensionality of man and his pathology, the researcher has to remain methodologically loyal to the juridical principles: A well set up matter is an almost solved matter. During the last century and at the end of the preceding one, the accelerated advance­ ment of our scientific knowledge and sciences has been of such a nature that we have reached a sort of Big-Bang of "psychiatric constellations" with self-sufficient pretensions of independent knowledge. Once again we have to remember the danger "the barbarism of specialization" (Ortega y Gasset), especially in psychiatry which is a "breakwater" which attracts all kind of fishers and fishing tools. The anarchic situation of world psychiatry has to come to an end. The starting point should be the basic knowledge of a medical-anthropological psychiatric pathology. This is a need on which I have insisted since long ago, in order to overcome a prevailing symptomatic and empiric-nosological psychiatry on the basis of casuistic, epidemiologies and items, etc., which forgots a basic etiopathogenic and epistemological knowledge. Psychiatric pathology requests an integrative synthesis which does not exist in psychiatric literature. Any attempt to structure that pathological psychiatry with new demands of casualty and motivation should be preceded by the knowledge of some historical facts or vicissi­ tudes, starting by the generally so-called pre-scientific stage. During that large stage it frequently was parted from -almost as in theology- the ancient and enigmatic Body-Soil dichotomy, passing through the Aristothelic "substantial unity", or, by the contrary, through the epiphenomenic conception and of "direct casualty" between cerebral activity and psychological manifestation. During this period the prevailing of clinical-empiric contributions was natural and along with it the symptomatic, syndromic, nosological and care-providing psychiatry along with the literary, fictional and romantic contributions. This long pre-scientific period ends in the middle of the last century. The true history of scientific psychiatry itself is much shorter. It begins with the histopathology of general paresis of the insane is discovered and confirmed in encephalitic and vascular

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processes with psycho-organic manifestations, findings which induced Griesinger to launch his daring and encouraging statement: "mental illnesses are or can be cerebral illnesses". The expectations were great in German psychiatry who just succeeded to obtain the "blue-ribbon" from french psychiatry, until reaching the Decade of the Brain of the Neuroscience and its consequences. I have been closely linked to this trend since the thirties when I worked at the Cajal Institute of Madrid and later in Germany and Switzerland with Bumke, K. Schneider, Riidin, Hess, Nobel Prize, C.G. Jung, Minkowski and Bleuler. What has happened during this half century? Which have been the hopes, errors and failures? Which would be the most suitable path to follow and why?. The doctrine of Brain Centers and Localizations according to Kleist, v. Economo and so many others, was forcing many researchers into a "Brain mythology". On the other hand psychological doctrines became very attractive parting from Freud and C.G. Jung and Adler to whom, by the contrary, there is no interest in brain function. In this cross-fire situation our knowledge was enlarged by three contributions who forced us, I insist, to new approaches in relation to the normal and abnormal mental processes. The first one is due to the "Columbus of Neurosciences", Cajal, the discoverer of the neuronal synapsis, we can also call "synaptic custom" for which here takes place the permanent "biochemical interchange" -known and yet to be known- which maintains the basic cerebral activity: normal or pathological; many psychiatrists took a long time to understand its importance. Some years later in the fifties, the discovery of psychotropic substances marks another crucial period for the basic and therapeutical knowledge in psychiatry. The discovery, almost by casualty of psychotropic substances or psycho-drugs, these substances also contribute to the better understanding of the synaptic custom and brain activity. Psychotropic medication brought with them an optimism which contrasted with the traditional therapeutic nihilism even to the point to believe in the "eradication of mental disorders" and to the "closing of mental hospitals", Utopias shared by the so called "antipsychiatry" which is full of ignorance and decalifications (3). The therapeutic effect of psychotropic drugs will increase in the future but it will have to face a limit of the functional frontier characteristical of psychiatric-medicalanthropological pathology (4). I made these predictions over 30 years ago in Germany in a period of full psychopharmacological euphoria and some colleagues qualified it as "exaggerated prediction" (5). Clinical experience and follow up of patients supports my point of view. In the middle of this century a third scientific contribution had an impact in psychiatry: the double helix, DNA or desoxidoribonudeic acid, which opens our investigations to the original dimension of man -its biogenetic matrix or human genome-, paradoxically the worst known dimension of personality till the development of the so called "molecular engineering" with the unavoidable ethical-juridical and social projections consubstantial to psychiatric pathology (6). Our knowledge or working-hypothesis are based on intuitions or empiric results starting by the "peas" of Mendel and his laws, passing by the vinegar-fly and the "twin studies".

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The structure of DNA is the most important discovery of the XXth century (Grisolia). Here the biogenetic determinism or the prevailing environment according to the ages, periods and cultures is the most decisive factor. What will reveal us the cartography of the genome in the next 2-3 years and which will be their demands on psychiatry?. What differences exist in the heredity of the somatic and psychological dimensions and how do they interfere between themselves? (7) Everything in life is linked to pshychological phenomena on which our own happiness or our unhappiness depends. The challenge that it represents for future psychiatric pathology does not surpass, until now, the field of mere casuistic and epidemiological empiricism, with little questioning of scientific interest. It seem as if the challenge that represents the knowledge of the cartography of the human genome and its consequences for the better understanding of man and its mental pathology, does not have that much significance as I end up seeing from the program of the recent Congress of the World Psychiatric Association held in Rio de Janeiro. I hope that the next World Congress will go into this with more interest and updating of this basic knowledge necessary for psychiatric pathology. In the heredity of somatic features a direct determinism predominates. The cartography of the Human Genome will locate more precisely and sequence the 100.000 genes which we now know. As Grisolia says there exist about 4.000 monocigotyc illnesses which determinate the kind of illness we are going to suffer", of which we only know some hundreds. To these possibilities we should add the countless hybridations, sometimes incredible with its unavoidable ethical problems when interfering with the natural modification of the natura naturata or the natura naturans. From all this it can be said up to now, that the biogenetic determinism with its different accents, normal or pathological, its manifestations and its evolution will remain in the limits of the somatic or unspecific bio-somatic dimension of man. In classic psychiatry -symptomatic, syndromic, casuistic and nosological- this biogenetic determinism continues almost valid in relation with the mentioned endogenous psychoses and some psycho-organic syndromes and cerebral abiotrophies, known and yet to be known (7). Now psychiatrist have to, besides, ask themselves: What significance has the Human Genome and in what relation with Mental Health of the populations when genetic determinism is not that severe and verifiable as in the greatest part of disorders of psychiatric pathology in any of its forms, races and cultures with the security and frequency as in the somatic processes? For which I know, one of the oldest and more prestigious schools was the KaiserWilhelm Institute for Genealogy and Demography in Munich and in the same building Kurt Schneider had its practice, who so much contributed also to the better understanding of the so-called psychopathies and its problems (8). When I worked in that Institute, the research on heredity in psychiatry, as in the rest of the world, was principally empirical, casuistic and statistical. With this limitations the monozygotic twins were the most and unique reliable proves. For this reason Lange published his work with a title as daring as committed: Crime as destiny which had its deserved recognition.

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Lange showed, as was to be foreseen, a great determined concordance which justifies the term "Endogeneity" in the etiopathogeny of some psychiatric sufferings or psychoses. At the same time the problem of uncertainty or indetermination appeared again: How when dealing with monozygotic twins, the correlation was not of a 100%?. In this sense I bring up the recent case presented by Friedhof in May 1993, in our recent National Congress in Bilbao: two mocigotyc twins, one of them suffering from chronic schizophrenia and the brother remained healthy, normal; both brought up and educated, as it seems, in the same familiar and school environment....When I asked Friedhof on the unexplainable rareness of this founding, he appealed, in the essential, to alleged "protective genes" in the healthy twin in front of the schizophrenic heredity...", explications and allegations I thought to be little convincing when talking about monozygotic twins. Basically there exist two initial particularities: a severe biogenetic or genomic determinism restricted to the somatic characters of the animal dimension or unspecific consubstantial to the living creatures and with it to the Homo natura. At the same time there must exist another heredity of the same origin but with another sequence, a more "liberal" determinism, more "tolerating" who allows the practice of conditioned liberty regarding the specific human psychospitirual ability. Along with these two biogenetic possibilities with its potentials and the so-called "talents", an essential question mark arises: Who executes and conditions more directly all this genetic codification, in which way and with what limitations? (7). In any case these and other realities along with the conceptual and operating handicaps in relation with the eternal enigma of the "mutual relations" Body-Soul or "Black Box", undecipherable, of human beings (9), all this brings up the lack of a "link" between the unspecific somatic dimension -Genome-Brain and the specifically human or psychospiritual. Up to my understanding this intermediate link is settled in the individual personality, as I come founding from long ago on and in a recent publication with the expressive title of: "Spanish and Occidental Psychiatry in search of its lost link" (10,11,13). Convinced of this pressing need, when trying to do the necessary and previous schema or operating conception of that bidimensional personality, but from the medicalanthropological psychiatric point of view with new approaches, I found myself infrontof a first difficulty. The classical and erroneous doctrine of casualty had to be revised, investigated and overcome with Kausa aequat efectum; overcome the Aristothelic "substantial unity" Body-Soul and cartesian dualisms so as the simple "Psychogenie" of the so-called Psychosomatic Medicine, establish "functional frontiers"....(1.9.10). The other condition was the need to achieve a doctrine of casualty able to surpass the old and lineal casualty of Limneo among others. Precisely to this process the natura naturata or natura naturans owes its creative power almost to the infinite with scarce "primary material"; this process which can be qualified -and like that I published it at that time- as "trick of nature" or "okonomischer Trick der Natur"; this casualty is also valid for psychiatric pathology in mentioned sense. Some decades have passed and still I have had not the need to make modifications: the model, the basic and principal questions are still valid in the essential (1,11,14). CONCLUSIONS

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1) In models of the personality structure we should integrate all compounds of its bidimensional unity. 2) The individuality of the personality should - in theory and in praxis, be mantained recuring to tipological classifications as classic psychiatry does. 3) Models of personality should establish correlations between the dimensions of psychospiritual and biosomatic casualties, preserving its constitutive unity. 4) Models of personality should allow to establish "functional frontiers", real or virtual ones, between the specific and the unspecific of the psychiatric phenomena with didactic, therapeutic or operating aims, as much as in the praxis as in the field of research. 5) Models of personality should allow to delimit -at least virtually- the "cerebral participation" as an indispensable instrumental cause and of the biogenetic potential in relation to the psychic dimension, be it healthy or sane. 6) Models of personality should allow to delimit the action fields of the somatic conditioning and of pharmacological or psychotherapeutic treatments in the psychiatric disorders. 7) Models of personality should facilitate the comprehension of the influences of the changing historical-cultural process over the evolution of personality -healthy or ill- and over the individual gravity point and its displacement along different ages, periods and cultures in the biographical happening with possible mutations of the consciousness. It should also keep that permanent reality which Kant formulated with a certain sentence: "Man is always himself but never the same". 8) The model of Personality should be an open one to allow to integrate new scientific, clinical, anthropological findings without violating the bidimensional unity of man. 9) The present crisis of basic knowledge; the lack of a psychiatric pathology and of an integrating casualty with new approaches has led to various independent "psychiatries". The new contributions of neuroscience along with the lack of interest for the contributions regarding the human genome -as seen in the program of the 9th World Congress of Psychiatry- obliges me to recommend that it should be dealt with on the program of the next congress. REFERENCES: Llavero. R, Symptom und Kausalitat. Grundfragen der Neurologie und Psychiatrie. Thieme Verlag. Stuttgart, 1953. Llavero. R, Grundlinien und Grenze Einer Synthese der Psychiatrie. Pd. 1957-58. Revista de Psiquiatria y Psicologfa Medica de Europa y America Latina, 1958. Llavero. R, Nihilismo y Optimismo terapeiitico en Psiquiatria medico-antropologica. An. PSIQUIATRIA (Madrid). Vol. 8, N29, pp. 329-338. 1992. Llavero. F. y Conde V., Tratamientos medico-psiquiatricos (Criterios, fundamento y aplicacion). Liade, Madrid, 1971. Llavero. R, Bemerkungen zu einigen Grundfragen der Psychiatrie anlaslich der Besprechung meines Buches "Symptom und Kausalitat" durch RAUCH. Nervennartz 1957. Llavero. R, Derecho, Psiquiatria, Libertad y Determinismo. (Cuestiones de principio). Revista Juridica General. N22/1992. Marzo-Abril. Madrid.

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Llavero. F., Patologia psiquiatrica y Genoma Humano. Ambientalismo y Determinismo. ARAN. Madrid, 1988. Llavero. F., El psicopata. Noticias Medicas. Enero, 1969. Llavero. F., Cerebro, Genoma, Personalidad y SU "CAJA NEGRA". (Doctrina de la Causalidad y cuestiones de principio). En prensa. Llavero. F., Psiquiatria espaiiola y occidental en busca de SU "Eslabon perdido". "Medio siglo de Psiquiatria en Espana". Editorial ARAN. Libro del aiio. Madrid 1992. Llavero. F., La Personalidad desde el punto de vista medico-psiquiatrico. PSIQUIATRIA. Toray. A.A. Barcelona. Tomo I. 1982. Llavero. F., Bases epistemologicas de las ciencias psiquiatricas. Folia Clinica Intemacional. Tomo XX. N21. 1970. Llavero. F., Crisis doctrinal a nivel mundial. Grandeza y miseria de la Psiquiatria actual. Ciudad Sanitaria. Madrid, Nfi5. Enero 1977.

DEVELOPMENT OF THE CLASSIFICATION OF MENTAL DISORDERS INCORPORATED IN THE INTERNATIONAL CLASSIFICATION OF DISEASE NORMAN SARTORIUS MD PhD FRCPsych Professor ofPsychiatry University of Geneva Geneva, Switzerland T. BEDIRHAN USTUN, MD PD Scientist Division ofMental Health World Health Organization Geneva, Switzerland JENNI VAN DRIMMELEN* Psychiatrist Division ofMental Health World Health Organization Geneva, Switzerland

ABSTRACT The International Classification of Diseases (ICD) in its tenth revision makes provisions for the classification of all diagnostic statements used in medical care, reflecting changes in our views. Significant new knowledge has become available in the past decade and health service systems have changed. The classification is divided into 21 chapters, each dealing with a group of diagnoses. One of the chapters - Chapter 5 (F) is intended to cover mental and behavioural disorders. ICD-10 Centres, governmental and non-governmental organizations, and individual experts have jointly with the World Health Organization (WHO) created the classification of mental disorders in the ICD-10. The ICD-10 is an essential part of a common language in the field of mental health - a language that will allow all those concerned with improving mental health care. This paper describes the basic features of the new ICD-10 Mental Health Adaptation.

*Paperpresented on behalf ofHeads of WHO designated ICD-10/MNH training and reference centres and of WHO staff working on ICD-10 MNH related matters. A full list of heads of centres, ofother individuals who haveparticipated in the development ofthe classification and of WHO staff participating in this effort is to be found in the ICD-10Classification of Mental and Behavioural disorders: Clinical Descriptions and Diagnostic Guidelines and its compound volume: "Diagnostic Criteria for Research".

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The International Classification of Diseases (ICD) makes provisions for the classification of all diagnostic statements used in medical care. The classification is divided into 21 Chapters, each dealing with a group of diagnoses (e.g., Chapter 9 contains those describing diseases of the circulatory system). One of the chapters Chapter 5 (F) is intended to cover mental and behavioural disorders. It does that for most of the so-called psychiatric diagnoses: there are however numerous other diagnoses which mental health workers and others dealing with mental health will use, for example, attempted suicide, which is located in another part of the ICD, i.e. Chapter 20, categories X60 - X84. Chapter 5(F) is different from other chapters in the ICD in several respects. First, since the 8th Revision of the ICD** the Chapter dealing with mental disorders contains a brief definition for each category. The decision to include this glossary-like definitions was reached in view of studies demonstrating that the diagnostic categories used in psychiatry are being interpreted differently by different schools of thought and in different countries and because there were as yet no definite laboratory tests which could be employed to make a diagnosis. Second, the classifications of mental disorders in the 8th, 9th and in particular the 10th Revision of the ICD are results of major international research and development projects. The classification for the 8th revision was developed in the course of a WHO project involving scientists and public health workers from some 30 countries1,2,3. The project (WHO Programme on the Standardization of Psychiatric Diagnosis, Classification and Statistics) produced the proposals for the classification, glossary definitions for each category as well as methods for the exploration of the diagnostic and classificatory process. In addition the programme brought together leading experts and centres active in this field and thus created a network which remained in action until now. The proposals for the classification of disorders included in the 10th Revision of the ICD have resulted from a collaborative project involving the National Institute of Health of the USA, WHO and leading research centres in a number of countries4. This programme, developed over the past decade helped the development of the ICD-10 and produced materials supporting the use of the Classification. These materials include several internationally and transculturally applicable instruments for the assessment of the mental state and psychiatric history5,6,7 several lexica8 defining syndromes and symptoms which are used in the formulation of criteria and diagnoses and a series of training materials. A network of centres in different parts of the world continues to participate in this programme. The proposals for the ICD-10 did not contain only glossary definitions similar to those in the previous revisions: on this occasion each category was also provided with a full description of the conditions which are grouped in it. These descriptions provide information about the diagnostic entities and give instructions about the necessary and sufficient criteria for reaching a large number of diagnoses. Specific The ICD is periodically revised. In all there have been 10 revisions since the ICD was first published in 1893.

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instructions are also provided for the classification of diagnoses which have not been defined in the ICD-10 and for the handling of diagnostic statements couched in obsolete terms on patient records. The ICD-10 classification of mental disorders has several features which make it different from other classifications in existence. First, the classification has been produced in several equivalent versions for different categories of users. There is a version for clinicians, another for researchers, another for primary care personnel. There is doubt that in the future other groups of users might develop versions which would serve them best. The versions which are now released have been thoroughly tested9 and it is recommended that other versions which may be necessary pass through similarly rigorous tests. The classification has been developed in close collaboration with hundreds of investigators, worldwide: other versions, should they be proposed, will also involve the vast international network engaged in this work. Second, the ICD-10 has been produced in several languages at the same time. The translators were leading experts who have not only examined the linguistic equivalence of the texts but also signalled any parts of the proposals likely to lead to a lesser acceptance of the classification in their countries. The process of translation was thus immensely useful because it lead to the discovery of unclear or untranslatable passages, and allowed the incorporation of parts necessary to harmonize the proposals in the different languages with the psychiatric traditions in different countries. Third, the classification is accompanied with instruments for the assessment of the patients' mental state. These instruments contain provisions which allow computerized conversion of assessments into ICD categories10. Other instruments linked to the ICD-10 serve to assess quality of psychiatric care, and the impairment and disability related to mental illness*** n . Fourth, the training in the use of the classification and the monitoring of its use is entrusted to a network of WHO collaborating centres. These centres coordinate work of numerous other institutions in their language or influence area. They are also collecting experience in the use of the classification with a view to using this material in the forthcoming 11th revision of the classification. Fifth, the ICD-10 has established bridges - and hopes to strengthen them further - with various national groups working on national classifications of mental disorders (such as the American Psychiatric Association's task force which has developed the Diagnostic and Statistical Manuals - DSM HI and IV). This collaboration proved invaluable in the course of work on the ICD-10 because it brought leading scientists working on classification into contact with each other and enabled them to ensure that the results of their research are taken into account in the development of the classifications. Bridges are also being developed with classifications produced by other •*• The International Classification of Impairments, Disabilities and Handicaps is also produced by the World Health Organization. This classification will be revised in the period of 1995 - 1997.

178 professional groups active in the field of mental health (for example psychologists) and with those representing other social sectors (e.g., insurance schemes, social welfare agencies). The classification of mental and behavioural disorders included in the ICD-10 is a product of international collaboration in the best sense of the word and its usefulness in contributing to the creation of a common language for mental health workers worldwide is undoubted. It is to be hoped that the future will allow the continuation of this work and a further development of a common language in the field of mental health - of which the classification and definitions of mental disorders are so important parts. It is also to be hoped that the lessons learned in this work about ways to develop equitable collaboration in science will be used in many other endeavours, in the field of mental health and elsewhere. References 1.

Sartorius, N. "Classification: an international perspective". Psychiatric annals, 6:22-35 (1976).

2.

Kramer, M. et al. "The ICD-9 classification of mental disorders: a review of its developments and contents". Acta psychiatrica scandinavica, 59: 241-262 (1979).

3.

Sartorius, N. "WHO's work on the epidemiology of mental disorders". Social Psychiatry and Psychiatric Epidemiology, 28: 147 155 (1993).

4.

Jablensky, A. "Diagnostic and classification of mental disorders and alcohol- and drug-related problems: a research agenda for the 1980s". Psychological medicine, 13: 907-921 (1983).

5.

"Composite International Diagnostic Interview (CIDI) 1.1" Washington, DC, American Psychiatric Press Inc., (1993).

6.

Wing, J.K. et al. "SCAN: Schedules for clinical assessment in neuropsychiatry". Archives of general psychiatry, 47: 589-593 (1990).

7.

Loranger, A.W. et al. "The WHO/ADAMHA International Pilot Study of Personality Disorders: background and purpose". Journal of personality disorders, 5: 296-306 (1991).

8.

"Lexicon of psychiatric and mental health terms". Vol. 1. World Health Organization, Geneva, (1989) (second edition in preparation).

9.

Sartorius, N. et al. "Progress towards achieving a common language in psychiatry: results from the field trials of the clinical guideliens accompanying the WHO Classification of Mental and Behavioural Disorders in ICD-10". Archives of general psychiatry, 50: 115-124 (1993).

10.

"Psychiatric Disability Assessment Schedule (WHO/DAS)", World Health Organization, Geneva (1988).

11.

"International Classification of Impairments, Disability, and Handicaps". World Health Organization, Geneva (1980).

ICD-10 PRIMARY CARE VERSION FOR RECOGNITION AND MANAGEMENT OF MENTAL DISORDERS T. BEDIRHAN USTUN, MD PD Scientist Division ofMental Health World Health Organization Geneva, Switzerland NORMAN SARTORIUS MD PhD FRCPsych Professor ofPsychiatry University of Geneva Geneva, Switzerland in collaboration with Collaborating investigatorsfromParticipating Centres*

ABSTRACT Primary Care Version of International Classification of Diseases (10th Revision) Chapter V. for Mental and Behavioural Disorders (ICD-10 PHC) lists on 24 conditions which are frequently seen in primary care and which can be managed effectively by general practitioners. It has been developed in the light of experience of primary care physicians. The classification is accompanied by one flipcard for each of the categories. The cards contain diagnostic guidelines on one side and management guidelines on the other. The applicability and acceptability of the draft ICD-10 PHC is being tested in more than 100 centres from some 50 countries. The trials will generate data about: (i) the applicability and usefulness, (ii) reliability and validity (in) appropriateness of the ICD-10 PHC for primary care practice. Initial results suggests that ICD-10 PHC version will be an important support to health care worldwide. Primary care physicians have found the classification useful in busy primary care settings and attractive. They raised the novelty of the approach that brings the management of mental health problems together with concise practice guidelines and links them to a statistical classification.

*Several Investigators contributed to the development of ICD-10 PHC. They are listed in the ICD-10 PHC printed version. Among the Advisory Group Members were: J Banda (Zambia), E. Busnello (Brazil), J.E. Cooper (UK), N. Dedeolu (Turkey), M.P. Deva (Malaysia), D. Goldberg (UK), O. Gureje (Nigeria), C. Hunt (Australia), C. Pull (Luxembourg), D. Roy (Canada), G. Simon (USA), M. Von Korff(USA), N. Wig (India); J. Gonzales, K Magruder, G. Norquist (NIMH/USA) andDrsJ.van Drimmelen, H.M. Kahssay, M. Leonardi, A. UHours, andH. Sell (WHO).

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Most people with psychological disorders that occur in the community do not reach specialist care1. Their recognition and management in primary health services is of great public health importance. At present however this is not happening: while psychological disorders (i.e mood, anxiety and somatoform disorders and neurasthenia) are very frequent in general health care attenders, only one half of them are recognized by health care providers2,3. This indicates the need to provide primary care workers with practical tools to improve recognition and management. The World Health Organization (WHO) has therefore, developed a Primary Care Version of International Classification of Diseases (10th Revision) Chapter V. for Mental and Behavioural Disorders (ICD-10 PHC)4 Existing classifications for mental disorders are of limited use for primary health care (PHC) workers (including physicians).5 These are perhaps appropriate for psychiatrists or researchers, however they are "unreasonably complex" for the busy primary health care clinicians. On average all over the world, PHC physicians can only spend ten minutes or less with a patient. Within this period they have to identify the problem, recognize the disorder(s) and explain the treatment. Materials which are intended to help them in dealing with any set of problems should be brief, easy to use in daily practice and contain familiar terms. A useful classification of disorders whioch is intended for use in primary care must also focus on only a limited number of conditions. The following criteria were used for inclusion in selecting the categories in the ICD-10 PHC: 1.

Public health importance: a. The condition is encountered frequently in primary care b. The amount of sickness and number of deaths associated with the condition is high c. Functional impairment for those with the condition is high so they are a burden on family or society. d. Public concern about the condition: conditions which are perceived by people as "a problem" and "a problem with a solution". e. health care resources are needed to help people with the condition.

2.

Availability of effective and acceptable management for these disorders:

3.

Existence of a reasonable consensus among psychiatrists and primary care physicians regarding the diagnosis and management of the condition.

4.

applicability in different PHC settings and cultures

The resulting ICD classification of mental disorders for the PHC is shown in table I

181 Table I. ICD-10 PHC List of Categories

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

FOO*

Dementia

F05 F10

Delirium Alcohol Use Disorders Drug Use Disorders Tobacco Use

Fll* F17.1 F20* F23*

F31

Chronic Psychotic Disorders Acute Psychotic Disorders Bipolar Disorder

F32*

Depression

F40* F41.0 F41.1

Phobic Disorders Panic Disorder Generalized Anxiety

F41.2

Mixed Anxiety And Depression

F43* F44*

Adjustment Disorder Dissociative Disorder (Conversion Hysteria)

F45

Unexplained Somatic Complaints Neurasthenia Eating Disorders Sleep Problems Sexual Disorders Mental Retardation

F48.0 F50* F51*

F52 F70 F90 F91 F98.0

Hyperkinetic (Attention Deficit) Disorder Conduct Disorder Enuresis

Categories accommodating other diagnoses will be added for coding purposes in the process of finalization of the ICD-10 PHC. When a code is followed by an asterix, this means that more than one codes of ICD10 Chapter V F are included; e.g. FOO* includes FOO - F04.

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These 24 conditions are presented on flipcards one for each of the conditions6. The cards contain diagnostic guidelines on one side and management guidelines on the other. The diagnostic information is given in the following format: 1. Presenting complaints - problems typically seen in primary care patients. 2. Diagnostic features - a concise representation of main ICD-10 diagnostic guidelines 3. Differential diagnosis - listing of other medical or mental conditions which show a similar presentation and need to be considered in diagnosis. In order to improve patient care and encourage general practitioners to use the new classification, each diagnosis is accompanied by a proposal for management which follow a consistent format: 1. Essential information for patient and family. General knowledge about the disorder such as the nature or cause of mental disorders given as general health education. 2. Specific counselling for patient and family: Advice and psychotherapeutic strategies concerning particular condition: how to cope, what to do. 3. Medication - Advice on the use of drugs (how to use, when to use, side effects, ways to increase compliance). 4. Specialist Consultation - indication on when and how to refer to a specialist. Support Tools for using the ICD-10 PHC: Row-charts: Several flow-charts accompany the PHC classification. They are intended for use during the everyday work of general practitioners and in their training. They lead the physician to the card which should be used. Symptom Index: is a guide for differential diagnosis. This provides different entry points to the classification system (e.g. differential diagnosis for key symptoms such as appetite loss, tiredness, insomnia, anxiety, fears, inattention, and so on). Patient Leaflets: To explain the disorder and its management to the patients and their families the ICD-10 PHC proposes the local production of patient leaflets which can be given to patients at the end of a consultation.

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Field Tests: The draft ICD-10 PHC has been tested for applicability and acceptability. Many centres from different countries participated in the ICD-10 PHC field trials to obtain data about: (i) the applicability and usefulness, (ii) reliability and validity (iii) appropriateness for primary care practice. The field trials will enable us to make further modifications to the ICD-10 PHC in the light of experience of its application in primary care. National Applications: The development of a universally applicable primary care management guidelines is very difficult because of vast differences in levels of primary care in different countries. The current system provides a model which can be used in presenting essential information. Information appropriate to specific countries should always be presented as a result of collaboration between primary care organizations and mental health workers. Future Work: Additional tools such as screening tests or evaluation instruments may be developed on the basis of experience gained in the use of Primary Care Version of CIDI (Composite International Diagnostic Interview)2. A brief training manual may also be developed based upon experience from the field trials. In view of the increasing role of computers in the primary health care settings, WHO is also exploring possibilities of developing a simple computerized expert system to help the PHC physicians in making their diagnoses, and providing information necessary for their decision making.

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References: 1.

Regier, D. Narrow, W.E. Rae, D.S. Manderscheid, R.W. Locke, B.Z. Goodwin, F.K., "The de Facto US Mental and Addictive Disorders Service System. Epidemiological Catchment Area Prospective 1-year Prevalence Rates of Disorders and Services". Arch of Gen Psychiatry 50,8594 (1993)

2.

Sartorius, N. OstUn, T.B. Silva, A. Goldberg, D. Lecrubier, Y. Ormel, J. Von Korff, M. and Wittchen, H., "An International Study of Psychological Problems in Primary Health Care" Arch Gen Psychiatry 50, 819-824 (1993)

3.

Goldberg D and Huxley P. "Common mental disorders - a biosocial model" . London: Routledge 1992.

4.

World Health Organization,. "ICD-10: The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines". Geneva: WHO, (1992).

5.

Goldberg, D., "A Classification of Psychological Distress for Use in Primary Care Settings" Soc Sci Med 54(suppl), 33-38 (1993)

6.

OstQn, T.B. Cooper, J£. Goldberg, D. Simon, G. Sartorius, N. "A New Classification for Mental Disorders with Management Guidelines for Use in Primary Care" Brit. J .General Psychiatry (in press)

ISSUES ON FORENSIC PSYCHIATRY EPIDEMIOLOGY J. ARBOLEDA-FLOREZ MD, FRCP(C), PhD Dept. of Psychiatry, University of Calgary, Calgary General Hospital, 841 Centre Av. E. T2E 0A1 Calgary, Alberta, Canada

E J . LOVE MD, FRCP(C), PhD Dept. of Community Health Sciences, University of Calgary, Health Sciences Centre, 3330 Hospital Drive Calgary, Alberta, Canada ABSTRACT This paper comments on the validity of forensic epidemiological studies and focuses on the difficulties in the use of some instruments to conduct such studies. Specifically, the study reviews the shortcomings of the DIS and the SCID. The authors state that an appropriate epidemiological instrument is still needed in forensic psychiatry and proposes some characteristics that such instrument should possess.

INTRODUCTION Research methodologies originally developed for a particular scientific purpose are often used by other sciences and applied in different research contexts. Blending and borrowing of research methodologies among sciences contribute to cross-fertilization and bring new freshness and insights when approaching researchable problems. For example, epidemiology, defined as "a basic medical science that studies the distribution and determinants of health-related states and events in specified populations and the application of this study to the control of health problems,"1 has benefitted, and has successfully made use of methods for large population surveys and sampling techniques as developed by sociology. Equally, methodologies traditionally associated with epidemiological studies are finding their way into other areas of research in the social and behavioural sciences. Casecontrol methodologies, for example, are now being successfully adapted to the study of criminological problems2 and the "epidemiological approach" has been advocated in criminology.3 Conversely, the use of cross-sectional, retrospective and prospective longitudinal methods, and ecological and areal methodologies are used extensively in both epidemiology4,5 and criminology.6'7 Epidemiology and criminology are now cooperating closely on issues of violence whose incidence and prevalence have made it a "social epidemic."8'9 In this paper, the authors wish to review some issues pertaining to forensic psychiatry research, specifically the use of epidemiological methodologies and instruments in forensic psychiatry, and draw attention to facts that, in their opinion, would affect the quality of such research.

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In addition, the authors will present some very preliminary comments regarding the use of two particular instruments, the DIS and the SOD, 10 the latter having been chosen by the authors to conduct a research project in a forensic sub-population. FORENSIC PSYCHIATRY RESEARCH Forensic psychiatry, or the branch of psychiatry that deals with the interface between psychiatry and the law, draws heavily from knowledge gained in psychiatry, and in justice and criminology. As a subspecialty in medicine, forensic psychiatry would have been expected to have drawn as heavily from epidemiology. Traditionally, though, forensic psychiatry research has focused on medico-legal matters such as fitness to stand trial or the insanity defense,11 and aspects of mental health legislation1213 that, because of jurisdictional definitions, tend to have a circumscribed geographical application. Other research has been oriented more towards criminological issues such as the classification of dangerous sexual offenders and the extensive research on the prediction of dangerousness.141516,17 Forensic psychiatry researchers have also dedicated effort and resources to the study of the relationship between crime and mental illness,1819'20,21 and to neurobiological correlates especially in relation to the study of violence.22 The use of epidemiological methodologies in forensic psychiatry research, however, is rather new vintage. In fact, it is only over the past two decades that these methodologies have given forensic researchers new insights into the usefulness of population-based studies to bring empirical evidence to the understanding of forensic problems. These studies have ranged from pre-trial assessments23,24 to the violent offender25 and deinstitutionalization,2627 from competency28 to commitability29 and psychiatric expertise,30 and from the prevalence and incidence of mental disorders among criminal populations31 to the treatment of the mentally ill offender.32 All of these studies can be placed under the rubric of epidemiological studies in as much as their common characteristic is the use of epidemiological, population-based research techniques.

CRITICISM OF FORENSIC EPIDEMIOLOGICAL STUDIES Apart from the methodologies, some of these studies are also making use of instruments that have been developed for the study of the prevalence of mental conditions in the general population, especially the Diagnostic Interview Schedule, DIS. This instrument has given a major impetus to psychiatric epidemiology in that, for the first time, through its use, it has been possible to use lay interviewers for large scale epidemiological studies in psychiatry. The DIS was developed by the National Institute of Mental Health in the United States, and is a well-tested, valid, and reliable semi-structured interview33 that allows researchers to estimate one-month, six-month, and life-time prevalence of a large number of mental disorders as diagnosed through the DSM-III-R.34

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As the DIS has become the standard for large scale epidemiological studies of the prevalence of mental disorders, its use has also been advocated among forensic populations).20,35,31 The use of epidemiological techniques or instruments, however, do not convey the rigour required in true epidemiological studies. Unfortunately, many forensic studies lack that rigour and fail to take into account, and to control for, potential biases such as selection, information, and misclassification, and most importantly, confounding factors. Apart from having been conducted in highly specialized institutions, thus precluding generalizability because of berksonian bias,36 many of these studies are based on case series, consecutive admissions, or opportunistic samples, hence they are prone to many threats to their scientific validity. Furthermore, many of these studies are also based on small samples that do not furnish enough power to make appropriate statistical analysis, and some do not provide standardization rates that would allow for comparability to specific sectors of the general population. Finally, a number of these studies have made liberal use of the DIS, an instrument which as indicated above, was designed for prevalence studies in large populations. The DIS, however, is not without problems; its ability to measure one month prevalence has been put into question, and it also seems to miss some major disorders such as paranoid disorders, atypical psychosis, and brief reactive psychosis.37,38 Regarding Axis II conditions, the DIS measures only Antisocial Personality, not the other eleven types given in the DSM-III-R.10 Flaws of this nature would render the DIS irrelevant for use among forensic populations, especially those at remand centres (jails), where pathology may include short-length adaptational reactions, or brief decompensation psychoses. These may be missed by the DIS. In addition, the DIS would also miss paranoid disorders, atypical psychoses, some non-antisocial personality disorders, and special forensic pathology such as kleptomania, intermittent explosive disorders, pyromania, and a proper diagnostic breakdown of paraphilias. As some of these conditions may cluster in particular correctional institutions, the setting in which the research project is conducted will have a major effect on the results. Because the DIS relies on the subject's report of symptoms to a lay interviewer who may not have sufficient clinical skills to perceive the faking or challenge the statement, this may cause problems with respect to its validity. It is not unusual for criminal populations to misrepresent symptoms (under-reporting or over-reporting), especially those with antisocial personalities and substance abuse disorders.39 Among these populations, a selfreport may not be the best instrument to use. Worse, the diagnosis of antisociality poses problems for the DIS in the same way as it does for the DSM-III-R. The diagnosis of antisocial personality disorder on the DSM-III-R has a circular definition with criminality. Despite the disclaimer that this diagnosis not be made on a history of crime alone, the majority of the diagnostic elements pertain to unlawful and punishable behaviour which is criminal, hence practically all inmates in a correctional institution could be diagnosed as suffering from an antisocial personality disorder. This fact would immediately inflate any

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estimates of prevalence of mental disorders in prisons. Under-representation of some disorders, and over-representation of others in the DIS are major drawbacks that should preclude the use of this instrument among criminal forensic populations. From the ethical point of view, and at a different level of discourse, it should also be mentioned that epidemiological studies in forensic psychiatry often deal with value-laden concepts. "Ideologies of error"40 are the extent to which a belief system within the text of a study drives the motivation of the researchers to undertake the study and colours what would, then, be the expected outcomes. Thus, "ideologies of error" would act as true ethical confounders, that is, the beliefs of the researchers would impinge on the exposure of the variable to be measured, and have an impact on their outcome. Related to these ethical considerations is also the fact that some epidemiological methodologies tend to rely heavily on databases, which at times would be advisable, or even required for research purposes, to link. Linking of databases may present major threats to the ethical validity of research projects in epidemiology, and especially more so in forensic because prisoners are by definition classified within the group of vulnerable subjects. The need, therefore, is pressing in forensic epidemiology to make sure that accepted ethical international standards for epidemiological studies are properly adhered to.41 COMMENTS ON THE USE OF THE SCID In a research study whose results are presently under analysis, the authors conducted a study among a population of remanded offenders. Given all of the difficulties already described regarding the most commonly used instrument in this kind of studies, the DIS, the authors chose to use the SCID or Structured Clinical Interview for DSM-III-R.10 This instrument was developed by a special grant of NIMH and allows to make diagnoses on Axis I and Axis II of DSM-III-R. As such, it does have an immediate advantage over the DIS in that, having an Axis II capability, it could capture personality disorders which the DIS misses entirely. The SCID has been proposed as an appropriate instrument for use in community surveys, and to characterize a study population in terms of current and past psychiatric diagnosis. The SCID has been considered reliable and valid, and has to be administered by a trained clinician who is also familiar with DSM-III-R classification and diagnostic criteria. Although the instrument was easy to administer, it was obvious that the SCID also fell short of the requirement for an exhaustive list of commonly seen conditions among forensic populations. These included the acute intoxications, paraphilias, dissociative reactions, impulse control disorders, and mental retardation. The SCID does not allow either for a diagnosis of dementia. These diagnoses had to be implemented and recorded among "Other Axis I Diagnosis" (not included in the SCID algorithms). The SCID falls short also on the exploration of suicidal and homicidal ideas and in a detailed family history of alcoholism (these are important aspects to be considered in forensic diagnosis).

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Although one of the advantages of the SCID over the DIS for forensic work is the inclussion of an Axic II module, The SCID diagnosis of antisocial personality disorder shares the same problems already described for the DIS diagnosis. Both are based on DSM-III-R behavioural dimension and circularity with criminality. To deal with that deficiency in the SCID, it was necessary to use a complemetary scale, the Hare Psychopathy Checklist,42 which is on a dimension of intrapersonal dynamics. An important element to be considered in forensic diagnosis is whether the symptoms started before or after the offense charged. This question, which is independent of the one-month or six-month prevalence, is of major importance in forensic psychiatry. It had to be added to the questionnaire. Minor problems arose with some of the questions of the SCID, in particular the "persecution question" number 18 of the Psychotic Screening B/C. 1 ("What about anyone going out of the way to give you a hard time, or trying to hurt you?"). This question is intended to elicit feelings about "being attacked, harassed, cheated, persecuted, or conspired against". Realistically, forensic subjects are under investigation by the police, and most feel the police are out to get them, and they feel harassed and persecuted. As expected, in a criminal population, it would be difficult to elicit a paranoid construct from this question, untinged by the reality of the situation. Question 18, therefore, required much clarification during the interviews. Finally, the interviewers felt that the structured qualities of the SCID create certain rigidity that could easily throw the interviewer into a mechanical question-answered based diagnosis, and which consequently has to be defended against in order to provide a modicum of personal interaction.

THE NEED FOR A NEW EPIDEMIOLOGICAL INSTRUMENT IN FORENSIC Given the many drawbacks for the use of the DIS in forensic epidemiology, and the fact that the SCID, which needs clinically trained interviewers and is, therefore, too expensive to use in large scale studies, needed to be complemented with other diagnoses considered essential in forensic work, a need exits to develop a reliable and valid instrument for epidemiological studies in forensic psychiatry. Such an instrument should have the following characteristics: 1)

like the DIS, it should allow for diagnosis to be made by lay-interviewers,

2)

it should be exhaustive in terms of comprehending not only ordinary psychiatric conditions, but also those that are most commonly expected among forensic populations,

3)

be forensic setting-free, so that it could be used in different forensic facilities (from remand centres to maximum security hospitals and penitentiaries),

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4)

like the MMPI,43 it should have an L Scale, or a mechanism to gauge in some way the veracity of the reporting, and

5)

it should have a diagnosis of antisocial personality disorder independent from the existence of criminality.

If forensic psychiatric epidemiology is to advance further, researchers in the area should consider the need to develop an appropriate instrument a matter of priority. Without such an instrument even simple questions like the total prevalence and condition-specific prevalence of mental disorders among forensic populations, and investigations into the relationship between specific conditions and criminality, will defy a proper answer. REFERENCES 1

Last, J.M. and Wallace, R.B. (eds). Public Health & Preventive Medicine, 13th ed., Norwalk: Appleton and Lange (1992).

2

Goodman, R.A., Mercy, J.A., Layde, P.M., and Thacker, S.B., "Case-Control Studies: Design Issues for Criminological Applications", Journal of Quantitative Criminology, 4:71-84 1988).

3

Monahan, J. and Stead man, H.J., "Crime and Mental Disorder: An Epidemiological Approach". In M. Tonry and N. Morris Crime and Justice - An Annual Review of Research, Vol 4, Chicago: The University of Chicago Press (1983).

4

Rothman, K.J., Modern Epidemiology, Toronto: Little, Brown, and Company (1986).

5

Arboleda-F16rez, J. and Holley, H.L., "Antisocial Burnout: An Exploratory Study". Bull Am Acad Psychiatry and Law, 19(2): 173-183 (1991).

6

Baldwin, J., "Ecological and Areal Studies in Great Britain and the United States". In N. Morris and M. Tonry Crime and Justice - An Annual Review of Research, Vol 1, Chicago: The University of Chicago Press (1979).

7

Farrington, D.P., "Longitudinal Research on Crime and Delinquency". In N. Morris and M. Tonry Crime and Justice - An Annual Review of Research, Vol 1, Chicago: The University of Chicago Press (1979).

8

Freed man, D.X., "Violence (and a Message for the 90s?)". Editorial. Arch Gen Psychiatry, 49:485486 (1992).

9

Eichelman, B., "Aggressive Behaviour: From Laboratory to Clinic - Quo Vadit?" Arch Gen Psychiatry, 49:488-492 (1992).

10

Spitzer, R.L., Williams, J.B.W., Gibbon, M., First, M.B., Structured Clinical Interview for DSMlll-R. Washington DC: American Psychiatric Association Press (1990).

11

Roesch, R. and Golding, S.L., Competency to Stand Trial. Chicago: The University of Chicago Press (1980).

191 12

Millar, R.D. Involuntary Civil Commitment of the Mentally III in the Post-Reform Era. Springfield, ILL: Charles C Thomas (1987).

13

Holley, H.L. and ArboIeda-F16rez, J. "Criminalization of the Mentally 111: Part I. Police Perceptions". Canadian Journal of Psychiatry, 33:81 -86 (1988).

14

Moore, M.H., Estrich, S.R., McGillis, D., Spelman, W., Dangerous Offenders. The Elusive Target of Justice. Cambridge: Harvard University Press (1984).

15

Webster, C D . , Ben-Aron, M.H. and Hucker, S.J, Dangerousness. Cambridge: Cambridge University Press (1987).

16

Steadman, H.J., "The Prediction of Criminal Violence". In F.N. Dutile and C.H. Foust (eds) The Prediction of Criminal Violence. Springfield, ILL: Charles C Thomas (1987).

17

Hall, H.V. Violence Prediction. Springfield, ILL: Charles C Thomas (1987).

18

Guze, S.B., Criminality and Psychiatric Disorders. New York: Oxford University Press (1976).

19

Gunn, J. "Criminal Behaviour and Mental Disorder". British Journal of Psychiatry. 130:317-329 (1977).

20

Abram, K.M. "The Effect of Co-occurring Disorders on Criminal Careers: Interaction of Antisocial Personality, Alcoholism, and Drug Disorders". International Journal of Law and Psychiatry, 12:133-148(1989).

21

Hodgins, S., "Mental Disorder, Intellectual Deficiency, and Crime. Evidence From a Birth Cohort". Arch Gen Psychiatry, 49:476-483 (1992).

22

Mednick, S.A., Pollock, V., Volvka, J., Gabriell., Jr. W.F., "Biology and Violence". In M.E. Wolfgang and N.A. Weiner Criminal Violence. Beverley Hills: Sage Publications (1982).

23

Webster, C D . , Menzies, R.J., Jackson, M.A. Clinical Assessment Before Trial. Toronto: Butterworths (1982).

24

Menzies, R.J. Survival of the Sanest. Order and Disorder in a Pre-Trial Psychiatric Clinic. Toronto: The University of Toronto Press (1989).

25

Toch, H., and Adams, K., 77?*? Disturbed Violent Offender. New Haven: Yale University Press (1989).

26

Teplin, L.A., "Criminalizing Mental Disorder - The Comparative Arrest Rate of the Mentally 111". American Psychologist. 794-803 ( July, 1984).

27

Hiday, V.A., Scheid-Cook, T.L., "Outpatient Commitment for 'Revolving Door' Patients: Compliance and Treatment". The Journal of Nervous and Mental Diseases. 179(2):83-88 (1991).

28

Appelbaum, .PS., Roth, L.H. "Clinical Issues in the Assessment of Competency". Am J Psychiatry, 138(11): 1462-1467 (1980).

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Schwartz, H.I., Appelbaum, P.S., Kaplan, R.D. "Clinical judgements in the decision to commit: Psychiatric discretion and the law". Arch Gen Psychiatry, 41:811-815 (1984).

30

Ennis, B.J., Litwack, T.R. "Psychiatry and the presumption of expertise: Flipping coins in the courtroom". California Law Review, 62:693-752 (1974).

31

Bland, R.C., Newman, S.C., Dyck, R.J., Om, H., "Prevalence of Psychiatric Disorders and Suicide Attempts in a Prison Population". Can J of Psychiatry, 35:407-413 (1990).

32

Gunn, J, Robertson, G., Dell, S., Way, C. Psychiatric Aspects of Imprisonment. London: Academic Press (1978).

33

Robins, L.N., Helzer, J.E., Croughan, J., Ratcliff, K.S. "The NIMH Diagnostic Interview Schedule: Its History, Characteristics and Validity". Archives of General Psychiatry, 38:381-389 (1981).

34

American Psychiatric Association Committee on Nomenclature and Statistics, Diagnostic and Statistical Manual of Mental Disorders - DSM-IU-R. Washington DC: American Psychiatric Association Press (1987).

35

Cote\ G., Hodgins. S., "Co-Occurring Mental Disorders Among Criminal Offenders". Bull Am Acad Psychiatry Law. 18(3):271-281 (1990).

36

Berkson, J. "Limitations of the Application of Fourfold Table Analysis to Hospital Data." In S. Greenland (eds), Evolution ofEpidemiologic Ideas: Annotated Readings on Concepts and Methods. Chestnut Hill, MA: Epidemiology Resources Inc. (1946)

37

Anthony, J.C., Folstein, M., Romanoski, A.L., Von Koff, M.R., Nestadt, G.R., Chahal, R., Merchant, A., Brown, C.H., Shapiro, S., Kramer, M., Gruenberg, E.M., "Comparison of the Lay Diagnostic Interview Schedule and a Standardized Psychiatric Diagnosis". Arch Gen Psychiatry, 42:667-675 (1985).

38

Wittchen, H.U., Sender, G., von Zerssen, D. "A Comparison of Two Diagnostic Methods". Arch Gen Psychiatry, 42:677-684 (1985).

39

Alterman, A.I. and Cacciola, J.S. "The Antisocial Personality Disorder in Substance Abusers: Problems and Issues". The Journal of Nervous and Mental Diseases, 179(7):401-409 (1991).

40

Tancredi, L.R. and Weisstub, D.N., "Ideology and Power: Epidemiology and Interpretation an law and Psychiatry". In L Ramanucci-Ross, DE Moerman, LR Tancredi (eds), The Anthropology of Medicine. New York: Bergin & Garvey (1991).

41

CIOMS (Council for International Organizations of Medical Sciences): International Guidelines for Ethical Review of Epidemiological Studies. Geneva: CIOMS (1991).

42

Hare, R., "Comparison of Procedures for the Assessment of Psychopathy", J Consul Clin Psychol, 53:7-16 (1985).

43

Carr, A.C., "Psychological Testing of Personality". In HI Kaplan and BJ Sadock Comprehensive Textbook of Psychiatry/TV, Vol I, 4th edt. Baltimore: Williams & Wilkins (1985).

PSYCHIATRIC SCREENING INSTRUMENTS FOR CHILDREN AND ADOLESCENTS CARLOS E. BERGANZA, INGRID GAITAN and LUCfA CAZALI Universidad Francisco Marroquin & Clinica de Psiquiatria Infantil Guatemala, Guatemala CA. and JUANE.MEZZICH University of Pittsburgh 3811 O'Hara Street Pittsburgh, PA 15213, USA. ABSTRACT Quality of care in mental health for children depends, not only on specialized mental health services, but also on how effectively primary care providers identify, treat and refer children with emotional and behavioral problems. There is evidence that the utilization of screening devices for different psychosocial problems increases the primary care practitioner's attention upon such problems, and improves their detection. This is a review of some of the efforts that have been made across countries in order to provide primary care workers with assessment devices for child psychiatric disorders. Data on the empirical validation of The Children's Health Scale, a screening device for use in primary care facilities, are discussed.

Primary care facilities are of critical importance in the delivery of mental health services,1 and a resource for epidemiological studies in child psychiatry address at: a) estimating the prevalence of disorders; b) identifying correlates of those disorders; and c) estimating the number of affected individuals for planning of services.2 Detection of emotional or behavioral disorders by the primary care services fall well below its real prevalence, in industrialized,3 as well as developing4 countries. Using a short screening scale Giel et. al.4 concluded that mental disorders are common among children attending primary care facilities and that adults taking care of them readily recognize and report common psychological and behavioral symptoms when explored through a simple set of questions. The need to increase the sensitivity and specificity of the primary care worker in the detection of psychosocial disorders has led to the development of a number of screening devices.5,6'7'8'9 Two important developments have improved the quality of research in this field: a) the refinement in case ascertainment and definition; and b) the use of the multimethod-multistage approach,10 using first screening scales,11'12'13 and then, semistructured or structured interviews, as way of determining categorical diagnosis.10 Three types of screening scales are more frequently used in community-based studies of child psychopathology: the Rutter Scales,14 The Child Behavior Checklist,6 and problem checklists designed to detect specific "functional" disorders (e.g., the Ontario Study,15 and the WHO Collaborative Study4). A good example of a screening device with a categorical approach based on modern taxonomic criteria is The Stony Brook Child Psychiatric Checklist? A different approach is used by The Pediatric Symptom Checklist (PSC).9 Through an empirically defined cut-off point, the PSC identifies dysfunctional children likely to benefit from further psychiatric evaluation.9 The definition of a case in psychiatric epidemiology requires more than just the fulfillment of specific diagnostic criteria, and includes considerations of severity, either of the symptoms as measured by the scale itself,11 or by degree of dysfunction, as measured

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by scales of adaptive functioning, such as the Children's Global Assessment Scale (CGAS) 16 17 « . Thus, the use of most of this scales results rather time-consuming for the normally strained primary care personnel of child services, and the provision of screening devices of easy applicability and time saving seems a real need. In an effort to fill this gap, especially critical in Spanish-speaking countries, Berganza, Mezzich and others18*19 developed in Guatemala two screening devices for use in the primary care setting: The Children's Health Scale and The Children's Problems Inventory The former is addressed at differentiating case from no case and the latter offers primary care workers criteria of discrete diagnostic categories of childhood psychopathology. The present study assesses the validity and reliability of the Children's Health Scale in a sample of Guatemalan urban subjects.

METHOD The Children Health Scale (CHS) is based on six " ^^"assessed by the current taxonomic systems in child psychiatry, and basic in the everyday diagnostic practice. Table 1 summarizes the axes and the criteria selected as item content for The Children's Health Scale. Table 1. Item Selection for The Children's Health Scale I.

II. III.

IV. V. VI.

Signs and Symptoms: Behaviors: Home, School. Other Physiological Functions: Sleep, Eating, Elimination Emotions: Depression, Anxiety Developmental Problems: Learning Physical Symptoms Pain, Nausea, Other Stressors: Losses, Trauma Global Functioning: School, Home, Social Perceived Need for Help: Caretaker's Perception

In order to assess the diagnostic accuracy of this instrument, a study was carried out in Guatemala City with a sample of 1820 subjects from three groups: a) Psychiatric, b) Pediatric, and c) School, respectively. Psychiatric Group: Composed by 100 consecutive admissions to Clinica de Psiquiatria Infantil. All presented at least one Axis I diagnosis from current taxonomic systems20*21. Pediatric Group: Composed by 147 subjects attending a private pediatric clinic. It included those attending for well-baby care, as well as those with somatic disorders such as epilepsy, asthma, and infectious diseases. School Group: Composed by 1573 preschool, elementary, and high school students, from three socioeconomic levels similar to those of the psychiatric and pediatric samples.

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Exclusion Criteria for the Pediatric and School Groups: In order to select a sample of "true negatives" as controls, the pediatric and school groups were subjected to several exclusion criteria: a) parents refused to participate voluntarily in the survey; b) the child was attending at the time of the survey or had attended during the previous year a psychiatric or psychological service; c) the child was receiving or had received during the previous year, some kind of special education or remedial therapy for learning difficulties; and d) the child presented mental retardation, autism, developmental disorders or "a mental disorder". instrument. The Children's Health Scale* : A 12-item self-applied scale to be filled by the parents or the child's guardian, and designed to measure levels of psychosocial dysfunction, based on conventional criteria used in the current taxonomic systems of child and adolescent psychopathology.

Procedure and Environment Parents of the Psychiatric Group completed the questionnaires as a routine assessment procedure of the Clinica de Psiquiatria Infantil. Parents of the Pediatric and School groups were invited to participate voluntarily and anonymously, and received a package containing the scale and instructions to filled it.-

RESULTS Mean age for the total sample was 9.71 years (SD = 3.74; range 1-20). The Pediatric Group was significantly younger than the other two (X2 [6]= 100.2, pleft) is associated with better neuropsychological performance (26). Finally, the inverse correlation between negative symptoms and lateral ventricles volumes confirm previous CT observations of the existence of a subgroup of schizophrenic patients characterized by a defective form of the disorder associated with cerebral structural damage (27, 28) Given the theoretical interest of the associations found between brain morphological characteristics and some of the core features of schizophrenic psychopathology, these results warrant further analysis and replication.

271 REFERENCES 1. Degreef, G., Ashtari, M., Bogerts, B., Barenstein, M , Lieberman, J. "Volumes of Ventricular System Subdivisions Measured from MRI in First-Episode Schizophrenic Patients", Arch. Gen. Psychiatry 49, 531-538 (1992). 2. Lieberman, J., Bogerts, B., Degreef, G., et al, "Qualitative Assessment of Brain Morphology in Acute and Chronic Schizophrenia", Am. J. Psychiatry 149, 784-794 (1992). 3. Suddath, R.L., Casanova, M.F., Goldberg, T.E., et al, "Temporal Lobe Pathology in Schizophrenia: a Quantitative Magnetic Resonance Imaging Study", Am. J. Psychiatry 146, 464-472, (1989). 4. De Lisi, L.E., Hoff, A.L., Schwartz, J.E., et al, "Brain Morphology in First Episode Schizophrenic-like Psychotic Patients: a Quantitative Magnetic Resonance Imaging Study", Biol Psychiatry 29, 159-175 (1991). 5. Zipursky, R.B., Kelvin, O. L., Sullivan, E.V. et al, "Widespread Cerebral Gray Matter Volume Deficits in Schizophrenia", Arch. Gen. Psychiatry 49, 195-205 (1992). 6. DeMyer, M.K., Gilmor, R.L., Hendrie, C.H., et al, "Magnetic Resonance Brain Images in Schizophrenic and Normal Subjects: Influence of Diagnosis and Education", Schizophrenia Bull. 14, 21-37 (1988). 7. Shenton, M.E., Kikinis, R., Jolesz, F.A., et al, "Abnormalities of the Left Temporal Lobe and Thought Disorder in Schizophrenia", New Engl. J. Med. 327, 604- 612 (1992). 8. Rossi, A., Presented at the Study Group on Language Development and its Anatomical Templates, ACNP Meeting, Puerto Rico, 10-14 December 1992. 9. Besson, J.A.O., Corrigam, F.M., Cherryman, G.R. et al, "Nuclear Magnetic Resonance Imaging in Chronic Schizophrenia", Br. J. Psychiatry 50, 161-163 (1987). 10. American Psychiatry Association, "Diagnostic and Statistical Manual of Mental Disorders. Ill Edition -Revised", American Psychiatric Association, Washington D.C.(1987). 11. Nieuwenhuys, R., Voogd, J., van Huijzen, C. (Eds), "The Human Central Nervous System. A Synopsis and Atlas. Third Revised Edition", Springer-Verlag, Berlin (1988). 12. Pomeranz, S.J., (Ed), "Craniospinal Magnetic Resonance Imaging", Saunders Company, Philadelphia (1989). 13. Andreasen, N.C., "Thought, Language and Communication Disorders: I. Clinical Assessment, Definition of Terms, and Evaluation of Their Reliability", Arch. Gen. Psychiatry 36, 1315-1322 (1979). 14. Wechsler, D., "Wechsler Adult Intelligence Scale-revised, Manual", Cleveland, Ohio: The Psychological Corp (1981). 15. Andreasen, N.C., "The Scale for Assesment of Negative Symptoms (SANS)", Iowa City, The University of Iowa, Iowa (1983). 16. Andreasen, N.C., "The Scale for Assesment of Positive Symptoms (SAPS)" Iowa City, The University of Iowa, Iowa (1984). 17. Gur, R.E., Pearlson, G.D., "Neuroimaging Studies in Schizophrenia", Schizophrenia Bull. 19, 337-354 (1993). 18. Barta, P.E., Pearlson, G.D., Powers, R.E., et al, "Reduced Superior Temporal Gyral Volume in Schizophrenia: Relationship with Hallucinations", Am. J. Psychiatry 147, 14571462 (1990). 19. Lewis, S., "Computed Tomography in Schizophrenia: 15 years on", Brit. J. Psychiatry 157 (suppl 9), 16-24 (1990). 20. Bogerts, B., "Recent Advances in the Neuropathology of Schizophrenia", Schizophrenia Bull. 19, 431-445 (1993). 21. Damasio, H.R., Damasio, A., "Lesion Analysis in Neuropsychology", New York, Oxford University Press (1989). 22. Galaburda, A.M., Sanides, F., Geschwind, N., "Human Brain: Cytoarchitectonic Left-right Asymmetries in the Temporal Speech Region", Arch. Neurology 35, 812-817 (1978). 23. Geschwind, N., Galaburda, A.M., "Cerebral Lateralization, Biological Mechanisms, Associations and Pathology", MIT Press, Cambridge, Mt (1987).

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24. Witelson, S.F., Kigar, D.L., "Asymmetry of Brain Function Follows Asymmetry in Anatomical Form: Gross, Microscopic, Postmortem and Imaging Studies", In: F.BoUer, J.Grafman (eds), Handbook of Neuropsychology, Elsevier Science Publ., Amsterdam, 111142 (1988). 25. Bornstein, R.A., Schwarzkopf, S.A., Olson, S.C. et al, "Third Ventricle Enlargement and Neuropsychological Deficit in Schizophrenia", Biol Psychiatry31, 954-961 (1992). 26. Golden, C.J., Maclnnes, W.D., Ariel, R.N., et al, "Cross-validation of the Ability of the Luria-Nebraska Neuropsychological Battery to Differentiate Chronic Schizophrenics with and without Ventricular Enlargement", J. Consult Clin. Psychol 50, 87-95 (1982). 27. Andreasen, N.C., Olsen S.A., Dennert, J.W. et al, "Ventricular Enlargement in Schizophrenia: Relationship to Positive and Negative Symptoms", Am. J. Psychiatry 139, 297-302 (1982). 28. Vita, A., Valvassori, G., Boato, P., et al, "Clinical and Prognostic Correlates of Lateral Ventricular enlargement in Schizophrenic Disorder", in: M. Casacchia, A.Rossi (Eds), Schizophrenia: a Psychobiological View, Kluwer Academic Publ., Lancaster, 79-90 (1989).

PART III

Advances in the Understanding of Mental Disorders

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BIPOLAR II: PREVALENCE AND CLINICAL SIGNIFICANCE OF THE SOFT BIPOLAR SPECTRUM HAGOP S. AKISKAL, M.D. Professor of Psychiatry, University of California at San Diego, La Jolla, on leave Senior Science Advisor on Affective and Related Disorders, Office of the Director, National Institute of Mental Health, 5600 Fishers Lane, Room 10C-16 Washington, D.C., (USA)

Abstract Between the extremes of full-blown manic-depressive illness where the person has one acute manic episode (bipolar I) and strictly defined unipolar depression without personal or family history of mania (unipolar I), there exists a large spectrum of "soft" bipolar conditions with depression and hypomania (variously referred to as bipolar II and unipolar II disorder). Temperamental dysregulation in the form of cyclothymia or hyperthymia is a prominent characteristic of this spectrum. Mood swings are recurrent, biphasic and abrupt, and often induced by antidepressants (or stimulant abuse) and/or by seasonal changes and, possibly, by transmeridian travel. Falling in and out of love - and other excitements that could lead to sleep deprivation - represent other common contributory factors to the instability of these patients. Hence the ease with which they can be (mis)labelled "borderline" or "narcissistic." Current data indicate intriguing associations between cyclothymia and artistic creativity on the one hand, and hyperthymia and leadership on the other. These considerations have significant implications for theory, practice and public health, especially in outpatient psychiatric settings where soft bipolar conditions are prevalent.

The temperamental terrain between depression and manic-depression is bridged by a range of subtle bipolar disorders with an extremely variable course.l Mood switches are recurrent, biphasic, and abrupt and may be seasonal and brought on by antidepressants. This chapter examines new research developments on this challenging interface. UNIPOLAR-BIPOLAR DISTINCTION OR CONTINUUM? The broad concept of manic-depressive illness proposed by Kraepelin was challenged in the 1960s by several European2"4 and American investigators.5 This led to a unipolar-bipolar distinction that considerably restricted the boundaries of bipolar (BP) disorder in favor of unipolar (UP) or major depressive disorder. Today, major depressive disorder is described as the most common mood disorder in widely used official classification systems. This is based on epidemiologic data showing a 10:1 ratio favoring UP6; clinical studies report a 4:1 ratio favoring UP.7 More recent studies8"13 - both in the clinic and the community - have revealed the existence of a large group of patients with "soft" or subtle signs of bipolarity at the subsyndromal level, typically expressed in the form of hypomania, explosive behavior

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or marked irritability. Depressions arising from such substrates are best classified as pseudo-unipolar illness.1 These pseudo-unipolar depressions, which are more prevalent than manic-depressive illness,1214 constitute a "bridge" between unipolar and bipolar disorders and indicate the need for a partial return to Kraepelin's broad concept of manic-depressive illness.15 These softer expressions of bipolarity have a prevalence of at least 4%,8"13 as opposed to the 1% rate for manic-depressive illness.6 DEFINING THE SOFT BIPOLAR SPECTRUM As depicted in table 1, between the extremes of classic manic-depressive illness, where the person has had at least one acute manic episode (bipolar I), and strictly defined unipolar depression, where there is no personal or family history of mania and its variants (unipolar I), there exists a spectrum of intermediate forms of bipolar illness.16 These forms, characterized by recurrent periods of depression and hypomania, have been variously referred to as "atypical" bipolar, bipolar II or III, or unipolar II disorder. Bipolar II disorder,17 the best characterized soft bipolar condition, may well represent the most common phenotype of bipolar illness.18

Table 1. The Spectrum of Bipolar Disorders Compared With Unipolar Depression* Bipolar I

-

At least one manic episode.

Bipolar II

-

Recurrent depressions with hypomania and/or cyclothymia.

Bipolar III

-

Recurrent depressions without spontaneous hypomania, but often with hyperthymic temperament and/or bipolar family history.

Soft. Bipolar

Unipolar depression -

No evidence for hypomania, cyclothymia, hyperthymia, nor bipolar family history

♦Summarized from Akiskal (1983).16

To properly understand soft bipolar conditions, the clinician must assess individuals who manifest affective dysregulation in lifelong cyclothymia or hyperthymia.19 Major depressive episodes often complicate the life course in these individuals (more so in those with cyclothymia than those with hyperthymia), and during these episodes, their conditions would warrant the additional diagnosis of bipolar II or III disorder. The common feature of these intermediate bipolar conditions is the occurrence of hypomania - a distinct period of at least a few days of mild elevation of mood, positive thinking, and increased activity level, typically without the impairment characteristic of manic episodes. Hypomania is distinguished from ordinary happiness

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by the tendency of episodes to recur and by the fact that it can sometimes be brought about by antidepressants.12 In persons with cyclothymia (Table 2), hypomania alternates with brief hypomania or minidepressions,8 whereas in those with hyperthymia (Table 3), hypomania is woven as a trait into the habitual self of the individual.19,20

Table 2. Biphasic manifestations of Cyclothymia* Elicited by interview: 1. Lethargy and somatic discomfort vs eutonia 2. Dulling of senses vs keen perceptions 3. Slow-witted vs sharpened thinking 4. Shaky self-esteem alternating between low self-confidence and overconfidence 5. Pessimistic brooding vs optimism and carefree attitudes Observable behavior: 6. Hypersomnia vs decreased need for sleep 7. Introverted self-absorption vs uninhibited people-seeking 8. Taciturn vs talkative 9. Unexplained tearfulness vs buoyant jocularity 10. Psychomotor inertia vs restless pursuit of activities ♦Summarized from Akiskal et al. (1977).8

Table 3. Attributes of the Hyperthymic Temperament* 1. 2. 3. 4. 5. 6. 7.

Irritable, cheerful, overoptimistic, or exuberant Naive, overconfident, self-assured, boastful, bombastic, or grandiose Vigorous, full of plans, improvident, and rushing off with restless impulse Overtalkative Warm, people-seeking, or extroverted Overinvolved and meddlesome Uninhibited, stimulus-seeking, or promiscuous

♦Summarized from Akiskal et al. (1979).19

In official diagnostic systems, bipolarity is characterized by the presence of alternating manic (or hypomanic) and depressive phases. But a more fundamental characteristic of bipolarity is the reversal of the basic temperament into its opposite episode!1 Recent collaboration with Cassano14 has shown that bipolar II disorder, which is characterized predominantly by depressive attacks, arises from a hyperthymic (or cyclothymic) temperament, whereas bipolar I disorder, which is characterized by a predominance of manic attacks, is as likely to arise in persons with a dysthymic or hyperthymic temperament. Thus, the biphasic disturbance in bipolar illness often consists of the development of episodes opposite in polarity to that of the antecedent temperament. In the case of bipolar II and III disorders, failure to recognize the

278 temperament will give rise to a false unipolar diagnosis with inappropriate characterologic labels (e.g. "borderline" or "narcissistic").8'21 Substance abuse is particularly prevalent among soft bipolar conditions,8 - especially among the juvenile offspring of bipolars22 - where temperamental dysregulation is prominent. Contrary to clinical stereotypes, it is often an attempt to enhance the "hyper" periods (with stimulants) rather than mere "self-treatment" for "down" periods.20 Interestingly, current data1'23'24 also suggest an intriguing association between soft bipolar - especially cyclothymic - conditions and artistic creativity; finally, individuals with hyperthymic temperament appear overepresented among prominent individuals in leadership positions. THERAPEUTIC IMPLICATIONS To recapitulate, the author's work on cyclic depressions has drawn attention to a large and neglected universe of subtle, softer bipolar conditions characterized by abrupt biphasic shifts in mood, cognition, behavior, and biologic rhythms. The ease with which certain classes of antidepressants (and stimulant abuse) may bring about changes in the cyclic nature of the illness812,25'26 is a reflection of the vulnerability of these individuals to abrupt shifts from depression to hypomania and the reverse, or from euthymia to mania or depression and the reverse. Hypothetically, such shifts in mood could also be brought about by situations leading to catecholammergic stimulation, such as falling in and out of love, REM-sleep deprivations, and seasonal variation in daylight.1216 This vulnerability has important implications for the treatment and prevention of mood disorders and suggests the need to use imipramine-type antidepressants with caution in depressed individuals who have tempestuous temperaments. What is reassuring is that rapid-cyling appears to be a transient phase in the course of bipolar illness, not an inexorable outcome of this illness.27 Given the high prevalence of patients with pseudo-unipolar mood disorders, research is needed to identify (or develop) antidepressants that can alleviate depressive attacks without inducing mixed states or cycling, as well as prophylactic agents for long-term use.28 Finally, clinicians must make greater use of psycho-educational approaches to manage these patients' disturbed biologic rhythms and must consider psychotherapertic approaches that are specifically geared to their temperamental dysregulation.1 These nonpharmacologic approaches are in their infancy, but they could become important therapeutic adjuncts for the treatment of bipolar disorders that fall short of the threshold of full-blown mania. The opinions expressed in this article are those of the author only, and do not necessarily reflect those of the National Institute of Mental Health References 1

2

3

Akiskal H.S. and Akiskal K., In: American Psychiatric Association Review, A. Tasman and M.B. Riba Eds., pp. 43-62, American Psychiatric Press, Washington, D.C., 1992. Leonhard K. (Translated by Berman R.) The Classification of Endogenous Psychoses, Irvington Publishers, Inc., New York (1957/1979). Angst J., "The Etiology and Nosology of Endogenous Psychoses", Foreign Psychiatry 2 1966/1973.

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Perris C , "A Study of Bipolar (Manic-depressive) and Unipolar Recurrent Depressive Psychoses", Acta Psychiatr. Scand. Suppl. 194 (1966). 5 Winokur G., Clayton PJ. and Reich T. Manic-depressive illness, C.V. Mosby, St. Louis (1969). 6 Robins L.N. and Regier D.A. eds, Psychiatric Disorders in America, The Free Press, New York, 1991. 7 Winokur G., "Is There a Common Genetic Factor in Bipolar and Unipolar Affective Disorder", Compr. Psychiatry 21 460-468 (1980). 8 Akiskal H.S., Djenderedjian A.M., Rosenthal R.H. and Khani M.K., "Cyclothymic Disorder: Validating Criteria for Inclusion in the Bipolar Affective Group", Am. J. Psychiatry 134 1227-1233 (1977). 9 Weissman M.M., Myers J.K. and Harding P.S., "Psychiatric Disorders in a U.S. Urban Community: 1975-1976", Am. J. Psychiatry 135 459-462 (1978). 10 Depue R.A., Slater J.F., Wolfstetter-Kausch H., Klein D., Goplerud E. and Fair D., "A Behavioral Paradigm for Identifying Persons at Risk for Bipolar Depressive Disorder: A Conceptual Framework and Five Validation Studies", J. Abnorm. Psychol. 90 381-437 (1981). 11 Casey P.R. and Tyrer P.J., "Personality, Functioning and Symptomatology", J. Psychiatr. Res. 20 363-374 (1986). 12 Akiskal H.S. and Mallya G., "Criteria for the 'Soft' Bipolar Spectrum: Treatment Implications", Psychopharmacol. Bull. 23 68-73 (1987). 13 Wicki W. and Angst J., "The Zurich Study. X. Hypomania in a 28- to 30-year-old Cohort", Eur. Arch. Psychiatr. Clin. Neurosci. 240 339-348 (1991). 14 Cassano G.B., Akiskal H.S., Savino M., Musetti L. and Perugi G., "Proposed Subtypes of Bipolar II and Related Disorders: With Hypomanic Episodes (or Cyclothymia) and with Hyperthymic Temperament", J. Affect. Disord. 26 127-140 (1992). 15 Akiskal H.S., In: Psychiatry: A World Perspective, Vol. 11, C.N. Stefanis, A.D. Rabavilas and C.R. Soldatos Eds., pp. 419-424, Elsevier, Amsterdam, 1990. 16 Akiskal H.S., In: Psychiatry Update: The American Psychiatric Association Annual Review, L. Grinspoon Ed., pp. 271-292, American Psychiatric Press, Washington, D.C., 1983. 17 Dunner D.L., "Sub-types of Bipolar Affective Disorder with Particular Regard to Bipolar II", Psychiatr. Devel. 1 75-86 (1983). 18 Simpson S.G., Folstein S.E., Meyers D.A., McMahon F.J., Brusco D.M. and DePaulo J.R. Jr., "Bipolar II: The Most Common Bipolar Phenotype", Am. J. Psychiatry 150 901-903 (1993). 19 Akiskal H.S., Khani M.K. and Scott-Strauss A., "Cyclothymic Temperamental Disorders", Psychiatr. Clin. North Am. 2 527-554 (1979). 20 Akiskal H.S., "Delineating Irritable and Hyperthymic Variants of the Cyclothymic Temperament", J. Pers. Disord. 6 326-342 (1992). 21 Levitt A.J., Joffe R.T., Ennis J., MacDonald C. and Kutcher S.P., "The Prevalence of Cyclothymia in Borderline Personality Disorder", J. Clin. Psychiatry 51 335-339 (1990). 22 Akiskal H.S., Downs J., Jordan P., Watson S., Daugherty D. and Pruitt D.B., "Affective Disorders in Referred Children and Younger Siblings of Manic-depressives: Mode of Onset and Prospective Course", Arch. Gen. Psychiatry 42 996-1003 (1985). 23 Andreasen N.C., "Creativity and Mental Illness: Prevalence Rates in Writers and their First-degree Relatives", Am. J. Psychiatry 144 1288-1292 (1987). 24 Goodwin F.K. and Jamison K.R. Manic-depressive illness, Oxford University Press, New York (1990). 25 Wehr T.A. and Goodwin F.K., "Rapid Cycling in Manic-depressives Induced by Tricyclic Antidepressants", Arch. Gen. Psychiatry 36 555-559 (1979). 26 Koukopoulos A., Reginaldi D., Laddomada P., Floris G., Serra G. and Tondo L., "Course of the Manic-depressive Cycle and Changes Caused by Treatment", Pharmakopsychiatr. Neuropsychopharmakol. 13 156-167 (1980). 27 Coryell W., Endicott J. and Keller M., "Rapidly Cycling Affective Disorder. Demographics, Diagnosis, Family History, and Course", Arch. Gen. Psychiatry 49 126-131 (1992). 28 Akiskal H.S., In: Long-term Treatment of Depression, S.A. Montgomery and F. Rouillon Eds., pp. 43-62, J. Wiley & Sons, Chichester, 1992.

RECURRENT BRIEF DEPRESSION J. ANGST and B. HOCHSTRASSER Psychiatric University Hospital Research Department P.O. Box 68 CH-8029 Zurich (Switzerland)

The original concept of affective illness we owe to Kraepelin (1889)l explicitly included short and mild depressive and hypomanic states bordering in part on normality. Yet, despite their frequency, these syndromes have so far been neglected in psychiatric research. Gregory (1908 ,1915^) of Bellevue Hospital in New York was thefirstto stress the importance of transient attacks of manic-depressive insanity lasting no longer than a week. He termed such attacks 'atypical' and emphasized their comorbidity with alcohol­ ism, dipsomania, periodic drinking, somatic smiptoms, migraine, neurasthenia and certain unexpected suicides. In 1929 Read"*, Patrick^ and Paskind" pointed out the frequency of short depressive mood changes in primary care patients and their significance for suicidality. More recently Clayton^et al mentioned (1988) 'very brief depression' and Montgom­ ery et al (1979°, 1983^) observed brief in patients with a pattern of repeated suicide attempts. Our own research in the community showed that brief depressive episodes occur very frequently and that it is the recurrent subtype, termed "Recurrent Brief Depression' (RBD) (Angst and Dobler-Mikola 19851"), which must be considered an important disorder. Extensive studies led to operational definitions based on DSM-HI, DSM-IH-R or ICD-10 criteria for depressive syndromes (Angst 1988 , Angst and Woggon 1988*2). One crucial point for the definition of RBD is the presence of a fully developed major depressive syndrome, i.e. the diagnostic criteria for a major depressive episode regarding mood and number of symptoms must be fulfilled (e.g. 5 out of 9 symptoms of depression according to DSM-III-R). The symptomatology of RBD is similar to that of major depression (Montgomery 1991) . in addition subjective work impairment is required for caseness. The episodes of Recurrent Brief Depression area shorter than two weeks (90% last one to three days). These short manifestations generally occur at irregular intervals of about one month or less; about half of the cases experienced more than 20 episodes per year. Table 1 shows the diagnostic criteria for RBD according to ICD-10 (1994). RDC intermittent depression (Spitzer et al 1978)^ is a category of minor depression differentiated from recurrent brief depression (Montgomery 1990) . Table 1.-F38.10 RECURRENT BRIEF DEPRESSION A. The disorder meets the symptomatic criteria for mild (F32.0), moderate (F321), or severe (F32.2) depressive episode. B. The depressive episodes have occurred about once a month over the past year. C. The individual episodes last less than 2 weeks (typically 2-3 days).

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D. The episodes do not occur solely in relation to the men-strual cycle. Our research demonstrated that the one year prevalence rate in the community between ages 20 and 30 was about 5% (males 2-5%, females 2-10%). The lifetime prevalence up to age 30 was 16.0% (males 11.0%, females 20.9%). RBD is also common in general practice patients with rates that vary between 7 and 10% as shown hy Weiller et al (1994) 16 in a study carried out in Paris and by Maier et al (1994) 1 ' in a study carried out in Mainz (Germany) . According to a worldwide study of general practitioners organized by WHO in 14 countries, the prevalence rate for recurrent depression is also about 7% (Ustiin 1993) . In our community study, a sex ratio of 1.1 was found for recurrent brief depression, of 1.5 for major depression and of 3.5 for the combined disorder with women predominating. The age of onset was, 11 years of age. A rather early age of onset was also confirmed bei Lupine (1992) iy and Staner (1992) 25 . Some seasonal variations m the occurrence of episodes was observed in 95% of the cases (Lepine et al 1992)1^, and Kasper et al (1992)2U identified a substantial group (30%) of seasonal affective disorders as recurrent brief depressives. Prospective studies reveal a considerable diagnostic change from recurrent brief depression to major depression, and vice versa to an equal extent. The stability of both diagnoses is the same. This suggests that recurrent brief depression belongs to the spectrum of all depressive disorders. The prospective studies of Montgomery et al (1989 , 1990^) showed a marked severity of illness, and the Zurich study showed that distress and impairment were the same as in major depression (Angst and Dobler-Mikola 1985)10. The term 'combined depression' (major depression overlapping with recurrent brief depression) was coined by Montgomery et al (1989)^1# In the Zurich community study this group was sigmficantly more socially impaired, more frequently treated and had a markedly increased suicide attempt rate, thus, clearly representing a more severely affected patient group compared to pure major depression or pure recurrent brief depression (Angst et al 1990)23. Our own study showed a high overlap between RBD and anxiety disorders (odds ratio 4.8) and especially panic disorder, panic attacks and 'recurrent brief anxiety', another syndrome described and operationalized in the Zurich study (Angst and Wicki 1992) . The high comorbidity with anxiety disorders was confirmed by Lepine et al (1992) iy . RBD was also found to be associated with obsessivecompulsive disorder and milder obsessive-compulsive syndromes, as well as with social phobia and agoraphobia, but not with simple phobia. 19.6% of recurrent brief depressives (N=148) had a history of suicide attempts, which gives a 3.6 fold risk compared to controls. Recurrent brief depression was also associated with concommitant functional somatic syndromes, especially with gastrointestinal, respiratory and cardiovascular symptoms. The relationship of-RBD with personality disorders needs further investigation. Staner et al (1992)^, examining 20 borderline subjects, identified 60% of them as recurrent brief depressives. In another sample of 25 patients meeting criteria for intermittent depression and recurrent brief depression, they found only 4% with a

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DSM-III-R axis-II diagnosis of personality disorder, in contrast to 14% among major depressives (Staner et al 1992)^. Our own studies indicate that sociopathy is not significantly associated with RBD. Personality trails^ measured by the Freiburg Personality Inventory FPI (Fahrenberg and Selg 1970)^° showed RBD patients to be more introverted, emotionally more labile and mor^-aggressive than controls. On the Symptom Checklist 90-R (Derogatis 1977)2' these patients showed an even higher morbidity than major depressives. The recurrence of the disorder increases the divorce rate among patients with RBD as well as among major depressives. There is a positive family history for depression among first degree r,eLatives,a finding also confirmed by the Belgian family studies of Staner et al (1992)^. In general practice recurrent brief depression was usually treated in the same way as major depression (L6pine et al 1992)1^. Studies of patients with a history of repeated suicide attempts, many of whom were suffering from RBD, have demonstrated the difficulty of treating such cases. A comparative trial with flupentixol versus placebo found some efficacy of the active compound (Montgomery et al 1979)°. However, studies with antidepressants failed to show any significant prophylactic action. A new trial based selectively on patients meeting the diagnostic criteria for RBD is under way (results not yet available). In single cases longterm medication with antidepressants and lithium has been shown to be useful. The question of suitable treatment for RBD patients remains open. They certainly need prophylactic medication and could be considered as unipolar rapid cyclers, a condition which may not be easy to treat. The high prevalence of RBD and its frequent association with suicidality makes this disorder a real challenge for psychiatry.

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REFERENCES 1. KRAEPELIN, E.: .(1889) Psychiatric Ein Lehrbuch fur Studierende und Arzte. (3. Aufl.) Barth, Leipzig 2. GREGORY, M.S.: (1908) Annual report of Bellevue and allied hospitals. 3. GREGORY, M.S.: (1915) Transient attacks of manicdepressive insanity. Med Record 88: 1040-1044 4. READ, C.F.: (1929) Brief attacks of manic-depressive depression. Arch Neurol Psychiat (Chicago) 22: 133 5. PATRICK, H.T.: (1929) Brief attacks of manic-depressive depression. Arch Neurol Psychiat (Chicago) 22: 133-134 6. PASKIND, H.A.: (1929) Brief attacks of manic-depressive depression. Arch Neurol Psychiat (Chicago) 22: 123-134 7. CLAYTON, P.J., MARTEN, S., DAVIS, M.A., WOCHNIK, E.: (1980) Mood disorders in women professionals. J Affective Disord 2: 37-46 8. MONTGOMERY, S.A., MONTGOMERY, D., MCAULEY, R. et al: (1979) Maintenance therapy in repeat suicidal behavior. A placebo controlled trial. Proceedings 10th International Congress for Suicide Prevention and Crisis Intervention, pp 227-229 9. MONTGOMERY, S.A., ROY, D., MONTGOMERY, D.B.: (1983) The prevention of recurrent suicidal acts. Br J Clin Pharmacol 15: 183S-188S 10. ANGST, J., DOBLER-MIKOLA, A.: (1985) The Zurich Study. A prospective epidemiological study of depressive, neurotic, and psychosomatic syndromes. IV. Recurrent and nonrecurrent brief depression. Eur Arch Psychiatry Neurol Sci 234: 171-178 11. ANGST, J. (1988) Recurrent brief depression. A new concept of mild depression. In: Abstracts of the XVIth C.I.N.P. Congress, Munich 1988. Psychopharmacology (Suppl) 96: 62 12. ANGST, J., WOGGON, B.: (1988) Lofepramine in the treatment of depressive disorders. Review of the past 10 years and future prospects. International Symposium organized by the Psychiatric University Hospital Zurich, in Lugano 1987. (editors introductory remarks, p III) Vieweg-Verlag, Braunschweig 13. MONTGOMERY, S.A. (1991) Recurrent brief depression. In: Feighner JP, Boyer WF: The diagnosis of depression. Perspectives in Psychioatry Vol 2. John Wiley & Sons, Chichester New York Brisbane

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14. SPITZER, R.L., ENDICOTT, J., ROBINS, E.: (1978) Research Diagnostic Criteria: rationale and reliability. Arch Gen Psychiatry 35: 773-782 15. MONTGOMERY, S.A. (1990) Brief depression. In: Montgomery, SA: Anxiety and depression. Wrightson Biomedical Publishing, Petersfield 16. WEILLER, E., BOYER, P., LEPINE, J.-P., LECRUBIER, Y.: (1994) Prevalence of recurrent brief depression in primary care. Unpublished Manuscript 17. MAIER, W., HERR, R., LICHTERMANN, D., GAENSICKE, M.: (1994) Brief depression among patients in general practice: prevalence and variation by recurrence and severity. Unpublished Manuscript 18. WEILLER, E., LECRUBIER, Y., MAIER, W., USTUN, T.B. (1994) The relevance of recurrent brief depression in primary care. A report from the WHO project on Psychological Problems in General Health Care. Submitted for publication 19. LEPINE, J.P., WEILLER, E., BOYER, P., PAYAN, C , LECRUBIER, Y. (1992) The comorbidity of recurrent brief depression and anxiety in primary care patients. 6eme Congres de 1'Association Europeenne de Psychiatric Barcelone 1992. Ann Psiquiat (Suppl 1): 10 20. KASPER, S., RUHRMANN, S., HAASE, T., MOELLER, H.-L: (1992) Recurrent brief depression and its relationship to seasonal affective disorder. Eur Arch Psychiatry Clin Neurosci 242: 10-26 21. MONTGOMERY, S.A., MONTGOMERY, D., BALDWIN, D., GREEN, M.: (1989) Intermittent 3-day depression and suicidal behavior. Neuropsychobiology 22: 128-134 22. MONTGOMERY, S.A., MONTGOMERY, D., BALDWIN, D., GREEN, M.: The duration nature and recurrence of brief depressions. Neuro-Psychopharmacol Biol Psychiatry 14: 729-734 23. ANGST, J., MERIKANGAS, K., SCHEIDEGGER, P., WICKI, W.: (1990) Recurrent brief depression. A new subtype of affective disorder. J Affective Disord 19: 87-98 24. ANGST, J., WICKI, W.: (1992) The Zurich Study. XIII. Recurrent brief anxiety. Eur Arch Psychiatry Clin Neurosci 241: 296-300 25. HOCHSTRASSER, B., ANGST, J.: (1994) Epidemiology of gastrointestinal complaints and morbidity with anxiety and depression. Eur Arch Psychiatry Clin Neurosci Submitted for publication 25. STANER, L., DE LA FUENTA, J.M., KERKHOFS, M., LINKOWSKI, P., MENDLEWICZ, J. (1992) Biological and clinical features of recurrent brief depression: A comparison with major depressed and healthy subjects. J Affective Disord 26: 241-246

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26. FAHRENBERG, J., SELG, H.: (1970) Das Freiburger Personlichkeitsinventar (FPI), Handanweisung fur die Durchfuhrung und Auswertung. Hogrefe, Gottingen 27. DEROGATIS, L.R.: (1977) Administration, scoring, and procedure manual for the R (revised) version and other instruments of the Psychopathology Rating Scales Series. Johns Hopkins University School of Medicine, Baltimore, MD

THE CAUSES OF PUERPERAL PSYCHOSIS IAN F. BROCKINGTON Professor of Psychiatry University of Birmingham, U.K.

ABSTRACT Puerperal psychosis was first described over 200 years ago, and complicates 1:1,000 pregnancies. Childbirth is the most potent risk factor known to psychiatry. There has been some progress in the last 10 years, mainly through clinical studies. It has been realized that postpartum psychosis belongs under the rubric of bipolar disorder, with some evidence for a specific puerperal factor. As in manic depression we are searching for a neurochemical explanation of a lifelong, often inherited, diathesis, but it may be subtly different in those with pure puerperal disease. A second group of neurochemical factors, which explain the polarity of the illness (manic, depressive or cycloid), may be the same as in other bipolar psychoses. The menstrual relapse phenomenon was discovered over 100 years ago, and there is an association with the rare menstrual psychosis. There is some evidence that psychoses can follow abortion and trophoblastic tumors in those who also suffer puerperal episodes. These observations favor a role for steroid hormones. The occurrence of psychosis complicating bromocriptine treatment in the puerperium favors a dopaminergic mechanism, but apomorphine-growth hormone challenge tests do not support the dopamine supersensitivity theory. It has recently been realized that a closely related psychosis can occur before delivery, and this is hard to reconcile with the effects of a 'hormonal cascade'.

INTRODUCTION Academic medicine has always been grounded in clinical description. Although everyone knows that single cases cannot establish general laws, they raise new ideas, suggest hypotheses and open up lines of investigation. The puerperal psychoses illustrate the usefulness of such an

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287 approach. During the last 15 years a number of new clues have emerged. THE RELATIONSHIP TO MANIC DEPRESSION. It is appropriate to begin with the most important clinical clue - the l relationship to manic depressive disease. Reich & Winokur showed that manic depressive women had the same high rates of puerperal mental illness as women with a previous episode of puerperal psychosis (about 2 0% in the 6 months after delivery); this was confirmed by Kendell's record linkage study, based on 54,087 births in Edinburgh 2 . He found that 10 mothers with a history of mania had 3 episodes of puerperal illness (starting within 90 days of parturition) after 14 pregnancies (21%). The similarity of the clinical picture of puerperal psychosis to manic depression was rediscovered by Brockington et al. 3 and Dean & Kendell 4 who found that 38% of puerperal illnesses met Research Diagnostic Criteria for mania or schizoaffective mania. PREMENSTRUAL RELAPSE In 1862 Marce 5 noticed the tendency for patients to relapse or develop their illness at the time of the resumption of menstruation after childbirth. This was confirmed by a number of authors between 1952-1984 and in 1988, Brockington et al. 6 published a series of 8 such patients. They also noticed an association with the rare menstrual psychosis, of which there are at least 7 other examples in the literature, starting with Krafft-Ebing's classic monograph of 1902 7. POST-ABORTION PSYCHOSIS There is little or no evidence for a specific post-abortion psychosis, but Brewer (1977) 8 encountered a patient with 2 episodes of puerperal psychosis and one post-abortion psychosis. A similar patient has been described by Vinogradov & Csernansky 9. We have observed the following patient with 2 episodes of puerperal psychosis and two following first trimester miscarriage: This patient developed depression at the age of 16. At 23 she suffered from alcoholism and had an attack of delirium tremens. She overcame this problem and settled down in a stable marriage. Her first pregnancy at 25 was followed by puerperal psychosis starting on the 4th day. Her second, at 26, was

288 followed by 2 weeks of elevated mood, but no medical treatment. At 28 she miscarried at 13 weeks, and suffered a postabortion psychosis. At 29 her third baby was born, and she developed a puerperal psychosis starting immediately after delivery. At 32 she miscarried at 12 weeks, and this was followed one month later by the onset of a psychosis. At 35 she had her 4th child; prophylactic treatment with neuroleptics was begun immediately after delivery, and she remained well. She also reports mid-cycle mood swings. Related to post-abortion psychosis is the patient described by Hopker & Brockington 10, who developed a psychosis following evacuation of a trophoblastic tumour: In 1985 her first baby was born, and she developed puerperal psychosis with manic and depressive features (including delusions of reference). In 1988 she became pregnant, but a hydatidiform mole was evacuated at 13 weeks. Within 4 weeks she developed a schizoaffective depression, with similar delusions of reference. In 1990 her second baby was born, and within one week she developed a puerperal manic illness. The importance of this case is that it raises the possibility of a previously unsuspected connection between psychosis and the withdrawal states which follow the successful treatment of hormone-secreting tumours. Trophoblastic tumours have a very varied output, mainly of progesterone and gonadotrophic hormones, but there are other tumours which secrete individual hormones. Of particular interest are the granulosa cell tumours which secrete oestrogens. BROMOCRIPTINE In 1978, Vlissides et al.11 described a mother who developed mania after receiving bromocriptine to stop lactation. At least 8 other cases have been described since then. Two of these mothers recovered from the psychosis without any intervention except stopping the bromocriptine. Kempermmann & Zwanikken n described a 30 year old woman who was given 2.5mg bromocriptine b.d. She developed mania and was committed to hospital on the 15th day. Bromocriptine was stopped and she recovered within one week. Canterbury et al. B described an 18 year old woman who received 2.5 mg bromocriptine every 12 hours starting on the 3rd day after delivery. 2 days later she developed a schizoaffective depression. She was

289 admitted to a psychiatric unit on the 5th day and bromocriptine was stopped. She began to improve 2 days later, without any other treatment, and was discharged well in 2 weeks. These may be chance associations. It is difficult to determine how often bromocriptine is used to stop lactaton, let alone establish a relative risk of puerperal psychosis after bromocriptine treatment. However the 2 patients who recovered without any additional treatment suggest that it has a role. These patients are similar to those who develop a manic illness during treatment with 1-dopa (Murphy et al., 1971). Bromocriptine is a dopamine-2 receptor agonist; its effect in precipitating puerperal psychosis is compatible with the dopamine supersensitivity theory. Chateau 14 wrote a thesis on bromocriptine and puerperal psychosis, but the theme is exactly the opposite successful treatment by bromocriptine. She gave details of 9 patients. Most (but not all) of her patients who improved had depression, while most (but not all) postbromocriptine psychoses have been manic. DOPAMINE SUPERSENSITIVITY Kumar, Wieck and their colleagues 15 have championed the theory that dopamine supersensitivity is in some way related to puerperal psychosis. This is plausible because dopamine probably plays a part in the chemistry of mania, as well as other forms of psychosis. They also believe that high circulating levels of oestrogens produce this supersensitivity, and they have pioneered the direct study of neurotransmitter systems in the postpartum period. They showed that 8 patients at high risk of puerperal psychosis, who subsequently developed a recurrence, had a growth hormone response to apomorphine challenge on day 4 after delivery (a test of dopamine sensitivity) about 4 times as high as 7 similar mothers who did not suffer a recurrence, and mothers with no history of mental illness. However, two of the three women who suffered a recurrence and had peak growth hormone levels above the level found in controls, were suffering from depression, not puerperal psychosis. Their claim, therefore, depends on the equivalence of 'postnatal depression' (which is common) to 'puerperal psychosis' (much is one or two orders of magnitude rarer), which is not agreed. Their most interesting finding is against their hypothesis, since two mothers who were already ill on day 4 had virtually no growth hormone response. We have encounted a similar patient, who had apomorphine-growth hormone challenge tests on day 4 and day 11, showing little growth hormone

290 response; she developed a manic illness, whose onset was traced to the 10th day. Meakin has how repeated the study with negative results - 3/9 high risk patients developed puerperal psychosis, and none had elevated growth hormone after apomorphine challenge. He showed that the puerperium was a time of relatively low dopamine receptor sensitivity

PREPARTUM ONSET In 1990 Brockington, Oates and Rose n drew attention to patients with psychosis, exclusively pregnancy-related, who had both postpartum and prepartum episodes. This is a typical example: In 1986 she developed anxiety and depression at 34 weeks of pregnancy; she was referred to Dr. Oates but did not attend. On the second day postpartum she developed insomnia, auditory hallucinations, delusional misinterpretations, emotional lability (elation and fear), perplexity and bewilderment, disinhibition, overactivity and pressured speech (a typical postpartum episode with cycloid or schizomanic features). In 1988 she was referred to Dr. Oates 3 days before delivery with an acute onset of insomnia, emotional lability (elation, perplexity and fear), auditory hallucinations, ideas of misidentification, and delusional mood. The clinical picture was almost identical to the first episode. Neuroleptic treatment was begun while she was still pregnant, and she recovered and remained well during the puerperium. The importance of patients with prepartum onset, who are much rarer than those with postpartum onset, is that they challenge the role of postpartum hormonal cascade in the pathogenesis of this disease. CONCLUSION Puerperal psychosis is a disease which is easy to define and diagnose. It is a biological disorder, and its aetiology will probably be unravelled by neurochemical studies carried out during the prodromal phase after delivery. But the possible systems are numerous, the neurochemistry obscure and the investigations so expensive that there is a need to narrow down the possibilities by clinical observation. A great deal has already been

291 learnt, and we can expect that vigilant clinicians will make other observations in the next few years which will guide and inform the laboratory scientists. As Hughlings Jackson wrote, 'The study of the thing caused must precede the study of the cause of the thing'. REFERENCES 1. Reich T, Winokur G (1970). Postpartum psychoses in patients with manic depressive disease. Journal of Nervous and Mental Disease 151: 60-68. 2. Kendell RE, Chalmers JC, Platz C (1987). The epidemiology of puerperal psychoses. British Journal of Psychiatry 150: 662-673. 3. Brockington I F, Cernik K F, Schofield EM,, Downing A R, Francis A F, Keelan C (1981) Puerperal psychosis: phenomena and diagnosis. Archives of General Psychiatry 38: 829-833. 4. Dean C, Kendell RE (1981) The symptomatology of puerperal illness. British Journal of Psychiatry 139: 128-133. 5. Marce Mentales,

L

V

(1862)

Traite

Pratique

des

Maladies

6. Brockington I F, Kelly A, Hall P, Deakin W (1988) Premenstrual relapse of puerperal psychosis. Journal of Affective Disorders 14: 287-292. 7. Krafft-Ebing R (1902) Psychosis Menstrualis: eine klinisch-forensische Studie, Verlag von Ferdinand Enke, Stuttgart. 8. Brewer C (1977) Incidence of post-abortion psychosis: a prospective study. British Medical Journal 1: 476-477. 9. Vinogradov S, Csernansky J G (1990) Postpartum psychosis with abnormal movements: dopamine supersensitivity unmasked by withdrawal of endogenous estrogens ? Journal of Clinical psychiatry 51: 3 65-3 66. 10. Hopker S W, Brockington I F (1991) Psychosis following hydatidiform mole in a patient with recurrent puerperal psychosis. British Journal of Psychiatry 158: 122-123.

292 11. Vlissedes D N, Gill D & Castelow J (1978) Bromocriptine-induced mania? British Medical Journal 1: 510. 12. Kemperman C J F, Zwanikken G J (1987) Psychiatric side-effects of bromocriptine therapy for postpartum galactorrhoea. Journal of the Royal Society of Medicine 80: 387-388. 13. Canturbury R J, Haskins B, Kahn N, Saathoff G, Yazel J J (1987) Southern Medical Journal 80: 1463-1464. 14. Chateau A (1982) Psychose puerperale et bromocriptine ? Thdse, Paris. 15. Wieck A, Kumar R, Hirst A D , Marks M N, Campbell I C, Checkley S A (1991) Increased sensitivity of dopamine receptors and recurrence of affective psychosis after childbirth. British Medical Journal 303: 613-616. 16. Meakin observations.

C

J,

Brockington

I

F.

unpublished

17. Brockington I F, Oates M, Rose G (1990) Prepartum psychosis. Journal of Affective Disorders 19: 31-35.

THYROID FUNCTION IN DEPRESSED PATIENTS: MAPROTTLINE VS FLUVOXAMINE C.A. DE MENDONCA LIMA and R. CARRON Service de Consultation Psychiatrique, IPVR, lS,ruedeVHdteldeVille, 1920 Martigny, Switzerland and S. VANDEL and P. BECHTEL Service de Pharmacologie Clinique C.H. U. de Besanqon 25000 Besancon, France

ABSTRACT The thyroid function was evaluated in 40 depressed outpatients, before and after a 21 day treatment with maprotiline (75 mg/day) or fluvoxamine (100 mg/day). T3 and T4 weren't significantly modified after treatment but, basal TSH and its response to TRH were significantly different between the two groups. Authors concluded to a different action on HPT axis between fluvoxamine and maprotiline.

The TRH has been used in psychiatry since 1973 and one of the most interesting result is that it could identify a subgroup of depressed patients which had improved after treatment but which had presented a significant change in the blunted response to the test1,2,3. This subgroup presents a great risk of relapse 6 months after stopping treatment. To confirm that clinical evolution has a significant influence on TRH test, it's necessary to demonstrate the intrinsic absence on influence of antidepressants on TRH test. That's why we have realized an open, and randomized study, equilibrated for sex, comparing in parallel the efficacy and the influence on T3, T4, basal TSH and on its response to TRH (evaluated by dmaxTSH and AUC) of a 21 day treatment by 75 mg/day of maprotiline or 100 mg/day of fluvoxamine. Forty outpatients (10 men and 10 women for each group) were studied. They were chosen by DSMIII-R criteria for major depression or dysthymia and they should have scored 25 minimum at MADRS scale. All patients haven't any organism disturb or they didn't follow any treatment which could influence the HPT axis hormones. Blood samples for T3, T4 and basal TSH dosages were made before intranasal administration of 2 mg of protirelin at D l and D21. Dosages were made by an RIA automatic method (ACS 180). We didn't find any significant difference between the 2 groups before treatment for clinical (sex, age, depression intensity or endogenous character of depression) and biological parameters (T3, T4, basal TSH and TSH response to TRH). Patients presented a good clinical improvement with both treatments which were considered as equivalent by the MADRS scores comparison (Fluv: dMADRS = 16,95 +/- 7,11. Mapr: dMADRS = 17,10 +/- 6,84. t = 0,07, NS). The T3 variation (Fluv:

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dT3 = 0,02 +/- 0,46 nmol/1. Mapr: dT3 = 0,12 +/- 0,43 nmol/.l. t = 0,71, NS) and T4 variation (Fluv: dT4 = 0,45 +/-13,35 nmol/1. Mapr: dT4 = 6,20 +/-18,37 nmol/1. t = 1,13, NS). weren't significantly different between the two groups. Basal TSH was increased on maprotiline group (dbasalTSH = -0,23 + /- 0,66 mUI/ml. paired t = 1,31, NS) and diminished on fluvoxamine group (dbasalTSH = 0,31 +/- 0,76 mUI/ml. paired t = 1,86, NS). The difference between the two groups was significant (t =2,40, p < 0,02). The TSH response to TRH variation between before and after treatment dosages, and evaluated by dmaxTSH showed that fluvoxamine group diminished the TSH response (ddTSH = 0,24 +/- 6,65 mUI/ml. Paired t = 0,16, NS) while the maprotiline group increased it (ddTSH = -3,59 +/-5,88mUI/ml. Paired t = 2,73, p < 0,02). The difference between the two groups was near of signification (t = 1,93, NS). When this result was evaluated by AUC, this difference becomes significant (Fluv: dAUC = 103,98 +/-596,84 mUI/ml. MapndAUC = -355,80 +/-505,67 mUI.min/ml. t = 2,63, p 18 years old) admitted to the hospital with a diagnosis of a mood disorder were included in the study. Information was acquired from an existing data base and comprised: Diagnosis : Mood disorder (DSM III R) (5) - , Month of admission : Clustered into seasonal totals. The seasons were derived as follows : Spring : September/October/November Summer : December/January/February Autumn : March/April/May Winter : June/July/August Locally, September is recognized as signifying the onset of Spring. However, a Southern Hemisphere Study of a similar nature has also used this clustering (6). Data for non-mood disorder admissions was also acquired in terms of frequencies per season. Cross tabulations on actual versus expected mood disorder frequencies by season as well as versus non-mood disorder frequencies by season were statistically analysed using the SPSS programme, with Chi squares being computed for the data. The analysis assumed no seasonal effect on mood disorder presentation. RESULTS For the period of review, the seasonal totals for mood disorder (NMD) admissions were as follows: MD Spring : 150 Summer : 116 Autumn : 110 Winter : 140

mood disorder (MD) and nonNMD 496 569 589 503

Mood disorder admissions show peaks for Spring and Winter (Spring > Winter), whereas non-mood disorder admissions peak in Summer and Autumn. Statistically, the analysis of the data demonstrated a significant seasonal pattern for mood disorder presentation with regard to expected versus actual frequencies. Chi square = 8.465 d.f = 3 Significance (p) = 0.037 as well as for actual mood disorder frequencies versus actual non-mood disorder frequencies by season : Chi square = 17.05 d.f = 3 (p) = 0.0007 The finding of a Spring peak for mood disorder presentation, is similar to that of an earlier study conducted in the Southern hemisphere (6).

331 DISCUSSION Whilst it appears that for the period of review a significant seasonal pattern for mood disorder presentation exists with Spring and Winter peaks, this finding needs to be seen within the context of certain limitations : 1. It is a retrospective hospital based study of a specific racial group in a discrete geographical location. 2. Inter observer reliability in terms of diagnosis has not been controlled for (DSM III R criteria are used exclusively by all members of staff in the department however). 3. Symptom onset may precede hospital admission by some weeks (7); the noted seasonal pattern does not take this into account. 4. The period of review pertains to a single year. Notwithstanding these limitations, the study whilst preliminary appears to provide the basis for further exploration of this phenomenon in the South African context. The study also provides the first data on this phenomenon in Africa. ACKNOWLEDGEMENT Thanks to Martin Terre Blanche for statistical advice and Dorothy Tristao for preparation of the manuscript. REFERENCES 1. 2. 3.

4.

5.

6.

7.

Torrey, E.F., Torrey, B.B., Peterson, M. R., "Seasonality of Schizophrenic births in the United States", Archives of General Psychiatry 34, 1065-1070 (1977) Silverstone, T. and Romans-Clarkson S., " Bipolar Affective Disorder : causes and prevention of relapse ", British Journal of Psychiatry 154, 321 - 335 (1989) Rosenthal, N.E., Sack, D.A., Gillin, J.C., et al,"Seasonal Affective Disorder. A description of the Syndrome and Preliminary Findings with light therapy ", Archives of General Psychiatry 41, 72 - 80 (1984) Eastwood, M.R., Whitton, J.L, Kramer, P.M., et al " Infradian Rhythms, a comparison of affective disorders and normal persons ", Archives of General Psychiatry 42, 295 - 299 (1988) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. revised Washington DC : American Psychiatric Association, 213-233(1987) Parker, G. and Walter, S., "Seasonal Variation in Depressive disorders and Suicidal deaths in New South Wales ", British Journal of Psychiatry 140, 626 632 (1982) Myers, D.H. and Davies, P., "The Seasonal incidence of Mania and it's relationship to climatic variables", Psychological Medicine 8, 433 - 440 (1978)

MODERN VIEWS ON THE TREATMENT OF THERAPY-RESISTANT DEPRESSION KALLE ACHTfe, KIMMO KUOPPASALMI and HANNU NAUKKARINEN Department of Psychiatry University of Helsinki Helsinki, Finland

ABSTRACT Treatment-resistant depression is an ongoing depressed state which has been adequately treated. It has been made a distinction between "absolute" and "relative" treatment resistance. The majority of relative resistors can be helped with TCA, MAOI, ECT, or serotonin uptake inhibitors. One should measure the plasma levels of drugs in order to exclude insufficient doses. Reassessment of diagnosis should be done. If the treatment is ineffective other antidepressants may be considered. The other possibility is the use of ECT especially if there is any risk for suicide. Lithium is presumed to potentiate TCA response. Another alternative is thyroid hormone potentiation. The combination of MAO inhibitor to TCA is a treatment with risk. The combi­ nation of serotonin uptake inhibitor can have some addictive effect to TCA. Combination of carbamazepine as well as light therapy has some augmentation for TCA effect. Addition of estrogens, sympatomimetics and even psychostimulants to TCA are alternative treatment sched­ ules. If the disorder is atypical consider a change to MAOI. There are several alternatives for the treatment.

1. TREATMENT-RESISTANT DEPRESSION Treatment-resistant depression is an ongoing and unremitting depressed state in a patient which has been adequately treated with at least two different antidepressants. Despite advances in treating depressive disorders during the past decade, a consid­ erable number of patients are characterized as treatment resistant or refractory. The extent of the problem is difficult to estimate because of differing definitions of treatment resistant depression. It has been made a distinction between "absolute" and "relative treatment resistance. Absolute resistance is defined as failure to respond to a course of "adequate treatment" and relative resistance as failure to respond to an "inadequate" treatment. It has been presented that only a minority of patients categorized as treatment resistors are absolute resistors, and that the majority of relative resistors can be helped substantially by appropriate treatment with TCA, MAOI, ECT, or serotonin uptake inhibitors. Furthermore, many of these patients may be merely slow responders to antidepres­ sants rather than being nonresponders. However, the faster the effect of antidepressant treatment has shorter will be the duration of the suffering of the patient and need for hospital treatment, and lower are the economical costs needed for the recovery of the patient. Therefore, also in case of slow responders, treatment strategies which may fasten the recovery should be used.

332

333

2. THE THERAPEUTIC STRATEGIES FOR TREATMENT RESISTANT DEPRESSION If the patient has received tricyclic antidepressant about 4 weeks without response, you should measure the plasma level of drug in order to exclude insufficient doses of the drug as a reason for inefficacy. In case the level is low you should increase the dose to maximum level if necessary, for example for imipramine to 300 mg/day. In case adequate plasma levels cannot be reached due to the side effects, change to another second generation antidepressant may be useful. Trazodone, maprotiline, miaserine are all drugs available in Finland for that purpose. Reassessment of diagnosis should be done, together with a repeat of physical and laboratory examinations to exclude medical illness. If the antidepressant treatment is ineffective with adequate plasma levels, another tricyclic one of the second generation antidepressants, monoamine oxidase inhibitor and especially serotonin uptake inhibitor may also be considered. In Finland several serotonin re-uptake inhibitors are now available. These drugs seem to be quite effective in the treatment of depressions of various degrees of severity. Moclobemide is used routinely in the treatment of depressions of various degrees of severity. It seems that at least in cases of atypical depression it is quite useful, even the drug of first choice. TABLE 1 Strategies for the Treatment of Resistant Depression tricyclic antidepressant

nonresponse

reassess diagnosis and measure drug plasma levels

increase dose (e.g. imipramine up to 300 mg/day)

ECT

second antidepressant _ other T C A _ s e c o n d generation antide­ pressant MAO inhibitior serotonin uptake inhibitor

3. THE AUGMENTATION OF THE THERAPEUTIC EFFECT OF THE TRICYCLIC ANTIDEPRESSANTS The other possibilities in case of nonresponse to adequate duration with therapeutic plasma concentration are the use of electroconvulsive therapy as well as the augmentation of the tricyclic antidepressant effect. In case that two antidepressants have been ineffec­ tive, the use of ECT, especially if there is any risk for suicide is recommended.

334 TABLE 2 Augmentation of TCA Effect fluoxetine or other serotonin uptake inhibitors lithium thyroid hormones MAO inhibitor anticonvulsant light therapy

Lithium may be used as a supplement to the TCA. Lithium is presumed to potentiate TCA response by facilitating presynaptic serotonergic neurons in the presence of postsynaptic supersensitivity associated with the TCA. Clinical experience shows that some patients seem to respond quite fast, in 1 to 2 weeks, to lithium augmentation but others seem to need a longer duration of treatment before any significant response can be seen. Other alternatives that can be used to treat TCA-resistant depression include thyroid hormone potentiation. Theoretical explanation of thyroid hormone potentiation in­ cludes correcting mild or subclinical hypothyroidism in some depressives and augmenting central norepinephrine receptor sensitivity. Thus, patients who appear refractory to TCA treatment should have thyroid function tests performed, in particular TRH stimulation test. Patients with confirmed laboratory evidence of hypothyroidism or subclinical hypo­ thyroidism should be treated with thyroxine therapy until euthyroid. In euthyroid patients who are refractory to TCA or to other antidepressants low doses of thyroid hormones may be used to augment treatment for a limited, 2 to 3 weeks period. Thyroid indices should be monitored on a routine basis in order to avoid hyperthyroid situations. The combination of MAO inhibitor to TCA is a treatment with risk, it is unclear if the combination provides substantial gains over aggressive use of either drug alone. A usual pattern of treatment is to try a typical tricyclic antidepressant or a serotonin uptake inhibitor first at least for month with increasing doses according to the patient's clinical tolerance, and possibly with confirmatory plasma assays of drug concentration. If the response remains unsatisfactory, one can introduce MAO inhibitor with careful monitor­ ing of the patient's cardiovascular and mental status at first in an inpatient setting. Recent studies have shown that the combination of serotonin uptake inhibitor, e.g. fluoxetine, can have some addictive effect to TCA in cases which have been resistant for TCA treatment alone. However, further studies are needed to clarify the benefits and side-effects of this combined treatment. Combination of carbamazepine and tricyclic antidepressant as well as light therapy has been used in our clinic in some cases as an augmentation for TCA effect. ' Car­ bamazepine has been used in cases where mood stabilizing effect has been needed at the same time, and light therapy in cases where depression has been of seasonal affective disorder type. Addition of estrogens, reserpine, sympatomimetics and even psychostimulus to TCA has been presented as alternative treatment schedules for nonpsychotic therapy-resistant depression. However, our experience from these augmentation methods is scanty.

4. SYMPTOM CONTROL WITH THE COMBINATION OF DIFFERENT DRUGS Other drugs can be used together with antidepressants when symptom control cannot be achieved only by using them. If the disorder is diagnosed as psychotic, consider either

335

ECT or the combination of a serotonin uptake inhibitor or a TCA with antipsychotic drug.11 In every case when the disorder is severe or incapacitating or has a high potential for suicide, consider a course of ECT. If the assessment of diagnosis shows that the patient has a family history or course of illness suggesting a latent or undiagnosed disorder, lithium is worth a trial. Also the use of carbamazepine or valproate should be taken into consideration. If the disorder is nonendogeneous or atypical or is associated with panic attacks or disorder, consider a change to MAOI. In addition the use of alprazolam in combination with antidepressants can be useful in cases where panic disorder occurs together with depression.

5. CONCLUSIONS As a summary it can be said that probably great part of so called nonresponders has only a relative treatment resistance. Only minor part of patients are absolute treatment resistant patients. This group of patients has been studied too little with straight opera­ tional criteria, but there are already several alternatives for the treatment of their depression. In addition the clinician should look more for possible psychosocial or situational factors as a cause of poor response for treatments. Further studies are needed to clarify the importance and significance of the alternative treatment schedules for treatment-resistant depression.

6. REFERENCES 1. Guscott, R., Grof, P.: The clinical meaning of refractory depression: a review for the clinician. Am J Psychiatry 1991; 148:695-704. 2. Quitkin, F.M., Rabkin, J.G., Ross, D., McGrath, P.J.: Duration of antidepressant drug treatment: what is an adequate trial? Arch Gen Psychiatry 1984; 41:238-245. 3. Glassman, A.H., Schildkraut, J.J., Orsulak, P.J.: Tricyclic antidepressants - Blood level measurements and clinical outcome: an APA Task Force report. Am J Psychiatry 1985; 142:155-162. 4. Prudic, J., Sackheim, H.A.: Refractory depression and electroconvulsive therapy, in Treatment Strategies for Refractory Depression. Edited by Roose SP, Glassman All. Washington, DC, American Psychiatric Press, 1990. 5. Price, L.H., Charney, D.S., Heninger, G.R.: Variability of response to lithium augmentation in refractory depression. Am J Psychiatry 1986; 143:1387-1392. 6. Prange, AJ. Jr., Loosen, P.T., Wilson, I.C., Lipton, M.A.: The therapeutic use of hormones of the thyroid axis in depression, in the Neurobiology of Mood Disorders, vol 1. Edited by Post R, Ballenger J. Baltimore, Williams & Wilkins, 1984. 7. Schmaub, M., Kapfhammer, H.P., Meyr, P., Hopf, P.: Combined MAO-inhibitor and tri(tetra)cyclic antidepressant treatment in therapy resistant depression. Progr Neur Psychopharmacol Biol Psychiatry 1988; 12:523-532. 8. Rosenthal, N.E., Sack, D.A., Carpenter, C.J., Parry, B.L., Mendelson, W.B., Wehr, T.A.: Antidepressant effects of light in seasonal affective disorder. Am J Psychiatry 1985; 142:163-170. 9. Cullen, M., Mitchell, P., Brodaty, H., Boyce, P., Parker, G., Hickie, I., Wilheim, K.: Carbamazepine for treatment-resistant melancholia. J Clin Psychiatry 1991; 52:472-476. 10. Chiarello, R.J., Cole, J.O.: The use of psychostimulus in general psychiatry. Arch Gen Psychiatry 1987; 44:286-295. 11. Spiker, D.G., Weiss, J.C., Dealy, R.S., Griffin, S.J., Hanin, I., Neil, J.F., Perel, J.M., Rossi, A.J., Soloff, P.H.: The pharmacological treatment of delusional depression. Am J Psychiatry 1985; 142:430-436.

PSYCHOSOCIAL VULNERABILITY FACTORS AND LONG-TERM TREATMENT OF DEPRESSION: PERSPECTIVES FOR FUTURE STUDIES F. BAUWENS, J. MENDLEWICZ, L. STANER, D. PARDOEN Erasme Hospital 808 Route deLennik 1070 Brussels, Belgium

ABSTRACT We prospectively investigated psychosocial factors in 27 bipolars, 24 unipolars and 26 con­ trol subjects during 12 months at prophylactic treatment. All patients were remitted since at least 6 months and under prophylactic treatment with lithium for bipolars and antidepressants for unipolars. Clinical status and psychosocial variables were assessed every 2 months with the Research Diagnostic Criteria, the Hamilton Rating Scale for Depression, the Social adjust­ ment Scale, the Rosenberg Self-Esteem Scale, the Interview for Recent Life Events and the So­ cial Support Network Inventory. Social adjustment scores predicted recurrences more strongly than all other tested variables, while fife events and initial clinical variables seemed to have little impact on the course of both bipolar and unipolar disorders. These results are in line with previous studies showing that patients with recurrent depression tend to report fewer life events before recurrences than at the beginning of the illness. Furthermore, our data sug­ gest a relationship between bipolar and unipolar affective disorders course and long-term so­ cial maladjustments. This argues for further research on psycho-social and pharmacological integrated strategies for the treatment of affective disorders.

1. INTRODUCTION Placebo-controlled studies on the long term course of affective disorders have shown that, despite the efficacy of pharmacologic treatments compared to placebo, a rather high rate of patients still fail to respond to lithium or antidepressants prophy­ laxis. For instance, Shea et al, in their study with major depressive patients included in the NIMH Treatment of Depression Collaborative Program, have observed that only 19-30% of patients remained well during a 18 months follow-up period (1). In order to identify predictors of prophylactic response to antidepressants, research has focused on the psychosocial context in which affective illness emerges and may develop. Partic­ ular areas of interest appeared to be: in the social and family environment of de­ pressed patients, in their cognitive functioning, in their social adjustment and in the triggering role of stressful life events before affective episodes. Numerous studies found that depressed patients rely on smaller and less supportive social networks than control subjects without psychiatric history and nondepressed psychiatric patients (2). Prospective studies such as those of Paykel and Weissman's group have described in depressive patients the course of various social maladjustments from acute episode to recovery (3,4). They showed that specific social dysfunctions as impaired work perfor­ mance, anxious rumination or submissive dependency were most related to the affec­ tive episode, while other social maladjustments, in particular interpersonal friction and inhibited communication, persisted long after the depressive episode was over. Re­ search has also shown a consistent association between life events and onset of affec­ tive episodes, especially at the beginning of the illness (5,6,7). Hypotheses concerning the way these variables may influence to occurrence of affective episodes have evolved from external stressor models to diathesis-stress models which define mediating psy­ cho-social factors between life-events and the occurrence of affective episodes. For

336

337 instance, Brown and Harris (8) propose a model including four vulnerability factors : early loss of mother, having three or more children at home, unployment and lack of a confiding relationship with a husband or boyfriend. These factors do not exert in isolation a triggering effect on affective episodes but do so in association with provoking agents (life-events or chronic difficulties) via an effect on patients' self-esteem. Dohrenwend et al (9) developped another model, called the "additive-burden model of depression". Contrary to the previous type of model, it views personal dispositions and social conditions as bringing independent causal contributions to the onset of depressive episodes rather than mediating the experience of stressful life events. It is to note that most of the studies on psychosocial factors conducted with psychiatric patients have assessed these factors either retrospectively, in an uncontrolled design or after an insufficient period of remission, casting some doubt on the episode-independance of the psychosocial dysfunctions hypothesized to affect the course of the depression. Our study was aimed at exploring prospectively the incidence of psychosocial factors on the response to prophylactic treatment of affective disorders after recovery defined as being remitted since at least 6 months. 2. METHODS We prospectively followed up during 12 months 27 bipolars (16 type I and 11 type II), 24 unipolars and 26 control subjects matched for age, sex and socio-economic status. All patients were recovered and under prophylactic treatment with lithium for bipolars and tricyclic antidepressants for unipolars. Recovery was defined according to RDC criteria (10) as the absence for at least six months of manic, hypomanic, major depressive and minor depressive episodes. Using these criteria, we observed HRSD-17 (11) scores of 4.1 for bipolars (range 0-10) and 5.0 for unipolars (range 0-11). Plasma levels were monitored regularly troughout the study period. Analyses of several dimensions of the past course of illness at inclusion into the study, showed no significant differences between the 2 patients groups for the following variables, age of onset, mean number of episodes per year and in the previous four years, mean number of weeks in hospital per year in the four previous years, duration of illness, duration of prophylaxis and family history of psychiatric disorder. However, a significant difference was found in mean duration of hospitalisations per year over lifetime with bipolars having stayed on average three times longer in hospital than unipolars (t=2.43, df=36.82, p 85 on any of the subscales) or "personality disorder absent" group (a score < 85 on any of the subscales). Because of the small number of patients in this study analysis of individual subscales was not possible, thus personality disorder was only evaluated in terms of clusters. Outcome was determined using the Morgan and Russell Interview scores to extract DSM-III-R criteria for AN. Patients with a score of 5 or less were assigned to the 'poor' outcome category and those scoring higher than 5 to the 'good' outcome category. Prevalence of personality disorder and its relationship to outcome for each patient group is summarized in Tables 2 and 3. For the AN-R patients the x 2 analysis revealed a significant relationship between good outcome and absence of personality disorder for clusters A (x 2 =3.6, p=0.05) and C (x 2 =4.0, p=0.05). For AN-B patients there was a relationship between the two measures in the same direction in all three clusters, A (x 2 =5.1, p=0.02), B (x 2 =5.1, p=0.02), and C (x 2 =4.3, p=0.04).

Insert Tables 2 and 3 about here

DISCUSSION Results of this study support the hypothesis that the absence of concomitant personality disorder diagnosis at the time of leaving hospital is predictive of a good outcome in patients with anorexia nervosa. For AN-R patients this was true of personality disorder cluster A and C and for AN-B patients was the case in all 3 clusters. With a larger sample size it will be possible to evaluate the predictive value of each individual personality disorder.

699

Acknowledgements The authors would like to acknowledge Cynthia Kirsh for her assistance with data collection and Christina Neitzert for her contribution to editing this manuscript. REFERENCES Gartner, A.F., Marcus, R.N., Halmi, K., et al., "DSM-III-R Personality Disorders in Patients With Eating Disorders" Am. J. Psychiat. 146, 1585-1591 (1989). Kennedy, S.H., McVey, G. and Katz, R., "Personality Disorders in Anorexia Nervosa and Bulimia Nervosa", J. Psychiat. Res., 24, 259-269, (1990). Millon T. Millon Clinical Multiaxial Inventory Manual (3rd ed.), Minneapolis MN. National Computer Systems, (1983). Morgan, H.G. and Russell, G.F.M., "Long Term Outcome in Anorexia Nervosa. Follow Up Study of 41 Patients", Psychol. Med. 5, 355-371, (1975). Spitzer R.L, Williams J.B.W., Gibbon M., First M. Structured Clinical Interview for DSM-III-R (patient version). New York: New York State Psychiatric Institute Biometrics Research. (1988). Wonderlich, S.A. and Mitchell, J.E., "Eating Disorders and Personality Disorders", in J. Yager, H.E. Gewirtsman and C.K. Edelstein (Eds)., Special problems in managing eating disorders. Washington, DC: APPI, (pp 51-86), (1992).

700

Table 1 D e m o g r a p h i c C h a r a c t e r i s t i c s of A N - R a n d A N - B patients

Age

AN-B ( N = 1 6 ) Mean SD 22.7 4.1 60.8 44.1 16.7 2.4 19.5 1.8

A N - R ( N = 19)

Variables ( y e a r 8)

Length of Illness BMI (adm.) BMI (d/o).

Mean 26.6 " 92.7 * 15.0* 18.6

SD 7.2 50.2 2.0 2.5

Table 2 O u t c o m e x Personality d i s o r d e r A N - R (19) patients * p < 0.05 d u s t e r

P o r s o n a l Ity Disorder

Q o o d

P o o r

A

Prosont Absent

O

3

1

6

6-4

3

2

2 6

T

~T

T-*

Q

6 3

1 O

Present Absent

B

Present Absent

85. According to the goals of the study there was no obligatory reference to known allergy history of the patients. Of the 49 children (47 boys; 2 girls) starting treatment four had to be excluded because they did not fulfil the case criteria in baseline II. Thus results are based on 45 children, 36 of them received stimulant medicatioa

Instruments The assessment procedure included behavior ratings in three highly standardized situations: (1) Ratings of hyperactivity, impulsiveness, attention deficit, and conduct behavior, mainly based on a two hours observation during play activity on ward (2) Ratings of hyperactivity, impulsiveness, and attention deficit, during a 40-minutes test situation including a Paired Associate learning Task (PAT) and a Continuous Performance Task (CPT). (3) Classroom behavior was rated by teachers of our clinic school using the Conners Abbreviated Parent-Teacher Questionnaire 9. Raters and children were blind as to what kind of diet was given.

Response Definition Examination of only group statistics in this field of research can mask some important

770

results, as there is certainly a portion of non-responding individuals. Therefore an individual response analysis is indispensable. We demanded that a clinically relevant behavior change must be assessed by independent raters across different situations. For behavior ratings are known as most comprehensive measures for assessing treat­ ment success in child psychiatry, response definition was based on ratings. According to convention, 25% improvement in behavior rating 7 ; 1 ° was considered a clinically significant change. A patient was considered a responder if (1) two out of three behavior rating scores (test, play, school situation) were signi­ ficantly improved (> 25 %) over baseline II (step 1); (2) improvement was to be confined to diet, not present as well under control diet (step 2); (3) as a next step response definition additionally included results of the second assessment point (day eigth) during diet and control diet (repeated measure­ ment). Responder in the strictest sense should reveal significant improvement in both diet assessments but no respective improvement in none of the control assessments (step 3).

RESULTS Behavior in Test/Play/School Situation: Group Comparison Initially the statistical significance of treatment effects were examined for ratings of play, test, and school behavior (dependent variables). Separate repeated measures analysis of variance (MANOVA) resulted in significant within-subject effects for play behavior (F (df 2;43) = 7.45; p = .002), for test behavior (F (df 2;43) = 5.57; p = .009), but not for school behavior (F (df 2;41) = 0.24; p = .79). Play and test rating scores during the diet phase were significantly lower as compared with baseline phase (p < .001), diet and control diet ratings however did not differ significantly, indicating presence of placebo effects.

Behavior in Test/Play/School Situation: Individual Changes Comparing diet and baseline assessment for each individual, out of the 45 children behavior of 26 improved significantly (> 25 %) in test situation and of 21 in play situation; behavior deteriorated only in few children (test: N=7; play: N=6). The number of'improved' and 'worsened' children was nearly equal for classroom behavior. In those children who improved significantly under diet, the amount of change as related to baseline II ranged between 50% and 70%. On the other hand a similar amount of change was seen in children with significantly increased problem behavior. Comparing behavior ratings under diet and control diet we found nearly as many children improved (resp, worsened). The amount of change was similar too. This indi­ cates substantial placebo effects. According to our response definition (step 1) 20 children (44,4%) improved signifi­ cantly in two of three behavior ratings, in contrary only 5 showed significantly more problem behavior. Checking for placebo effects and excluding those children who

771

improved substantially also under control diet (step 2) we identified 9 children (20%) who significantly improved only under diet condition. 5 children (11 %) showed significantly more problem behavior following these criteria. Under the condition of repeated measurement (step 3) four children (9%) remained stable responder, keeping their behavior improvement for 9 days. Only two children (4 %) showed continuously more behavior problems under diet

Responder Characteristics Compared to non-responder the 9 responder after 'placebo' control (step 2) were not found to differ significantly as to age, diagnosis (ADHD and CD), degree of severity, and frequency of allergic disposition (only one child). Also average improvement under diet was comparable to that of all improved children (53 % in both test and play situation).

Comparison of Individual Diet / Methylphenidate Effects In those children who additionally received stimulant medication most positive behavior changes were observed under stimulant medication: the highest number of children improved (24 = 67 %) and only few children did not show any behavior change or deterioration. The extent of behavior improvement under diet and stimu­ lant medication was about the same. However, those three children who did not respond to stimulant medication showed most impressive increases of problem behavior.

DISCUSSION Method and Results Our findings resulting in response rates to an oligoantigenic diet between 9 % and 20% (depending on in-/exclusion of repeated measurement) are less optimistic than those reported in recent studies of Kaplan et al. 7 and Egger et al. 8 (58 % resp. 63 % responder). As the present study applied more restrictive response criteria (crosssituational consistent improvement in at least two situations without respective improvement under control diet) it is not surprising to find lower success rates. Furthermore, the patients investigated in the present study (unselected child psychiatric clinic sample not pre-selected for somatic symptoms) comprise a more general child psychiatric patient population. Nevertheless the oligoantigenic diet hypothesis meets some support by our study and seems to merit further investigation. Final conclusions regarding dietary effects should be withhold until careful repli­ cation studies have been carried out Clinical research is necessary in particular to assess the range of response (hyperactive and/or disruptive behavior aspects) and long-term outcome. For methylphenidate was not given under controlled conditions with individual balanced dosage, caution should be exercised when interpreting the results. Though markedly more patients responded to methylphenidate (67% compared to 20%), the actual amount of behavior change was about the same. 3 children exclusively responded to diet Following, not only for a small group of hyperactive children dietary treatment forms a possible alternative to medication, but for a minority (contra-indication / missing response of stimulant medication) diet represents an alternative to stimulant treatment

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Implications for Clinical Practise A substantial number of children improved significantly on an oligoantigenic diet But still it was only a minority of children who appeared sensitive to dietary replacement and valide predictors for response are missing. Because diets are demanding and socially handicapping they should be only applied in severe disorders after respon­ siveness had been carefully tested in a controlled trial. A good compliance of the child and the whole family is absolutely basic. Finally, it should be made clear that diet even when effective - cannot replace a multi-modal treatment approach. Enthusiastic expectations of a break-through in treating hyperactive /disruptive disorder are exaggerated

REFERENCES 1.

Randolph T.G., "Allergy as a causative factor of fatigue, irritability, and behavior problems of children", Journal of Pediatrics 3 1 , 560-572 (1947).

2.

Speer F., "The allergic tension-fatigue syndrome" in: Speer F (ed): Allergy of the Nervous System. Springfield/Ill., Thomas, pp 14-28 (1970).

3.

Feingold B.F., Why your child is hyperactive. New York, Random House (1975).

4.

Kavale K.A. and Forness S.R., "Hyperactivity and diet treatment. A meta analysis of the Feingold hypothesis", Journal of Learning Disabilities 16, 324-330 (1983).

5.

Rumsey J.M. and Rapoport J.L., "Assessing behavioral and cognitive effects of diet in pediatric populations" in: Wurtman RJ, Wurtman JJ (eds): Nutrition and the Brain. New York, Raven Press, pp 101-161 (1983).

6.

Ferguson H.B., "Recent developments in diet therapy" in: Simeon JG, Ferguson HB (eds): Treatment Strategies in Child and Adolescent Psychiatry. New York, Plenum, pp 151-162 (1990).

7.

Kaplan B.J., McNicol J., Conte R.A., Moghadam H.K., "Dietary replacement in preschool-aged hyperactive boys", Pediatrics 83, 7-18 (1989).

8.

Egger J., Stolla A., McEwen L.M., "Controlled trial of hyposensitisation in children with food-induced hyperkinetic syndrome". Lancet May 9, 1150-1153 (1992).

9.

Conners C.K., "Rating scales for use in drug studies with children". Special issue: pharmacotherapy with children. Psychopharmacology Bulletin Suppl.: 24-84 (1973).

10.

Thurston C M . , Sobol M.P., Swanson J., Kinsbourne M., Effects of Methylphenidate (Ritalin) on selective attention in hyperactive children. Journal of Abnormal Child Psychology 1979; 7: 471-481

SUICIDAL BEHAVIOR IN HIV DISEASE: A CASE-CONTROL STUDY OF DELIBERATE SELF-HARM IN PEOPLE WITH HIV INFECTION JOSE CATALAN, ANDREA PERGAMI, DANIEL SEIJAS, ADRIAN BURGESS Department of Psychiatry Psychological Medicine Unit Charing Cross & Westminster Medical School (University of London) Chelsea & Westminster Hospital Nightingale Place London SW10 9NG, United Kingdom and TALIALIEF Social Work Department Chelsea & Westminister Hospital 369 Fulham Road London SW10 2NH, United Kingdom.

ABSTRACT A group of 22 individuals with HIV infection who had undergone psychosocial assessment following referral to hospital after an episode of deliberate self-harm (DSH) were compared with a sex and age-matched control group of individuals without known HIV infection who also had made acts of deliberate self-harm. Compared with all DSH individuals referred to the service during the same period, men were over-represented amongst HIV subjects and compared with matched controls, HIV subjects were more likely to include gay/bisexual men and not to be in employment; individuals with HIV infection were more likely to be receiving outpatient psychiatric care at the time of DSH and have received it in the past; a diagnosis of depression was given more frequently to HIV subjects, while alcohol misuse was more often diagnosed in controls. Concerns about their physical health were prominent amongst HIV subjects more often than to controls. Results showed that HIV disease is a potential contributing factor to deliberate self-harm, and highlight the need for efforts to identify individuals with HIV infection at risk of DSH, and to develop effective interventions to prevent suicidal behavior in this group of individuals.

INTRODUCTION Suicide in people with HIV infection has been the subject of much interest (see 1-2 for review) . Less attention has been given to non-fatal deliberate self harm (DSH) in this

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774 group of individuals who are known to be at risk of psychiatric and social problems related to their HIV infection (3). Retrospective studies of people with AIDS have suggested that the relative risk of suicide in people with AIDS may be up to 36 times higher than in sex and age matched general population samples (4). In addition, the risk of DSH and completed suicide in people with HIV infection is higher in individuals with a history of previous DSH, in those with a past psychiatric history/ and those with psychiatric disorders (5). This is consistent with what has been reported for the general population (6). However, adequate studies of suicidal behaviour in individuals with HIV disease are limited because of methodological problems such as study design, sample selection, operational criteria, the measurement of staging/progression of illness, and difficulties involved in attempting to study a relatively rare event in a stigmatized population (1,2,4). The aim of the study was to study the demographic and psychosocial characteristics of a series of individuals with HIV infection referred to general hospital following an episode of DSH, and to compare them with a sex and age-matched control group of DSH patients without HIV infection during the sameperiod and in the same health district.

MATERIAL AND METHODS 1. The clinical service: The Riverside Health District (North Thames Regional Health Authority) in London has reported the largest number of patients with HIV infection in the United Kingdom, and it has been estimated that about one quarter of all AIDS cases have received care in this District. A specialist liaison psyhiatry service based at Westminster Hospital was established in 1989 to deal with the psychosocial and neuropsychiatric problems associated with HIV disease in the District. In addition, Westminster Hospital had a well established service (Carlyle Unit) for the psychosocial assessment of patients referred to hospital following an episode of DSH. The Carlyle Unit is a multidisciplinary service which includes social workers, psychiatrists, and medical staff. The psychosocial assessment of people referred to hospital after an act of DSH is carried out following the approach described by Hawton & Catalan (6). Patients are assessed by the social workers and psychiatrists, and particular attention is payed to clarifying the circumstances of the act of DSH, the degree of suicidal intent, and the presence of psychiatric and social problems. As part of the

775 psychosocial assessment and as a matter of routine, data are collected about the patients, including their demographic characteristics, psychiatric status, circumstances of the act of DSH, and details of further care. During the study period (beginning of September 1989 - end of February 1991), the Carlyle Unit staff assessed a total of 655 individuals. 2. Subjects: Index group: All HIV seropositive individuals assessed by the Carlyle Unit staff after an episode of DSH during the study period. Control group: To increase the statistical power, each index subject was matched with two controls, obtained by identifying two individuals of the same sex and age, who had been referred to the Carlyle Unit at the same time (+ 3 months), and who at the time of assessment were not known to be HIV seropositive. 3. Procedure: Data about the subjects were collected as part of the routine clinical psychosocial assessment by the Carlyle Unit team. At the end of the study period, each index subjects was matched with two controls, as edescribed above. 4. Measures: Information was collected as part of the routine clinical assessment about sociodemographic data, psychiatric data, characteristics of the DSH episode, and further psychosocial care. 5. Statistical analysis: Data were analysed using the Statistical Package for Social Sciences (SPSS-PC). Chi-square, Fisher's eact test, t-tests and Mann-Whitney U-test were used as appropriate. RESULTS 1. Characteristics of the sample: HIV seropositive individuals included 8 (36%) asymptomatics (CDC group II & III) and 14 (64%) symptomatics (CDC group IV). The index group represented 3.3% of the total of 655 individuals assessed by the Carlyle Unit during the study period. The control group consisted of 44 individuals. Subjects were comparable in terms of age, but there was a much larger proportion of males amongst the index group compared with all referred patients (index group: men=21, or 95%; all referrals:men=358, or 55%). Index subjects had been aware of their HIV status for a mean time of 29.2 months (range 0-80). Index subjects were more likely to be gay/biseual men than controls (p 0.001). Control subjects were more likely to be in employment compared to

776 index subjects (p 0.05)but there were no other statistically significant differences between the two groups with regard to their demographic characteristics. 2. Psychiatric data: a) Psychiatric diagnosis: A psychiatric diagnosis was made in 15 (68%) index cases and 22 (50%) controls. Individuals with HIV disese were more likely to have received a diangosis of depressive disorders than controls [n=10 (44%) vs 5(11%), p 0.05] while a diagnosis of alcohol misuse was more frequent in the control group [16 (37%) controls vs 1 (4%) index, p 0.01]. b) Past psychiatric history: At the time of assessment, subjects in the index group were more likely to be reciving psychiatric outpatient treatment [n=9(46%)] compared to controls [n=8(17%)] (p 0.05). Similarly, past outpatient contacts were reported by 18 (82%) index subjects compared to 22(50%) controls (p 0.05). c) Previous DSH episodes: 10(45%) index subjects and 17(37%) controls had made a previous act of DSH. Among index group individuals, 6(23%) related thier previous DSH to HIV infection. d) History of alcohol and drug misuse: There were no statistically significant differences between groups regarding a past history of substance misuse. 3. The act of DSH: a) Methods used: There were no statistically significant differences between groups regarding methods used. Overdoses were the most common form of DSH in both groups [18(81%( index and 41(92%) controls]. Self-injury was the method used by 4(19%) index and by 4(9%) control subjects. b) Suicidal intent: No significant differences between groups were found regarding subjects' motivs for the act. A declared suicidal intent at the time of the act was reported at the assessment by 12(54%) index and 22(50%) controls. 4. Current social and other problems: There was more frequent presence of concerns about physical health amongst HIV seropositives [index:11(50%), controls:4(9%), p 0.001]. 5. Further psychosocial care: One(4%) individual with HIV infection and 7(16%) controls were admitted to psychiatric hospital voluntarily after psychosocial assessment. A psychiatric outpatient appointment was given to 17(77%) index subjects and 17(37%) controls (p 0.01).

777 DISCUSSION Our study show that HIV infected individuals who are involved in acts of DSH include a substantial number with depressive disorders, and that they often have a history of past and current psychiatric outpatient care, and of suicidal behaviour. Concerns about their physical health are common. There are few differences between HIv seropositves and comparable controls who make acts of DSH, and it could be argued that HIV infection is a possible contributing factor out of many potential ones which, in vulnerable individuals, can lead to suicidal behaviour. At a practical level, our findings highlight the need for more effective ways of identifying HIV individuals at risk of suicidal behaviour, and the need to develop effective therapeutic interventions to prevent such acts. ACKNOWLEDGEMENTS The authors would like to thank Barbara Jones for her help with data collection. Dr A Pergami was supported by a 1990-1993 research clinical fellowship from the Italian National Institute of Health, Rome, Italy. REFERENCES 1. Pugh, K., O'Donnell, I., Catalan, J., "Suicide and HIV disease", AIDS Care 5,391-340 (1993). 2. Beckett, A. & Shenson, D., "Suicide risk in patients with HIV infection and AIDS", Harv. Rev. Psychiatr. 1,27-35 (1993). 3. Gala, C , Pergami, A., Catalan, J., et al., "The psychosocial impact of HIV infection in gay men, drug users and heterosexuals: controlled study", Brit. J. Psychiatr. 163,651-659 (1993). 4. Marzuk P.M., "Suicidal behaviour and HIV illnesses", Int. Rev. Psychiatr. 3,367-374 (1991). 5. Gala, C., Pergami, A., Catalan, J., et al.. "Risk of deliberate self-harm and factors associated with suicidal behaviour among asymptomatic individuals with HIV infection", Acta Psychiatr. Scand. 86,70-75 (1992). 6. Hawton, K. & Catalan, J., Attempted suicide: a practical guide to its nature and management (2nd edition), Oxford: Oxford Med. Publ. (1987).

PSYCHOSOCIAL ASPECTS OF CANCER: IMPLICATIONS FOR QUALITY OF LIFE (QL) MEASUREMENT AND INTERVENTION David F. Cella, Ph.D. Rush University, Rush-Presbyterian-St.Luke's Medical Center, 1725 W. Harrison Street, Chicago, IL, USA. ABSTRACT In the treatment of chronic illness, increasing attention is being paid to the quality of the life that may be preserved by these treatments. Measurement approaches in the cooperative clinical triads setting have been refined over the past ten years. These refinements include clarification of the construct of quality of life, construction of measures and, most importantly, implementation of research in the clinical setting. Numerous pitfalls to successful research have been confronted and resolved. Important considerations include identifying the appropriate source of information; establishing the best timing of assessment; facilitating staff collaboration; allocating scarce resources; and managing multifactorial data. Lessons learned over time in these areas are shared, with the recognition that like chronic illnesses, many psychiatric disorders are not cured but controlled. Therefore, the psychiatrist must consider the impact of treatment upon the broader well-being of patients and family members.

INTRODUCTION Modern medicine has resurrected a balanced regard for the total well-being of health care recipients. After three centuries of movement away from holistic medicine and toward a Cartesian perspective of mind/body dualism, health care researchers are reemphasizing the importance of evaluating the outcome of their treatments from the broadest of perspectives. This has emerged in part because multiple treatments have become available for chronic conditions, including those in psychiatry, and the extent of benefit provided by those treatments has been questionable. Cost-consciousness has also been a factor which works both ways: A costly intervention may be justified if it improves quality of life in the absence of having any other measurable effect upon the disease process; conversely, an intervention with limited benefit must be evaluated in the context of its cost. The term quality of life (QL) has come to incorporate this growing interest in determining the impact of medical and psychiatric treatments upon the functioning and overall well-being of patients. Medical interventions are rarely evaluated on the basis of cure or survival benefit alone. This is a concept quite familiar to psychiatrists, who have always dealt primarily with non-life-threatening conditions. Interventions are deemed justifiable if they provide comfort, palliation, or support of some kind; in short, if they improve quality of life. This has opened up a new window of opportunity in evaluating QL. Related to this opportunity are extensive recent efforts to improve QL measurement.

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779 Other factors have contributed to the increased interest in measuring QL as part of health outcome. These factors, more relevant in the context of this paper, include methodological improvements in the development of psychological tests and improvements in the development of more general health status indicators. This paper will elaborate upon these latter two factors as they have affected the practice of contemporary clinical research with chronic illness in the United States. Some lessons have been learned in conceptualizing and measuring quality of life as an endpoint in clinical trials, and these will be shared in the hope that they can be transferred to the psychiatric setting, where common themes of chronicity and non-specificity of outcome also apply.

DEFINITION OF QUALITY OF LIFE A consensus has developed which suggests that the construct of QL is both multidimensional and strongly influenced by subjective factors.1"5 Its multidimensionality incorporates physical, functional, psychological and social dimensions. Given that QL is multidimensional, scales which do not measure more than one domain are best not referred to as QL measures, even if they are expected to have an association with the construct. Pain scales, symptom and toxicity ratings, or mood scales would therefore be excluded. Global (1-item) ratings of quality of life are also without explicit dimensions. Though they may provide a summary index which synthesizes input from many dimensions, oneitem measures make it impossible to determine anything specific about the nature of a change in the score over time or across treatments. The subjective nature of the QL construct is reflected in the following definition: "Quality of life refers to patients' appraisal of and satisfaction with their current level of functioning as compared to what they perceive to be possible or ideal."3 When estimating a subjective endpoint such as QL, it is important to obtain an appraisal of the extent of dysfunction as well as a rating of how this appraisal matches expectations. The appraisal documents the patient's report of actual dysfunction. An expectation rating is useful because it allows one to assess the patient's perceived impact of that dysfunction. With the psychiatric population, this is critically important because these ratings can deviate dramatically from one another due to the influence of underlying mood or thinking disturbance. Some patients with minimal actual dysfunction are extremely dissatisfied, while others seem quite able to tolerate severe impairment and may even feel fortunate to be obtaining therapy. Many decisions about treatment are best made with this knowledge. Patients' perceptions of their illness are extremely variable, and factors other than actual disability enter into that perception. For example, two patients with major depression may experience the same lifting of symptomatology after initiating tricyclic therapy very differently. One may continue with dysfunctional thinking, and remain dysthymic and withdrawn, despite clear improvement in sleep, appetite and energy level. The other might perceive the lifting of vegetative symptomatology as a hopeful sign that has positive effects upon cognition, outlook and social contacts. To assume that the same symptom profile in these two individuals would reflect comparable quality of life would be an obvious error.

780 IMPLEMENTING A SUCCESSFUL STUDY Selecting Measures There is little wisdom in selecting a single measure as useful for all or even most applications. There is no gold standard. Indeed, there can't possibly be a gold standard measure until the construct as it applies to a specific illness or treatment is clarified. Even then, it wouk^ probably be unwise to name such a standard. If a measure is too easily accepted as ^mprehensive, an investigator surrenders the opportunity to assess components not included in the scale even if they have major implications for QL. The measure selected^ any given study should be derived from the investigators' questions. Too often the revise is true, where an investigator selects a measure because it seems popular or "acceptable," and then draws study questions from the content of the scale. A psychopharmacologist may want to routinely measure symptoms such as anxiety, depression, fatigue and sleeplessness; but there are other areas of function that may, on occasion, be important to assess (e.g., confusion; erectile function; social contact). These more specialize areas are best selected by individual investigators who are most aware of the anticipated outcomes of treatment, based upon the disorder being treated and the agent(s) being used. To address the competing needs between using standardized measurement and including illness- and treatment-specific assessment, many have used a mixed approach. In this approach, a core of general items given to all patients is supplemented with illness-and treatment-specific items. Typically, the general items are developed and standardized prior to the study in question, and the specific items are developed bjy the investigators. These specific items are based upon specific areas of interest implicated by the new intervention being tested.2,6"8 One of the most difficult tasks in QL research is to select a measure which: (1) demonstrates a clear and significant contribution to patient care; (2) does not constitute an unacceptable burden to patients or staff; (3) is sufficiently sensitive to changes in quality of life; and (4) is perceived as relevant to patients §nd staff. Failure to meet any one of these requirements will compromise the quality or even validity of the data collected. Population Characteristics It is important to select an instrument according to the characteristics of the population to be studied. For example, when measuring quality of life in an elderly depressed population, consider instruments more oriented to physical function and activities of daily living. If psychotic patients are being studied, instruments which place more emphasis upon thinking abnormalities would be important. Any chosen instrument should be sensitive to change and have overall clinical relevance. Source of Information If resources permit, it is best to combine self-report with observer rating. Obtaining both perspectives can be particularly useful in validating new instruments, where some correlation would be expected between instruments and yet the uniqueness of the perspectives can be demonstrated. Observer ratings, including input from family members as well as professionals, are also crucial in rating improvement in cognitively impaired or psychotic individuals. If one is trying to examine methods to improve socialization in

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patients after discharge from psychiatric hospitalization, it is useful to obtain information from the patient, a family member, and an objective interviewer. Each of these information sources provide different data, so the omission of one or two of them could decrease comprehensiveness of measurement. Interview versus questionnaire In general, questionnaires are less sensitive than a probing interview in obtaining accurate QL data.9 Experience has uncovered many pitfalls to relying solely upon questionnaires to assess QL.10"12 Missing items, misunderstood instructions, inconsistent responses, and language and reading barriers are some of the untoward consequences that can result from careless dependence on written self report. The main resistance to interviewing patients is cost, not attitude, for most would agree that the richness of interview data is unmatched by other methods. Therefore, it is prudent where possible to supplement a questionnaire with a clarifying interview. At the very least, it is advisable whenever possible to use an "interviewer" rather loosely, as an on-site data collector to check the respondent's comprehension of items and completion of forms. Failure to monitor the quality of data at the time it is collected is perhaps the most common reason for failure of a quality of life investigation once it is underway. When it is impossible to employ a monitor of data collection for minimal quality assurance checks, it becomes crucial to use clearly written, well-organized forms presented in simple English. Complicated or lengthy forms often distort information given by people with a range of educational and cultural backgrounds. Responder Burden As the burden on any respondent (patient, staff, family member) rises, accrual rate drops. After successful entry of a patient to a study, high expectations for compliance with completing long and tiresome forms will encourage many to drop out of the study. This problem forces the investigator in most cases to settle for less than optimal measurement. It is tempting to select special items or subtests from previously validated tests. Assuming it is acceptable to the test author, this approach is reasonable so long as the investigator realizes that assurance of validity may be lost in the process. These selected items could, however, be re-validated on their own in new samples. This has been done with the Profile of Mood States,13 and with the RAND Corporation Medical Outcome Study.14 It is also now being done with the Hospital Anxiety and Depression Scale.2 Timing and Time frame Timing refers to the decision as to when a measurement sample will be taken; time frame refers to the period of time across which people are asked to report. Both considerations are of critical importance in obtaining interpretable data. If timing of assessment is determined judiciously, QL assessment is feasible across the span of treatment. For example, one could study quality of life at four time points across the course of treatment and follow up. Specific assessment times would be determined to some extent by the natural history of the condition being treated and the expected course of treatment. It is possible to obtain thorough longitudinal data by

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including as few as four time points of assessment: Baseline; middle of treatment; end of treatment; and long term follow up. It is useful, of course, to establish a baseline assessment prior to initiation of treatment. After that, it is important to obtain information during the middle phase of the usual treatment course. A third assessment would be valuable at the end of therapy, or when the patient is evaluated as non-responsive to treatment. This time point will obviously have different meaning for different patients, depending upon whether or not they respond to therapy. For those who were successfully treated, a final long term follow up evaluation (e.g., 6-12 months posttreatment) will measure lasting improvements or disruptions in QL following treatment. For those who did not respond to treatment, this assessment time could measure response to second line therapy or to no treatment. The time frame of assessment, or the period of time during which the patient is asked to report, typically ranges from a few days to a month, depending upon the instructions for the selected scale and the interest of the investigator. If the investigator has control over setting the time frame, it is suggested that it be short, perhaps a week. Asking patients about a longer period of time increases bias due to memory loss and the tendency of some people to complain more than others. Providing people with a shorter time frame helps prevent them from confusing specific information (usually of greater interest in a treatment study) with general complaints of dissatisfaction.15 Sampling Considerations Random or even truly representative samples are rarely attainable. One must usually identify an available study population and decide upon inclusion and exclusion criteria. Unless everyone will be seen, a selection strategy for eligible patients is needed. Without such a strategy, the sample will likely be reduced to one of convenience. This approach can bias study conclusions because results could be confounded by some factor which is correlated with the selection method. A telephone study using a sample of convenience at home may over-represent phobic or withdrawn patients who are more likely to be there to answer the phone.

CONCLUSION There is an expanding interest in evaluating and improving quality of life (QL) among people with chronic conditions, including mental disorders. Planning a successful quality of life evaluation in a clinical trial setting is a balancing act. The researcher must weigh the advantages and disadvantages of competing approaches and measures. Comprehensiveness of coverage must be balanced with implementation feasibility in any multicenter collaborative trial. What might be sacrificed in comprehensiveness of measurement may be gained in quality assurance of data collected. Transfer of clinical trial QL evaluation methodology which has been worked out in other chronic illnesses can be applied in the psychiatric setting. There is an opportunity for mental health professionals to expand their role by contributing to the evaluation of interacting physical, social and mental aspects of health-related QL. The psychiatrist embarking on a drug trial can extend the treatment outcome inquiry into broader areas of function and well-being than those defined by the symptom profile of the condition being treated. The decision to do this increases the chance that a real improvement in the overall functioning of the

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patient will be detected. The decision also makes more valid the exploration into the true costs and benefits of a given treatment.

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8.

9. 10. 11. 12. 13. 14. 15.

Cella DF: "Quality of life: The concept", Journal of Palliative Care 8(3), 8-13 (1992). Aaronson NK, Bullinger M, Ahmedzai S: "A modular approach to quality-of-life assessment in cancer clinical trials:, Recent results in cancer research 111, Berlin: Springer-Verlag, 231-249 (1988). Cella DF, Cherin EA: "Quality of life during and after cancer treatment", Comprehensive Therapy 14(5), 69-75 (1988). Brook RH, Ware, JE Jr, Davies-Avery A, Stewart AL, Donald CA, Rogers WH, Williams KN, Johnston SA: "Overview of adult health status measures fielded in Rand's Health Insurance Study", Med Care 17 (Suppl.), 1-131, (1979). Schipper H, Levitt M: "Measuring quality of life: Risks and benefits", Cancer Treat Rep 69, 1115-1123 (1985). Selby PJ, Chapman JAW, Etazadi-Amoli J, Dalley D, Boyd NF: "The development of a method for assessing the quality of life of cancer patients", British Journal of Cancer, 50, 13-22 (1984). Izsak FC, Medalie JH.: "Comprehensive follow-up of carcinoma patients", Journal of Chronic Diseases 24, 179-191 (1971). Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J, Eckberg K, Purl S, Blendowski C, Goodman M, Barnicle M, Stewart I, McHale M, Bonomi P, Kaplan E, Taylor S, Thomas C, Harris J: "The Functional Assessment of Cancer Therapy (FACT) Scale: Development and validation of the general measure", Journal of Clinical Oncology, 11(3), 570-579 (1993). Anderson JP, Bush JW, Berry CC: "Classifying function for health outcome and quality of life evaluation: self- versus interviewer modes", Med Care 24(5), 454469 (1986). Yates, J. W., & Edwards, B: "Practical concerns and pitfalls in measurement methodology", Cancer, 53(10-Suppl), 2376-2379 (1984). Ganz PA, Haskell CA, Figlin RA et al: "Estimating the quality of life in a clinical trial of patients with metastatic lung cancer using the Karnofsky Performance Status and the Functional Living Index-Cancer", Cancer 61, 849-856 (1988). van Dam FSAM, Aaronson NK: "Practical problems in conducting cancer-related psychosocial research", In NK Aaronson & J Beckmann (Eds.): The quality of life of cancer patients. New York: Raven Press (1987). Cella DF, Jacobsen PB, Orav EJ et al: "A brief POMS measure of distress for cancer patients", J Chron Dis 40(10): 939-942 (1987). Stewart AL, Hays RD, Ware JE: "The MOS Short-form General Health Survey: Reliability and validity in a patient population", Med Care 26: 724-735 (1988). Huisman SJ, van Dam FSAM, Aaronson NK, Hanewald GJFP: "On measuring complaints of cancer patients: Some remarks on the time span of the question", In NK Aaronson & J Beckmann (Eds.): The quality of life of cancer patients. New York: Raven Press (1987).

PSORIASIS: PSYCHOSIS OF THE SKIN MARIA DE FEDERICIS and SERGIO LANARI Ospedale Civile Regionale Ancona - Italy

ABSTRACT This research has been carried out on a sample of 39 patients suffering from psoriasis (27 males 12 females from 16 to 83 years of age, of medium-low education). Each patient underwent a Machover Test (Human body Test) and an anamnestic interview both for somatic and psychic information. The research showed, in a high percentage of patients, the following personality features: insecurity, anxiety, conflictual identification of sexual role, psychic rigidity, marked but repressed aggressiveness, difficulty in communicating with the external world. All these features indicate a psychotic personality. On surveying the psoriatic symptom from a merely symbolic point of view, the authors find that some of these elements emergedfromthe Machover Test. Therefore the psoriatic symptom is interpreted as a "Psychosis of the Skin": The patient turns a psychotic illness into a delirium "drawn on the skin".

Psoriasis is a skin disease whose relationship to the psyche has already been extensively described: in few other pathological skin complaints does this intersection of psychic element with the spreading of cutaneous manifestations, appear so clear and consequential. Many authors today classify Psoriasis among pure psychosomatic diseases. Skin disorders such as those that occur in patients suffering from psoriasis can change the relationship both with themselves and with others. Consequently, the person may withdraw from society, experience states of depression and disorders of bodily image as well as developing a feeling of inferiority (1). According to Bahnson's psychodynamic interpretative model, the Psoriatic patient tends to deny his inner conflict, his anxieties, distress and suffering, channelling them through his body, and expressing them by sketching a symptom on his skin. Didier Anzieu observed (2) that every time there was a psychosomatic conversion sustained by the skin, the extent of the cutaneous alteration was proportional to the extent of the mental trauma. We decided to investigate the psychodynamic aspects present in Psoriatic patients with the purpose of outlining some sort of parallel between Psoriasis and psychosis. If it is true, as Bion observed (3) that the actual concept of psychotic personality is not always equivalent to a psychiatric diagnosis, but rather to a pattern of mental behavior, in as much as the psychopathological way of living is in a certain sense, accepted by the psychotic patients, who rather than fighting lives with his illness; we cannot help observing how the same way of living with the illness is found in most Psoriatic patients, who end up showing more pathophilic traits than pathophobic ones concerning their dermatosis. In the personality profiles of the Psoriatic patients we observed, we often discovered psychic rigidity, "that inability to feel emotions, develop personal experiences

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785 and communicate with oneself, which are also so frequently verifiable in the psychotic patients. This disharmony, this conflict, this mechanical feeling, devoid of life and warmth, is common to both personalities. We examined a group of 33 Psoriatic patients (24 male and 9 female) aged between 20 and 83 years who underwent a two-year observation. Regarding the patients' school education: There were eighteen patients who had attended only the Primary school (leaving age 11), seven had attended Primary and Middle school (leaving age 13), two had obtained their Senior school Diploma. One patient had a degree. Four patients had left school during the first years of Primary school, one patient was illiterate. A low academic level itself produces a personality more inclined to express himself through his body than verbally. The patients were first interviewed for their case history: the protective tests MMPI (or Minnesota), Rorschach's test and the Machover test were then carried out. Only a few managed to complete the MMPI test, probably due to their low academic standards and the intrinsic difficulty of the test itself. The Rorschach test evoked so few answers to render an evaluation of the results difficult. However all patients responded to Machover's "human-form" test. We found this test particularly useful for the advantages the figurative activity afforded us in individuals such as Psoriatic patients who are so little disposed to verbal communication. The deeper subconscious functions of the individual are often expressed through a figurative or graphic activity, which is more archaic than the verbal one and therefore nearer to psychosomatic thought. Somatic regression expresses a change from a more differentiated structural level to a more disorganised and undifferentiated state (4). Although a drawing may be conditioned by the expressive ability of the individual, it represents a graphic form which is able to symbolically translate the inner contents of the patients. The following data emerged from the case history and the Machover test: - An insecure ego with a strong sense of inferiority - Dependent personality, often very sensitive to social critisism - A very conflicting identification with sexual role - Mental rigidity - Very marked but inhibited aggressiveness - Anxiety - Difficulty in comunicating and relating to the outside world - Sometimes exhibitionism. We found no dissociative traits, probably due to the fact that these patients have already carried out their dissociation through Psoriasis. We have already pointed out that the essence of psychosis could be characterized by an inability of adequate evaluation of what is real and an emotional detachment from reality. What could be the essence of Psoriasis? The semiological element that best characterizes Psoriasis are of course the scales. (The term Psoriasis itself comes from the Greak Psora meaning scale). These scales cover and hide an underlying Erythema, caused itself by a capillary dilation to such a degree as to take the twisted capillaries of the dermic papilla nearly back to the stratum corneum, giving rise to slight bleeding after removal of the last lamella (Auspitz sign). According to psychosomatic concept every cutaneous symptom can be read symbolically, what symbol could we attribute to the presence of the scales? On further

786 examination of various symbolic interpretation of the cutaneous symptoms (5), we noted that desquamation brings to mind dryness, rigidity, defence; in the same way the Erythema would evoke anger, pain, aggressiveness, while the haematic seeping could stand for separation, a cutting off, difficulty in communicating with the surrounding world. Thus we can highlight symbolically how in a Psoriatic patch a situation of emotional rigidity hides an underlying aggressiveness, conditioned and determined in its turn by a difficulty in relating to the outside world. One could say that the fragile Ego of Psoriatic patients takes its defence behind this armour of scales. The soul Daphne, desperate and furious for the inability to communicate and feel affection, induced by the sorcery of the vengeful god Eros's blunted arrow (6), shuns the life-giving embrace of Apollo the god of beauty and light, to hide peevishly inside the bark of a tree, covering herself with a thick scaly crust. As we saw previously, aggressiveness, mental rigidity and difficulty relating to the outside world, emerged from the personality profiles of our patients. For this reason we would suggest that the Psoriasis skin symptom represented the symbolic equivalent of a psychosis. It has also been observed how the first Psoriatic eruptions coincide with a particularly traumatic event for the Ego, loaded with emotion (a death, the end of a relationship, work problems), situations where the Ego is put hard to the test. We well know from clinical experience that the same events are capable of sparking off a psychotic crisis, because the Ego cannot tolerate the frustrations and face the events that bombard it. In the psychotic mechanism, the fragile and insecure Ego, cannot keep control and becomes disorientated. The distress then invades the whole body. The patient, disorientated in time and space channels his distress through delirious expression. Delirium therefore represents a form of liberation that solves his existential tragedy. In Psoriasis the patient channels his anguish and denied suffering through his body, expressing it by drawing a parakeratosic patch on the skin that we can liberally call a cutaneous delirium or a delirium drawn on the skin. We would go as far as to say that if he had not manifested a Psoriasis, the same patient could have suffered a psychotic crisis. Finally we would like to mention a case, we observed in which the alteration seen in the Machover test appeared parallel to a clinical symptomatological improvement. The case was a 21 year old bachelor, a labourer with a school leaving age of 14. He showed an extensive Psoriatic eruption which had exploded after a series of dramatic family events (a brother who had drowned some years earlier, his mother who had died from cancer more than a year before, and recently the suicide of his father). The patient on admittance showed large patches on the body and limbs. In the Machover test he drew extremely poor (fig. 1), simple figures of" modest dimensions, typical expressions of an insecure and inhibited Ego. After a one-month stay in hospital, in which the young man was made to feel welcome and built up a satisfactory relationship with the other patients and hospital staff, he was discharged clinically cured. On dismissal he sketched a drawing (fig. 2) which showed that he had clearly recovered some aspects of his Ego (a larger drawing with more attention given to detail). Finally we would like to mention how the local ointment cures, abundantly used especially in the initial phase of the therapeutic cycle (in combination with the other cures), probably provided a further beneficial soothing effect. With the removal of the scales of the anguish (that impedes contact with others) and with the attenuation of the Erythema, we remove the anguish which has been

787

converted into a cutaneous symptom and are then able to blanch the repressed aggressiveness (due to lack of communication). The patient will later have to be helped to take possession of his own psyche again: the soul Daphne, victim of Eros's sorcery, which caused her to flee from Apollo's love, hid herself behind a bark of scales. The soul Psyche fell into the underworld of the illness: only the god of love Eros, moved by pity, descending into that darkness, will save her bringing her back to the light.

References * Williams, R., "The psychosocial aspects of Psoriasis", Physiotherapy Canada 36/5, 257-260 (1984). 2

Didier Anzieu, "Le moi peau", Bordas Paris (1985). 3 Grinberg, L., Sor, D., Tabak De Bianchedi, E., "Introduction a las ideas de Bion. Grupos, conocimiento, psicosis, pensamiento, trasformaciones, practica psicoanalitica", Nueva Vision, Buenos Aires (1972). 4 Pancheri, P., "Medicina psicosomatica", in Reda, G.L., "Trattato di psichiatria", USES, Firenze, 216 (1968). 5 Cossidente, A., "II significato psicologico della pelle", in Panconesi, E., "Lo stress le emozioni e la pelle", Masson Milan, 41 (1989). 6 Graves, R , "Greek Myths" (1955).

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Fig. 1 - Patient's drawings on admission to hospital

Fig. 2 - Patient's drawings when discharged

ANXIETY PRE- AND POST-SURGERY: AN EVALUATION IN LAPAROSCOPIC SURGERY RODOLFO FAHRER, M. TARACIUK, B. ORTEGA, J. DIEZ, N. SAKAMOTO Department of Mental Health School of Medicine University Hospital University of Buenos Aires Argentina

ABSTRACT This study was undertaken with patients submitted to Laparoscopic Cholecystectomy. We evaluated: 1) Anxiety pre and post surgery; 2) Relation between the appearance of the somatic symptoms & the psychosocial factors; 3) Pain perception; 4) Expectations regarding surgery. Material and methods: We have studied 52 patients between 19 and 78 years of age, with a mean age of 49 years; 15 men and 37 women. A psychiatrist-psychological interview was effected prior to surgery and a week after we used AXIS V of DSM-III-R and the Hamilton Anxiety Scale. Results: 1) We found more anxiety in the post-surgery period; 2) In 18 patients the relation between the appearance of the somatic symptoms and the psychosocial factors was evident, although the patient himself was not aware of this; 3) 40% of the patients experienced moderate intensity pain, which was more upsetting because of its unexpectedness; 4) All patients were expecting a "magical", pain free and rapid recovery period. Conclusions: Feelings of hostility and anger in those patients (3) who could not be operated with this method and the unexpected pain felt by many of them in the post surgery period have led us to believe that the advertising of this technique and its actual application must be handled with great care. The patient cannot be led to believe that the operation is in any way spectacular or "magical".

After the first cholecystectomy was described in Berlin in 1882, this operation was considered the ideal treatment for patients with symptomatic vesicular lithiasis. Lately with the advance of endoscopic equipment, it has been possible to arrive at laparoscopic cholecystectomy, entering a new era in mini-access surgery. Although pelvian laparoscopic surgery has been employed for many years with good results, some time passed until the general surgeon recognized and accepted this new treatment. The first publications on human laparoscopic cholecystectomy appeared in 1989 and since then this method spread all over the world. Its principled advantages are: greater post surgery comfort; less pain; absence of scars; shorter hospitalization period and expenses; rehabilitation within a week. In Argentina, this surgical method was started in October 1990 and in March 1991 it was adopted in the University Hospital of the University of Buenos Aires. There have been no publications to date on the psychosocial aspects of patients with cholecystectomies via laparoscopies.

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1. OBJECTIVES This study was carried out in the University Hospital of Buenos Aires and patients undergoing laparoscopic surgery were studied in connection with: 1) Anxiety pre and post surgery 2) Relation between the appearance of somatic symptoms and psychosocial stress factors 3) Pain sense 4) Expectations 2. MATERIAL AND METHODS Fifty five patients were studied who were undergoing laparoscopic cholecystectomies, of which 3 were excluded when due to technical difficulties the operation was converted into open surgery. The patients were studied as follows: A) One week before surgery a semi structured psychiatric interview took place, where personal and family data on the patient was collected, the appearance of the disorder, the patient's attitude to it and the treatment proposed. Information of the disease which the patient possessed, as well as the treatment and his expectations were also evaluated, and Hamilton's Anxiety Scale was administered. B) A week later the patients were interviewed again to study their progress which was compared with their previous expectations and the Hamilton Scale applied. 3. PATTERN Fifty two patients were included, 15 men and 37 women. It should be noted that in the general population the incidence of women suffering this disorder is greater. Ages varied from 19 to 78, with an average of 50 years. The socioeconomic level of the patients that visit the University Hospital is middle lower class, of which 56% were born in urban environments, 44% rural. There were 35 married patients, 7 single, 7 widowed and 3 divorced. The educational background included 2 patients with no formal schooling, 6 incomplete primary, 29 complete primary, 6 complete secondary, 6 complete tertiary and 3 university graduates. 4. RESULTS The patients studied were referred by the GP (12 cases), the gastroenterologist (4), the surgeon (5), spontaneously (10), other (family, friends, other patients) (21 cases). Their attitudes towards the treatment proposed: acceptance (21 patients), fear (15), anxiety (8), anger (6), serenity (2) and apathy (none). Their attitudes to the treatment proposed included acceptance (45 patients), doubt (4) and rejection (3). Information regarding surgery was obtained by 29 patients through the physicians, 4 from mass media and 19 through others (family, friends and other patients).

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On inquiring into the reasons for having laparoscopic surgery, in 21 cases this was recommended by a surgeon, in 5 cases by another professional and 26 patients chose this type of surgery because of its rapid recuperation period.

4.1 Pre and Post Surgery Anxiety The pre and post surgical points on the Hamilton Scale which the patients obtained were evaluated through the Wilcox Test for paired samples which evaluates the relative magnitude and the direction of the variables. For this data the differences obtained WERE NOT statistically significant (p = 0.1563; Sum of Negative Traits: 775-5; Sum of Positive Traits: 469.5). In this respect, we observed that during the pre-surgery interviews the patients used defense mechanisms which could decrease the points in the Hamilton Scale. Clinically speaking, the defense mechanisms that predominate are rationalization and isolation. The age of the patients studied should be borne in mind - several over 50 - where we found some rigidity within their defense mechanisms. On the other hand, the little variation of the pre and post surgery Hamilton Test could be due to the failure of the patient's magical expectations - which we will refer to under 4.4. Another important factor in this respect could be the lack of information about the operation: 33% of the patients requested this information from the psychiatric interviewer. 4.2 Relation Between the Appearance of Somatic Symptoms and Psychosocial Stress Factors In accordance with the DSM-IV-R classification referring to the severity of the psychosocial stress factor related to the appearance of the disease, we found that of the 52 patients the factor was: 1. None 16 patients 2. Slight 12 patients 3. Moderate 8 patients 4. Serious 12 patients 5. Extreme 4 patients 6. Catastrophic None Although in most cases we found a trigger factors, in general the patients did not relate the appearance of the disorder to stress except in a few cases. We think that this is related to previous personality. In some patients mechanisms such as negation or lack of contact with their feelings, "Alexithimia". The majority of patients were classified within the DSM-R as Dependent Personality, followed by Histrionic Personalities and lastly the Obsessive Compulsive Personalities. It was also observed that during the post surgery interview conflicts which were hidden in the first interview appeared of if they were present, the patient's whole attention was centered on the operation. Coinciding with the appearance of the disorder or during the year prior to this, we found in 21 patients bereavement for the loss of a family member. In those patients showing a more intense sense of bereavement (as in the loss of a son or the death of several siblings in a short period of time), during post surgery a clinical depression is observed which fits all the items to be classified in accordance with DSM-R as dysthymia.

792

43 Pain Sense In the pre surgery interview, 40 patients indicated that they would not suffer pain and 12 said they could possibly have "some pain". Of the first group, 22 indicated in the post surgery interview that they had pain and of the second group 9 patients suffered pain. Of the 31 patients who reported having had pain, 10 patients had undergone surgery previously, some of them serious operations such as complete lung surgery, hysterectomy, etc.

4.4 Expectations Regarding Surgery All the patients expected a quick recuperation period with no pain, almost magical. Many of them thought that the solving of their organic disorder would also solve other vital problems. For example, they thought that after the operation they would be happy, would lose weight, get rid of menopausal symptoms, that their family would take them more in consideration, solve all their problems and feel well. These magical expectations would explain in part the intense complaints about having suffered pain, and in some cases the appearance of multiple somatic symptoms and the delay in taking up their work and social life.

5. CONCLUSIONS Feelings of hostility and anger in those patients (3) who could not be operated with this method and the unexpected pain felt by many of them in the post surgery period have led us to believe that the advertising of this technique and its actual application must be handled with great care. The patient cannot be led to believe that the operation is in any way spectacular of "magical". This obliges us to be on the alert regarding the care which must be taken when applying this technique and the need to provide the patient with precise and realistic information on this surgery, in order to fit the expectations to reality.

VULNERABILITY TO PSYCHIATRIC DISTRESS IN INDIVIDUALS WITH HIV DISEASE COSTANZO GALA, ANDREA PERGAMI & GIORDANO INVERNIZZI Psychiatric Clinic I Institute of Psychiatry University of Milan Medical School ViaFSforza35 20122 Milan, Italy and JOSE CATALAN & ADRIAN BURGESS Department of Psychological Medicine Chelsea & Westminster Hospital Charing Cross & Westminster Medical School (University of London) Nightengale Place London SW10 9NG, United Kingdom

ABSTRACT The aim of the study was to identify psychosocial factors associated with increased vulnerability to psychiatric distress in HIV seropositive subjects and a control group of HIV seronegative subjects. 279 HIV seropositive subjects belonging to groups II and III defined by the Center for Disease Control (157 intravenous drug users, 94 gay men, 28 heterosexuals) and 159 seronegative subjects (91 intravenous drug users, 38 gay men, 30 heterosexuals) were entered in the study. Outcome measures included socio-demographic data, psychiatric history, current psychological status (Zung Anxiety and Depression scales, Symtom Check List 9 0-Revised), Social Support and Locus of Control Scales, and information on changes in work, social and sexual life after HIV diagnosis and testing. Multiple regression regression analysis were used to study factors predicting psychiatric distress. Results showed that five psychosocial characteristics were associated to vulnerability to psychiatric distress: an external locus of control, significant changes in social life after HIV diagnosis and testing, low social supports, psychiatric history before HIV diagnosis and testing, and low education level.

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794 INTRODUCTION A number of early studies have found significant levels of psychological morbidity and social problems in asymptomatic HIV- seropositive (HIV+ve) and comparable HIV-seronegative (HIV-ve) individuals (1/2)'. It has been suggested that HIV infection itself is not necessarily the main factor in the development of psychosocial distress Factors such as a past psychiatric history (3,4), disease stage (5), hopelessness (4), and early life events in childhood (3) were related to psychological and psychiatric distress, regardless of serostatus and possibly to a greater extent than HIV disease itself. It is therefore important to study further factors which may interact with HIV status and, in so doing, increase the risk of psychological disorders in individuals at risk of HIV infection and in those already infected. As a second part of a controlled study on the psychosocial aspects of HIV infection, we aimed at identifying psychosocial factors associated with increased vulnerability to psychiatric distress in a group of 279 HIV+ve subjects belonging to Center for Disease Control (CDC) group II & III (94 gay men, 157 intravenous drug users, 30 heterosexuals) and a group of 159 HIV-ve controls (38 gay men, 91 intravenous drug users, 30 heterosexuals).

METHODS 1. Subjects: A) Index group (HIV+ve subjects): 348 consecutive attenders seek- ing HIV testing at the Outpatient Department of Infectious Diseases of the University of Milan, Italy were approached and a total of 279 subjects agreed to enter the study (response rate: 80%). All individuals had been tested for HIV antibodies before study entry, and all knew their serological status for some months. B) HIV control group (HIV-ve subjects): 212 consecutive attenders requesting HIV testing at the same centre as the index group and during the same period were approached and a total of 159 subjects agreed to enter the study (response rate: 75%). All subjects had been tested negative for HIV antibodies at the time of interview.

795 MEASURES Socio-demographic data, psychiatric history, current psychological status, social supports, locus of control, changes in social, work, and sexual life after HIV diagnosis and testing were studied and are described elsewhere (6). STATISTICAL ANALYSIS Data were analysed using the Statistical Package for Social Sciences (SPSS-PC). Multiple regression analyses using the SCL 90-R global score as the dependent variable, and socio-demographic data such as age and gender, HIV status, psychiatric history, psychological status, social supports and locus of control, current social, work, and sexual life as independent variables were performed to study factors associated with psychological morbidity.

RESULTS 1) Characteristics of the subjects; A total of 279 HIV+ve subjects, including 101 CDC group II & 178 CDC group III individuals (Index group) and 159 HIV-ve individuals (Control group) were included in the study. The characteristics of the subjects are described elsewhere (6). 2) Factors associated with psychological morbidity: Multiple regression analyses showed that five psychosocial variables: an external locus of control, significant changes in social life after HIV testing and diagnosis, lack of social supports, outpatient-inpatient psychiatric history before HIV diagnosis and testing, and low education level, in this order, were found to be independently associated with the SCL 90-R global score, and to account for 19% of the cumulative variance.

DISCUSSION Our study confirmed that a number of factors may play an important role in the development of psychological morbidity in individuals with HIV disease and in those undergoing HIV testing. The finding that an external locus of control was the first factors associated with psychiatric morbidity is not surprising. This is likely

796 to be determined by the large proportion of drug users in our sample which reflects HIV prevalence in Italy and is in agreement with the evidence that "external" subjects have less favourable scores for psychological status than those with internal coping mechanisms (4) . The second findings showed that our subjects experienced significant changes in social life. Unfavourable social adjustment following HIV diagnosis/testing is not uncommon in individuals undergoing an HIV test (5) and this evidence may explain that perceived lack of social supports was another factor accounting for psychological distress. This latter finding is particularly worrying because may be associated with increased risk of deliberate self-harm acts and suicidal behaviour (7). Past psychiatric history was found once again as one of the major factors predicting vulnerability to psychiatric disturbances in HIV disease emphasizing early and recent studies in different transmission categories (3-7). Finally, it is important to take into accont that subjects a low level of education may have less resources to deal psychologically with problems caused by HIV diagnosis/testing and this may be negatively associated with psychological help-seeking (8). In summary, our findings showed that a variety of psychosocial factors may predict psychiatric morbidity of HIV+ve and HIV-ve subjects. Such predictors of vulnerability to psychological distress could be used to identify and assist people requiring more intensive psychological intervention. ACKNOWLEDGEMENTS Dr A Pergami was supported by a 1990-1993 research clinical grant from the Italian National Institute of Health, Rome, Italy.

REFERENCES 1) Atkinson, J.H., Grant I., Kennedy C.J., et al., Prevalence of psychiatric disorders among men infected with Human Immunodeficiency Virus: a controlled study, Arch. Gen. Psychiatry 45, 859 -864 (1988). 2) Williams, J.B.W., Rabkin, J.G., Remien, R.H., et al., Multidiscipiinary baseline assessment of homosexual men with and without HIV infection. II. Standardized clinical assessment of current and lifetime psychoapthology, Arch. Gen. Psychiatry, 48, 124- 130 (1991).

797 3) Cazzullof C.L., Gala, C , Martini, S., Pergami A., et al., Psychopathologic features among drug addicts and homosexuals with HIV infection, Int'l J. Psychiatr Med., 20, 285-292 (1990). 4) Catalan, J., Klimes, I., Bond, A,, et al., The psychosocial impact of HIV infection in gay men: controlled investigation and factors associated with psychiatric morbidity, Br. J. Psychiatry 161:774-778, (1992). 5) Catalan, J., Klimes, I., Bond, A., et al., The psychosocial impact of HIV infection in men with haemophilia: controlled investigation and factors associated with psychiatric morbidity, J. Psychosom. Res. 36:409-416, (1992). 6) Gala, C , Pergami, A., Catalan, J., et al., The psychosocial impact of HIV infection in gay men, drug users and heterosexuals: controlled investigation, Br. J. Psychiatry 163, 651-659, (1993). 7) Gala, C , Pergami, A., Catalan, J., et al., Risk of deliberate self-harm and factors associated with suicdal behaviour in asymptomatic individuals with HIV infection, Acta Psychiatr. Scand. 86,70-75, (1992). 8) Gala, C , Pergami, A., Catalan, J., et al., Factors associated with psychological help-seeking in HIV disease, J. Psychosom. Res., 36:667-676, (1992).

PSYCHOLOGICAL DISORDERS IN GENERAL MEDICAL SETTINGS: RESULTS OF THE WHO STUDY DAVID GOLDBERG, J. COSTA E SILVA, YVES LE CRUBIER, HANS ORMEL, NORMAN SARTORIUS, BEDIRHAN USTUN, MICHAEL VON KORFF AND ULIWITTCHEN Division of Mental Health, WHO, Geneva

This study reports an identical two stage strategy carried out in 15 centers. 26,000 patients attending general medical clinics were screened, and detailed research assess­ ments were carried out on 5,438 patients in addition to ratings made by the physician seeing the patient. Three methods of case identification - screening questionnaire, re­ search interview (the CIDI) and physician assessment - agreed reasonably well between themselves about the level of disorder in each center. 24% of consecutive attenders were found to have psychological disorders according to ICD-10, and 8% had multiple mental disorders. There was considerable variation between centres, with Santiago report 53% and Shanghai reporting only 7.3% Pains and other somatic complaints account for 61.2% of presenting complaints, with complaints about sleep and fatigue a further 6.9%, and psychological complaints only 5.2%. There is no centre where mental disorders usually present with psychological complaints: the highest is Santiago, and even here only 13.2% present in this way. There is a wide spread of prevalence rates for depressive illness, with Santiago, Rio, Groningen, Manchester and Paris being well above the mean, and Verona, Nagasaki, Shanghai and Ibadan being well below it. Educational level has a significant effect upon the prevalence of depression, with those having had the most years of full-time education having lower rates than those who are educationally disadvantaged. Rates for anxiety also vary widely, with Ankara, Shanghai, Seattle and Ibadan all having very low rates, and the two South American centers very high ones. Anxiety is more prevalent among the least educated; but now there are also significant effects for physical ill-health and parity as well, with both of these variables being significantly associated with anxiety. It is notable that anxiety is much more common than depression in Rio, Nagasaki and Athens, while the reverse is true for Groningen and Ankara. The commonest mental diagnosis was current depression, with an overall prevalence of 10.4%; after this came generalized anxiety (7.9%), neurasthenia (5.4%), harmful use of alcohol (3.3%) and somatization disorder (2.8%). Only 50.1% of the mental disorders were recognized by the treating physician: rec­ ognition [as mental disorders, not as specific diagnoses] was highest for agoraphobia (68%); then somatization disorder (64%); panic disorder (62.5%); dysthymia (61%); hypochondriasis (60%); current depression (54%); neurasthenia (48%); generalized anx­ iety (46%); alcohol dependence (45%) and harmful use of alcohol (33%). Recognition was highest in most European centers and centers in the Americas. Drug treatment was prescribed in 51.3% of recognized cases: sedatives were pre­ scribed more often than anti-depressants (26% versus 15%). Antidepressants were pre­ scribed in only 22% of recognized cases of depression, and in 21% of recognized cases of anxiety. 52% of cases were treated with discussion or counselling, and 11.6% of recog­ nized cases were referred to a mental health professional.

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PREVALENCE OF PSYCHOSOCIAL MORBIDITY IN SPINAL CORD INJURED PATIENTS MARINA LOBERA l/nidad de Lesionados Medulares, Servicio de Rehabilitation, Hospital Miguel Servet, Paseo Isabel la Catolica, 50009 Zaragoza, Spain and

PEDRO SAZ, ANTONIO LOBO Servicio de Psiquiatria, Hospital Clinico Universitario y (Jniversidad de Zaragoza San Juan Bosco, 50009 Zaragoza, Spain.

ABSTRACT Rationale: To study the prevalence and clinical profiles of psychiatric morbidity and social problems in spinal cord injured patients; to analyze the relationships between injury factors and psychosocial problems. Methods: We studied 185 patients from the Spinal Cord Unit of the Hospital Miguel Servet, in Zaragoza, Spain. Two phases screening: First phase: Socio-demographic and medical data. A screening battery, which includes Spanish versions of the General Health Questionnaire (GHQ-28), the Goldberg's Anxiety and Depression Scales (EADG) and the Social Problems Questionnaire (SPQ), was administered. Second phase: The psychiatric "cases" and a control group of "probable noncases" were assessed with the Standardized Polyvalent Psychiatric Interview (SPPI), a new structured psychiatric interview which generates DSM-III-R diagnosis. Results (First phase data): 48.6% of patients scored as psychiatric "cases" (GHQ criteria). With the EADG, the prevalence rate was 59.5% (the anxiety scale identified 45.9% "cases" and the depression scale identified 51.9% "cases"). In respect to social problems, 50.8% of patients scored as SPQ "cases". Both, the psychiatric and the social problems prevalence rates tended to be slightly higher in men when compared with women; in the 56-65 years age-group when compared with other age-groups; and in the acute patients when compared with the chronic ones; however, only in this last comparison the differences were statistically significant.

1. INTRODUCTION In developped countries, the prevalence of spinal cord injuries are becoming more and more frequent 1. In Spain, the Asociacion de Paraplejicos y Minusvalidos (Aspaym) documented that twenty new cases per million inhabitants are registered every year. The impact of this catastrophic injury, mainly in respect to the development of psychopathology and social problems, and its influence on outcome and on the rehabilitation process, have attracted a great deal of interest2. But few studies with standardized methods have been reported3-6. The principal aims of this study were: 1. To determine the prevalence and characteristics of psychopathology and social problems in spinal cord injured patients. 2. To analyze the relationships between spinal cord injury variables and psychosocial problems.

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2. METHODS 2.1 Study Subjects One hundred and eighty five patients from the Spinal Cord Unit, Hospital Miguel Servet, in Zaragoza (Spain) were evaluated. Approximately two thirds (69.3%) of them were men and the mean age was 44.6 ± 16.5 years (range 16-82; four children under 15 years were previously removed from this study sample).

2.2 Case finding procedures and study design An epidemiological, two phases screening study was designed: In phase I, socio-demographic and medical data were collected. A screening battery, which includes, among other instruments, Spanish versions of the General Health Questionnaire (GHQ-28)'-8, the Goldberg's Anxiety and Depression Scales (EADG)9"10 and the Social Problems Questionnaire (SPQ)11"12, was administered. The individuals were designed to be "probable psychiatric cases" on the basis of GHQ and/or EADG scores, with the standard cut-off points. The "probable cases" and a 10% control group of "probable non-cases" were then examined in Phase II with the Standardized Polyvalent Psychiatric Interview (SPPI)13, a new structured psychiatric interview to assess patients in a multiaxial schema; it also generates DSM-III-R diagnosis. We also administered an original questionnaire about patients' attitudes and illness behaviour.

3. RESULTS AND DISCUSSION A total of 48.6% of psychiatric "cases" (GHQ criteria) were found in phase I. This rate is rather high, but we have previously raported even higher rates in some medical wardsl4. However, authors such as Mayou & Hawton15, have argued that the rates in spinal cord injured patients tend to be higher than in other general hospital patients. Table I shows the distribution of GHQ scores: in "non-cases" (0-5 points, according with the Spanish standard cout-off point) and "cases" (mild, 6-11 points; moderate, 12-17 points and severe ones, 18+ points). The prevalence of psychiatric disturbance was higher in acute patients (=< 8 months after spinal cord injury, 70.4%) than in chronic patients (>8 months after lesion, 41.8% of prevalence). These data did not differ from those documented by Krause & Crewe16. The GHQ prevalence rates were slightly higher in men (50.0% of "cases") compared with women (44.8%). It was also higher in the age-group 56-65 years. However, the differences did not reach statistical significance.

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TABLE I. PREVALENCE OF PSYCHIATRIC DISTURBANCES (GHQ CRITERIA), BY TIME SINCE SPINAL CORD INJURY. Caseness

GHQ Scores

Acute Pts. %

N

Chronic Pts. % N

N

%

Total

"Non-case"

0-5

13

29.5

82

58.2

95

51.3

Mild Moderate Severe

6-11 12-17

11 15 5

25.0 34.1 11.4

32 17 10

22.7 12.1

43 32 15

23.2 17.3 8.1

44

100.0

141

100.0

18+

TOTAL

7.1

185 100.0

We identified 85 "cases" (45.9%) with the anxiety scale of Goldberg's EADG and 96 "cases" (51.9%) with the depression scale (Table II). In total, 110 "cases" (59.5%) were identified by the EADG either with the anxiety scale, the depression one or both together. Judd et al have reported considerably lower depression rates 5 * 17 in spinal cord injured patients, but they studied only 71 individuals. On the other hand, our results are similar to those published by Frank et al 4 . Anyway, as these results derived from our screening phase, they should be interpreted with caution until SPPI data analysis is done. Again, we found that psychopathology was more frequent in acute patients when compared with chronic ones (Table II). TABLE II. PREVALENCE OF ANXIETY AND DEPRESSION PROBLEMS, MEASURED WITH EADG, BY TIME SINCE SPINAL CORD INJURY. Caseness

Acute Pts. N %

Chronic Pts. N %

Total N

%

Anxiety

"Non-cases" "Cases"

19 25

43.2 56.8

81 60

57.4 42.6

100 85

54.1 45.9

Depression

"Non-cases" "Cases"

18 26

40.9 59.1

71 70

50.4 49.6

89 96

48.1 51.9

Finally, only 50.8% of patients scored as SPQ "cases", despite of the severe dependence and adjustment problems that the spinal cord injury implies. As Table III reveals, the social problems prevalence is also higher in acute when compared with chronic patients. According to Lundqvist et al 18 and Krause19, during the first year after discharge (8-20 months after injury) the prevalence of social dificulties increases to maximum values. As expected, the main problems identified by the SPQ were in the occupational and economical areas, being the family problems considerably less frequent.

802 TABLE III. PREVALENCE OF SOCIAL PROBLEMS (SPQ CRITERIA), BY TIME SINCE SPINAL CORD INJURY. 8 - 2 0 months (n=12) N %

>20 months (n=134) N %

Total (n=185) N %

SPQ Scores

=