Table Of ContentNEUROSCIENCE PERSPECTIVES
Editor: Peter Jenner
Pharmacology Group
Biomedical Sciences Division
King's College London
Manresa Road
London SW3 6LX
Forthcoming titles in this series:
Roger Horton and Cornelius Katona (eds). Biological Aspects of Affective
Disorders
Judith Pratt (ed),The Biological Bases of Drug Tolerance and Dependence
Trevor Stone (ed), Adenosine in the Nervous System
Biological Aspects
of Affective Disorders
edited by
R.W.Horton
Department of Pharmacology & Clinical Pharmacology
St George's Hospital Medical School
London, UK
and
C.L.E. Katona
Department of Psychiatry
University College & Middlesex School of Medicine
London, UK
ACADEMIC PRESS
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United States Edition published by
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This book is printed on acid free paper
Copyright © 1991 by Academic Press Limited
All Rights Reserved
No part of this book may be reproduced in any form by photostat, microfilm, or any other
means, without written permission from the publishers
A catalogue record for this book
is available from the British Library
ISBN 0-12-356510-3
Typeset by P&R Typesetters Ltd, Salisbury, UK
Printed and Bound in Great Britain by
the University Press, Cambridge
Contributors
Janis L. Anderson Laboratory for Circadian & Sleep Disorders Medicine
Brigham & Women's Hospital and Harvard Medical School, 221 Longwood
Avenue, Boston, MA 02115, USA
Dennis S. Charney Department of Veterans Affairs Medical Center &
Department of Psychiatry, Yale University School of Medicine, West
Haven, Connecticut 06515, USA
S.C. Cheetham Boots Pharmaceuticals Research Department, R3, Pennyfoot
Street, Nottingham NG2 3AA
Pedro L. Delgado Department of Veterans Affairs Medical Center &
Department of Psychiatry, Yale University School of Medicine, West
Haven, Connecticut 06515, USA
J.M. Elliott Department of Pharmacology & Toxicology, St Mary's
Hospital Medical School, Norfolk Place, London W2 IPG
Hugh Gurling Molecular Psychiatry Laboratory, Academic Department
of Psychiatry, University College & Middlesex School of Medicine, Riding
House Street, London W1P 7PN
R.W. Horton Department of Pharmacology & Clinical Pharmacology,
St George's Hospital Medical School, London SW17 ORE
C.L.E. Katona Department of Psychiatry, University College & Middlesex
School of Medicine, London WIN 8AA
Stephen Merson St Charles' Hospital, London W10 6DZ
James C. Pryor Department of Psychiatry, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, USA
Larry Rifkin Molecular Psychiatry Laboratory, Academic Department of
Psychiatry, University College & Middlesex School of Medicine, Riding
House Street, London W1P 7PN
Sir Martin Roth Professor Emeritus of Psychiatry, Academic Department
of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Hills
Road, Cambridge CB2 2Q&
Trevor Silverstone Professor of Clinical Psychopharmacology, Medical
College of St Bartholomew's Hospital, University of London, London EC1
Fridolin Sulser Departments of Psychiatry & Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232, USA
Peter Tyrer St Charles' Hospital, London W10 6DZ
Anna Wirz-Justice Chronobiology Laboratory, Psychiatrische Universi
tätsklinik, Wilhelm Klein Strasse 27, CH-4025 Basel, Switzerland
ix
Series Preface
The driving force for the production of this series lies in my own inability to
keep up with the advances occurring in those areas of neuroscience in which
I am especially interested. So many times I have been frustrated by being
unable to find a current review of an important research area. Even when I
resort to bothering colleagues who are experts in a particular field, I am told,
more often than not, that such an overview does not exist. In my own area
of expertise I frequently send away students empty-handed who have asked
me to direct them to a definitive article on a well researched topic.
Although regretable, perhaps this situation is not surprising since the
neurosciences are one of the most diverse and rapidly advancing areas in the
biological sphere. By definition research in the neurosciences encompasses
anatomy, pathology, biochemistry, physiology, pharmacology, molecular
biology, genetics and therapeutics. Indeed, there are few individuals capable
of maintaining a grasp of the literature in all these aspects of their own research
interests let alone in other fields.
My answer was to establish Neuroscience Perspectives and to develop gradually
a series of individual edited monographs dealing in depth with issues of current
interest to those working in the neuroscience area. Each volume is being
designed to bring a multidisciplinary approach to the subject matter by
pursuing the topic from the laboratory to the clinic. As a consequence I have
asked the editors of the individual volumes to produce a balanced critique of
their topic which will be read, understood and enjoyed by as wide an audience
as possible within the realm of neuroscience.
The choice of the topics for the series is a difficult matter. In the first
instance these were largely dictated by my own interests or by my awareness
of important and fundamental work being undertaken by colleagues. More
recently, I have been recruiting subject matter and editors through attending
a variety of diverse symposia in the neuroscience area. However, the choice
of topics should reflect the needs of the audience reached by the series. So I
invite you to let me know of areas which you feel are of importance and to
give me suggestions for individuals who would be keen to edit a book for
Neuroscience Perspectives.
Finally, it only remains to thank those individuals at Academic Press who
have already worked for several years to develop Neuroscience Perspectives. In
particular, Dr. Carey Chapman who has the unenviable task of recruiting
the editors that I suggest and then harassing them for the completed work.
My hope is that the series will fill the gap that I perceive and provide for my
colleagues in the neurosciences a collection of interesting books which will
become reference volumes in their field. I hope you will enjoy Neuroscience
Perspectives.
Peter Jenner
xi
Preface
Biological research in the affective disorders has been an international growth
industry for several years. Researchers in the field come from a wide variety
of scientific disciplines and there has been relatively little integrative work,
particularly between preclinical and clinical approaches.
This volume attempts to bring together up-to-date reviews from a number
of distinguished research groups, in order to provide a comprehensive
introduction to our current understanding of the clinical features and
management of patients with depression and mania, as well as of the biological
abnormalities that may underlie their disease.
Roth provides a comprehensive review of the classification of affective
disorders, incorporating not only his own distinguished contribution but also
the theoretical framework of current European and American classificatory
systems. Merson and Tyrer address the practicalities of physical treatment,
and Silverstone provides an account of the clinical features and biological
aspects of mania, a relatively neglected area of research.
Pryor and Sulser describe the evolution of this monoamine hypothesis which
has dominated our thinking since the early 1960s and is likely to do so into
the 21st century. Research on neurotransmitter abnormalities in depression
has used three main strategies, which are covered in the next three chapters.
Studies of peripheral blood components have been widely used as accessible
models for neurones: Elliott describes the rationale for such work and
summarises results to date. Delgado and Charney describe the neuroendocrine
challenge tests that have been developed as 'windows' through wh:ch
neurotransmitter function has been examined; and Cheetham et al. describe
the current state of post-mortem brain research, the most direct and yet
under-utilised approach to brain abnormalities in depression.
The final chapters review emerging research using more novel approaches
likely to become increasingly fruitful in the coming years. Anderson and
Wirz-Justice provide a lucid guide to the complex theoretical framework of
research into abnormal biological rhythms in depression. Rifkin and Gurling
review the most fundamental of recent advances: the shift of focus from
neurotransmitter to genetic substrate.
We have chosen areas in which important research is certain to continue.
We have not included areas which, though of undisputed clinical importance
have yet, in our view, to 'come of age' as areas of biological research. In
particular, it is likely that the next few years will see important advances in
the application of novel neuroimaging techniques in affective disorder. Our
primary aim is that this volume should serve as a sourcebook for young
researchers from all disciplines contributing to our evolving understanding of
the biology of depression.
We would like to thank Dr. Carey Chapman of Academic Press for her
patience and encouragement.
R.W. Horton and C.L.E. Katona
xiii
CHAPTER 1
CLASSIFICATION OF AFFECTIVE AND
RELATED PSYCHIATRIC DISORDERS
Sir Martin Roth
Academic Department of Psychiatry, University of Cambridge,
Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
Table of Contents
1.1 Introduction 3
1.2 Psychiatric Classification and the 5
Hierarchical System
1.3 Levels of Classification of Affective and 6
Anxiety Disorders
1.4 Differentiation of Depressive (or Anxious) 6
Disorder from Normal Variation in Mood
1.4.1 Normal affective states 6
1.4.2 Minor disorders and threshold conditions 7
1.4.2.1 Minor depression 7
1.4.2.2 'Below threshold' and 'post-threshold' neurotic 7
depression
1.5 Psychotic, Endogenous and Neurotic 7
Affective Disorders (Level II)
1.5.1 Psychotic and endogenous depression 7
1.6 Bipolar and Unipolar Depression and 11
Neurotic Depression (dysthymia in DSM-III-R)
1.6.1 Criteria for the diagnosis of major depression 11
1.6.2 Differentiation of bipolar and unipolar endogenous 13
depressions from neurotic depressions (Level III)
1.6.3 Similarities and differences between bipolar and unipolar 15
endogenous depression (Level III)
1.7 Bipolar Endogenous Depression (Level IV) 17
1.7.1 Bipolar I 17
1.7.2 Bipolar II 17
1.7.3 Bipolar III 18
1.7.4 Recurrent mania 18
1.7.5 'Mixed'bipolar disorder 18
1.7.6 Paranoid manic psychosis 19
1.7.7 Cyclothymic disorder (DSM-III-R) 19
1.8 Expanded Bipolar Spectrum 21
BIOLOGICAL ASPECTS OF AFFECTIVE DISORDERS Copyright © 1991 Academic Press Limited
ISBN 0-12-356510-3 All rights of reproduction in any form reserved
Sir Μ. Roth
1.8.1 'Episodic'group 21
1.8.2 Persistent and intermittent group 21
1.8.2.1 Chronic mania 21
1.8.2.2 Cyclothymia 22
1.8.2.3 Protracted 'mixed' states 22
1.8.2.4 The irritable temperament 22
1.8.2.5 Subaffective dysthmia 23
1.8.2.6 The hyperthymic temperament 23
1.8.2.7 Continuous and rapidly cycling variants of bipolar 23
disorder
1.9 Distinction between Unipolar and Bipolar 24
Disorders
1.10 Neurotic Depression (dysthymiain DSM-III-R) — Level IV 25
1.10.1 Other concepts of premorbid personality in neurotic 27
depression
1.11 Anxiety Disorders 28
1.11.1 Generalized anxiety disorder 28
1.11.2 Somatic illness anxiety disorder 29
1.11.3 Agoraphobia 29
1.11.4 Panic disorder 30
1.11.5 Social phobia 30
1.11.6 Simple phobia 31
1.11.7 Obsessive-compulsive neurosis 31
1.11.8 Post-traumatic stress disorder 31
1.12 Anxiety and Depression 31
1.12.1 Relationship of anxiety to depressive disorders (Level IV) 31
1.12.2 The co-morbidity of depressive disorders with panic 34
and agoraphobic disorders
1.13 Atypical Psychoses Related to the Affective 35
and Anxiety Disorders
1.14 Conclusions 38
1.14.1 Need for openness and experiment in relation to systems 38
of classification
1.14.2 Conflict between taxonomic orthodoxy and the 39
objectives of scientific enquiry
1.14.3 Conflict between official classification and clinical 40
practice
1.14.4 Rift between the new and old concepts of disorders of 40
affect
2
Classification of affective and related psychiatric disorders
1.1 Introduction
The introduction by Meduna of the first effective physical treatment for
depressive illness in the 1930s and its later transformation into electro
convulsive therapy (ECT) by Cerletti and Bini provided a powerful stimulus
to enquiries into the classification of depressive and related forms of psychiatric
disorder. The new treatment proved highly successful in certain forms of
depression, less successful in others, and in a proportion of patients with
affective disorders symptoms were unrelieved or exacerbated. In these cases
the therapy was contraindicated. It seemed essential to differentiate classes
of patients in whom the treatment could be expected to promote recovery
from those in whom little or no alleviation of symptoms would follow.
A reliable classification for purposes of prediction became an even more
pressing need with the discovery of pharmacological treatments for depression.
The antidepressant action of iproniazid was discovered by Crane (1957) and
Kline (1958) and the first report of the efficacy of Imipramine was published
in 1958 by Kuhn. In the early clinical trials iproniazid was reported to be
effective in endogenous depression (Kiloh et al., 1960) and Imipramine more
successful in endogenous than in non-endogenous depression (Kiloh et al.,
1962), but a substantial proportion of those with neurotic depressions were
improved. Numerous other trials followed.
Psychopharmacology soon provided one powerful means of testing the
validity of models of classification within the domain of the affective disorders.
However, findings from controlled trials of treatment alone could rarely
provide decisive answers to questions posed and results had to be interpreted
with caution.
Investigation of the effects produced by the new drugs also led to the
formulation of pharmacological and biochemical hypotheses regarding the
biological causes of disorders of affect. It became clear that their submission
to stringent tests demanded the assembly of homogeneous cohorts of patients
selected with the aid of reliable diagnostic criteria to ensure that significant
findings would not be obscured by 'noise'.
It was in the halcyon years between 1949 and 1960 that most of the
discoveries of contemporary clinical psychopharmacology were made. The
imagination of many clinicians and basic scientists was stirred by the
introduction into psychiatric practice of effective treatments for schizophrenia,
depressive illness and anxiety disorders; in all these forms of illness the efficacy
of the drugs previously available for the alleviation of suffering had been
dubious or inadequate and their administration in some cases ascribed
unacceptable hazards or side-effects.
It became increasingly apparent that more objective and replicable systems
3
Sir Μ. Roth
of diagnosis and classification were needed to promote scientific progress in
psychiatry. Many ideas were advanced during this period. The most detailed
and comprehensive taxonomy to evolve was the third version of the Diagnostic
and Statistical Manual of the American Psychiatric Association (DSM-III;
American Psychiatric Association, 1980). This classification, and the modified
version that followed (DSM-III-R), was subjected to considerable criticism
within the USA as well as in many other countries (Spitzer and Williams,
1983) but it succeeded in gaining worldwide acceptance by many psychiatrists
in research and clinical practice.
Its beginnings can be traced to a set of diagnostic criteria, developed in
the Department of Psychiatry at Washington University, St Louis, for a limited
number of psychiatric disorders in relation to which there was sufficient
evidence for criteria for inclusion and exclusion of cases to be formulated
(Feighner et ai, 1972). Definitions for depressive illness, anxiety states and
some personality disorders were included. The central objective was to refine,
objectify and improve replicability of diagnoses in clinical research. The
Feighner criteria were followed by the Research Diagnostic Criteria (RDC)
of Spitzer et al. (1978a, 1978b), again intended mainly for the use of
investigators. After a period of field trials the publication of DSM-III followed
in 1980. It provided operational criteria for diagnosis and a system of
classification for all classes of psychiatric disorder. It had been endowed with
a new identity as an instrument for everyday clinical practice as well as
research.
Among the features claimed for the classification were its 'atheoretical'
nature and its reliability as proved in the course of extensive field trials. The
former represented a reaction against the psychoanalytic concepts of causation
which had inspired DSM-II, the classification that had preceded DSM-III.
The creators of DSM-III had come to regard these concepts as unfruitful,
unscientific, conjectural and obsolete. They were therefore expunged from
DSM-III.
As regards the second feature, the new diagnostic definitions were
undoubtedly a forward step towards reliability and replicability of clinical
observations. However, a high measure of agreement among a group of
individuals with a common interest in creating a new diagnostic instrument
does not establish scientific reliability in the more general context of clinical
practice in a variety of settings. The influence of psychoanalysis may have
been largely expunged, but it is open to question whether it is possible to
create a theory-free taxonomy of psychiatric disorders. Certain theoretical
concepts are clearly discernible, for example in the egalitarian categorical
system into which the syndromes under Axis I are classified.
We shall encounter some of these undeclared theoretical assumptions as we
consider the separate stages in the classification of affective disorders in the
sections that follow.
4
