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Melancholia

This book provides a comprehensive review of melancholia as a severe disorder of mood,

associated with suicide, psychosis, and catatonia. The syndrome is defined with a clear
diagnosis, prognosis, and range of management strategies, diVerentiated from other similar
psychiatric, neurological, and general medical conditions. It challenges accepted doctrines in
the classification and biology of the mood disorders and defines melancholia as a treatable
mental illness. Described for millennia in medical texts and used as a term in literature and
poetry, melancholia was included within early versions of the major diagnostic classification
systems, but lost favor in later editions. This book updates the arguments for the diagnosis,
describes its characteristics in detail, and promotes treatment and prevention. The book oVers
great hope to those with a disorder too often misdiagnosed and often fatal. It should be read by
all those responsible for the management of patients with mood disorders.

Michael Alan Taylor is Professor of Psychiatry Emeritus at Rosalind Franklin University of

Medicine and Science, North Chicago, IL and Adjunct Clinical Professor of Psychiatry at the
University of Michigan School of Medicine, Ann Arbor, MI, USA.

Max Fink is Professor of Psychiatry and Neurology Emeritus at the State University of New
York at Stony Brook, USA.
Melancholia
The diagnosis, pathophysiology, and
treatment of depressive illness

Michael Alan Taylor, M.D.

Professor of Psychiatry Emeritus at Rosalind Franklin
University of Medicine and Science, North Chicago, IL,
and Adjunct Clinical Professor of Psychiatry at the
University of Michigan School of Medicine,
Ann Arbor, MI, USA

Max Fink, M.D.

Professor of Psychiatry and Neurology Emeritus,
State University of New York at Stony Brook, USA
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo

Cambridge University Press

The Edinburgh Building, Cambridge CB2 8RU, UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521841511

© M. A. Taylor and M. Fink 2006

This publication is in copyright. Subject to statutory exception and to the provision of

relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Cambridge University Press.
First published in print format 2006

ISBN-13 978-0-511-22105-7 eBook (NetLibrary)

ISBN-10 0-511-22105-3 eBook (NetLibrary)

ISBN-13 978-0-521-84151-1 hardback

ISBN-10 0-521-84151-8 hardback

Cambridge University Press has no responsibility for the persistence or accuracy of urls
for external or third-party internet websites referred to in this publication, and does not
guarantee that any content on such websites is, or will remain, accurate or appropriate.
 Contents

List of patient vignettes page ix

Preface xi
Acknowledgments xv

1 Melancholia: a conceptual histor y 1

Origins of the concept 2
The psychodynamic interruption 6
The recognition of melancholia in psychiatric classification 7
Notes 10

2 Melancholia defined 15
Melancholy 15
Manic-depressive illness 18
Psychotic depression is melancholia 24
Depression with catatonia or stupor is severe melancholia 30
Melancholia defined by a specific event 32
Notes 37

3 Defining melancholia by psychopathology 45

DSM depression categories and diagnostic criteria 46
Consensus and empirical approaches defining a syndrome 51
Psychopathology data supporting the validity of melancholia 53
The nature of melancholia 56
Conclusions 58
Notes 59

4 Defining melancholia: laborator y tests 62

Neuroendocrine measures in mood disorders 62
The hypothalamic–pituitary–adrenal axis 64
The hypothalamic–pituitary–thyroid axis 72
Electrophysiologic measures 72

v
vi Contents

Conclusions 76
Notes 78

5 Examination for melancholia 85

Examination strategy 86
Examining mood 87
Examining psychomotor functioning 88
Examining for vegetative signs 88
Examining for psychotic features 89
Examining for suicidal thoughts 90
Examining cognition 90
Examining for personality disorder 91
Rating scales of depression 91
Notes 95

6 The diVerential diagnosis of melancholia 97

Non-melancholic depressive mood disorders 97
Melancholia in children and adolescents 103
Melancholia in the elderly 104
Melancholia in a patient with a psychotic disorder 106
Distinguishing melancholia from anxiety and
obsessive-compulsive disorders 108
Distinguishing melancholia from drug-related depressive-like states 109
Melancholia associated with general medical illnesses 110
Avolitional, apathetic, and bradykinetic syndromes 112
Neurologic disease associated with apathy and
depression-like syndromes 113
Notes 118

7 Suicide in melancholia 125

Errors in suicide prevention 126
Suicide risk assessment 134
The eVect of specific treatments on suicide rates 139
Management of the suicidal melancholic patient 143
Notes 146

8 Electroconvulsive therapy for melancholia 153

ECT in melancholia 155
ECT for psychotic depression 157
ECT and suicide risk 159
ECT for catatonia and depressive stupor 161
ECT in pregnancy and postpartum depression 163
ECT in children and adolescents 165
ECT in the elderly 170
ECT and characterological conditions 171
vii Contents

ECT in unipolar and bipolar depression 172

Conclusion 174
Notes 174

9 Achieving eVective ECT 181

Patient selection 181
Technical considerations 183
Conclusions 190
Notes 190

10 The validity of the pharmacotherapy literature in melancholia 196

Industry influence undermines conclusions about newer agents 197
Head-to-head comparisons are biased to favor newer drugs 199
Antidepressant drug eYcacy: TCA versus pure SSRI 201
Antidepressant drug eYcacy: pure SSRIs compared to non-TCA agents 204
Conclusions 206
Notes 207

11 Basic pharmacotherapy for melancholic patients 211

Acute treatment 212
Combining drugs and psychotherapy 218
Continuation and maintenance treatment 219
Pharmacotherapy for melancholia 220
Treatment of severe melancholia 222
Optimizing treatments for manic-depressive illness 229
Notes 231

12 Pharmacotherapy for melancholic patients in

complicating circumstances 239
Melancholia in pregnancy and breast-feeding 239
Melancholia in childhood and adolescence 244
Melancholia in old age 250
Melancholia with co-occurring alcohol or drug abuse 255
Melancholia with co-occurring neurologic disease 257
Melancholia co-occurring with general medical conditions 261
Melancholia with co-occurring personality disorder 265
Summary recommendations 266
Treatment-resistant depression 268
Notes 273

13 Proposed treatments for melancholia 284

Light therapy 284
Transcranial magnetic stimulation 286
Magnetic seizure therapy (MST) 288
Vagal nerve stimulation (VNS) 289
viii Contents

Glucocorticosteroid receptor agonists 289

Targeted neurotransmitter system agents 290
Hormones 291
Herbal remedies 292
Notes 294

14 The pathophysiology of melancholia 298

Genetic predisposition 299
Environmental factors 303
Abnormal stress response 307
Abnormal neurochemical functioning 311
Abnormal brain structure 317
Abnormal brain metabolism 318
Electrophysiologic abnormalities 320
Cognitive deficits 327
Why some melancholic patients have manic episodes 328
Conclusions 330
Notes 333

15 Future directions 346

Changing the DSM classification of depression 347
Changing the DSM diagnostic criteria for melancholia 348
Changing the standards of pharmacotherapy research 349
Changing treatment guidelines: endless drug trials elicit chronicity 351
Improving the education of medical practitioners in mood disorders 351
Studies of the mechanism of convulsive therapy 353
Preventive approaches to reduce the burden of melancholia 354
Pharmacogenetics 359
The pathophysiology of melancholia 360
Coda 364
Notes 365

References 371
Index 522
 Patient vignettes

2.1 A woman with melancholia (Hopewell-Ash) page 17

2.2 A woman with melancholia (Hopewell-Ash) 17
2.3 A man with melancholia (Hopewell-Ash) 17
2.4 A woman with melancholia (Hopewell-Ash) 17
2.5 A woman with cycloid psychosis (Hopewell-Ash) 22
2.6 A man with a psychotic melancholia (DSM-IV Casebook) 28
2.7 A man with psychotic melancholia (Fink) 28
2.8 A woman with Cotard syndrome (Hansen and Bolwig) 29
2.9 A woman with melancholia (Taylor) 30
2.10 A catatonic woman with psychotic melancholia (Kalhbaum) 31
2.11 A 15-year-old girl with psychotic melancholia and catatonia (Hoch) 32
2.12 A woman with a postpartum melancholia (Protheroe) 35
2.13 A woman with postpartum melancholia (Hamilton) 35
3.1 A man with an apathetic frontal lobe syndrome meeting criteria for major
depression (Vaidya and Taylor) 49
5.1 A melancholic man with a psychotic depression (Taylor) 89
6.1 An epileptic man with brief depressions (Taylor) 116
7.1 An 87-year-old woman with a psychotic depression (Taylor) 128
7.2 A 44-year-old melancholic man misdiagnosed with PTSD who committed
suicide (Taylor) 130
7.3 A hospitalized depressed woman with a suicide plan (Taylor) 131
7.4 A melancholic woman who received poor treatment (Taylor) 132
7.5 A 30-year-old man with a ‘‘postpartum’’ melancholia (Taylor) 133
7.6 A man who refused hospitalization and committed suicide (Taylor) 133
7.7 A 70-year-old man who hanged himself (Taylor) 137
7.8 A 21-year-old woman who made a suicide attempt following a
psychodynamic interview (Taylor) 145
8.1 A 66-year-old woman with melancholia (Fink) 157
8.2 A professor of surgery describes his psychotic depression (Nuland) 158
8.3 A former medical school dean describes his depression (Rosenberg) 160
8.4 A 58-year-old woman with melancholia and catatonia misdiagnosed as
having Alzheimer’s disease (Fink) 162
ix
x Patient vignettes

8.5 A psychotically depressed mother who killed her five children

(Ottosson and Fink) 164
8.6 A 16-year-old boy with melancholia unresponsive to medications and
psychotherapy who responded to ECT (Fink) 168
8.7 A 17-year-old boy with manic delirium who responded to ECT (Fink) 168
8.8 An 8 1/2-year-old girl with melancholia and catatonia, unresponsive to
medications, who responded to ECT (Cizadlo and Wheaton) 169
8.9 A 76-year-old melancholic man with a recent surgical repair of an aortic
aneurysm who responded to ECT (Fink) 170
8.10 A 68-year-old man with Parkinson’s disease and depression who
responded to ECT (Fink) 171
8.11 A woman with hypochondriasis (Roueché) 171
8.12 A woman with manic-depressive illness (Sienaert and Peuskens) 173
11.1 A man with a psychotic depression (Taylor) 223
12.1 A pregnant woman with a psychotic depression (Taylor) 240
12.2 A 78-year-old depressed woman; antidepressant medication-associated
status epilepticus (Taylor) 253
12.3 A 26-year-old woman with recurrent depression not adequately
evaluated (Taylor) 269
 Preface

O Lord, all my desire is before you;

From you my groaning is not hid.
My heart throbs; my strength forsakes me;
The very light of my eyes has failed me.
My friends and neighbors stand back
Because of my aZiction;
My neighbors stand afar oV. Psalm 38

At any point in time on this planet, almost two and a half times as many persons are
depressed as are demented. Counting all variations on the theme, about 10% of men
and 20% of women are at lifetime risk for experiencing a depressive illness. Based on
numbers of persons aVected, the World Health Organization estimates that depres-
sive illnesses are the fourth highest cause of medical disability and premature death
worldwide in years of illness, treatments required, lost productivity during episodes,
and death rates.1
Ten to 15% of depressed persons die by suicide. This rate translates into about one
million persons annually, worldwide, and 30000–90000 persons annually in the USA.
The first figure is the accepted count and the latter figure is estimated from analyses
that acknowledge underreporting. In the USA, suicide is the 11th leading cause of
death. Most persons over age 50 have known at least one individual who has
committed suicide. Among depressed persons, suVerers of melancholia have the
highest suicide rates.
Depressive illness is increasing in frequency among persons born closer to the
present (a period eVect), and first episodes are occurring at younger ages (a cohort
eVect). These trends result in more ill persons with more years of illness.
Of the persons who kill themselves annually in the USA, nearly 50% (15000–45000
individuals) seek help from a physician within the 3 weeks before they commit
suicide – a sad sign of a public health failure because suicide is preventable. In
treating depressed patients, psychiatrists meet minimal standards of care about 80%
of the time, whereas generalist physicians, who see most suVerers of depression, meet
the standards of care only 20% of the time. Although the mood is often recognized,
a depressive illness is frequently interpreted as disappointment, bereavement, or

xi
xii Preface

demoralization, and is ignored as the brain disease that it is. Although misfortune can
precipitate a depressive episode, once the sequence of pathophysiologic events that
become a depressive illness unfolds, the changes in brain functioning sustain the
expression of the illness. Depressive illness is highly responsive to proper treatment,
but more often than not, depressed persons are inadequately treated.
Many forms of depressive illness are recognized. The most prominent are identified
as the mood disorders of major depression, dysthymia, bipolar depressive disorder,
and depressive illnesses associated with a general medical condition. To this list are
added specifiers of frequency (single or recurrent), severity, psychosis, catatonia, and
pattern (typical or atypical). Other syndromes of depressive mood are found
throughout the Diagnostic and Statistical Manual (DSM) classification system. This
varied taxonomy lacks supporting psychopathological or pathophysiological evidence
and, as a consequence, the taxonomy lacks validity. Reliable diagnosis, prognosis,
selection of treatment, and outcomes for suVerers of depressive illness are often
poor.2 Decades of research, however, identify a central pathophysiology in the
neuroendocrine system. This theme is melancholia, and identifying this syndrome
clarifies diagnosis, prognosis, and treatment for more successful outcomes.
Melancholia is a severe disorder of mood, often fatal, that has been described for
millennia in medical texts and by poets, novelists, and playwrights. Melancholia is
definable by measurable signs and symptoms, characteristic neuroendocrine and
neurophysiologic profiles, and its treatment-responsiveness to electroconvulsive
therapy (ECT) and to pharmacodynamically broad-spectrum antidepressant drugs.
Melancholia is often associated with stupor, catatonia, psychosis, suicide, and
manic-depressive illness.3 Melancholia is a lifelong process with a genetic risk.
Early International Classification of Diseases (ICD) editions and DSM-I and
DSM-II classifications identified melancholia, but these classification systems were
not helpful in prescribing newly introduced treatments (e.g., insulin coma, psycho-
surgery, convulsive therapy) that were found to be eVective in schizophrenia and then
in manic-depressive illness. The eYcacy of psychotropic drugs was also weakly
correlated with heterogeneous DSM categories, discouraging the search for treatment
response as a feature of classification. The DSM-III and subsequent classifications,
introduced as operationally defined and more ‘‘scientific,’’ produced no better results.
To achieve the approval of the largest segments of the diverse memberships of
professional organizations, the DSM definition of mood disorder became overly
broad and criteria for the diagnosis of major depression overly liberal. The ‘‘worried
well’’ with characterological depressive moods were conflated with melancholia into
the category of ‘‘major depression.’’ The neuroendocrine, neurophysiologic, and
psychopathologic delineators of melancholia were confounded, and discarded as
diagnostic and prognostic clinical laboratory aids. Under the DSM-III system, the
dexamethasone suppression test (DST) identified melancholia in 50% or more of
depressed patients, but rather than concluding that the other 50% represented
diVerent forms of distress, the DST was discarded as a measure of melancholia.4
In the decades after the introduction of DSM-III, intrusive actions of the pharma-
ceutical industry encouraged a weakening of criteria to justify the use of antidepressant
xiii Preface

drugs in the largest number of persons. The safety and eYcacy of the older, no
longer patentable agents (tricyclic antidepressants, monoamine oxidase inhibitors,
and lithium) were maligned through aggressive marketing that relied on unsound
industry-sponsored comparison studies. Academic psychiatry went to the highest
bidder.5
In response to weakened criteria and confusing classification, we reintroduce
melancholia as the classic depressive illness with definable diagnostic criteria and
eVective treatment algorithms. We write this book for physicians and other health
care professionals who treat severely ill depressed patients. It is intended to spur
better modeling of disorders in psychiatric classification schemes.6 Our approach is
that of the clinician-scientist, not the bench researcher, although we detail the biology
of depressive illness and the evidence that it is a brain disease.
We set the historical stage and describe the remarkably consistent conceptual image
of melancholia over millennia. We describe the disorder and review studies that
systematically delineate melancholia, mirroring the historical record, and validating
melancholia as a definable syndrome. Laboratory findings that support the melan-
cholia syndrome and its variations (e.g., psychotic depression) are presented. We
oVer a systematic examination for the classic psychopathology of melancholia.
A variety of labels have splintered the melancholia concept. We show these to
be variations of melancholia. We oVer criteria on how to separate melancholia
from depressive-like syndromes that have been inappropriately attached to it, and from
other conditions in which apathy and psychomotor slowing are features. Suicide
is a principal risk in melancholia, and we discuss the recognition of suicide and
suicide prevention. Convulsive therapy is the syndrome’s most eVective treatment
and we discuss how to maximize its eVect. We detail medication management of
patients suVering from melancholia. Newly proposed treatments are critiqued. We
review the evidence that depressive illness is a lifelong process, discuss its patho-
physiology, and oVer the evidence that melancholia is an expression of brain
dysfunction. Finally, we oVer our conclusions that melancholia is a syndrome that
warrants separate classification in the mood disorders category. We present pre-
vention strategies, and how research needs to be refocused to provide a better
understanding of melancholia.
We come to this book after decades of treating depressed patients, often those so
severely ill that their deaths seemed imminent. One of us, (MAT) has been a career-
long student of descriptive psychopathology in the nineteenth-century tradition,
detailing the characteristics of patients with mania, depression, psychosis, and cata-
tonia. He has been a teacher of neuropsychiatry for medical students, psychiatric
residents, neurologists, and psychologists. He prescribes and administers ECT.
The other (MF) has encouraged the development and administration of modern
ECT, which is recognized as the most powerful antidepressant treatment. He has
an extensive experience in clinical and experimental psychopharmacology, in the
electrophysiology of psychoactive drugs, and in psychopathology.
Together, we have witnessed the birth and infancy of the psychopharmacology era
and experienced its promises to treat patients with mood disorders better. We are
xiv Preface

concerned about the eVects on psychiatric practice, education, and research, as well as
on popular culture that we see in the unhealthy relationships between academia and
the pharmaceutical industry. Despite the escalation of new agents, remission rates are
lower than ever and ‘‘treatment resistance’’ is said to be common.7
We write this book, however, with optimism because we know that when phys-
icians ‘‘get it right’’ – the diagnosis and treatment – depressed patients have a good
response and many achieve remission of their symptoms and return to productive
lives. There is nothing more elating in clinical psychiatry than to see an animated and
cheerful person who only a few short weeks before was immobilized with indecision
and overwhelmed by apprehension, gloom, and thoughts of death.
To understand melancholia is to understand depressive illness and the care of
patients with mood disorder. If we improve this understanding, we will have achieved
our goal.

NOTES

1 Murray and Lopez (1996); Uston et al. (2004).

2 At a 2003 presentation of brain metabolic abnormalities in depressive illness to a large group
of depression researchers, the chairperson opened the session by stating that the present
DSM depression taxonomy was inconsistent with clinical evidence and unhelpful in research
and clinical practice. The audience agreed. (University of Michigan Depression Center
symposium series: M.A. Taylor, personal observation.)
3 We prefer the classic term ‘‘manic-depressive illness’’ to that of ‘‘bipolar disorder.’’ It oVers
historical continuity and captures the essence of the disease better. Chapters 2 and 5 discuss
manic-depressive disorder and its relationship to melancholia.
4 Chapter 4 provides a discussion of laboratory tests for melancholia.
5 Chapter 10 discusses industry influence on antidepressant treatment trials.
6 We have taken a similar approach in presenting the evidence for catatonia as a distinct
syndrome (Fink and Taylor, 2003; Taylor and Fink, 2003).
7 Montes et al. (2004).
 Acknowledgments

Documenting points of view is never easy, and gathering supporting citations is a

daunting task. Toward that eVort Georgette PfeiVer tirelessly compiled and corrected
our large list of citations. We are in her debt.
We are also grateful to Drs. Bernard Carroll and Edward Shorter who helped us
understand the history of the melancholia concept and its pathophysiology.

xv
 1

Melancholia: a conceptual history

Depression, most people know, used to be termed ‘‘melancholia’’. . . Melancholia would still
appear to be a far more apt and evocative word for the blacker forms of the disorder, but it was
usurped by a noun with a bland tonality and lacking any magisterial presence, used indiVerently
to describe an economic decline or a rut in the ground, a true wimp of a word for such a major
illness . . .
The Swiss-born psychiatrist Adolf Meyer had a tin ear for the finer rhythms of English and
therefore was unaware of the semantic damage he had inflicted by oVering ‘‘depression’’ as a
descriptive noun for such a dreadful and raging disease. Nonetheless, for over seventy-five years
the word has slithered innocuously through the language like a slug, leaving little trace of its
intrinsic malevolence and preventing, by its very insipidity, a general awareness of the horrible
intensity of the disease when out of control.1

A scientific classification of behavior disorders is still an unreachable goal. The eVorts

in the past two centuries are reminiscent of the many attempts to bring order into the
universe of plants and animals before the singular rules of Linnaeus and Mendel
allowed meaningful classifications to emerge. The maladaptive variations in human
mood, thought, and motor behavior observed over the millennia oVer a myriad of
images that have captured the attention of one observer or another who attempted to
formulate these observations into an understandable framework. More organized
systems emerged at the end of the Eighteenth Century with the attentions of German
and French physicians.2 The classifications often lacked a central thesis and, for the
most part, clinicians have been attracted by one aspect of behavior or another,
allowing the behaviors to be classified by the dominant symptom or presumed
etiology. Patients have been lumped or split into classes or described as categories
or continua according to idiosyncratic opinions.3
Neurosyphilis is an interesting neuropsychiatric disorder that oVered a potpourri
of images and therapies. So varied were its presentations that clinicians dubbed it the
‘‘great imitator.’’4 Descriptions filled volumes, but once the common cause was
identified and a laboratory test developed, the variations assumed less significance.
An eVective treatment gave descriptive syphilology the coup de grâce.
The classification of mood disorders presents the same dilemma. Which disorders
of mood are expressions of a common pathology and which are not? How many
pathopathologies are represented in the mood disorders? How many disorders are

1
2 M. A. Taylor and M. Fink

derived from one cause? Acknowledging our limited understanding of human neuro-
biology, is it prudent to support the many disorders of mood characterized in the
Diagnostic and Statistical Manual (DSM) classification or is it better to seek a simpler
basis?
For a medical classification to be useful it should be precise in its criteria of
diVerentiation, predict the probable course of an illness, and guide the selection of
the most optimal intervention. It should also oVer the scientist a lodestone for the
selection of homogeneous populations for research study.5
The psychiatric classifications embodied in DSM-IV and the 10th International
Classfication of Diseases (ICD-10) are not precise, and do not predict the course
of illness nor eVectively guide intervention. A simplified classification of depres-
sive mood disorders under the rubric of ‘‘melancholia’’ achieves these aims better.
‘‘Melancholia’’ is recognized as a syndrome of gloom, apprehension, inhibited motor
activity, slowed thoughts, homeostatic distress, and psychosis. Clinical criteria of the
disorder are definable, laboratory tests oVer support, and course of illness is predict-
able with the available therapeutic options. The burden of this report is to establish
melancholia as a definable syndrome in psychiatric classification.6

Origins of the concept

Melancholia is a concept of depressive illness with an extensive literature and a

detailed history. Its recognition as a form of ‘‘madness’’ with ‘‘bodily causes’’ has
been consistent for 3000 years. Except for two periods in western history – the Middle
Ages, when church teachings dominated western thought, and again in the twentieth
century, particularly in the USA, when psychoanalytic notions dominated psychi-
atric thinking – melancholia was identified as a disorder in brain function. Modern
writers who oVer detailed histories of the syndrome are Hopewell-Ash (1934), Lewis
(1934a), Schmidt-Degenhard (1983), Jackson (1986), Goodwin and Jamison (1990),
and Parker and Hadzi-Pavlovic (1996). Discussions of melancholia are to be found
in Hunter and Macalpine’s Three Hundred Years of Psychiatry (1982), Berrios and
Porter’s A History of Clinical Psychiatry (1995), Shorter’s A History of Psychiatry
(1997), and Porter’s Madness (2002). Literary writings are presented by HeVerman
(1995) and Radden (2000). A review of the role of psychotherapies in the history of
depression is oVered in a special number of Psychiatric Annals.7
Melancholia was identified by Hippocrates in the fifth century BCE as a persistent
sadness and morbid thoughts that had their source in a disorder of the brain. In ‘The
Sacred Disease,’ he wrote:
And men ought to know that from nothing else but thence [from the brain] come joys,
delights, laughter and sports, and sorrows, griefs, despondency, and lamentations. And by this,
in an especial manner, we acquire wisdom and knowledge, and see and hear, and know what
are foul and what are fair, what are bad and what are good, what are sweet and what are
unsavory . . . And by the same organ we become mad and delirious, and fears and terrors assail
us, some by night, and some by day, and dreams and untimely wanderings, and cares that are
not suitable, and ignorance of present circumstances . . . All these things we endure from the
3 Melancholia: a conceptual history

brain when it is not healthy, but is more hot, more cold, more moist, or more dry than natural
. . . And we become mad from humidity [of the brain].8

Hippocrates described a specific syndrome, not a vague dysphoria or dourness of

character. Although rooted in beliefs in the essential balance of four body humors for
health, other early images of melancholia define the same syndrome. Galen and
Arateus, both writing in the first century CE, considered melancholia as an aZiction
of the brain. Arateus described:
And yet in certain of these cases there is mere anger and grief and sad dejection of mind . . .
they are suspicious of poisoning or flee to the desert from misanthropy or turn suspicious or
contract a hatred of life. Or if at any time a relaxation takes place, in most cases hilarity
supervenes. The patients are dull or stern, dejected or unreasonably torpid . . . they also become
peevish, dispirited and start up from a disturbed sleep.9

Plutarch noted that when a man is melancholic:

Every little evil is magnified by the scaring spectres of his anxiety. He looks on himself as a man
whom the gods hate and pursue with their anger . . . Awake, he makes no use of his reason; and
asleep, he enjoys no respite from his alarms. His reason always slumbers; his fears are always
awake. Nowhere can he find escape from his imaginary terrors.10

In western Europe from the tenth to the eighteenth centuries, mental disorders were
often ascribed to demons and witchcraft.11 Relief was theorized to come with
exorcism. The medical teachings that psychiatric disorders resulted from aberrations
in the brain were oYcially denied. Many physicians, however, continued to recognize
melancholia as disease. Bright (1586) described a ‘‘natural’’ form of mental disorder
that resulted from ‘‘the mind’s apprehension’’ and an ‘‘unnatural’’ illness of the
humors of the body. The ‘‘natural’’ is recognized today as ‘‘reactive depression’’, the
‘‘unnatural’’ as ‘‘major depression.’’12 A similar division is presented by Robert
Burton in The Anatomy of Melancholy (1621), the most detailed and poetic descrip-
tion of melancholia in the literature.13 Another description is that of Richard Baxter
(1716) (Hunter and Macalpine, 1982, p. 241):
Melancholy Persons are commonly exceedingly fearful . . . Their Fantasie most erreth in aggravat-
ing their Sin, or Dangers or Unhappiness . . . They are still addicted to Excess of Sadness, some
weeping they know not why, and some thinking it ought to be so . . . They are continual Self-
Accusers . . . They [apprehend] themselves forsaken of God . . . They are utterly unable to rejoyce in
anything.
A great part of their Cure lieth in pleasing them, and avoiding all displeasing Things, as far as
lawfully can be done . . . As much as you can, divert them from the Thoughts which are their
Trouble.
If other means will not do, neglect not Physick; and tho’ they will be averse to it . . . yet they must
be perswaded or forced to it . . . I have known a Lady deep in Melancholy, who a long time would
not speak, nor take Physick; nor endure her Husband to go out of the Room; and with the Restraint
and Grief he Died, and she was Cured by Physick put down her Throat, with a Pipe by Force.14

In the nineteenth century melancholia was recognized as a core illness among many
forms of insanity. One writer defined six classes of insanity: melancholia, mania,
4 M. A. Taylor and M. Fink

fatuitas, stupiditas, amentia, and oblivio’’.15 Another oVered five ‘‘species’’ of insanity:
melancholia, mania with and without delirium, dementia, and idiocy.16 Yet another
author divided insanity into three orders, with mania and melancholia combined as
one.17 Mania was considered a higher form of melancholia or as the same illness in a
diVerent form. A specific view is expressed by the apothecary of London’s Bethlem
Hospital, John Haslam, in 1809 (Hunter and Macalpine, 1982, p. 580):
As the terms Mania and Melancholia are in general use, and serve to distinguish the forms under
which insanity is exhibited, there can be no objection to retain them; but I would strongly oppose
their being considered as opposite diseases. In both there is an equal derangement.18

Other observers emphasized the connection between the mood disorders of depres-
sion and mania. Descriptions of a circular insanity were detailed by Falret (1854) and
Baillerger (1854).19 Falret described melancholia:
At the commencement of this phase . . . the patients begin to withdraw and now speak only
rarely. Sometimes they express remorse over their previous condition . . . the patients withdraw,
remaining all alone and motionless . . . they are now meek, and their humility may go so far as
for them to refuse treatment in the belief that they do not deserve it. This despondency
becomes more pronounced daily . . . [and] the patient is transformed into a statue . . . were
he not coaxed to eat, the patient would not bother to seek food . . .
The thought processes are very slow; rarely this may result in complete cessation of all
intellectual activity . . . his movements are sluggish or absent. The face is pale; the features sag,
suggesting dejection rather than anxiety . . . Appetite is decreased, and the patient eats little;
digestion is equally slow and defecation is laborious.
Nevertheless, there are a certain number of patients who present with specific preoccupations,
among which we have noticed ideas of humility, of ruin, of being poisoned, or of guilt.20

The lack of a coherent formulation of psychiatric disorders encouraged two camps

to develop, one dividing the behaviors into many conditions and the other oVering
a single disorder of the brain as the basis for many forms of psychiatric illness.21 The
single cause for psychiatric disorders was formulated when anatomic studies showed
diverse forms of mental illness to be associated with thickening of the brain’s
meninges, later seen as secondary to cerebral syphilis.22 The brain diseases took
various forms, one dissolving into another, and arguments ensued as to the relevance
of a single brain disorder (Einheitspsychose) or multiple disorders.23
Of many attempts to develop a coherent nomenclature, Emil Kraepelin’s formu-
lation of melancholia as an abnormal mood state was widely accepted.24 An active
and agitated form of the illness was grouped with manias, and the periodicity of
recurrences was highlighted. He recognized two forms of the psychoses – a progres-
sive deteriorating illness of dementia praecox (Verblödungsprocesse) and a non-
deteriorating form of periodic illnesses (das periodische Irresein). The latter term
was replaced in his next edition by das manisch-depressive Irresein which established
a condition of manic-depressive illness. Melancholia was retained as a separate
depressive syndrome that occurred in a perceived ‘‘involutional period.’’ In writings
in the first half of the Twentieth Century it became the syndrome of involutional
melancholia.
5 Melancholia: a conceptual history

For mania, Kraepelin described a progression in severity from hypomania to

mania to delirious mania. For melancholia, he described a parallel progression of
simple retardation, retardation with delusions and hallucinations, and stuporous
conditions.25
Various attempts to distinguish depressive mood disorders were made. One at-
tempt divided depressed patients with anxiety as ‘‘reactive’’ to stress (psychoneurotic),
and an autonomous form that had a systemic or biologic basis.26 The arguments
were of popular interest at the beginning of the twentieth century, with prominent
British authors arguing for a unitary model.27
Melancholia was described as a specific disorder by Aubrey Lewis (1934b) in his
detailed study of 61 melancholic patients:
Melancholia is one of the great words in psychiatry. SuVering many mutations, at one time the
tenacious guardian of outworn schemes or errant theories; presently misused, cavilled at,
dispossessed, it has endured into our own times, a part of medical terminology no less than
of common speech. It would seem profitable to consider the history of this word, and of the
states of fear and distress with which it has from the beginning been associated.28

The concept of melancholia was brought to life in the description by Hopewell-Ash

(1934).29
MELANCHOLIA is a depressed state [meaning subdued, not a diagnostic category] of the entire
personality reaction. Depression of spirits, psychomotor retardation and general torpidity of
mind and body are its essential features. Invariably associated with these are insomnia, indiges-
tion and constipation. It is true that morbid, restless anxiety often colours the depression, but in
typical cases it is the general slowing up of the rhythm that characterizes the clinical picture.
Mental depression may be due to many causes, both physical and mental; toxemia reflex
irritation and physical fatigue on the one hand and psychological stress on the other are
responsible for many instances. But in the melancholic state – using that term to indicate a
particular clinical condition – there is a sluggishness of mind manifested by diYculty in thinking,
poverty of ideas and loss of attentive control that is not found in any kind of simple nervous
depression. In well-developed cases the ‘‘slow-motion’’ life of melancholia is extraordinarily
characteristic; slow movements, retarded reaction and diYculty of ready response combine to
present us with appearances that are familiar to all who have much to do with cases of mental
disease. It is a clinical picture accentuated by the foetid breath, furred tongue and story of
digestive troubles which express the inhibited gastro-intestinal functions. The lacklustre expres-
sion, lifeless hair and greasy complexion, which are equally common, complete a characteristic
facies. In more severe degrees of melancholia one finds, as will be noted later, such symptoms as
the above combined with hallucinations and delusions. The latter are usually concerned with
ideas of wrong-doing, evil, disaster and death. The man who believes that he has committed the
‘‘unpardonable’’ sin and will not admit any doubt about it is always suVering from melancholia.
No anxiety state representing a psychoneurosis ever produces a reaction of this kind.

A contemporary, Denis Hill (1968), found no merit in the subdivisions of the mood
disorders, concluding that the treatments defined the condition:
It is a striking fact that the antidepressant drugs and ECT have their profoundest therapeutic
eVect when the primary functional changes of depression are most in evidence and that, given
6 M. A. Taylor and M. Fink

these, the secondary symptoms disappear as the primary functional changes are alleviated. To
put the matter at its greatest simplicity there is little to contradict in the statement that
biological therapeutic agents operate only on biological functional systems.30

The psychodynamic interruption

Kraepelin’s formulation of melancholia as a core mental disorder had many critics.

The strongest attacks came from Freud and his followers, who oVered a ‘‘mental’’ or
‘‘psychological’’ basis for melancholia.31 Their theory pictured active exchanges of
energies within a tripartite mental apparatus defined as the superego, ego, and id.
Mourning for the loss of a love object deranged the energetics so that melancholia
emerged. The physical attributes of the illness resulted from a displacement of
energies from the ego – the emotional part that related to the outside world – to
the id – the hidden source of drives and emotions. When a loss could be associated
with a specific subject or event in the subject’s history, ‘‘reactive depression’’ ensued.
When a loss was not identifiable and the condition seemed unrelated to history,
a ‘‘psychotic depression’’ ensued.32 As psychodynamic theory came to dominate
American psychiatry, interest in the biological aspects of melancholia diminished.
Adolf Meyer, a leading professor of psychiatry in the USA, is described as:
desirous of eliminating the term melancholia, which implied a knowledge of something that we
did not possess, and which had been employed in diVerent specific ways by diVerent writers. If,
instead of melancholia, we applied the term depression to the whole class, it would designate in
an unassuming way exactly what was meant by the common use of the term melancholia; and
nobody would doubt that for medical purposes the term would have to be amplified so as to
denote the kind of depression . . . We might distinguish the pronounced types from the simple
insuYciently diVerentiated depressions. Besides the manic-depressive depressions, the anxiety
psychoses, the depressive deliria and depressive hallucinations, the depressive episodes of
dementia praecox, the symptomatic depressions, non-diVerentiated depressions will occur.33

Meyer stated that depressive mood disorders were individualized ‘‘reactions’’:

The conditions which we meet in psychopathology are more or less abnormal reaction types,
which we want to learn to distinguish from one another, trace to the situation or condition
under which they arise, and study for their modifiability.34

Meyer’s formulations were adopted in the concept of ‘‘reactions’’ that became the
basis for the American Psychiatric Association classification of psychiatric disorders
(Table 1.1) in DSM-I (1952) and the revision of DSM-II (1968).35
The concepts of Freud or Meyer, or those of the adherents to their philosophies,
would not have been so widely accepted had there been a competing biological model
of psychiatric illness or eVective treatments for psychiatric disorders. Neuroscience
technologies and laboratory procedures were primitive and no somatic treatment was
established. The introduction of malarial fevers (1917), insulin coma (1933), convul-
sive therapy (1934), and leucotomy (1935) challenged the psychodynamic model.
The success of these treatments in quickly relieving the most severe psychiatric
7 Melancholia: a conceptual history

Table 1.1. Diagnostic and statistical manual, 2nd edition (DSM-II) ‘‘depression’’
formulations

DISORDERS OF PSYCHOGENIC ORIGIN OR WITHOUT CLEARLY DEFINED PHYSICAL CAUSE OR STRUCTURAL

CHANGE IN THE BRAIN

Psychotic disorders
Disorder due to disturbance of metabolism, growth, nutrition, or endocrine function
Involutional psychotic reaction
Disorders of psychogenic origin or without clearly defined tangible cause or structural
change
AVective reactions
Manic-depressive reaction, manic type
Manic-depressive reaction, depressive type
Manic-depressive reaction, other
Psychotic depressive reaction
Schizophrenic reactions
Schizophrenic reaction, schizoaVective type
Psychoneurotic disorders
Disorders of psychogenic origin or without clearly defined tangible cause or
structural change
Psychoneurotic reactions
Anxiety reaction
Depressive reaction

illnesses changed clinical psychiatric practice and once again directed attention to the
brain as central to psychiatric disorders.36 A new therapeutic optimism improved the
tenor of psychiatric institutions.37

The recognition of melancholia in psychiatric classification

New typologies were envisioned as the basis for more eVective prescription of the
available treatments. Altered mood states were now labeled as vital or personal,
primary or secondary, atypical, vegetative, endogenomorphic depressions and anxious
thymopathy.38
In an unusual study, Klein and Fink (1962a, 1962b) randomly assigned patients
of varying diagnoses (depression, mania, psychosis) referred for medication treat-
ments in an inpatient hospital setting to one of three treatments – imipramine,
chlorpromazine (combined with the antiparkinson agent, procyclidine), or placebo.39
Imipramine relieved depressed mood in both the retarded and agitated forms.
Chlorpromazine relieved psychosis but also relieved depressed mood. The labeling
8 M. A. Taylor and M. Fink

of the new psychoactive substances as either ‘‘antidepressant’’ or ‘‘antipsychotic’’ was

challenged.
The diagnostic criteria of DSM-II served as poor guides in the prescription of the
compounds.40 Many psychopharmacologists described their frustration with DSM-II
criteria for the selection of treatments.41 They struggled with a confusion generated
by the varying proposed causes of depression: being rooted in life events (reactive
depression) or in body physiology (endogenous, vital depression), or dominated by
neurotic symptoms (neurotic depression, dysthymia), psychosis (psychotic depression),
or character pathology.
By the late 1960s it was no longer acceptable to treat all depressed patients as if they
were suVering from a single condition because some treatments were eVective for
some patients and not for others. One group, for example, examined 33 studies that
had assessed medication treatments of depression and could not find a diagnostic
formulation that had predictive strength.42 The DSM-II and ICD-8 classifications had
poor reliability, best demonstrated in international studies.43
An operationally defined diagnostic scheme was oVered in the Research Diagnostic
Criteria (RDC).44 Its usefulness encouraged the American Psychiatric Association
to update the oYcial classification in DSM-III of 1980.45 Lacking a defined theory of
psychiatric illness, however, the classes represented a consensus among observers who
used diVerent texts, idiosyncratic personal clinical experiences, and diVerent psycho-
logical and pharmacologic theories as guidelines. For some disorders, a Kraepelinian
template can be recognized (e.g., the schizophrenia criteria); for others, a psycho-
logical template is apparent (e.g., dissociative disorders). The committees represented
diverse constituencies and the final formulations were designed to be accepted by the
average psychiatrist who would vote it up or down in an American Psychiatric
Association election.46 Within a few years, dissatisfaction with the classification called
for revisions (DSM-IIIR) in 1987 and in 1994 (DSM-IV).47
Melancholia was ignored as each revision added new categories in response to the
needs of diVerent practitioner groups. In the first DSM classification, four diVerent
depressive reactions were identified, with four subtypes for ‘‘aVective reactions.’’ In
the 1968 version, two additional subtypes were added. By 1980, four major mood
disorders were identified, with 10 subtypes. For major depression, an additional three
subtypes were listed. ‘‘Melancholia’’ could still be specified as either present or absent
for major depression but was not recognized as a specific disorder. As the core
disorder of mood, the DSM-III commission oVered a single concept of ‘‘major
depression’’ (with descriptors of single episode or recurrent) and with the variant
bipolar depression (with mixed, manic, and depressed variants). Depressive disorder
not otherwise specified and abnormal bereavement were two additional entities. Psych-
osis became a specifier of mood disorders. A syndrome of ‘‘dysthymia’’ was revived.48
The concepts of melancholia, melancholic depression, and involutional depression
were discarded.49
Bipolar disorder was distinguished as a separate class by the occurrence of excite-
ment, distractibility, agitation, and talkativeness in the patient’s life history. Parallel to
9 Melancholia: a conceptual history

the subtyping in the DSM category of major depression, the bipolar disorders were
divided into bipolar I with a single manic episode (with more recent episode mixed
or depressed or unspecified), bipolar II (with hypomanic but not manic episodes), and
cyclothymic disorder.50 The list of specifiers is similar to those in the major depressive
category, with the addition of rapid cycling.
The new classification and specific criteria were quickly challenged by clinicians
who could not fit their patients within the defined categories. In response, new
diagnostic classes were included in the 1987 revision (DSM-IIIR) and again in the
1994 iteration (DSM-IV).51 The number of recognized diagnostic entities dramatic-
ally increased. The episodic nature of emotional illnesses was recognized in the
definition of major depressive, manic, mixed, and hypomanic episodes that were com-
bined into major depressive disorder (either single or recurrent), and further divided
by the specifiers of chronic and severity/psychotic/remission and by the features of
catatonia, melancholia, atypical, or postpartum onset. To the recurrent disorders, two
additional specifiers of course and seasonal pattern were oVered.
This extended list of diagnoses was still considered insuYcient. Clinicians labeled
variations in the duration of the illness, its seasonal features, diVerential response
to medication, and mixtures of psychopathology as seasonal aVective disorder, atyp-
ical depression, double depression, brief recurrent depression, and endogenomorphic
depression.52 Mood disorders were separated by assumed precipitants and labeled
major depression following childbirth (postpartum depression), in menopause (invo-
nal depression), with aging (geriatric depression), and after the loss of a loved one
(abnormal bereavement). The labels were oVered as if the psychopathology, course,
outcome, or treatment of the condition was diVerentiable from other depressive
disorders. In clinical practice, however, these situational precipitants do not define the
presentation of the illness, the response to treatments, or the endocrine markers.53
The limitations of the present DSM classification are well recognized. The DSM-V
iteration planned for the years 2007–2010 seeks a basis in experimental studies
of genetic, neuroanatomic, neuroimaging, developmental science, and family cri-
teria.54 Whether the neurosciences will oVer suYcient data to define a more useful
classification is unpredictable.
Instead of looking to an unsure future classification based on models and studies
yet to be reported, there is merit in a simplified classification of the mood disorders
based on the classical principles of clinically defined signs and symptoms and course
of illness, as oVered by nineteenth-century psychopathologists. The psychodynamic
and psychopharmacologic interruptions are false trails, misjudgments in the devel-
opment of a psychiatric science that were attractive for a time. In addition to clinical
criteria, biological treatments are remarkably eVective and they may be used to define
diagnostic criteria. Some laboratory tests hold promise for supplementing treatment
response. To redress the present false trail on which psychiatric classification is
embarked, a single image of depressive mood disorders is parsimonious. Melancholia,
recognized as a central theme of depressive illness throughout much of medical
history, provides the standard on which to judge mood disorder.
10 M. A. Taylor and M. Fink

NOTES

1 Styron (1990), pp. 36–7.

2 Wallace (1994); American Psychiatric Association (1980, 1994).
3 Parker (2000).
4 Osler, Wm. Cited among aphorisms. See: http://www.vh.org/adult/provider/history/osler/5.
html.
5 Sadler et al. (1994).
6 The evidence for these conclusions is detailed in subsequent chapters.
7 Beck et al. (1977).
8 Adams (1939), The Sacred Disease, p. 344. Hippocrates describes a patient:
In Thasus, a woman, of a melancholic turn of mind, from some accidental cause of
sorrow, while still going about, became aVected with loss of sleep, aversion of food and
had thirst and nausea . . . On the first, at the commencement of night, frights, much
talking, despondency, slight fever; in the morning frequent spasms, and when they
ceased, she was incoherent and talked obscurely; pains frequent, great, and continued.
On the second, in the same state; had no sleep; fever more acute. On the third, the
spasms left her, but coma, and disposition to sleep, and again awaked, started up, and
could not contain herself; much incoherence; acute fever; on that night a copious
sweat all over; apyrexia, slept, quite collected; had a crisis. About the third day . . . a
copious menstruation (The Epidemics, p. 346–7.)
Hippocrates oVers treatments such as abstaining from all excesses, a vegetable diet,
exercise short of fatigue, sexual abstinence, and bleeding, if necessary.
9 Mathews M. Theories of depression before the 20th century. http://www.priory.com/
homol/dephist.htm
10 Zilboorg (1941).
11 Middle Eastern physicians such as Avicenna (980–1037 CE) recognized melancholia as a
brain disease and not due to the influence of the supernatural (Jackson, 1986, pp. 62–4).
12 Bright (1586). See Hunter and Macalpine (1982), pp. 36–40.
13 Burton’s scholarly work is encyclopedic, describing many forms of the illness. It was often
reprinted and is now considered a literary classic. Burton was himself a suVerer. For a
delightful frontispiece of Burton’s fourth edition, see Hunter and Macalpine (1982), p. 99.
A reprint of the three volumes, published in 1932, was recently published by the New York
Review of Books and also a fully annotated six-volume series by Oxford University Press
(Rosen, 2005).
14 Hunter and Macalpine (1982), pp. 241–3. For a detailed description of psychotherapy
recommended for this condition, see Timothy Rogers (1691), ibid. pp. 248–51. For a
description of the use of opium for melancholia, see George Young (1753), ibid. pp. 395–8.
15 Ascribed to Vogel (1772) by Lewis (1934a).
16 Pinel (1806).
17 Melancholia is ‘‘a chronic afebrile, brooding delirium fixed on a small number of objects’’
Boissier de Sauvages, quoted by Lewis, 1934a, p. 6.
18 From Haslam’s Observations on Madness and Melancholy, quoted by Shorter (2005),
pp. 36–7.
19 Portions of Falret’s book are translated by Sedler (1983). Falret’s description of la folie
circulaire is acknowledged by Kraepelin in his formulation of manic-depressive insanity.
A circular insanity was recognized by many authors, including Baillerger (la folie à double
11 Melancholia: a conceptual history

forme), Neftel (periodical melancholia), Lange (periodic psychic depression), Kahlbaum

(cyclothymia), and Hecker (cyclothymia). The separation of depressed and manic disorders
is a feature of modern classification.
20 Sedler (1983), p. 1131.
21 Engstrom (2003).
22 Shorter (2005).
23 The concept of an Einheitspsychose became the basis for a popular school of psychiatric
thought that was developed by writers such as Joseph Guislain and Wilhelm Griesinger.
Ewald Hecker supported a more diverse classification based on course of the illness and
Karl Kahlbaum elaborated a Linnean classification of disorders based on clinical description
and course (van Renynghe de Voxvrie, 1993; Shorter, 1997; Engstrom, 2003).
24 Kraepelin (1896, 1921).
25 As quoted by Jackson (1986; pp. 191–2), Kraepelin divided the depressive states:
the mildest form of depression . . . without either hallucinations or prominent delusions.
The onset is generally gradual . . . mental sluggishness, thought becomes diYcult [as does]
coming to a decision or expressing themselves. . . . The process of association of ideas is
remarkably retarded . . . they have nothing to say; there is a dearth of ideas and a poverty
of thought. . . It is hard to remember most commonplace things. They appear dull and
sluggish, and explain that they really feel tired and exhausted. . . The patient only sees the
dark side of life. They are unsuited to their environment; are a failure in their profession;
have lost religious faith . . . express a desire to end their existence.
26 Gillespie (1926, 1929).
27 Mapother (1926), Lewis (1934a).
28 Quotation is from page 1. In 1934 Lewis reviewed the records of 61 patients admitted to
the Maudsley Hospital in 1928 and 1929 who met his understanding of melancholia (Lewis,
1934a). These ‘‘pure’’ examples of a well-defined illness met the professional consensus of
that era as to diagnosis and course. EVective treatment was unavailable, and Lewis could
not know that insulin coma and induced seizures had been described in Vienna and
Budapest in 1933 and 1934. The phenomenology oVered by Lewis is cited in Chapter 2.
29 Hopewell-Ash (1934), pp. 1–2. His descriptions of the many varieties of melancholia are
discussed in Chapter 5.
30 Hill (1968). Quotation, p. 455.
31 The most dedicated followers of Freud writing about melancholia were Karl Abraham,
Sandor Rado, Otto Fenichel, Grete Bibring, and Melanie Klein.
32 Abraham (1927); Freud (1984).
33 Quoted by Jackson (1986); pp. 197–8.
34 Quoted by Jackson (1986); p. 198.
35 American Psychiatric Association, 1952. The formulation was modified in 1965 as DSM-II.
36 Kraepelin (1918); Kraepelin (1896); DuVy (1995); Pressman (1998); Braslow (1997);
Shorter (1997); Porter (2002).
37 The conflicts between the psychodynamic and the biological views of psychiatric disorders
were outspoken. The attacks by the Group for the Advancement of Psychiatry on convulsive
therapy set the stage for public stigmatization of the somatic treatments. For a detailed
history of these conflicts see Ottosson and Fink (2004); Fink (1979, 1999a); and Shorter and
Healy (in preparation).
38 Vital depression and personal depression were descriptive replacement terms for endogenous
and reactive depression. The defining characteristic of vital depression was its inexplicable
12 M. A. Taylor and M. Fink

onset. The patient may not necessarily feel sad, but rather physically dragged down. Vital
depression was proposed as an endogenous illness, in contrast to a reactive form.
Shorter (2005) considers the term endogenous as borrowed from the eighth edition of
Kraepelin’s textbook in 1913, where it was used as a qualifier for dementia praecox
(schizophrenia). Endogenous depression represented a disturbance of the body’s ‘‘vital’’
feelings. ‘‘In such a feeling we grasp life itself, and in this feeling something is imparted to
us: ascent, decline, health, illness, [and] danger.’’ Endogenous depressions, therefore, were
unprovoked or autonomous disorders of vital feelings; reactive depressions were mental
disorders caused by situational problems. Endogenous depressions were characterized by
disturbances of the body’s physical functions, such as diurnal variation (feeling worse in
the morning), loss of weight, and irregularities in menstruation. Vital depression and
endogenous depression were synonymous.
‘‘Primary vs. secondary’’ depression: dividing aVective disorders (depression and mania)
into primary and secondary forms – ‘‘primary’’ meaning patients with no previous history
of psychiatric illness, and ‘‘secondary’’ patients who had ‘‘a preexisting, diagnosable psychi-
atric illness, other than a previous primary aVective disorder’’– was suggested by the Faculty
of Washington University Department of Psychiatry in the 1970s (Robins and Guze, 1972;
WoodruV et al., 1974).
‘‘Vegetative’’ depression associated aVective disorders with autonomic disturbances
characterized by an anxious-depressed mood and autonomic symptoms.
Atypical depression, a subset of depressive patients who responded to the drug iproniazid
(Marsilid), an inhibitor of brain monoamine oxidase, was identified. The subset did not have
the classic picture of endogenous depression, with self-reproaches and early-morning
worsening, but rather were highly anxious, phobic, and greatly fatigued. These patients ‘‘may
. . . have become bad tempered, irritable, hyperreactive and aggressive, quite unlike so many of
the more endogenously depressed patients.’’ Sargant’s work represents one of the first attempts
to identify a class of depression patients diVerentially responsive to a given medication.
Marsilid was subsequently withdrawn from market as toxic and usage of the concept lapsed.
The concept of atypical depression was revived by a group at Columbia University. They
described the patients as dysphoric, mood-reactive, with symptoms such as overeating,
gaining weight, oversleeping, sensation of leaden fatigue, and taking rejection poorly. They
were thought to respond to monoamine oxidase inhibitors. Atypical depression was
accepted as an oYcial psychiatric diagnosis (‘‘atypical features specifier’’) in DSM-IV
(American Psychiatirc Assocation, 1994).
Endogenomorphic depression was proposed by Klein (1974) to cut across the reactive
versus endogenous distinction in depression nosology. Although the diagnosis was not
adopted in DSM-III, the loss of interest and of pleasure were considered the core criteria
of this depressive mood disorder and anhedonia was accepted as a mood state equivalent
to depressed mood.
Anxious thymopathy was formulated by López Ibor (1950-: La Angustia Vital : (Patologia
General Psicosomatica)), who argued that anxiety and anguish represented an autonomous
disease of an ‘‘endogenous’’ nature; anxious thymopathy possessed deeply somatic roots
and was not at all psychogenic.
39 It was early in the psychoactive drug era and the medicines were considered ‘‘research
treatments.’’ All patients referred for medication were randomly assigned to the three
treatment regimens regardless of the dominant psychopathology. All medicines were
administered in a liquid formulation that contained 75, 150, 225, or 300 mg imipramine;
13 Melancholia: a conceptual history

300, 600, 900, or 1200 mg chlorpromazine with appropriate doses of the antiparkinson
agent procyclidine, or no active psychoactive substance (placebo). Neither the patients nor
the assessors knew which medication was being administered. Trials were for 6 weeks with
weekly increments in dosing. The first study, completed in 1961, included 152 patients.
Klein replicated the study in a second population (Klein, 1967).
40 The studies confirmed imipramine as an antidepressant and chlorpromazine as an anti-
psychotic (Klein and Fink, 1962a, b; Fink et al., 1965; Klein, 1967). That phobia was relieved
by imipramine was a specific finding that has encouraged the present use of selective
serotonin reuptake inhibitors for this illness (Klein and Fink, 1962a ; Klein, 1964). The
finding that chlorpromazine was an eVective antidepressant heralded the recognition
of psychotic depression (Klein and Fink, 1962b). Imipramine worsened the psychosis of
adolescent psychotic patients (Klein and Fink, 1962a; Pollack et al., 1965).
41 Klerman (1971), Klein (1974), and Paykel (1975) are a few of the active writers who oVered
diVerent solutions to the diagnostic dilemmas. The frustrations among the psychopharma-
cologists are documented in their interviews, annotated by Healy (1996, 1998, 2000), also in
his The Anti-Depressant Era (1997) and The Creation of Psychopharmacology (2002).
Additional personal essays by psychopharmacologists are presented in the biennial volumes
of the history of the Collegium Internationale Neuropsychopharmacologicum (CINP)
published by Ban et al. in 1998, 2000, 2002, and 2004.
42 Nelson and Charney (1981).
43 Sandifer et al. (1969); Spitzer and Fleiss (1974); Robins and Barrett (1989).
44 Feighner et al. (1972); Spitzer et al. (1978); Meier (1979); Overall and Hollister (1979).
45 American Psychiatric Association (1980). DSM-III lists 265 disorders. The number is
increased in DSM-IIIR to 292 and in DSM-IV to 295 (Shorter, 1997, p. 303).
46 The vote was taken by its membership prior to the May 1979 annual American Psychiatric
Association meeting. As with many bills enacted in the USA congress, few of the voters had
read the proposal in detail.
47 A planned revision of DSM-V is in progress.
48 DSM-III oVers ‘‘major depression’’ as the principal depressive syndrome and revives
‘‘dysthymia’’ (1980). Among the many disorders to be reconfigured were the depression
diagnoses (‘‘aVective disorders’’) in a manner sharply diVerent from the RDC of 1978.
DSM-III created three new disease labels in the mood area: (1) ‘‘major depression’’ (anti-
cipated in 1978), which was a mixture of psychotic and non-psychotic depressive con-
ditions; (2) ‘‘dysthymic disorder,’’ which was a new label for what had been known as
‘‘neurotic depression’’; and (3) ‘‘adjustment disorder with depressed mood’’ for minor
depressions supposedly treatable with psychotherapy alone.
Manic-depressive illness, for which the DSM drafters adopted Karl Kleist’s label ‘‘bipolar
disorder’’: the Kahlbaum label ‘‘cyclothymic disorder’’ was adopted for less serious manic-
depressive illness. To meet the criteria for major depressive episode, the patient had to
have a dysphoric mood for a certain period of time plus four of a list of eight other
criteria that included poor appetite, insomnia, and loss of pleasure in formerly pleasurable
activities.
Dysthymia was a term devised as a replacement for melancholia by Carl F. Flemming in
1844. It was used by Kahlbaum to distinguish a systemic depressive disorder that seems to
meet modern descriptions of endogenous depression (Shorter, 2005). Dysthymia was out of
fashion until revived in DSM-III as equivalent for depressive neurosis, i.e., a low-grade
chronic depressive illness.
14 M. A. Taylor and M. Fink

49 The formulations are almost wholly based on the clinical experiences of committee
members, not on experimental studies. The formulations are imprecise, the overlaps great,
and the classification was not associated with any objective test. See Chapters 3, 6, and 15
for discussions of DSM criteria.
50 Clinicians have added additional varieties of bipolar disorder as bipolar spectrum
prototypes I, II, III, and IV (Akiskal and Pinto, 1999).
51 American Psychiatric Association (1994).
52 Double depression is the overlapping of two depression categories in RDC – a major
depressive disorder superimposed on an underlying chronic depression (‘‘dysthymic dis-
order’’). The prognosis for patients with double depression is considered worse than for
those with major depression alone.
Seasonal aVective disorder (SAD) (1984) was postulated as a depressive mood disorder
that routinely worsened in the winter months. Treatment with bright light was proposed.
The concept was incorporated in DSM-IIIR in 1987 as a ‘‘specifier’’ for major depression
and for bipolar disorder defined as ‘‘a regular cyclic relationship between onset of the mood
episodes and a particular 60-day period of the year,’’ especially the time from early October
to late November. It is retained in DSM-IV.
Recurrent, brief depression (1985). In the context of a longitudinal study of a cohort of
young adults in Zurich, Angst realized that many of the patients suVered recurrent bouts
of depression too brief to qualify as ‘‘major depression’’ or ‘‘dysthymia’’ in DSM termin-
ology. Angst (1985). proposed the diagnosis of ‘‘recurrent, brief depression’’ (RBD) as a
subtype of aVective disorder. No characteristics were specified except the timing.
53 The number of published ‘‘expert’’ treatment algorithms have increased markedly in the
past decade. The most frequently cited are the Practice Guidelines endorsed by committees
of the American Psychiatric Association, the Texas Medication Algorithm Project (TMAP),
and an expert consensus panel of the Journal of Clinical Psychiatry. These projects recognize
two forms of depressive mood disorder (with or without psychosis) and bipolar disorder in
adults. Individual guidelines have been formulated for other psychiatric disorders (schizo-
phrenia, substance dependence, dementia, delirium, and panic disorder). The available
evidence for treatment eYcacy is reviewed and the guidelines formulated by consensus. The
hierarchies of treatments are idiosyncratic. Four of the algorithms are under multisite
studies under National Institute of Mental Health contracts.
54 Helzer and Hudziak (2002); Kupfer et al. (2002).
 2

Melancholia defined

Melancholy

(n.) - c.1303, ‘‘condition characterized by sullenness, gloom, irritability,’’ from O.Fr. melan-
cholie, from L. L. melancholia, from Gk. melankholia ‘‘sadness,’’ lit. ‘‘black bile,’’ from melas
(gen. melanos) ‘‘black’’ (see melanin) þ khole ‘‘bile.’’
Medieval physiology attributed depression to excess of ‘‘black bile,’’ a secretion of the spleen and
one of the body’s four ‘‘humors.’’
Adj. sense of ‘‘sullen, gloomy’’ is from 1526; sense of ‘‘deplorable’’ (of a fact or state of things) is
from 1710.1

The precision of medical diagnostic terms is essential to establish the reliability and
validity of proposed disease states. While the term ‘‘depression’’ is widely used in
society, its meaning varies with the user, an attitude best expressed by Alice in
Wonderland’s Humpty-Dumpty, ‘‘When I use a word, it means just what I choose it
to mean – neither more nor less.’’2 In psychology, depression represents a decrease in
psychomotor activity or intellectual agility. Within neurophysiology, depression
refers to a decrease in the brain’s functioning, measured in electrical activity or
cerebral blood flow. For the pharmacologist, depression means the decrease in body
functions induced by sedatives, soporifics, and anesthetics. In clinical practice,
depression describes a normal human emotion, a pathologic state if it is retained
too long or too deeply, or a psychopathologic syndrome that may be mild or severe.
A clinical depressive episode may be defined by its associated adverse life events or
it may strike a subject without cause.3 Accepting ‘‘depression’’ as a medical diagnosis
is equivalent to accepting ‘‘infection’’ as a definitive diagnostic term in clinical
medicine.4
‘‘Melancholia’’ has a more precise meaning. As a central organizing model of mood
disorder, melancholia is a recurrent, debilitating, pervasive brain disorder that alters
mood, motor functions, thinking, cognition, perception and many basic physiologic
processes.
Pathological mood is expressed as pervasive and unremitting apprehension and
gloom that colors all cognitive processes, resulting in a loss of interest, decreased
concentration, poor memory, slowed thinking, feelings of failure and low self-worth,
and thoughts of suicide. Regardless of antecedent events, whether a personal loss or a

15
16 M. A. Taylor and M. Fink

Table 2.1. Melancholia syndromes as commonly

labeled in present classifications

Manic-depressive illness
Melancholic ‘‘major’’ depression (unipolar depression)
Manic-depressive depression (bipolar depression)
Psychotic depression
Catatonic and stuporous depression
Puerperal depression
Abnormal bereavement

general medical illness, a persistent and unrelieved feeling of gloom is essential to the
diagnosis.
Psychomotor disturbance, either as retardation or agitation, is the second character-
istic.5 Retardation varies from a reluctance and hesitation to participate in daily
activities, to prolonged inactivity that is so severe as to be labeled a stupor simulating
death.6 Agitation appears as restlessness, hand-wringing, and inability to remain still.
It may be expressed as pacing and continuous movement progressing to purposeless
activity so severe that it has been described as furor or frenzy.
Vegetative functions are severely aVected. Sleep is disrupted, appetite and weight
lost, sex no longer arouses interest, and the response to stress and chronobiologic
functioning are disturbed. Patients describe these changes as beyond their under-
standing or control, or the signs of illness are obvious in a loss of weight, unkempt
appearance, body odor, and haggard look. Neuroendocrine dysfunctions are identified
in laboratory studies.7
Psychosis is recognized when the disorder is severe and occurs in over 30% of
melancholic patients.8 Like psychomotor dysfunction, it is an integral part of melan-
cholia.9 Melancholic patients are preoccupied with thoughts of guilt, worthlessness,
and helplessness, often so severely distorted and exaggerated as to dominate daily
living.
Melancholia is a well-defined clinical picture that can be honed by laboratory tests,
course of illness, and treatment response.10 Understanding the many putative mood
disorders in the present classification as they relate to melancholia oVers an oppor-
tunity to define a common biology and to simplify and improve therapeutics.
A revival of the concept of a single manic-depressive illness with the depressed phase
recognized as ‘‘melancholia’’ is also parsimonious and best fits the evidence. From
this perspective, many of the disorders of mood that are described in psychiatric
classifications can be considered melancholic illness (Table 2.1). The mood disorders
that do not meet the definition of melancholia are discussed in Chapter 6.
Descriptions of individual patients with a depressive mood disorder oVer rich
imagery of the patients who meet the criteria for melancholia. The vignettes from
Hopewell-Ash’s Melancholia in Everyday Practice (1934) oVer pictures before the
present psychiatric classifications and modern therapies evolved.11
17 Melancholia defined

Patient 2.1
An unmarried woman, aged 38. Independent and socially well situated. Chief symptoms:
Depression, insomnia, slowness of mental and physical reaction, with great reluctance to
carry out even the simplest occupations, for example, writing letters. Associated obsessing
and ‘‘anxious thoughts.’’ Morbid ideas of unworthyness in regard to the man she had
been going to marry; on account of this had broken off her engagement. There had
been a previous attack of depression lasting some months. The severe depression, psycho-
motor retardation [were] completed on the physical side by indigestion, constipation and
melancholic expression. Recovered.12

Patient 2.2
Unmarried woman, age 39. Independent. Very strict Calvinist religious training. History of
several minor attacks of depression. Had become very depressed with onset of early
menopausal symptoms associated with anxiety and some agitation; much obsessed by
ideas of dereliction of duty, questions of conscience and religious salvation. On various
occasions wrote: ‘‘I am not ungrateful for all the help you have given me; but there is
nothing but blankness and darkness and less and less strength to meet it with. I wish I could
end it all, but the fear of death and eternity would be still worse.’’ . . . After several attacks of
profound depression following quickly one on the other without definite recovery this
patient returned to normality.13

Patient 2.3
A middle-aged clergyman. Crisis of depression; melancholia, ‘‘suicidal feelings.’’ There was a
history of some two years increasing mental depression. The present crisis arose because he
had suddenly left home and travelled a long way to relatives with the object of ‘‘obtaining
peace.’’ Described himself as ‘‘an agonized atom through an utterly incomprehensible and
torturing universe.’’ There was some improvement under treatment [suggestion] and a few
days later patient said he felt ‘‘like a person who has crawled out of a morass and is lying
on the brink.’’ . . . He appeared much brighter and better. He came to see me unaccompan-
ied . . . but instead of going home he went to a station and took a train to —, where he
wandered about and eventually gave himself up to the police. He had sent postcards to his
friends and one to me which read: ‘‘I am tormented by evil spirits and must flee them. You
will never see me again. Your most unfortunate patient.’’ However, he was brought back by
friends and found to be depressed. Recovery was slow.14

Patient 2.4
An acute crisis of melancholia, involutional type, is exemplified here, the patient suffering
from a combination of agitated excitement with depression . . . although there was excite-
ment the affective tone was depressive and . . . not the least elated or exalted. She was a
married woman, aged 52, mentally depressed and very reticent. ‘‘What is really wrong with
me is that I am mad.’’ . . . Four days afterwards the patient became uncontrollable
‘‘bellowing like a bull, banging her head on the wall and generally uncontrollable.‘‘ She
was treated with hyoscine and Nembutal (pentobarbital) which resulted in a deep sleep of
several hours duration with a subsequently calm night . . . The next day she was mildly
excited, asking to be sent to a lunatic asylum and potentially suicidal.15
18 M. A. Taylor and M. Fink

The recent literature has equally compelling descriptions. In a memoir of his illness,
the novelist William Styron oVers a poignant description of melancholia.16 After
depending on alcohol ‘‘as a conduit to fantasy and euphoria, and to the enhancement
of the imagination’’ for more than 40 years, he was suddenly unable to drink without
experiencing nausea, ‘‘wooziness,’’ and epigastric distress. He slowly became melan-
cholic. At first he experienced malaise; the shadows of nightfall seemed more somber,
the mornings less buoyant. Insomnia and a host of bodily fears followed and
everything ‘‘slowed down.’’ He became suicidal, explaining that: ‘‘The pain of severe
depression is quite unimaginable to those who have not suVered it, and it kills in
many instances because its anguish can no longer be borne.’’17 Frightened of these
thoughts, he turned to a hospital for asylum. Its protection and the support of
antidepressant medication and of friends allowed him to heal slowly; he avers that
the protection served him well.
A physician describes his experience with melancholia:18
Depressive illness is probably more unpleasant than any disease except rabies. There is constant
mental pain and often psychogenic physical pain too. If one tries to get such a patient to titrate
other pains against the pain of his depression one tends to end up with a description that
would raise eyebrows even in a medieval torture chamber. Naturally, many of these patients
commit suicide. They may not hope to get to heaven but they know they are leaving hell.
Secondly, the patient is isolated from family and friends, because the depression itself reduces
his aVection for others and he may well have ideas that he is unworthy of their love or even that
his friendship may harm them. Thirdly, he is rejected by others because they cannot stand the
sight of his suVering . . . Fourthly, the patient tends to do a great cover-up . . . he does not tell
others how bad he feels.

Additional vignettes of melancholic patients are to be found in Chapter 8 (patients

8.1, 8.3, 8.6–8.8).19

Manic-depressive illness

In psychiatric classifications today, mood disorders are divided along the faultline of
the presence or absence of manic or hypomanic periods in the patient’s personal
history. The 1980 Diagnostic and Statistical Manual (DSM) classification recognized a
disorder of depressed mood as a major depression. The presence of mania or hypo-
mania, either in the examination or in the history, categorized the illness as a bipolar
disorder.
In the seesaw of psychiatric history, the mood disorders were seen either as two
disorders or as a single entity. Defining the intimate connection between depression
and mania is usually ascribed to the French authors Falret (1854) and Baillerger
(1854), who described patients with both disorders at diVerent times in their illness.20
Karl Kahlbaum (1882) applied the term cyclothymia to a syndrome of circular
disorders of excitement and depression that did not end in dementia.21 The concept
was adopted by Kraepelin (1921) when he diVerentiated manic-depressive illness
from that of dementia praecox. In Kraepelin’s view, the moods in manic-depressive
illness included:
19 Melancholia defined

certain slight and slightest colouring of mood, some of them periodic, some of them continu-
ously morbid, which are to be regarded as the rudiment of more severe disorders . . . [or] pass
without sharp boundary into personal predisposition . . . I have become more and more
convinced that [manic-depressive] states represent manifestations of a single morbid process.22

The groundwork for splitting manic-depressive illness into bipolar and unipolar
disorders was laid by Leonhard (1995). In family studies he described patients
suVering an endogenous illness with a history of mania who had a higher than
expected prevalence of relatives with mania (labeled bipolar illness). These patients
were distinguished from patients and their families with depressive illnesses only
(monopolar illness). The binary model was quickly supported by family history
studies.23 It was incorporated in the DSM-III classification.
This change in nosology encouraged the elaboration of new subtypes of bipolar
disorder. Hospitalized depressed patients were divided into those with a history of
mania and those who experienced hypomania into bipolar I and bipolar II groups.24
Unipolar depressed patients were divided into familial pure depressive disease, spor-
adic pure depressive disease, and depressive spectrum disease based on the family
history of alcoholism and antisocial personality.25 Additional variants were proposed
in studies of less severely ill patients using criteria of family histories and statistical
analyses of rating-scale items.26
The argument to classify unipolar and bipolar depression separately was challenged
by Taylor and Abrams, first in literature reviews and then in a prospective clinical
study of hospitalized, acutely ill patients with mood disorders and their first-degree
relatives.27 The family illness patterns were not clearly dichotomous. The most com-
mon mood disorder in the first-degree relatives of patients with bipolar disorder was
recurrent depressive illness (unipolar disorder). The morbid risk (age-corrected
prevalence) for unipolar disorder in the families of the bipolar patients was greater
than the morbid risks for unipolar depression in the families of unipolar patients.
The authors reviewed reports of mixed concordance for the two forms of mood
disorder in twins, concluding that they could not distinguish the unipolar and
bipolar patients by any family, psychopathological, treatment response or laboratory
variable as long as depression was defined as melancholia. They could not justify
separating mood disorders by the presence of mania or hypomania, or by the clinical
features of depression.
In another detailed analysis, Goodwin and Jamison (1990) examined the course,
epidemiology, family history, physiological measures, and similar criteria for the
unipolar and bipolar forms of depression. These are assessed as either ‘‘less’’ or
‘‘more,’’ ‘‘younger’’ or ‘‘older,’’ ‘‘lower’’ or ‘‘higher’’ and other descriptive, non-
quantitative diVerences.28 Similar qualitative factors assess the incidence of the
clinical signs of anxiety, anger, psychomotor agitation, mood lability, sleep time, pain
sensitivity with the items rated as unipolar > bipolar or unipolar < bipolar.29 Even in
the absence of defined criteria these authors conclude:30
Despite the heterogeneity in both the bipolar and unipolar groups, the breadth of reported
bipolar–unipolar diVerences is impressive. They include four separate spheres of data – genetic,
20 M. A. Taylor and M. Fink

clinical, biological and pharmacological. Bipolar and recurrent unipolar disorders, neverthe-
less, appear to be very similar in some important respects (e.g., prophylactic response to
lithium). Taken together, the data suggest that they are best considered as two subgroups of
manic-depressive illness rather than separate and distinct illnesses. The available data also
support a continuum model, with ‘‘pure’’ bipolar illness at one end and unipolar illness at the
other.

Clinical studies of the bipolar–unipolar dichotomy

In the 15 years since the Goodwin and Jamison review, the separation of unipolar and
bipolar depression has been increasingly questioned, and the diYculty in separating
mood disorder patients into two clusters is exemplified by evidence of frequent
misclassification. A review of the records of 48 patients identified as having bipolar
disorder and 4 patients considered schizoaVective disorder (bipolar type) found that
40% (19/48) were previously diagnosed with a unipolar major depressive disorder.31
An average of 7.5 years elapsed before the patients were relabeled as suVering from
bipolar disorder. Over the course of illness, depression was the predominant mood
disturbance found in a literature review assessing the incidence of depressive phases
of patients with bipolar disorder.32 The authors concluded that the label of bipolar
disorder is more often associated with psychosis, melancholia, psychomotor retard-
ation, ‘‘atypical’’ symptoms, and higher suicide rates, and that the depressed phase is
the major contributor to the disability in this illness. This understanding follows the
conclusion by Taylor and Abrams (1980; Taylor et al., 1980) that mood disorders
should be separated by the presence or absence of melancholia and not by the
presence of mania or hypomania.
Psychopathologic studies of unipolar and bipolar disorder are rife, with overlaps in
psychopathology, course of illness, and family illness. An examination of patients with
rapid-cycling mood disorder found major depression in 85% and salient manic
features were identified in at least half the patients with recurrent depression.33
An assessment of depressive features in 36 patients with bipolar disorder and 37
patients with unipolar major depressive disorder was unable to separate the two
groups.34 The authors concluded that ‘‘bipolar disorder is characterized by some
depressive features less likely to be found in unipolar depression,’’ but that otherwise
the two conditions are alike. In yet another study, a sample of 313 patients with bipolar
I disorder with an index episode of depression, signs of agitated depression were readily
identified in 61 (20%) as the only distinction from recurrent depressive illness.35
A prospective longitudinal study of 86 patients with the bipolar II designation re-
examined patients at 6- and 12-month intervals over a mean course of 13.4 years.36
The patients were symptomatic in 53.9% of all follow-up weeks. Depressive symp-
toms occurred in 50.3% of the weeks and dominated over hypomanic symptoms
(1.3% of weeks) and over cycling or mixed symptoms (2.3% of weeks). The authors
note that bipolar II, like bipolar I and unipolar depression, is a chronic longitudinal
illness with the modal expression dominated by depressive symptoms. They conclude
that ‘‘longitudinally, BP-II is a chronic aVective disorder expressed within each
patient as a fluctuating dimensional symptomatic continuum, which includes the
21 Melancholia defined

full severity range of depressive and hypomanic symptoms, but dominated primarily
by minor and subsyndromal depression.’’37 Examining the impact of treatments on
the course of the illness, the authors note:
that symptomatic chronicity occurred even in the context of relatively more (rather than less)
medication therapy leads us to conclude that we are describing the true naturalistic expression
of BP-II as it unfolds across the life cycle.

The same conclusion of a singularity of manic-depressive illness is described in

numerous reports by Angst, Benazzi, and Akiskal.38 In one study, two distinct
mixed types of mania and depression were identified in the more severely ill
hospitalized patients.39 Overlaps in criteria for the subtypes of bipolar disorder
are reported. A distinct bipolar II disorder was not supported in a sample of 194
bipolar II outpatients.40 Examining the criteria of psychomotor agitation or psy-
chomotor retardation, agitation was more common in bipolar II patients and
retardation more common in bipolar I outpatients, a distinction of weak signifi-
cance.41 Patients meeting criteria for bipolar II had more atypical features and more
evidence of depressive mixed states than those meeting criteria for major depressive
disorder, leading the author to conclude: ‘‘finding no zones of rarity supports a
continuity between BPII and MDD (meaning partly overlapping disorders without
clear boundaries.)’’ Other iterations of these failures to support a bimodal model are
reported.42
In yet another study seeking to reinforce the image of a bipolar mixed state to
encompass psychotic agitated depression, 336 outpatients with major depressive
episodes without a history of mania were identified.43 Based on evidence of hypo-
mania, 206 were assigned to bipolar II and 130 to major depressive disorder. The
investigators found numerous permutations of major depressive episodes in the
bipolar I patients and concluded that bipolar depression is melancholia:
Agitated depression is validated as a dysphorically excited form of melancholia, which should
tip clinicians to think of such a patient belonging to or arising from a bipolar substrate. Our
data support the Kraepelinian position . . .

Other investigators have had similar diYculties in supporting a mood disorder

dichotomy. In a sample of 117 subjects with recurrent unipolar depression and 106
with bipolar I disorder, the authors of a large multisite Italian study identified those
who had achieved partial or complete remission of their index episode.44 They
assessed 140 items in an extensive psychopathology interview and could not distin-
guish two groups in the distribution of the overall scores or in the number or severity
of depressive or manic items. Paranoid ideation, auditory hallucinations, and suicide
attempts were, however, more common in the lifetime experience of patients defined
as bipolar I.45 The authors discuss their experience:
Cumulatively our empirical findings support a continuous view of the mood spectrum as a
unitary phenomenon that is best understood from a longitudinal perspective. Our data suggest
that unipolar disorder and bipolar disorder are not two discrete and dichotomous phenomena
but that mood fluctuations – up and down – are common to both conditions . . .46
22 M. A. Taylor and M. Fink

Considering the extent of the studies seeking a distinction between unipolar depres-
sion and the two subtypes of bipolar depression, the two disorders are best considered
variations of a single disorder. Patient 2.5 meets criteria for bipolar disorder.
Patient 2.547
A typical cyclical psychosis in a married woman aged about 55, with alternating phases of
melancholia and excitement lasting approximately six months over a number of years. The
story was always the same; after six months occupation in ‘‘having a really good time’’ which
included an endless round of social engagements and great popularity, patient suddenly
‘‘felt ill’’ and then within a few days became ‘‘livery ’’ and depressed. The crisis intensified . . .
and the patient complains of indigestions and burning pains above the epigastrium, easily
nauseated. Very depressed, especially in the mornings. Much worried about her ‘‘inside’’ . . .
slow motion very conspicuous.

Antidepressant drug-induced mania48

The induction of mania by antidepressant treatments is often cited as support for a
mood disorder dichotomy. When tricyclic antidepressants (TCAs) and monoamine
oxidase inhibitors (MAOIs) were introduced, concepts of unipolar and bipolar
depression were not in use, so that the treatment was oVered to all patients who
met criteria for a depressive episode. Manic episodes that appeared during the course
of treatment were interpreted as a medication side-eVect. The reports did not
recognize a personal history of mania nor cycling into mania as natural features of
a depressive mood disorder. No direct experimental studies of this eVect were oVered.
After reviewing the literature of induced mania with antidepressant treatments,
Goodwin and Jamison (1990) concluded:
In summary, absolutely incontrovertible evidence of antidepressant induced mania and cyclic
induction is still lacking . . . The available evidence strongly suggests, however, that antidepres-
sant drugs can precipitate mania in some bipolar-I patients, especially those who respond to
antidepressants, and that some bipolar-II patients appear to be vulnerable to hypomania while
taking antidepressants. Although antidepressant-induced rapid cycling does occur in some
patients, its frequency is not easy to determine, and therefore, the generalizability of the
observation is unclear.49

Since that review, little new evidence has been published. Assessments of the inci-
dence of manic episodes in patients with depression oVer the conclusion that 10–15%
will have a manic or hypomanic episode in the next decade.50 The reports recognize
that the patients most likely to do so have a history of depressive disorders early in life
or an initial psychotic depression or melancholia.51 Cross-sectional clinical features
do not distinguish a first recurrent depression from the initial depression in a manic-
depressive course.52 A review of the databases of several pharmaceutical companies
reported that the switch in unipolar patients was 11.2% for TCA, 3.7% for selective
serotonin reuptake inhibitors (SSRIs), and 4.2% for placebo.53
The Stanley Foundation bipolar network assessed the spontaneous and treatment-
associated switch rates in patients with bipolar depression.54 In a group of 258
outpatients examined for 1 year, the number of days depressed was three times
23 Melancholia defined

greater than the number of days manic. In a second study, 127 bipolar depressed
patients were randomized to 10 weeks of augmentation of mood stabilizers with the
non-TCAs bupropion, sertraline, or venlafaxine. They reported that 9.1% were
associated with switches to hypomania. In 73 continuation-phase antidepressant
trials, 16–19% were associated with manic and hypomanic switches. Despite the low
switch rates that did not exceed natural switch rates in manic-depressive patients, the
authors conclude that depression and depressive cycling are a substantial problem in
intensively treated bipolar outpatients.
A consequence of the belief in the risks of antidepressant drugs is the intensive
search for alternative treatments for bipolar depression. While the eYcacy of lithium
for the manic phase is established, its merits as an antidepressant received mixed
reviews.55 The introduction of carbamazepine for mania encouraged a belief that
mania resulted from the kindling of abnormal seizure-like activity and started a
search for anticonvulsants as treatments for bipolar disorder.56 Several anticonvul-
sants are now recommended as ‘‘mood stabilizers’’ in the long-term management of
bipolar depression.57 The relatively weak therapeutic eVect of anticonvulsants as
mood stabilizers, however, is reflected in the recommended algorithms requiring a
complex polypharmacy of mood stabilizers, SSRI antidepressants, antipsychotic
agents, and benzodiazepine sedatives for reasonable eYcacy. Another tactic has been
to recommend the combination of newly introduced agents such as olanzapine–
fluoxetine.58 A more formal dependence on psychotherapy, now presented as psy-
choeducation, is also oVered.59 To optimize a treatment strategy for clinical practice,
the National Institute for Mental Health has recently contracted with a consortium of
medical centers to test a complex algorithm known as the STEP-BD.60
Despite the absence of experimental evidence, trials of antimanic agents among
bipolar patients often cite drug-induced cycling, without accounting for natural
cycling rates as a justification for the use of these agents.61

Bipolar and unipolar conditions genetically overlap

After the original studies by Leonhard and by Perris reported that familial diVerences
between recurrent depressive illness and manic-depressive illness, subsequent family and
genetic studies commonly reported an overlap between the two forms of mood disorder,
supporting a unitary construct.62 Both forms of illness occur with increased frequency in
the families of patients with manic-depressive illness.63 When recurrent depressive illness
is defined as melancholia, families have an increased risk for manic depression.64
Twin studies show this overlap.65 In an analysis of 30 monozygotic and 37
dizygotic twin pairs, the proband concordance was higher for monozygotic than
for dizygotic twins, with heritability estimated at 89%.66 In almost 29% of the
monozygotic pairs, one twin had both manic and depressive episodes while the other
had recurrent depressive illness. Among the dizygotic pairs 13.5% had a mixed
concordance. The investigators tested several liability models and concluded that
manic-depressive illness was not simply a more severe form of recurrent depressive
illness, but that nevertheless, there was substantial genetic overlap between the two
forms (about 30%) that may represent the risk for depressive illness.
24 M. A. Taylor and M. Fink

Conclusion
The scientific evidence fails to distinguish unipolar and bipolar depressive disorders.
About 10% of melancholic patients exhibit manic features. The overlap is clearly
expressed in the many descriptions of ‘‘mixed’’ and ‘‘spectrum’’ depressive and manic
conditions. Patients may exhibit depressive and manic features during the same
episode or episodes may recur in cycles, changing from one to another within
weeks, days, or even within hours. The depressive state that is identified in a patient
with a history of a manic or hypomanic episode cannot be distinguished from the
depressive state in a patient without such a history. Neither family history nor course
of illness successfully separates the two conditions. Nor does the putative induction
of mania by antidepressant drugs assure the separation as the incidence of manic
switches is no greater than the natural switch rate; it is suYciently uncommon as not
to be useful as a diagnostic test.
The responses to lithium and to anticonvulsants are cited as justifications for
bipolarity.67 To support such a view, the evidence of the antidepressant eYcacy of
lithium is minimized, and the control of manic episodes by anticonvulsants maxi-
mized. Lithium is both an eVective antidepressant, especially in maintenance therapy,
and an eVective control for mania. Anticonvulsants are weak mood stabilizers; the
treatment algorithms commonly require the polypharmacy of mood stabilizers (often
two), antipsychotic, and sedative agents. Yet patients in both the depressive and
manic phases of the illness respond rapidly to electroconvulsive therapy (ECT).68
The neuroendocrine and sleep laboratory tests that demarcate severe depressive
mood disorders from other psychiatric disorders are abnormal during both the manic
and depressive phases of their illness.69 The degree of abnormality is apparently less
for patients in the manic phases but the diVerence is not suYcient to support the
concept of bipolarity.
Bipolarity as a separate psychiatric disorder is not supported by psychopathology,
family studies, laboratory tests, or treatment response. A single disorder of melan-
cholia circumscribes the present knowledge and oVers a better model for continuing
scientific eVorts.

Psychotic depression is melancholia

Approximately one-third of melancholic patients are psychotic.70 Psychotic features

in melancholia are reported at all ages, although the recognition of psychotic depres-
sion increases with the patient’s age. In some reviews nearly all patients with
psychotic depression are melancholic.71

Historical background
In nineteenth-century psychopathology, disorders of thought were identified in
patients classified as manic-depressive insanity, involutional and melancholic depres-
sion, dementia praecox, and dementia paralytica (neurosyphilis). Psychosis was not
pathognomonic for any condition. During the early and mid twentieth century,
however, ‘‘first-rank’’ psychotic features (e.g., complete auditory hallucinations,
25 Melancholia defined

experiences of alienation and control) were associated with the hereditary disorder
of dementia praecox, later redefined as ‘‘schizophrenia.’’ The presence of these
signs was considered pathognomonic of schizophrenia regardless of the presence of
a concurrent mood disorder.
The view that schizophrenia encompassed almost all episodes of psychosis was
favored in the USA but not in Europe. Cross-Atlantic diVerences in the prevalence
of schizophrenia and of manic-depressive psychosis were reported, and to assess
the basis for the discrepancy, a cross-national group of investigators examined
patients in the UK and in the USA. DiVerences in diagnostic perceptions, not
national distinctions in populations, best explained the diVerences in prevalence of
the disorders.72 The broad definition of schizophrenia in the USA materially in-
creased the numbers of patients who were labeled schizophrenic while reducing the
numbers diagnosed with mood disorders.
The place of psychotic mood disorder in psychiatric classification remained un-
clear. Some considered these states to be more severe forms of manic-depressive
illness while others preferred to define them as ‘‘schizoaVective’’ and to include
them among the psychotic disorders.73 One understanding of psychosis in patients
with mood disorders derived from the clinical trials of TCAs. Among depressed
hospitalized patients treated with imipramine with serum blood levels monitored
to assure adequate dosing, some patients failed to respond to imipramine but did
respond to ECT.74 The presence of delusions discriminated the patients who had
not improved with imipramine alone. A decade earlier, a large Italian study by
De Carolis et al. (1964) had also reported that the psychotic depressed patients had
not responded to imipramine but had recovered with ECT.75 The association between
depression, psychosis, poor response to TCAs, and rapid response to ECT was quickly
confirmed and is now widely accepted.76
The DSM classifications of 1980 and 1994 still give preference to psychotic features
as defining schizophrenia, and they primarily link catatonia with schizophrenia
despite its strong association with mood disorder.77 Psychotic features are recognized
as a non-specific psychopathologic phenomenon, appearing within diVerent diag-
nostic classes, and delusions in a mood disorder are considered signs of severity,
not distinctions in pathophysiology, but this classification is only permitted when
directly linked to a disturbed mood state. If the patient has delusions that last longer
than the mood symptoms or the psychotic features are deemed more pronounced,
the schizoaVective diagnosis is preferred and the patient assigned to the psychotic
disorders, not mood disorder, category. Nevertheless, for each principal mood dis-
order – major depressive disorder, bipolar I disorder, and bipolar II disorder, depressed
type – the presence of psychosis could be recognized by coding the severity/psychotic/
remission specifier in the fifth digit.78
Once a condition of ‘‘psychotic depression’’ or ‘‘delusional depression’’ was recog-
nized, attention was paid to its delineation from other depressive illnesses. Focusing
on the motor aspects of melancholia, Parker and Hadzi-Pavlovic (1996) envisioned
three forms of depressive illness – psychotic depression, non-psychotic melancholia,
and non-melancholic depression.79 They oVered criteria of discrimination by age of
26 M. A. Taylor and M. Fink

onset,80 degree of cognitive impairment,81 and prominence of personality and life

events.82 Non-melancholic depression was characterized by early onset of illness, little
cognitive impairment, deviant personality traits, and little psychomotor disturbance.
Severity of psychomotor disturbance and cognitive impairment characterized psych-
otic melancholia.83 Psychotically depressed patients exhibited more severe psycho-
motor disturbance, including facial immobility, slumped posture, slowed and limited
movements and speech, poverty of associations, and poor responsiveness. Non-
suppression on the dexamethasone suppression test was recorded in 72% of the
patients. The mood was characterized as ‘‘non-reactive.’’84 While the distinction
was clear between non-melancholic depression and the other two forms of depressive
illness, psychotic and non-psychotic melancholia were not shown to be diVerent
diseases.
Other authors focused on abnormalities in neuroendocrine and neurocognitive
measures, course of illness, familial transmission, and response to treatment as
distinguishing psychotic and non-psychotic depression.85 Among the criteria were
greater guilt feelings and psychomotor disturbances, biochemical diVerences in
glucocorticoid activity, dopamine beta-hydroxylase activity, levels of dopamine and
serotonin metabolites, severity of sleep measures, and ventricle-to-brain ratios.
Neuropsychological deficits were found to be greater in degree among psychotic
depressed patients than among the non-psychotic depressed.86 None of these eVorts
identified a clearly distinguishing variable.
In a retrospective examination of patients in Denmark who had a diagnosis of a
single depressive episode at their first ever discharge during the period 1994 through
1999, patients were identified as with or without the International Classification of
Diseases, 10th edition (ICD-10) diagnosis of melancholia (n ¼ 248 and 293 respect-
ively), and with and without psychosis (n ¼ 1275 and 1639, respectively).87 Relapse
rates were highest in the psychotic depression group. The groups did not diVer in
suicide rates or melancholic features. Compared to non-melancholic depressed
patients, the melancholic patients were less likely to be diagnosed as having a
personality disorder, stress-related disorder, or ‘‘nervous’’ disorder.
It is diYcult to recognize the presence of psychosis in melancholic patients. The
more severely ill depressed patients are common in referrals for ECT. In an analysis
of ECT referrals, only 2/52 patients had been adequately treated for psychotic
depression.88 The authors assumed that, had the referring physicians recognized the
presence of psychosis, the medications prescribed would have been more appropriate
for psychotic depression.
Other than the recognition of psychosis, no measures distinguish the psychotic and
non-psychotic forms of melancholic illness.

Mood-congruent and mood-incongruent delusions

In the 1980 DSM classification attention was directed to mood congruence of psycho-
tic thoughts. If the patient’s delusional content was deemed depressive (e.g., low self-
worth, guilt), the delusion was defined as congruent with the mood state and the
27 Melancholia defined

patient was deemed as most likely suVering from a mood disorder. If the delusional
content was deemed ‘‘bizarre’’ (e.g., delusions of passivity), the delusion was defined
as incongruent with the mood and the patient was considered to be schizoaVective
or schizophrenic. Patients with an aVective syndrome with mood-incongruent as
well as mood-congruent delusions, however, were allowed within the class of major
depression.
In a review of the writings that supported a concept of a mood-incongruent
psychotic mood disorder, three hypotheses were considered: it was a form of depres-
sive illness, a subtype of a schizoaVective disorder, or a subtype of schizophrenia.89
After reviewing the evidence of demographic studies, degree of risk in families of
probands, laboratory test data, and treatment response, Kendler concluded that
mood-incongruent psychotic depression was best viewed as a subtype of mood
disorder and not as a feature of schizophrenia or schizoaVective disorder.
In an examination of the clinical, genetic, and prognostic significance of mood-
incongruent psychotic symptoms, Abrams and Taylor (1983) further concluded that
mood-incongruent psychotic symptoms did not identify a unique subpopulation
of melancholic patients. In another large clinical study, the authors were unable
to define diVerences in the congruence of delusions among patients classified as
schizophrenia, schizoaVective disorder, psychotic, or mixed mania.90
Neither a history of psychosis nor mood-incongruent delusions has prognostic
significance for the treatment of bipolar depression.91 It is reasonable to conclude
that mood congruence of delusions does not distinguish patients with a mood
disorder from those with a non-mood disorder psychotic illness. Delusions represent
degrees of severity, not unique psychopathology.92

Psychotic depression meets criteria for melancholia

Patients who are depressed and who are also psychotic are best included within
the concept of melancholia. The manifestations of depressed mood, family
history and course of illness, laboratory test findings, and response to treatments
are indistinguishable for those with and those without evidence of psychosis
(Table 2.2).

Table 2.2. A comparison of psychotic depression and melancholia

Psychotic depression Non-psychotic melancholia

% ECT referrals 30% 70%

HPA tests abnormal 80% 60%
Sleep tests abnormal Positive Positive
Family illness Positive Positive
Treatment response
TCA 20–30% 50–70%
ECT 90% 75–85%
28 M. A. Taylor and M. Fink

Clinical vignettes are consistent with the view that psychotic depression is a severe
form of melancholia and not a distinct entity.93 An example of psychotic depression
is described in Chapter 8, patient 8.2. Another representative vignette is abstracted
from the DSM-IV casebook.94
Patient 2.6
Mr. D. O’M is a small, bent disheveled 63-year-old man, referred to a psychiatric clinic after
telling his internist that he was hearing voices. A few weeks earlier he heard a stranger call
him ‘‘an Irish fag.’’ He said his mood was ‘‘lousy,’’ ‘‘nervous’’ and ‘‘shaky’’. He lost interest in
seeing friends or ‘‘doing anything’’ since his mood deteriorated. He had no appetite, lost
weight, but his sleep was not disturbed. He denied thoughts of suicide ‘‘because, as a
Catholic, I would not go to heaven if I committed suicide; but I would be better off if my
heart stopped.’’ A similar illness occurred 12 years earlier when he heard blaspheming
voices and became preoccupied with religious ‘‘scruples.’’ Treatment with medicines at that
time was successful and he returned to work as a cab driver. He had retired five years earlier
because of worsening diabetes and ulcerative colitis. He denied drinking alcohol in 30 years.
His wife confirmed his history.
He was hospitalized and treated with antipsychotic medication. A few weeks later, when
the voices diminished, the depressive mood and retardation became more obvious. Nor-
triptyline was prescribed and he left the hospital four weeks later, improved and less
anxious, but still complaining of the voices. He recovered slowly in the next year.

The editors describe Mr. D. O’M as suVering from a major depressive disorder,
recurrent, with mood-incongruent psychotic features.95 Even a cursory reading of
the literature will show that this patient’s delusional thoughts are expressions of his
depressed mood, are fully congruent, and are classic for melancholia. The discussant,
however, agreed with the proVered diagnosis but suggested that had the patient been
oVered ECT, he might have had a better outcome and a shorter duration of illness.
The next patient with a psychotic depression was successfully treated to a full
resolution of his illness.
Patient 2.7
A 69-year-old business executive had fretted about the sale of his company. His work had
been the main interest in his life. When his wife become ill and was unable to manage their
home, he grew despondent, slept during much of the day, was up much of the night, bathed
irregularly, ate poorly, complained of constipation, and thought that his food was poisoned.
He insisted, contrary to fact, that he had cancer and would soon die. He accused his wife of
infidelity and refused to talk to her. He watched the street from behind curtained windows
for hours at a time believing that his neighbors were spying on his home. After nine months
he was hospitalized.
His wife reported a single episode of severely depressed mood when the patient was
age 45, following business reversals and fears that he would lose his business. After the
business difficulties resolved, he became well.
On examination he walked slowly, appeared emaciated, disheveled and unkempt, and
had an unpleasant body odor. He refused to answer questions and was reluctant to be
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