Depression as seen by the psychiatrist

DEPRESSION AS SEEN BY THE PSYCHIATRIST ARNOLD M. COOPER, M.D. CHARLES A. SHAMOIAN, M.D.

0011-5029/79/09001-64504.50 9 1979 Year Book Medical Publishers, Inc.

TABLE OF CONTENTS PREFACE

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S E L F - A s s E S S M E N T QUESTIONS

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I. DEPRESSION AND A D A P T A T I O N

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I I . DEPRESSION: MOOD, SYMPTOM, SYNDROME AND D I S E A S E

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I I I . CLASSIFICATION OF D E P R E S S I O N . I V . EPIDEMIOLOGY

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V . ETIOLOGY OF DEPRESSION

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VII. TREATMENT . . . . . . . . . . . . . . . .

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DIAGNOSIS

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DIAGNOSIS AND T R E A T M E N T O f C H I L D R E N

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IX. S U M M A R Y

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SELF-AssESSMENT ANSWERS

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PREFACE In October, 1977, a DISEASE-A-MONTH monograph entitled Depression as Seen by the Internist was published, following which we received several letters from psychiatrists who believed that the monograph did not represent the opinions of a majority of psychiatrists nor accurately portray the latest attitudes toward the therapy of depression. Accordingly, the Editorial Board requested Drs. Arnold M. Cooper and Charles A. Shamoian to prepare an article on depression that would convey to internists their conception of the present status of the knowledge of its etiology, pathophysiology, diagnosis and treatment. We are sure our readers will find it interesting and informative and will benefit from the opportunity to compare the opinions expressed in the two monographs. THE EDITORS

SELF-ASSESSMENT QUESTIONS 1. All of the following are true except one. (a) Depression can be viewed as a sign or symptom. (b) Depression has been viewed as being on a neuroticpsychotic continuum. (c) Some depressions can be considered as endogenous whereas others m a y be exogenous. (d) Depressions m a y be classified as unipolar or bipolar. (e) Depression always is manifested by sadness. 2. In the following series of statements label each one either true or false. (a) Depression is a homogeneous group. (b) The Two Disease Model of Depression has been advanced as an explanation of depression. (c) Homovanillic acid (HVA) is the end product of serotonin metabolism. (d) Vanillylmandelic acid, also known as 3-methoxy-4hydroxymandelic acid (VMA), is a reflector of norepinephrine metabolism in the periphery. (e) Monoamine oxidase inhibitors (MAOI) m a y be used with tyramine-containing products without fear of any clinical consequence. 3. The following numbered names are associated with which lettered phrases? 1. Freud (a) Catecholamine hypothesis 2. Kallman (b) Learned helplessness 3. Schildkraut (c) Anger directed inward 4. Seligman (d) Studies of identical twins 4. Norepinephrine metabolism is associated with all except one of the following: (a) 3-Methoxy-4-hydroxy-phenylglycol (MHPG). (b) Tyrosine. (c) P-chlorophenylalanine. (d) Catechol-o-methyltransferase (COMT). (e) Monoamine oxidase (MAO). 5. Epidemiologic studies have shown all except one of the following: 4

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(a) That the number of first admissions per year for manic-depressive illness are decreasing. (b) That the ratio of males to females is 2:1 for the affective disorders. (c) That manic-depressives, unlike the schizophrenic, do not drift to lower socioeconomic classes. (d) That the morbidity risk for affective disorders for the general population is approximately 1 - 2%. The permissive-amine hypothesis of the affective disorders is associated with: (a) Norepinephrine. (b) Serotonin. (c) Depression. (d) Mania. (e) The assumption that a vulnerability to the illness exists. (f) All of the above. (g) None of the above. Psychotherapy is indicated in: (a) Depressive neurosis. (b) Grief reactions. (c) Reactive depression. (d) Manic-depressive illness. (e) All of the above. (f) None of the above. Tricyclic antidepressants may: (a) Be classified as tertiary amines. (b) Be classified as secondary amines. (c) Block the reuptake process of norepinephrine and/or the reuptake of serotonin. (d) Be contraindicated in patients with s e v e r e cardiac disease. (e) Be characterized as indicated in a, b & c above. (f) Not be characterized as indicated in a, b & c above. Electroconvulsive therapy (a) Is contraindicated in patients with increased intracranial pressure. (b) May be used in psychotic, suicidally depressed females who are pregnant. (c) In the treatment of depression m a y be associated

with a high relapse rate if not followed by treatment with a tricyclic antidepressant drug. (d) Does not result in permanent, testable cognitive impairment. (e) May not be characterized by any of the above. (f) May be characterized by a, b, c and d. 10. Studies pertaining to hereditary factors in affective dis~ orders have shown all except: (a) A higher incidence of affective disorders in first-degree relatives. (b) A higher incidence of unipolar illness in the relatives of a proband with bipolar illness. (c) A higher concordance rate for affective disorder in monozygotic twins when compared to dizygotic twins. (d) Father-to-son transmission in some studies. Answers appear at the end of the article.

is Professor of Psychiatry and Director of Training, The New York Hospital-Cornell University Medical Center, Payne Whitney Clinic and Westchester Division. Dr. Cooper received his M.D. from the University of Utah School of Medicine, and took his internship at Presbyterian Hospital in New York. He completed a psychiatric residency at Bellevue Hospital in New York, and received psychoanalytic training at the Psychoanalytic Clinic for Training and Research, College of Physicians and Surgeons. Dr. Cooper is a lecturer at Columbia University College of Physicians and Surgeons and Columbia College, and is a training and supervising psychoanalyst at Columbia University Psychoanalytic Center. His scientific interests include medical education and psychopathology of the severe character disorders.

is Clinical Associate Professor of Psychiatry and Pharmacology, Cornell University Medical Center, and Director of Geriatric Services, New York Hospital, Westchester Division. Dr. Shamoian received his M.D. from Tufts University in Boston, and took his internship in medicine at Cornell Division, Bellevue Hospital in New York City. He completed his residency in psychiatry at Payne Whitney Psychiatric Clinic, New York Hospital, Cornell Medical College, New York City. Dr. Shamoian is a Diplomate, National Board of Medical Examiners. His medical interests include pharmacology and geriatrics.

D E P R E S S I O N is a u b i q u i t o u s h u m a n d i s o r d e r t h a t w a s recognized in a n t i q u i t y a n d is e x q u i s i t e l y described b o t h in t h e e a r l i e s t m e d i c a l l i t e r a t u r e a n d b y poets f r o m H o m e r ' s t i m e to t h e p r e s e n t . D e p r e s s i o n p r o b a b l y is t h e m o s t f r e q u e n t init i a t i n g c a u s e for a v i s i t to a p h y s i c i a n . T h e s y n d r o m e h a s

multiple manifestations ranging from a mild alteration of mood and a mysterious loss of "zest," an excessive concern with bodily functions, an increase in alcohol intake or a complaint of multiple somatic symptoms to a psychotic preoccupation with suicide. In mild cases, depression can exist for prolonged periods with little apparent effect on functioning; in severe cases, it is a leading cause of death, through suicide. It has been estimated that three-fourths of the patients seen in general medical clinics have significant emotional problems deserving psychiatric attention and, of these, a large number are clinically depressed. It is also suggested that approximately 1 2 - 1 5 % of the adult population will have symptoms of depression of sufficient severity to warrant treatment at some point during their lives. 1 It is clear, then, that the clinician must maintain a high index of suspicion for the disorder and have knowledge of the many guises in which it appears if he is to make the diagnosis. In those cases that do not present a clear-cut picture of depression, a few minutes devoted to history taking and listening to the patient speak about his feelings, about himself and his dissatisfactions will give a high yield of diagnostic information concerning depression. A recent survey revealed that more than 214 million prescriptions for psychotropic agents were written during a single year. Importantly, 83% of these were prescribed by physicians other than psychiatrists and neurologists, and more than 60% were written by internists and family practitioners. Twenty-one million prescriptions were for antidepressant medications and it has been suggested that more than 90% of these were prescribed in placebo doses. 2 Allowing for a variety of errors in the collection of data, there seems little doubt that m a n y depressions are untreated, are treated inappropriately with major or minor tranquilizers or are treated inadequately with antidepressant medication. This is especially unfortunate since proper treatment will alleviate the depressive state in more than 85% of patients suffering from this entity. Accurate diagnosis and either appropriate treatment or referral are of the utmost importance.

I. DEPRESSION AND ADAPTATION Charles Darwin, in The Expression of the Emotions in Man and Animals, pointed out the continuity of emotional expression in lower animals and m a n and the adaptive importance of emotions for survival. 3 In recent years, studies of infant and child development, primate behavior and psychodynamics have all emphasized that some form of the depressive syndrome is a primary affective expression serving important adaptive functions. 4-9These include: 1. Social. Beginning in infancy and continuing throughout life, the series of alterations in facial expression, body tonus, crying, etc., which typify depression, serve as vital messages to the caretakers that a state of need in the organism exists. Most h u m a n beings instantly recognize manifest depression in another person and are moved to respond with pity and concern. 2. Physiologic. Depressive affect has been postulated as a part of a conservation-withdrawal syndrome designed to aid survival in the infant and child by reducing energy expenditure under conditions of the loss of maternal care2 Clear proof of this hypothesis is lacking, b u t many studies now clearly indicate that major neurobiologic changes accompany depressive affect. 3. Psychologic. It is likely that depressive affect signals the organism of the occurrence of damaging psychologic events (e.g., loss of self-esteem, sense of failure, etc.) and serves to institute defense mechanisms that m a y help to repair the damage. 8 Depression is an internal indicator of failures of self-esteem and failures to meet one's own inner standards. As a primary affect, then, it serves as a regulator of behavior, providing internal signals of success or failure of adaptive behavior and as an initiator of defense mechanisms.

II. DEPRESSION: MOOD SYMPTOM, SYNDROME AND DISEASE The term depression is part of our everyday language, has multiple meanings and is used to describe a vast array of states.

As a mood, depression m a y be brief or long-lasting. It is common and is a part of everyday normal living. Rejection, frustration, loss or disappointment commonly are accompanied by feeling ~'low," "blue," "down at the mouth," '~sad," ~'gloomy" and "discouraged." These same feelings often occur in varying degrees without obvious precipitating events in life as part of the normal mood fluctuations of daily life. It often is difficult to demarcate sharply the boundary between ordinary expectable low moods and clinical depression. In general, a depression of clinical significance is longer-lasting and will be accompanied by lowered self-esteem and some degree of feelings of helplessness and h o p e l e s s n e s s - a despairing sense of a loss of capacity to cope with life. Many individuals are readily aware of the change in the magnitude of a depressed mood beyond their own norm and will express their concern and seek help. Others, for a variety of psychologic reasons, may deny significant depression or attempt to hide i t - t h e so-called "masked" or "smiling" depressions. Empathic observation and a careful history, however, usually can detect those degrees of depression that exceed the norm. Depression m a y be a presenting symptom of a variety of psychiatric or medical conditions, including viral diseases, endocrine disorders, medication responses, multiple sclerosis, cancer of the pancreas, organic brain syndrome, schizophrenia or severe character disorders.l~ A good history usually will provide evidence of the underlying illness. Generally, it is advisable to think of depression as a syndrome that has multiple etiologies. 11 In addition to, or instead of, the sad and painful depressed mood and the feelings discussed above, the depressed patient may complain of or reveal any combinations of the following12: a. Loss of the capacity to experience pleasure (anhedonia). b. Appetite change, usually manifested by weight loss. c. Sleep disturbance, usually some variety of insomnia, although occasionally excessive sleep. d. Feelings of tiredness, fatigue, lethargy or loss of zest. e. Agitation, experienced as restlessness, hyperactivity and irritability. f. Retardation of movement, speech and thought. g. The typical facies and posture of depression. 10

h. Diminished sexual interest and activity or loss of power of arousal. i. Lowered self-esteem, with feelings of helplessness, pessimism and hopelessness. j. Feelings of guilt, shame and self-reproach. k. Loss of the capacity to concentrate and inability to carry out complex tasks over time. 1. Anxiety, which may present as feelings of dread, doom and foreboding or as autonomic nervous system manifestations such as sweating, palpitations and tachycardia. m. Somatic complaints, which may represent any organ system and include muscle aches, headaches, diarrhea or constipation, heartburn, abdominal pains of all kinds, back pains, etc. n. Suicidal thoughts or attempts. Sadness itself may not be a presenting complaint. The depressive syndrome m a y manifest itself in every aspect of living-psychologic (affective and cognitive), social and somatic. The term ~vegetative signs" refers to the combination of loss of appetite, early-morning awakening and psychomotor retardation and always is an indicator of severe depression requiring medical treatment. In severe forms, reality testing may be impaired and delusions and hallucinations m a y be prominent. Although the m a n y manifestations of depression may present in unlimited combinations, two syndromes are particularly common and these will be described in detail: the retarded depression and the agitated depression. RETARDED DEPRESSION The retarded depression in its fully developed form is characterized by the presence of a depressive affect, a psychomotor retardation and a disturbance in t h i n k i n g - i . e . , a slowing down of the cognitive processes. The patient appears unkempt and wears the same clothes day after day. His personal hygiene has deteriorated so t h a t he no longer shaves, combs his hair, brushes his teeth or bathes. He no longer has the energy to undertake the activities of normal daily living. His facial appearance is t h a t of one who is dejected and appears constantly unhappy. His expression is dull and he lacks spontaneity in affect, speech 11

or actions. When seated, he remains motionless for hours, staring off into space. He speaks in a very soft voice, hardly audible, and his thoughts and vocal productions are very slow. A great deal of effort is required for him to speak or move. He will respond to questions b u t with monosyllabic r e s p o n s e s - n o t in sentences. His concentration is poor, and because of it, especially if elderly, he will appear to have the beginnings of a dementia. The patient feels hopeless about himself and his future is perceived as nonexistent. He feels that he has failed and disgraced his family and is not worthy of the attention, affection and understanding of his relatives or staff. He wants to be left alone to die. The patient has no appetite and does not eat, as a result of which he m a y have lost anywhere from 10 to 30 pounds over a relatively short period. He has difficulty falling asleep and usually arises very early in the morning feeling exhausted. His sexual appetite and activity have disappeared. Because of the selfdeprecatory thoughts and the intensity of the pain attached to this state, the patient m a y feel trapped and hopeless and believe that suicide is the only solution to the problem. Suicide always is a possibility, even when the depression begins to lift. If, suddenly, and for no apparent reason the patient is smiling, shows more spontaneity in activity and thoughts, he m a y have resolved his dilemma by deciding to commit suicide. Similarly, the patient who has begun to respond to treatment and is beginning to be more energetic and effective, initially may use these energies to plan and carry out a suicide that his severe depression had precluded. Thus, the appearance of an amelioration of the depression ought not lead to diminished vigilance. The suicide potential is very high for depressed patients, especially the middle-aged, white male who is divorced, widowed or single and has a history of alcoholism and/or a debilitating illness. This issue must be discussed frankly and openly with the patient. AGITATED DEPRESSION In the agitated depression, many of the signs and symptoms described in the retarded state are also manifest. However, the overriding feature of this clinical picture is that of motor restlessness. The patient cannot remain seated for 12

any length of time, feels uncomfortable and agitated whether he is seated, standing or lying. He constantly is moving from place to place, pacing and wringing his hands. He appears depressed, sad and dejected b u t also gives the appearance of irritability and hostility. His thoughts tend to center around his past sins, worthlessness and intense guilt about his family and work. He believes firmly that he has brought shame to his family and that everyone who comes in contact with him will suffer. He may be clinging, dependent and demanding of attention in an irritating way. His ability to concentrate has markedly decreased and his future appears black and bleak. His appetite is nonexistent, he is constipated and he may even be dehydrated and in a state of malnutrition. He may hold the delusional belief that his insides are rotting away. He has difficulty sleeping. Furthermore, he firmly believes that he deserves to die and, of course, is a high risk for suicide. This syndrome usually is found in the older patient, and in the past has been referred to as "Involutional Melancholia." Presently, however, some investigators believe that this clinical state is typical of the patient who is diagnosed as unipolar depression (i.e., just having episodes of depresTABLE 1.-NOSOLOGIC CLASSIFICATION OF DEPRESSION* Primary/Bipolar Affective ~. . /Ulsoraers--. / ~lTn~nn]~r ~ / ---'~ .... ~ Clinical/ Depres.sion ~ Psychiatric~/~f~ /Disorders Secondary/// Affective- Disorders~ ~ \ S y s t e m i c ~ Diseases~

Depressive

Spectrum (?) Pure Depressive Disease (?) Alcoholism Schizophrenia Personality Disorders, etc. Central Nervous System Drugs Systemic Illnesses Viral Endocrine

*Modifiedafter Klerman and Barrett. ~3 13

sion) whereas the retarded state is more consistent with bipolar depression (i.e., patients with episodes of both m a n i a and depression). Some recent investigations into the biochemistry of depression 14 indicate t h a t certain of the depressions m a y represent specific disease entities with particular biochemical limits and consistent genetic patterns. 1~-17 F u r t h e r knowledge of the heredity and biochemistry of these entities m a y lead to the description of groups of depressions with specifiable onset, course, duration and treatment. It seems likely, however, that, as with all disease entities, even in this group of depressions, psychosocial stresses play a significant role as precipitants of illness even though biologic factors are etiologic. 18 Psychologic understanding is significant in the t r e a t m e n t of all depressions, including those being treated somatically, and is of prime importance in the t r e a t m e n t of some depressive disorders. Depression m a y be a final common pathway for groups of biologic, psychologic and social variables, with any given individual representing quantitatively different susceptibilities to the three factors (Table 1).

III. CLASSIFICATION OF DEPRESSION Many attempts have been made to provide an orderly classification of the depressive syndromes t h a t will appropriately guide therapeutic interventions. TABLE 2.-DSM II CLASSIFICATIONOF AFFECTIVE DISORDERS* I. Manic-DepressiveIllness: A. Manic-DepressiveIllness, Manic Type B. Manic-DepressiveIllness, Depressed Type C. Manic-DepressiveIllness, Circular Type 1. Manic-DepressiveIllness, Circular Type, Manic 2. Manic-DepressiveIllness, Circular Type, Depressed II. InvolutionalMelancholia III. PsychoticDepressive Reaction *Adapted from the Diagnostic and Statistical Manual of Mental Disorders, secondedition (DSMII).TM 14

The current Diagnostic and Statistical Manual of Mental Disorders, second edition (DSM II), classifies the manic-depressive disorders essentially in accord with the classification that Kraepelin devised in his original studies 19,2~ (Table 2). However, this classification provides insufficient information concerning the important differences in intensity and etiology that are discernible among depressions. An immense amount of new knowledge concerning the biology, psychology and epidemiology of the depressive syndrome has been acquired, and this has led to a number of new classification schemata, which will be described. These schemata dichotomize depressions according to ~'endogenous-reactive," ~neurotic-psychotic," ~primary-secondary" or ~unipolar_bipolar."11, 1:~ ENDOGENOUS-REACTIVE CLASSIFICATION OF DEPRESSION This classification divides depression into subgroups according to whether the etiology seems to be primarily internal or external. Reactive depression refers to the depressive syndrome occurring in relation to a clearly definable life crisis or s t r e s s - for example, loss of a job, divorce, death of a loved one. It is important, in understanding this group of patients, to distinguish normal grief reactions from pathologic depressions, which last longer and include distortions of self-perception (inappropriate feelings of guilt and selfaccusation). Endogenous depression refers to those in which the onset seems unrelated to an identifiable life stress, suggesting some inherent biologic mechanism. The usefulness of this classification has been diminished by the many studies that have demonstrated the importance of external events and of early developmental factors in the understanding of most adult depressive disorders, even in those instances in which there is strong reason to believe that a biologic etiology is playing a role. Similarly, some seemingly reactive depressions respond to antidepressant medication.4, 5, ~,-23At either end of the spectrum there seems to be a group of patients whose depression is more clearly reactive or endogenous, b u t the bulk of patients show mixtures of the two factors. 15

NEUROTIC-PSYCHOTIC CLASSIFICATION OF DEPRESSION

Classification along this continuumattempts to dividethe depressive syndrome primarily accordingto intensity. The neurotically depressed person retains intact reality testing and a capacity for social functioning,although with impairment of pleasure. The psychoticallydepressed patient has impaired reality testing. His feelings about himself and his body begin to take on delusional qualities (~mybrain is rotting" or "I have done suchterrible things that God wants me to die") and the suicide risk is high. The distinction of psychotic versus neurotic has significantclinical consequences. The neurotically depressedpatient may neither require nor benefit from somaticinterventions and is a likely candidate for psychotherapy as the major treatment moda]ity. The psychotically depressed patient almost surely will require somatic treatments in the form of antidepressant medication or electroconvulsivetherapy (ECT). Despite the clinical value of separation of depressions along this continuum,the classification suffers, again, because of a lack of clear etiologic distinction. In the past there has been a tendency to equate neurotic with reactive and psychotic with endogenous. This equation, however,often is invalid, since many psychotic depressions are precipitated by external life events. Conversely, although neurotic depressions always can be related to elements of the character structure and events that have psychodynamicmeaning, it is not always clear that these factors have been etiologic for the depression. PRIMARY-SEcONDARY CLASSIFICATION OF DEPRESSION

This is a more recent approach to the classification and understanding of depressive syndromes based on the history of the depressive episode and the associated psychopathology.24 Primary affective disorder refers simply to the appearance of the depression uncomplicated by other psychiatric diagnoses in the present or past. Previous psychiatric episodes were of depression or mania only. The term secondary affective disorder is reserved for patients in whom other psychiatric diagnoses in the past or present account for the 16

major psychopathology, with depression appearing as an associated symptom. The term secondary depression also includes those depressions found in association with medical illnesses-e.g., viral infections, pancreatic carcinoma, etc. This classification directs the clinician's attention toward the treatment of the major source of disturbance, rather than the intensity of the depression, and emphasizes the multiple etiologies of depressive disorder. UNIPOLAR-BIPOLAR CLASSIFICATION OF DEPRESSION The division according to bipolar or unipolar requires consideration of the longitudinal history of the illness. 25 Those patients with recurrent episodes of depression alone (unipolar) are clearly delineated from those patients with a history of both depression and mania (bipolar). In the past, both of these groups were classified under manic-depressive illness with the assumption that mania and depression occurred along a single continuum in all cases. At present, however, there are strong pharmacologic and genetic data suggesting that the group of patients who manifest depression alone are distinct from the group who show mania at some point in the course of the disorder. '6, 26 For example, lithium has been shown to be an effective antidepressant agent for those with bipolar depressive disorder whereas the results are equivocal for those with unipolar depressionY -3' One of the earlier studies reported that first-degree relatives of unipolar probands have a high incidence of depression alone, and a recent study suggests that there are biochemical differences between the unipolar and bipolar groups. '5, ,6 The unipolar group, however, still needs further clarification. The distinction of depressive disorders according to the unipolar-bipo]ar dichotomy seems to have a number of epidemiologic and therapeutic implications. DIAGNOSTIC AND STATISTICAL MANUAL OF THE MENTAL DISORDERS, THIRD EDITION (DSM III) A new official classification of the mental disorders probably will be released during 1979-80. 32 The draft of the 17

m a n u a l th at c u r r e n t l y is under consideration (see Table 3) suggests the classification of affective disorders according to: (1) major affective disorders, (2) chronic minor affective disorders and (3) atypical affective disorders. Within each group one notes w h e t h e r the illness is manic, depressive or bipolar, and severity is rated from mild to psychotic. Under the major affective disorders one also notes w h e t h e r the illness is a single episode or recurrent. The DSM II classification, in effect, combines desirable characteristics of several of t h e previous classifications. Major emphasis is given to w h e t h e r the syndrome is unipolar or bipolar, chronic or episodic and mild or severe. F u r t h e r m o r e , in the DSM III schema, the patient's psychologic status mus t be indicated along five different axes: 1. The clinical psychiatric syndrome(s)-that is, the primary diagnosis(es). (With regard to depression, axis 1 deals with the various categories of the major affective disorders. Thus, all the subheadings of Table 3 can be found along axis 1. However, to make a complete diagnosis, each additional axis must be considered, for example, axis 2 for personality disorders, axis 3 for concurrent medical diagnosis, etc., as indicated below.) 2. Personality disorders for adults and development disorders for children and adolescents. (Persons with a major diagnosis from axis 1 also may have complicating personality disorders along axis 2 or their primary diagnosis may lie along axis 2.) 3. Concurrent medical diagnoses. 4. An estimate of the severity of psychosocial stressors that relate to the onset and course of the illness. 5. An estimate of the highest level of adaptive functioning during the past year. (This provides an opportunity for indicating the extent of loss of capacity as a result of the illness as well as the effects of chronicity and is a good predictor of functioning in the future.) This system of classification, although seemingly complex, provides the opportunity to combine the most significant elements of previous conceptualizations and allows specification of the time course of t he illness, its intensity, its relation to psychosocial and medical stresses and the special characteristics of each individual's depressive disorder (Tables 3 - 5). A careful history will provide the information necessary for multiaxial-classification, which, in turn, is a valuable guide for t r e a t m e n t planning. 18

TABLE 3 . - D S M III CLASSIFICATION OF AFFECTIVE DISORDERS*

Manic Disorders Manic Disorder, Single Episode Manic Disorder, Recurrent

Major Depressive Disorders Major Depressive Disorder, Single Episode Major Depressive Disorder, Recurrent

Bipolar Affective Disorders Bipolar Affective Disorder, Manic Bipolar Affective Disorder, Depressed Bipolar Affective Disorder, Mixed

Chronic Affective Disorders Chronic Hypomanic Disorder (Hypomanic Personality) Chronic Depressive Disorder (Depressive Personality) Cyclothymic Disorder (Cyclothymic Personality)

Atypical Affective Disorders Atypical Manic Disorder Atypical Depressive Disorder Atypical Bipolar Disorder *Adapted from the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM III). 32

TABLE 4 . - D I A G N O S T I C CRITERIA FOR A DEPRESSIVE EPISODE* A. Dysphoric mood or loss of interest or pleasure in all or almost all usual activities. The dysphoric mood is characterized by the following symptoms: depressed, sad, low, blue, hopeless, irritable, etc. B. At least four of the following: 1. Poor appetite or weight loss or increased appetite and weight gain 2. Sleep disturbance or sleeping too much 3. Loss of energy, fatigability 4. Psychomotor agitation or retardation 5. Loss of interest or pleasure in usual activities or decrease in sexual drive 6. Feelings of self-reproach 7. Diminished ability to think or concentrate 8. Thoughts of death or suicide C. Duration of the illness of at least 1 week from time of first noticeable change *Adapted from the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM III). 32

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TABLE 5.-DIAGNOSTIC CRITERIA FOR CHRONIC DEPRESSIVE DISORDER A. During past 2 years has been bothered by most of the symptoms characteristic of the depressive syndrome. However, the symptoms have not been of sufficient intensity to meet the criteria of a depressive episode B. The symptoms of the depressive syndrome may be relatively persistent or separated by periods of normal mood C. In the depressive periods there is either a depressed mood or loss of interest in all activities D. During the depressive episode there are at least three of the following: 1. Insomnia or sleeping too much 2. Chronic tiredness or low energy level 3. Feelings of inadequacy 4. Decreased effectiveness at usual work 5. Decreased concentration or attention 6. Social withdrawal 7. Loss of interest in sex 8. Decrease in pleasurable activities 9. Feels slowed down 10. Less talkative 11. Pessimistic about the future 12. Tearful 13. Recurrent thoughts of death or suicide E. Absence of delusions or hallucinations *Adapted from the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM III)22

IV. EPIDEMIOLOGY E p i d e m i o l o g i c d a t a a r e i m p o r t a n t in h e l p i n g to d e t e r m i n e p o p u l a t i o n s a t r i s k , in f u r n i s h i n g clues to t h e e t i o l o g y of t h e i l l n e s s a n d i n h e l p i n g to p r o v i d e g u i d e l i n e s for m e n t a l h e a l t h care. M o s t e x i s t i n g e p i d e m i o l o g i c s t u d i e s , h o w e v e r , w e r e c o n d u c t e d p r i o r to t h e c u r r e n t c l a s s i f i c a t i o n s of d e p r e s sion a n d t h e y t e n d to g r o u p t o g e t h e r d e p r e s s i o n s of v a r y i n g t y p e s . U n t i l v e r y r e c e n t l y , p s y c h i a t r i s t s i n d i f f e r e n t count r i e s w e r e u s i n g d i f f e r e n t c r i t e r i a for t h e d i a g n o s i s of d e p r e s sive d i s o r d e r s a n d d e r i v i n g d i f f e r e n t d a t a . F o r e x a m p l e , in a recent collaborative study between the United States and t h e U n i t e d K i n g d o m , it b e c a m e c l e a r t h a t A m e r i c a n p s y c h i atrists diagnosed schizophrenia more frequently than the E n g l i s h w h e r e a s t h e l a t t e r d i a g n o s e d affective d i s o r d e r 20

more frequently t h a n the Americans. 33, 34 Current epidemiologic studies are likely to provide information of far greater usefulness as the d a t a become available. With the reservations indicated concerning the reliability of the data, the following guidelines m a y be considered. The incidence of manic-depressive illness throughout the world is estimated at 4 per 1000. TM 13 Estimates are t h a t 1 - 2% of the general population in America will have an affective disorder sometime during their lifetime. TM 31, 35, 36 In 1970, manic depressive illness accounted for 31/2% of all psychiatric admissions as compared to 22% for the schizophrenias.11, 37 Epidemiologists generally agree t h a t only a small number of depressed patients, perhaps as low as onefifth to one-third of the entire cohort, receive t r e a t m e n t or consult a physician for their depressive illness? s The number of untreated patients who go on to suicide is not known. Unlike schizophrenia, which is found in greater numbers in the lower socioeconomic classes, affective disorders are not consistently associated with a n y specific socioeconomic group? ~, 39-4, Neither is there any consistent correlation with migratory patterns or urban versus rural living. Epidemiologic studies consistently reveal a greater incidence of depression for females over males of approximately 3:2 or 2: 1. TM 35, 42 For every type of depression studied, the female is at significantly greater risk, ranging from perhaps 1.5:1 for manic-depressive disorder to 5:1 for neurotic depression. Males show the highest incidence of first hospitalization at ages 50-65. whereas for females this peak is reached at ages 60-70. The incidence is approximately equal in single and married patients, again unlike schizophrenia, where the majority of patients have been unmarriedY, 41, 43 There is some indication t h a t the incidence and prevalence of depressive illnesses are not constant over t i m e presumably varying with social conditions. Between 1900 and 1950, the rate of admission to state hospitals for diagnosed manic-depressive illness fell about one-half from the initial rate of 18%. This was paralleled by a reported decline in admissions to private hospitals and was prior to the era of trieyelic antidepressant and lithium t h e r a p y . " Between 21

1951 and 1963, the yearly number of first admissions to American state hospitals with the diagnosis of affective disorder had fallen from 5000 to 1500.11 Preliminary studies suggest the possibility t h a t affective illness, again unlike schizophrenia, m a y not be universal in occurrence. In a few primitive societies examined, the illness seemed to be rare.l' Suicide, an outcome of depressive illness, is the tenth most frequent cause of death in the United States and the second most frequent cause between the ages of 20 and 40. 44 The number reported on a yearly basis is approximately 22,000; however, the actual number of suicides probably is much higher t h a n that, since m a n y suicides are unreported. The suicide rate in the United States is approximately 10 - 12 per 100,000. Rates vary greatly among countries and even by cities. Austria, H u n g a r y and Japan, for example, have higher suicide rates t h a n the United States whereas the Netherlands and Spain have lower ones. The suicide rate for men is above t h a t for women but women have a greater incidence of suicide attempts. It should be noted t h a t the frequency of suicide attempts rises with age and t h a t the person at highest risk for suicide is the white male in his mid-fifties, recently divorced or widowed, especially if he is an alcoholic or has a debilitating medical illness. 44 There has been a prevalent m y t h t h a t those who talk about suicide are unlikely to attempt it and those who have a history of suicide gestures are unlikely to carry out a fatal act. Both opinions are untrue. 44 Although adequate epidemiologic data are unavailable, it should be emphasized t h a t depression occurs both in adolescence and in childhood and t h a t suicide is a significant risk, particularly in adolescents, for whom it ranks fourth as a cause of death. 45

V, ETIOLOGY OF DEPRESSION There have been major advances in our understanding of the immediate and remote etiologic factors leading to depressive illness and we will discuss them under three headings: (A) psychodynamic and psychosocial factors, (B) the role of heredity and (C) biochemical factors. 22

A. PSYCHODYNAMIC AND PSYCHOSOCIALFACTORS RELATED TO THE ETIOLOGY OF DEPRESSION 1. THE PSYCHODYNAMICPOINT OF VIEW.--During the past several decades there have been a number of studies t h a t demonstrate the powerful effects of early events on later development and suggest, in particular, a relationship between early experiences of m a t e r n a l loss/deprivation and depression. 4~ Spitz 5 showed t h a t infants brought up in orphanages where physical care was excellent, but opportunities for loving, intimate, playful attachment with a single maternal figure were unavailable, failed to thrive. They '~looked unhappy," cried or stared at the wall, were not comforted by the approach of adults, showed severe developmental lags both socially and intellectually, lost weight and often died. Spitz demonstrated the necessity for a m i n i m u m of adequate love, including being held, cuddled, talked to and played with if the children were to develop any capacity for curiosity, joy and zest. 5, 48 Another set of data was developed primarily by Bowlby and his associates, who were interested in the effects of mother-child separation. They studied children separated from their mothers during World War II, or because of hospitalization, and noted t h a t children between the ages of 6 months and 3 years underwent what seemed to be a clear grief-depression sequence when separated from the mother.4, 5, 49 The first phase of t h a t sequence was labeled protest, during which the child is crying, in a state of panic, seems agitated, irritable and hostile. He calls or searches for his mother and actively looks and listens for any sign of her. During this protest phase, the child seems clearly angry, m a y have temper t a n t r u m s or exhibit head-banging. The phase may last up to a week, and gradually passes into the second phase of despair. The phase of despair is primarily one of withdrawal. The child looks dejected and unhappy and his interest in the environment diminishes markedly. He loses appetite and weight, is dully compliant with environmental demands, but shows no enthusiasms or pleasures. This period m a y last for several weeks and is readily terminable by the mother's return. 23

However, if the mother's return is delayed longer than approximately 3 months, a stage of detachment will succeed. If the mother now returns, the infant will show no signs of pleasure or interest in her. She is treated as an ordinary person without special meaning for the child. Superficially, the child in a stage of detachment may seem successfully adapted, but, in fact, the child has abandoned his strong emotional ties to his mother or to anyone else in the environment and, unless remedial measures are taken, he may have damaged the capacity for forming such ties in the future. In the presence of the mother and her consistent effort to re-establish a bond, the child gradually will begin to show feelings toward her, expressed primarily in excessive clinging, anxiety and rage over any threat of separation from her. The long-range future outcome will depend on the child's age, the quality of relationship between the mother and child, the adequacy of affection and the presence of mother surrogates. Studies with primates have yielded similar findings. 6, 7, 50~2 Infant monkeys separated from their mothers for varying periods manifest phases of protest and despair that seem identical to those seen in humans. These monkeys show motor retardation, a sharp decrease in their social exploration and play behavior, increased self-clasping and cuddling. This phenomenon in primates seems to have many of the cardinal features of depression and has been suggested as a possible animal model for depression. 52-54 When these infant monkeys are reunited with their mothers, they display intense clinging and great anxiety on brief separation. If separation from the mother is excessively prolonged, the infant monkeys show serious arrest or regression of social development, loss of capacity for exploration and play and tendencies toward self-mutilation. These stages in response to loss, which can be demonstrated in h u m a n and primate infants and children, seem to parallel the experience of adults undergoing grief in response to loss. It has been suggested that early childhood loss, therefore, may be one of the factors that contribute toward the likelihood of depressive episodes in adulthood. Reports by Beck and his colleagues ~5 and by Sethi 56 seem to demonstrate clearly the significance of early loss in later depres24

sion, but t h a t relationship was inconsistent in some other studiesY Psychoanalytic contributions to understanding early predispositions toward depression have focused on disturbances in the areas of (1) oral dependent ties to the mother, (2) ambivalent feelings toward the loved object, (3) hostility toward the loved object and self-punitive guilty feelings and (4) vulnerabilities of self-esteem. 58-62 In abbreviated form, psychoanalytic data suggest t h a t disturbances of the earliest ties of mother and child lead to both an excess of angry feelings toward loved and needed dependency objects (persons) and an instability of favorable inner self-representations. Early disturbances of the mother-child tie m a y occur because of failures of"good enough" mothering or because of excessive need on the part of an infant, perhaps for constitutional reasons. With a disturbance in the areas of self-regard and of object-related love, the individual is particularly susceptible to depressive reactions whenever real or symbolic events signal either a loss of loving supplies from the environment or a failure to meet one's own inner standards. Faced with an external loss or failure, these individuals experience an excess of anger because of the disappointments and anxieties aroused by the loss of a needed source of love. This process is internalized and they punish themselves as they would like to punish the lost loved object. Guilt prevents direct expression of the hostility and the individuals accuse themselves of the failings t h a t they attribute to the now disappointing loved one. Events t h a t would occasion grief for an individual not so disposed to depression become an occasion for self-reproach and self-punishment in those whose capacities for relationships to objects are distorted. Similarly, because of the damage in the area of the regulation of self-esteem, the loss of the loved object or a failure in an external role will produce an abnormal decrease of selfesteem, with feelings of hopelessness, helplessness and worthlessness. The loss m a y be a real one (loss of a job or a spouse) or a symbolic one (an imagined humiliation, loss of a pet, a minor setback in one's vocation). Since these individuals experience all blows to their narcissism as severe threats of the withdrawal of all needed dependency supplies, 25

they experience intense anxiety, hostility and self-blame. In effect, the depression-prone individual is caught between excessive need for the loving care of others or the reassurance of external success and his hostile disbelief in the reliability of loving persons or the meaningfulness of any successful achievement. The maintenance of self-esteem requires a degree of harmony between the self as subjectively perceived and the self as wished for or idealized; whenever these two aspects of the self do not coincide there may be a fall in self-esteem and some degree of depression may ensue. According to the psychodynamic point of view, then, issues of self-esteem are central in understanding the etiology of depression, and anything tending to damage self-esteem is likely to precipitate a depression in a vulnerable individual. It is important to realize that because of the h u m a n capacity for symbolic alteration of the meaning of events, the precipitant of a depression m a y seem fantastically trivial to an outside observer; e.g., past minor episodes of cheating, an evidence of middle age, a loss of favor in the eyes of a superior or the failure of a relationship that did not previously seem important. 6~ 63, 64 These external events may symbolically represent conflicts that are unconscious and dynamically important or they m a y represent attempts to provide a coherent explanation to one's self of a depression that, perhaps, is brought on because of internal biologic changes. One of the serious causes of a loss of self-esteem is physical illness itself, especially those illnesses that in reality or in the patient's fantasy threaten prolonged helplessness, loss of previously attained activities that were important for the individual's pride or physical mutilation. Every physician should be on the alert for depression in patients who are ill or who fantasize that they are. The death of a loved one, or significant failures in work and social relations are, for everyone, serious psychologic events that require a period of grief, bereavement, working through and recovery. Attempts to circumvent the time required for those natural processes are most likely to lead to later depression.57 It is a task of the physician to distin26

guish when the normal work of grieving has passed into depression with its attendent high rates of mental and physical breakdown. 2. BEHAVIORISTPOINT OF VIEW.--In recent years, behavioral psychology has directed its attention to the phenomenon of depression, and several conceptions and treatments have resulted from this work. Hopelessness and helplessness are viewed as the core features of clinical depression, and studies report these two feeling states as having the highest correlation with depression intensity. 4~, 65 Seligman and his colleagues have investigated the feeling of helplessness, defined as the perception of having no control over the future, and, with the aid of animal experimentation, they have postulated the concept of "learned helplessness. '6G-68 According to this hypothesis, patients who are prone to depression have failed to learn that they have the ability to avoid painful external events or situations or, conversely, have learned that they are unable to avoid those painful events. Therefore, response patterns that would terminate such t r a u m a are not initiated. A negative attitude about one's effectiveness leads to passive behavior with regard to the environment, which in extreme form is manifested as a decrease in spontaneous responses to the environment. This is an analogue of the psychomotor retardation seen in depression. 66 The concept of ~learned helplessness" has stimulated the development of various behavioral treatments of depressed patients. ~'-72 Another behaviorally related conception of depression derives from theories of cognitionY 3, 74 The cognitive theory of depression postulates a series of errors or failures of cognition, which would include a negative view of one's self, a negative view of one's ongoing experience and a negative view of the future as well as a negative view of the world in which the criteria for any feelings of success are stacked against one's self. Furthermore, those individuals who are subject to depression make logical errors in their thinking that further confirm their negative views. According to the proponents of this view of depression, these failures of appropriate cognition are correctable through specific cognitive therapy and they report therapeutic results in unipolar-

27

depressed patients that compare favorably with those of tricyclic antidepressant therapy. 73, 74 However, the validity of this finding needs further verification. B. HEREDITARY FACTORS Kraepelin in his original studies stated clearly that the affective disorders could not readily be explained solely on the basis of reactions to environmental stresses or events. He suggested the possibility of a genetic factor. 2~ Many investigations have been conducted since that time in hopes of establishing the presence and role of the presumed hereditary factors. Investigations have been conducted along three major lines: family, twin and linkage studies. 1. F A M I L Y STUDIES. - - I t has been a longstanding clinical impression that the families of patients with affective disorders have a higher incidence of the illness than the population at large. This has been substantiated in many reports that demonstrate the incidence of affective disorder to be significantly higher in both the parents and siblings of the proband as compared to the controls. 13, ,6, 7~, 76 The prevalence rate for first-degree relatives is considered to be within the range of 10-25%. 13,75,76 Also, the morbidity risk for affective disorders has been found to be the same among parents, siblings and children of the proband. This risk is approximately 15% compared to a morbidity risk of 1 - 2% for the general population. 77 The data from studies of families provide evidence for a genetic factor in affective illness, and the similarity of morbidity risk for the identified patient and first-degree relatives has been interpreted as evidence for a dominant mode of genetic transmission. It should be pointed out that family studies, although important and suggestive, are not as meaningful as twin or linkage studies.

2. TWIN STUDIES.-- The first major study of twins with affective disorders, by Kallmann, concluded that there was a strong genetic component at work in the illness. Kallmann found a concordance rate of virtually 100% for monozygotic twins. TM Subsequent studies have not confirmed the concordance rate found by Kallmann, but have substantiated his 28

finding of a significant difference between the concordance rates for monozygotic and dizygotic twins. TM When the data from these different studies are compiled, the concordance rate for affective disorders is 68% for monozygotic twins and 20% for dizygotic twins. TM These rate differences provide powerful substantiation for the hypothesis t h a t a genetic factor is involved and suggest an autosomal dominant type of inheritance with incomplete penetrance. The gene is thought to be an autosomal dominant because of the similar morbidity risk for first-degree relatives regardless of sex. Incomplete penetrance is postulated to explain the lack of 100% concordance in monozygotic twins, suggesting t h a t psychologic, interpersonal, experiential and social factors m u s t play a role. Twin studies t h a t separate the affective disorders into bipolar and unipolar groups demonstrate a much stronger genetic component in the bipolars as compared to the unipolars.'7

3. LINKAGE STUDIES.--Linkage studies, in addition to attempting to establish a genetic role in the illness, attempt to clarify the mode of transmission and the locus of the relevant gene. There have been few such studies, primarily by Winokur et al2 ~ 8, The initial reports of a high incidence of bipolar affective disorder in females and investigations indicating t h a t there was no father-to-son transmission of the illness suggested an X linkage for affective disorders. 76, 82 Moreover, studies of some families with bipolar manic-depressive illness revealed a high correlation of this entity with protan-deuteran (red-green) color blindness and the Xga blood system2 ~ 8, Both of these markers are located on the short arm of the X chromosome and the linkage therefore leads to the conclusion t h a t the gene for bipolar affective illness is also located on the X chromosome. The previously cited conclusions of family and twin studies suggest an autosomal inheritance and thus are at odds with this conclusion of linkage studies suggesting sex-linked inheritance. The apparent discrepancy m a y relate to the heterogeneity of depressive disorder, and the inheritance of bipolar illness m a y differ from t h a t of unipolar illness. Others have reported the presence of X linkage with color blindness and X~a in the bipolar group, but not for the unipolar affective disorders. 83 However, these data and conclusions suggesting X linkage 29

of a group of the affective disorders have been challenged. Father-to-son transmission of affective illness has been demonstrated, which would require that the gene be on an autosomal chromosome2 4, 85 Furthermore, based on the current knowledge of the loci of genes, the distance between the markers for protan-deuteran color blindness and Xya system appears too great to account for a tight linkage of manic-depressive illness with these two markers. 86 These studies and the discrepancies among them strongly suggest t h a t affective disorders form a heterogeneous group with several different modes of genetic transmission. Such a conclusion is strongly supported by the family studies on bipolar and unipolar affective disorders. 1~,25 These investigations have shown t h a t bipolar probands have a higher percentage of first-degree relatives with manic-depressive episodes as compared to the unipolar probands, whose relatives rarely show a manic state. TMIt already has been stated t h a t bipolar monozygotic twins have a higher concordance rate for affective illness t h a n unipolar monozygotic twins. 17 Linkage studies of the unipolars with color blindness and X ga have been negative 83 F u r t h e r investigation of the unipolar group suggests t h a t at least two subgroups can be distinguished within t h a t category. The first, the depressive spect r u m disease, shows a higher incidence of alcoholism among male relatives whereas the depression occurs most often in the female relative. The second group, the pure depressive disease, shows depression with equal frequency in both male and female relatives with no increased incidence of alcoholism in the group. 87, 88 There are some suggestions of an increase in sociopathy associated with the first group but not the second. 88 It seems possible t h a t sharper clinical delineation of subgroups of depressive illness will demonstrate t h a t each group has a characteristic mode of genetic transmission. C. THE ROLE OF BIOCHEMICAL FACTORS

The powerful evidence for the role of a genetic factor in the etiology of depressive disorder raises the question of the mode of action of the gene. W h a t does the gene affect and how does it produce the final clinical picture? A variety of 30

studies have proposed a range of possibilities from a specific weakness of the ego to a metabolic abnormality. 11 Even assuming a genetic influence on a biochemical derangement, there remains the question of the translation of t h a t biochemical defect into the clinical syndrome of depression with its cognitive, emotional, vegetative and motor patterns. It is clear t h a t an explanation of any illness of such complexity will require more t h a n biochemical knowledge alone. Nevertheless, the establishment of the role of biochemical factors is of vital importance for our understanding. Within the past 20 years there has been a marked interest in the role of neurotransmitters in the genesis of the affective disorders. Numerous studies have shown these transmitters to be modulators of intercellular communication within the central nervous system. 89, 9o Other reports have demonstrated t h a t psychoactive agents, such as the tricyclic antidepressants, monoamine oxidase inhibitors and lithium, powerfully affect these transmission processes. 91-93 Clinical experience with reserpine, one of the earlier antihypertensive agents, revealed t h a t 10- 15% of patients receiving this drug developed a significant depression. This clinical finding plus the discovery t h a t reserpine depletes the stores of brain cell catecholamines led to the hypothesis t h a t this class of CNS neurotransmitters is in some way associated with the genesis of depression. The three major neurotransmitters t h a t have been implicated in schizophrenia and the affective disorders are dopamine, norepinephrine and serotonin, and, of these, norepinephrine and serotonin seem at present to be of paramount importance to the development of the depressive state .92, 93 1. THE NORADRENERGIC (NOREPINEPHRINE) SYSTEM.-- The noradrenergic cell bodies are contained primarily in the pons and medulla. The tracts originating from these nuclei extend rostrally, mainly via the forebrain bundle tract, and ventrally. Ultimately, these tracts innervate specific thalamic and hypothalamic nuclei, the olfactory bulb, cerebral and cerebellar cortices, mesencephalon and spinal cord. The cortical receptors of these tracts appear to be/~ adrenergic in nature. 94 The synthetic and degradative pathways of norepinephrine are outlined in Figure 1. The major degradative end

31

Tyrosine Hydroxylase

Dopa Decarboxylase

opamine Beta-hydroxylase Norepinephrine~ Normetanephrine

I

3-methoxy-4-hydroxymande,ii a l d e h y d ~ . . . ~ . ~ , 3-methoxy-4-hydroxymandelic acid (VMA)

~

.

" ~ MAO 3-methoxy-4-hydroxyphenylglycol (MHPG)

" " ~ ' ~ 3 , 4 di hydr o x y - ~ mandelic aldehyde< Fig 1.-Synthesis and metabolism of norepinephrine. COMT = catechol-o-methyltransferase, MAO = monoamine oxidase, MHPG = 3methoxy-4-hydroxy-phenyglycol,VMA = vanillylmandelic acid. product of norepinephrine in the CNS is 3-methoxy-4-hydroxy-phenylglycol (MHPG), which was first isolated from the cerebrospinal fluid (CSF) of rats and subsequently identified in the urine and CSF of humans. MHPG, whether it be from urine or CSF, has been equivocally accepted as a reflector of CNS norepinephrine activity2 ~ Another major metabolic derivative of norepinephrine is 3-methoxy-4-hydroxymandelic acid (VMA), which reflects peripheral noradrenergic activity (i.e., from the spinal cord out). Of these two end products, M H P G currently is being used as a gauge of norepinephrine metabolism in affective disorders and more re32

cently as a biochemical marker for typing subclasses of depression.~5, 95 Within the presynaptic neuron, norepinephrine is synthesized and stored in granules known as vesicles (Fig 2). On the arrival of a physiologic impulse, the stored amine is released by a process of exocytosis into the synaptic cleft. Some of the norepinephrine in the cleft remains free whereas a fraction of it binds momentarily with the postsynaptic receptor to continue the propagation of the impulse. Subsequently, the receptor-bound norepinephrine is released back into the synaptic cleft. Thus, the ~Tree" norepinephrine has to be inactivated, and this is accomplished by two different mechanisms. The first is achieved by the enzyme catecholo-methyltransferase (COMT), which metabolizes norepinephrine to its methylated derivatives. This, however, is not the major process, since it inactivates only a small fraction of the free norepinephrine. The major fraction is rem o v e d from the cleft via an active reuptake of the amine into the presynaptic terminal. Approximately 80% of the released norepinephrine is taken back into the presynaptic neuron via this process. In the presynaptic terminal, norepinephrine m a y be stored again in the granules (major fraction) or metabolized by mitochondrial monoamine oxidase. Until recently, all of the tricyclic antidepressants were thought to achieve their clinical effect by blocking the reuptake process. However, current findings would suggest that primarily the secondary amines of the tricyclic antidepressants (i.e., desipramine, protriptyline, nortriptyline) are most specific for blocking the reuptake process of norepinephrine.96, 97 There are exceptions to this statement (see Table 8). Based primarily on pharmacologic studies in animals, Schildkraut proposed the catecholamine hypothesis of affectire disorders2 8 Stated simply, the hypothesis postulates that in depression there is a deficiency, relative or absolute, of norepinephrine at the functional sites in the CNS, and in mania there is a relative or absolute increase of norepinephrine at the functionally important adrenergic receptors in the CNS. During the past 10 years, this hypothesis has been vigorously tested and extensively studied. Some investigators have reported decreased levels of M H P G in states of 33

Tyroslne Presynaptic Terminal

Dd)a

Deaminated<_~ Metabolites

~

Dopamine

Vesicle

NA

Synaptic Cleft Demethylated Metab~

~, 1 NA

Postsynaptic

Fig 2.-Simplified schematic representation of noradrenergic synapse. NA = noradrenalin (norepinephrine), COMT = catechol-o-methyltransferase, MAO = monoamine oxidase, TCA = tricyclic antidepressant, dotted line = blockade of uptake of NA by TCA.

34

depression whereas others have found that M H P G levels were relatively normal in some depressed patients but decreased in others2 ~-1~ This latter finding has been substantiated in a number of different investigations and subsequently has been used to delineate subtypes of depression. 1~176 Different groups of investigators have reported independently that depressed patients with relatively normal levels of M H P G responded clinically to the tricyclic antidepressant drug amitriptyline whereas patients with low levels of M H P G preferentially responded to the antidepressant imipramine25, 99, 106-107More recently, Schildkraut et al. have reported that urinary M H P G levels were significantly lower in bipolar manic-depressive patients when compared to patients with unipolar depression. 15 These findings still need to be verified. However, should they be substantiated, those patients who are depressed and have a history of bipolar illness should be treated with either a secondary amine or imipramine whereas the unipolar depressed patients should receive a tertiary amine such as amitriptyline. Thus, the clinical, biochemical, pharmacologic and genetic evidence strongly supports the idea that patients with bipolar disease are different from patients with unipolar disease. A careful history of the depressive illness is necessary if the physician is to prescribe optimal treatment. 2. THE SEROTONINERGIC SYSTEM. Until recently, the serotoninergic system was considered, at least in the United States, to play no significant role in the genesis of the affective disorders. However, this thinking has changed recently and serotoniri now is regarded as an important factor in depression. Interestingly, only 1 - 2 % of the serotonin of the whole body is found in the brain. Yet, it is an important CNS neurotransmitter, and relatively specific serotoninergic pathways have been delineated. The serotonin-containing neurons appear as discrete nuclei in the raphe region of the pons and upper brain stem. The more caudal nuclei project to the medulla and spinal cord whereas the more rostral nuclei projections ascend to the telencephalon and diencephalon. Ultimately, the serotoninergic fibers innervate the limbic system, thalamus and cerebral and cerebellar cortices24 -

-

35

5-Hydroxytryptamine (5-HT, serotonin), which does not cross the blood-brain barrier, is synthesized in the CNS from the amino acid precursor L-tryptophan (Fig 3). The end product of serotonin metabolism is 5-hydroxyindoleacetic acid (5-HIAA), which can be isolated from CSF and assayed. Cerebrospinal fluid 5-HIAA levels have been equivocally used as a reflector of CNS serotonin activity2 ~, ~o8 In the presynaptic terminal, serotonin is synthesized and stored in the granules. On the arrival of a physiologic impulse, serotonin is released into the synaptic cleft, where it m a y remain free or bound to the postsynaptic receptor. The bound serotonin ultimately is released back into the synaptic cleft. The transmitter in the cleft then must be inactivated, and this is accomplished by two separate metabolic processes. The first is the metabolic degradation of serotonin via the enzyme MAO, which presumably is present in the synaptic cleft. The second, which is the major route of inactivation, is via an active reuptake process whereby 5-HT is t a k e n back into the presynaptic terminal. Here it is stored again or is inactivated by the mitochondrial MAO (Fig 4). According to current thinking, the tertiary amines of the tricyclic antidepressants specifically block the reuptake process. However, there are exceptions to this statement (see Table 8). Fig 3.-Synthesis and metabolismof serotonin. MAO = monoamineoxidase, 5-HIAA= 5-hydroxyindoleaceticacid. Tryptophan

5_Hydro!yt r~::~:l: se I Decarboxylase

5-Hydrox'ytr yptamine j (MSI~t~

5-Hydrokyindolacetic acid (5-HIAA) 36

Tryptiphan

5-Hydroxyiryptophan

Presynaptic Terminal

Serotonin (5-iT)

5-HT

Vesicle

]L Deami hated Metabolites

5-HII

~-~

T Deaminated Metabolites ~

Synaptic Cleft

TC MAO

5-HT

1

Postsynaptic

Fig 4.-Simplified schematic representation of serotoninergic synapse. 5-HT = serotonin, MAO = monoamine oxidase, TCA = tricyclic antidepressant, dotted line = blockade of uptake of SHT by TCA.

What is the evidence that serotonin m a y play a role in affective disorders? 1~ L-tryptophan, especially when given with a monoamine oxidase inhibitor, m a y be an effective antidepressant for some patients.113-115 Furthermore, CSF 37

concentrations of 5-HIAA of both manic and depressed patients may be low relative to the controls. 11G,117 When probenecid was used to inhibit the effiux of 5-HIAA from CSF, depressed patients, even under these conditions, had low levels of the metabolite as compared to the controls. 117, l~s These findings suggest a decrease in CNS serotoninergic activity. However, CSF levels of serotonin are known to be affected by peripheral sources, lo8 Because of the relative serotonin deficiency found in both states, mania and depression, the permissive amine hypothesis ofaffective disorders was postulated. H9 According to this hypothesis, a serotonin deficiency, which is a necessary but not a sufficient condition, predisposes one to the vulnerability of developing an affective disorder. However, for the clinical state of depression to be manifest there m u s t be superimposed on this deficiency of serotonin a relative or absolute decrease of norepinephrine. In mania, the opposite state would exist for norepinephrine. This theory has not been consistently validated as such and appears to be fading in popularity. A more current approach to depression, which incorporates both serotonin and norepinephrine, is t h a t of the two disease model of depression. ~4 According to this hypothesis there are at least two types of depression, originally referrred to as types A and B (Table 6), which are distinct from each other as determined by certain parameters. TM 36, 97, 12o Type A depressed patients (1) have low MHPG levels, (2) respond with a brightening of mood to a test dose of amphetamine and (3) when treated with imipramine improve clinically. These findings suggest a deficiency or metabolic derangement on the noradrenergic side of the system. In type B, the following have been noted: (1) MHPG levels are relatively normal, (2) there is no change in mood after a test dose of amphetamine and (3) these patients respond best to amitriptyline. These findings suggest t h a t there is a serotoninergic deficiency or metabolic derangement whereas the noradrenergic side of the system is intact. In a simplistic way it can be postulated t h a t the type A patients are bipolar whereas the type B patients are unipolar. This hypothesis has some basis from the more recent findings of Schildkraut 38

TABLE 6.-SUBGROUPS OF DEPRESSION Group A 1. Low levels of MHPG 2. Respondsto imipramine 3. Brightening of mood to amphetamine Group B 1. Normal levels of MHPG 2. Respondsto amitriptyline 3. No change in mood to amphetamine. et al.l~ However, this issue has to await f u r t h e r clarification. Pr es en tly it would appear t h a t at least two, if not more, n e u r o t r a n s m i t t e r s are associated with the phenomenon of depression. No one presently is suggesting unequivocally t h a t th er e is a cause-and-effect relationship between a deficiency of these t r a n s m i t t e r s and depression. In fact, the whole concept of an altered metabolism of norepinephrine in depression has been questioned on the basis of findings suggesting t h a t anxiety, stress or physical activity m a y bring about various shifts in MHPG. 12~-~23Clearly, stress has been shown to alter MH PG levels in pilots on t h e i r first solo flight landing at night on aircraft carriers. 123 Even if these changes in M H P G and 5-HIAA in depression are valid, how can th ey result in a complex picture such as depression? Is there a t r a n s d u c e r to effect a biochemical change to an emotional state? Where m us t these metabolic changes occur specifically in order to induce a depressive state? Based on clinical symptoms noted in depression (i.e., motor, emotional, vegetative, etc.), it would not be unreasonable to hypothesize t h a t more t h a n two n e u r o t r a n s m i t t e r s (e.g., norepinephrine, serotonin, dopamine and acetylcholine) m i ght be involved. F u r t h e r m o r e , an extension of the hypothesis is t h a t it is not th e level of the t r a n s m i t t e r per se t h a t is import a n t but r a t h e r the relative ratios of the various transmitters t h a t are in a fine balance. This equilibrium m i g h t be modulated by neuropeptides, which have been implicated recently as playing a role in depression2 24 In f~ct, various neuroendocrine axes, which do involve neuropeptides, have been studied in depressed patients and m a y indeed be abnormal225, 126 For example, some depressed patients have 39

been reported to have a hyperactivity of the pituitary-adrenal axis, which m a y be resistant to feedback inhibition by dexamethasone, and an abnormal diurnal pattern ofcortisol excretion. 126

Vl. DIAGNOSIS It is clear from all that has been written up to now that the diagnosis of a depressive illness depends on the physician's having (a) a high index of suspicion, (b) a knowledge of the manifestations of depression, (c) a knowledge of the course of various depressive disorders and (d) a knowledge of the patient's recent life history and his character. When, for any reason, the suspicion of depression is aroused, the physician must take the time to develop a careful history that will include data concerning (1) significant recent life events, (2) changes in patterns of eating, sleeping, bowel habits and weight, (3) ability to concentrate and work; (4) maintenance of usually pleasurable activities, including sexual, (5) state of self-esteem, (6) changes in relationships to significant persons; (7) morbid preoccupations, increased somatic or social complaints and (8) suicidal ideation. Seriously depressed patients are known to be poor historians and they often will withhold information about their depressed state. They m a y do this either because they are ashamed to confess their feelings, because they cannot muster sufficient selfinterest to discuss themselves in detail or because they are quietly plotting suicide. It is of the utmost importance that a family member be interviewed to supplement the information obtained from the patient. It should be emphasized that if depression is strongly suspected, the patient should be asked directly about whether he has had thoughts of doing away with himself, whether he has thought that life was no longer worthwhile and whether he feels too tired to go on living. If the response to any of these questions is positive, the physician should inquire further as to whether he has had specific fantasies of how he plans to kill himself and when those fantasies last occurred, whether he has thought of making specific preparations or actually has made any preparations for a suicide attempt. To a considerable degree, the diagnosis depends on the 40

physician's readiness to t h i n k about and talk about depression. For m a n y of us, the close involvement with a depressed person m a y threaten our own emotional security, especially if the patient has been an active, effective person to whom the physician has felt close. When the presence of an emotional illness arouses the physician's anxiety, he m a y tend to avoid the source of his discomfort by failing to make the diagnosis and by conducting an u n w a r r a n t e d search for physical causes. If the diagnosis of depression is made, one should a t t e m p t further to classify it as unipolar or bipolar, episodic or chronic and mild or severe. The presence of significant suicidal tendencies is a major medical emergency. The differential diagnosis of depression should include consideration of the variety of physical illnesses of which depression may be a manifestation, which were mentioned earlier. These include metastatic carcinoma (especially of the pancreas), viral disorders, degenerative nervous system diseases (such as multiple sclerosis), anemias and endocrine disorders.lO, H The diagnosis depends on findings sustaining the medical diagnosis, but the extent of the medical search should be guided by reasons for suspecting another illness rather t h a n a reluctance to diagnose depression. The diagnosis of a physical disorder t h a t might explain the depression should not divert attention from the depressive symptoms until there is evidence t h a t they are responding to therapeutic measures. In some instances, the depression itself will require treatment, in addition to the t r e a t m e n t of the underlying disorder. Depression is especially common post partum, and the first weeks after delivery are a vulnerable time. The occurrence of unusual difficulties in m a t e r n a l recovery or infant care should arouse suspicion of depression. Depression may be a side effect of medication. Drugs t h a t are particularly likely to induce or enhance depression include reserpin, adrenocortical steroids, birth control pills, sedative hypnotics, alcohol and agents such as methyldopa and propranolol. Other psychiatric disorders m a y manifest depression. These include schizophrenia and, more often, a v a r i a n t of schizophrenia called schizoaffective disorder.H The diagnosis 41

depends on the demonstration of other signs of schizophrenia, including disorders of affect, thought, language, perception and social judgment. This differential diagnosis can, at times, be difficult because in severe depression reality testing can be impaired and delusions may be present. The history of the illness and a careful mental status examination will help to make the diagnosis. Organic brain syndromes, particularly in the aged, m a y present depression as a leading symptom. 11 The problem is particularly difficult in the elderly, because depression in this age group commonly results in some loss of the capacities of memory, calculation, attention, etc. The diagnosis is made by a careful physical and neurologic examination and the mental status examination. Psychologic testing m a y further aid in defining the presence of an organic dementia. The diagnosis of depression in children and adolescents is discussed in Section VIII. VII. TREATMENT

Today, the vast majority of depressive syndromes can be treated successfully. That achievement depends on an accurate diagnosis, a knowledge of the support systems available to assist the patient, a careful assessment of the suicidal risk, a knowledge of the appropriate use of at least several modalities of t r e a t m e n t and the ability to determine when psychiatric consultation is indicated. Many depressed patients not only feel rejected by friends and family but, through their disagreeable clinging, demanding and self-involved behavior, they often eventually are rejected. It can be vital to the success of a therapeutic regimen t h a t appropriate family members understand the problem and cooperate with the therapist. The quality of this support often is the crucial factor in deciding whether a patient can be treated as an outpatient or must be hospitalized. Hospitalization should be considered for reasons of possible or threatened suicide, inability to maintain physical self-care, inability to carry out a therapeutic regimen or selfdamaging social behavior. If the patient is acutely suicidal, this should be treated as a major medical emergency. S u c h patients cannot be left alone for a moment. Many patients 42

have leaped to their death during seconds while the physician was calling for a hospital bed or a nurse went to speak to a family member. The physician treating the depressed patient must attempt to provide some glimmer of hope and~relief from the intense pain and suffering that the patient experiences. This will be done most effectively when the physician has obtained an adequate history and has formulated a treatment plan designed for the individual patient's depression in terms of presumed etiology, course and intensity. In all cases, the physician's interest and ability to understand the patient's experience are themselves therapeutic and form the basis for the good physician-patient relationship that will help sustain the patient until the treatment is effective. Every physician should be prepared to provide supportive psychotherapy for the depressed patient whom he is treating. This includes listening, "being there" when the patient requires a sense of human support, providing reality testing and understanding the basic dynamics of the patient's depressive mechanisms. A recent study demonstrates that supportive psychotherapy is indicated even in severe and intense psychotic depressive states being treated pharmacologically or somatically. Klerman et al.ls have shown that depressed patients require psychotherapeutic assistance in restoring their adaptive and coping capacities and renewing their social interactions and skills. Conversely, patients with severe neurotic or characterologic disorders, in depressive episodes, may benefit from medication in addition to intensive psychotherapy or psychoanalysis. TM Medication and psychotherapy are not mutually exclusive forms of therapy. A. PSYCHOTHERAPY

In the broadest sense, psychotherapy-"talking treatm e n t " - is administered by every well-intended physician regardless of what other treatment may be undertaken. The physician indicates his interest and concern for the patient, his understanding of the patient's plight and his quietly hopeful attitude toward the patient's recovery. A willingness to listen to the patient, allowing him to express feel43

ings and concerns that he m a y be ashamed to admit in a nontherapeutic relationship, can be therapeutic in itself and also a source of valuable information for the treating physician. Psychotherapy alone is likely to be the treatment of choice in those mild depressions without vegetative signs and where there is no apparent suicidal risk. These patients may be chronically depressed as an aspect of their character or they m a y be acutely depressed in relation to specific life events. The former group of patients, those who chronically suffer an excessive depressive mood and have difficulty obtaining pleasure from appropriate life activities, are best treated by psychoanalysis or psychoanalytic psychotherapy, both of which aim at alterations of the underlying character structure of which the depression is one manifestation. Referral to a psychiatrist for precise psychologic diagnosis and t r e a t m e n t would be indicated. Patients whose depression can be, at least seemingly, understood in relation to particular life variables may be candidates for a focal psychotherapy, especially if the individual seems reasonably ~intact" as ascertained by an ability to maintain his outside social interests, work and relationships. The depression m a y be the first one or it m a y be recurrent. A distinction should be made between grief reactions (response to loss) and depression. Grief reactions usually will respond to time and sympathetic support and understanding. Depression, as discussed previously, is an exTABLE 7 . - D O S A G E RANGES FOR TRICYCLIC ANTIDEPRESSANTS* TOTAL DAILY DOSAGE (MG)

Tertiary amines Secondary amines

Amitriptyline Imipramine Doxepin Desipramine Nortriptyline Protriptyline

*Adapted from HollisterY 7 44

Outpatient

Inpatient

75-150 75 - 150 50-150 50-150 20 - 100 10 - 40

75-300 75-300 75-250 75-300 50-100 15-60

cessively prolonged reaction characterized f u r t h e r by diminished self-esteem, feelings of worthlessness and self-reproach. The n a t u r e of brief focal psychotherapy varies among physicians, but usually consists of up to a dozen sessions, aimed at u n d e r s t a n d i n g the exact n a t u r e of the trauma and the specific response mechanism of t h a t patient. T he internist or family practitioner who has had some t r a i n i n g and experience m a y feel quite competent to administer this t r e a t m e n t ; otherwise, a referral to a psychiatrist should be made. B. TRICYCLIC ANTIDEPRESSANT MEDICATIONS The tricyclic ant i depr e s s a nt (TCA) medications are divided into two major categories, t he t e r t i a r y and secondary amines (Table 7). The t e r t i a r y amines are imipramine, amitriptyline and doxepin whereas the secondary amines are desipramine, protriptyline and nortriptyline. According to recent studies, these drugs can be classified on the basis of t h e i r ability to block the active r e u p t a k e of norepi nephri ne or serotonin 96 (Table 8). Although a few of these drugs m a y block the r eu p tak e of both n e u r o t r a n s m i t t e r s , a general rul e is t h a t the secondary amines will inhibit the r e u p t a k e of norepinephrine whereas the t e r t i a r y amines block serotonin reuptake. Thus, if administration of a t e r t i a r y amine, such as amitriptyline, has been started and t her e is no clinical TABLE 8.-SUMMARY OF THE EFFECTS OF VARIOUS ANTIDEPRESSANTS ON THE BLOCKADE OF THE UPTAKE OF AMINES* DRUG

5-HT

NE

Amitriptyline IIII (1) o (2) ++ Nortriptyline -H++ Imipramine Ill Desipramine 0 llll (1) indicates most active (2) indicates lack of activity *Adapted from Maas26 5-HT = 5-hydroxytryptamine. NE = norepinephrine (noradrenalin). 45

response within 2 - 3 weeks, a secondary amine, such as desipramine, should be prescribed. This, of course, assumes that the patient had been treated with adequate doses of the original tricyclic compound, which may range from 150 to 300 mg/day (see Table 7) for 2 - 3 weeks. This approach is based on the current thinking that there are two types of depression, one serotonin-deficient and the other norepinephrine-deficient. Thus, if the depression is not due to a serotonin deficiency, it must be of the norepinephrine type. A patient with a known history of depressive episodes who has been successfully treated in the past with a specific TCA should be prescribed the same drug and at a minimum of the same daily dosage. If the personal history is negative for depression b u t a family history (first-degree relatives) is positive and the relative has been treated successfully with a specific TCA, this antidepressant should be prescribed. This is based on the reports that genetic factors are involved in the metabolism of TCA.12~ That the antidepressants are effective in ameliorating depression has been shown in approximately 75 of 100 studies. However, the question arises: In which types of depression are they effective? For some time, the TCA were reserved primarily for the endogenous type of d e p r e s s i o n i.e., the bipolar and unipolar or retarded and agitated depressions. More recently, the restriction of TCAs to these classes of depression has been questioned by the findings of Klerman et al., who showed that neurotically depressed patients also responded to TCA. TM However, until this is substantiated, we recommend the use of TCA for the endogenous, recurrent depressions and psychotherapy for the depressive neuroses. Recently, attempts have been made to determine whether there are specific symptom constellations that predict the response to a TCA. Bielski and Freidel, on reviewing available studies, found the following: Patients with vegetative signs and symptoms of loss of appetite, weight and libido and increased sleep disturbance will respond to the TCA. 12s Patients with social phobias, agoraphobia and severe anxiety do not appear to respond to the TCA. 12s Plasma levels of most of the TCAs now are available and have been studied extensively under a variety of condi46

tions.~2~, ~3o Interestingly, the secondary amines, and especially nortriptyline, have been shown to have a therapeutic window.~30, ~31 Specifically, Asberg's studies clearly demonstrated that below approximately 50 and above 140 ng/ml there is no clinical response TM (Fig 5). This has obvious clinical implications. A patient who is on a therapeutic oral dose of a secondary amine and does not clinically respond after 2 - 3 weeks should be given a reduced dose before the drug is discontinued; the patient's plasma levels might have been too high and would have placed the patient outside the therapeutic window. When the daily dosage is reduced, the plasma levels would fall in the therapeutic range. It should be noted that the plasma levels cannot be predicted accurately from the daily dosage. The tertiary amines have the usual sigmoid-like dose-response curve. However, the lower plasma levels needed for a clinical response are approximately 9 0 - 1 0 0 ng/ml. Once a patient has responded clinically to the TCA, how long should he remain on the antidepressant? Studies have shown that if the drug is stopped within 6 months after amelioration of the depression, a high percentage of these patients will have a recurrence of their original episode. TM 132 Thus, the general rule is that patients should remain on the TCA for at least 6 - 9 months to ensure complete abatement. 132 Once the depression lifts, after treatment, the question Fig 5.-Therapeutic window. ( M o d i f i e d after Asburg et al. TM) ,0. . . . . . . . . . . . . 0 . . . . . . . . . . . . . _0

Clinical

it

Improvement

/

/

/

/

sJ

/ / /

/

o <50

0 50

140

>140

nq/ml plasma of TCA (nortriptyline)

47

that often arises is whether the patient should be maintained on TCA permanently. Presently there are no unequivocal long-term studies to answer this question~ In this situation, sound clinical judgment must be the guideline. If the present depressive episode is the first one, there is no need to maintain the patient on medication beyond 6 - 9 months, b u t the individual should be educated to look for the signs and symptoms of a recurrence. However, when the patient has a history of a number of frequent, recurrent episodes, that patient probably should be maintained on TCA in the hope of completely aborting or at least ameliorating the intensity, of future depression. A fact that often is forgotten is that a high percentage of the patients who have a depressive episode will have another one. Furthermore, approximately 15% of the bipolar patients who are being treated for a depression with a TCA and are not on lithium will switch over into a state of mania. Thus, the bipolar depressed patient being treated with an antidepressant must be monitored carefully to avoid inducing a manic episode. Tricyclic antidepressants must be prescribed cautiously, especially for the suicidal, geriatric and cardiac patient. The lethal dose, although not known exactly, is anywhere from 1800 to 2500 mg. If a patient is taking 300 mg of a TCA per day and is given a week's supply (total of 2100 mg), a lethal dose is available to that patient. Thus, the suicidal potential of each patient must be evaluated carefully. In overdoses with TCA, both central and peripheral anticholinergic effects are obvious 133,134 (Table 9). Also, cardiac arrhythmias are common and m a y occur up to 48 - 72 hours after the overdose. Thus, careful cardiac monitoring is mandatory, and these patients should not be discharged shortly after gaining consciousness. TCA, because of their noradrenergic, anticholinergic and direct depressant effect on the myocardium, should be used cautiously in patients with cardiac disease. 135 Recent reports have shown these drugs to enhance conduction blocks and they have, in fact, been used to arrest arrhythmias. 1~ Thus, the concomitant use of quinidine and TCA m a y indeed be contraindicated. 135 Also, the geriatric patient must be treated cautiously with these drugs, especially since this population is prone to cardiac disease and hypertension. In this age group, TCA should be 48

TABLE 9 . -S OM E SIGNS AND SYMPTOMS OF TCA OVERDOSE 1) 2) 3) 4) 5) 6)

Confusion Disorientation Delirium Seizures Abnormal movements Hallucinations

7) 8) 9) 10) 11) 12)

Cardiac arrhythmias Hyperpyrexia Anhidrosis Distended bladder Decreased bowel motility Dilated and fixed pupils

started in very small doses and gradually increased, with constant monitoring of blood pressure and cardiac status. One of the most common side effects of TCA is orthostatic hypotension, and the consequences of such episodes, especially in geriatric patients, are a major source of clinical complications. Moreover, geriatric patients have been shown to need much smaller daily doses to achieve therapeutic plasma levels than the younger age group.'3G A number of reports have shown that plasma levels of TCA are decreased by tobacco, alcohol, barbiturates, chloral hydrate and conjugated estrogens. '37, ,38 Of interest is the finding that major tranquilizers will a u g m e n t the plasma levels of TCA whereas the minor tranquilizers, such as the benzodiazepines, appear to have no effect. '37, 138 Thus, the depressed patient with insomnia should not be treated with barbiturates but, if absolutely needed, should be prescribed a drug such as flurazepam. However, if the patient is severely agitated and delusional, a major tranquilizer such as chlorpromazine or perphenazine m a y be prescribed initially and the patient maintained on that drug alone until the psychotic process subsides. At that time, a TCA m a y be started. If the patient is on both a major tranquilizer (such as chlorpromazine) and a tricyclic (such as amitriptyline), the physician should be alert to the possibility that cardiac arrhythmias and an "atropinic psychosis" (anticholinergic syndrom) might be induced. Also to be noted is t h a t the TCA will block the pharmacologic effects of certain drugs such as the antihypertensive drug guanethidine.'3~, ,36 C. MONOAMINE OXIDASE INHIBITORS

The monoamine oxidase inhibitors (MAOI) were the first antidepressants available for clinical use. Initially they 49

were greeted with a great deal of enthusiasm but subsequent controlled studies questioned their effectiveness. 13~ Furthermore, a major disadvantage of these drugs was the severe associated side effects (such as hypertensive crises and hepatotoxicity) t h a t ultimately resulted in most of these drugs being withdrawn, with the exception of phenelzine and tranylcypromine.139 Recent surveys have suggested t h a t this class of drugs should be used in the atypically depressed patient with social phobias, agarophobia, somatization and severe anxiety or the patient who is refractory to TCA. 14o Other studies have demonstrated phenelzine to be an effective antidepressant when used in relatively high doses of 4 0 - 8 0 mg/ day. 141 The suggestion has been made t h a t possibly a combination of a MAOI and a TCA should be used in the depressed patient who is refractory to treatment. 142 Once a patient has been started on a MAOI, a tricyclic should not be added subsequently. The patient must be drug free for at least 2 weeks before beginning the TCA. However, if the patient already has been on a TCA, a MAOI m a y be prescribed subsequently. 142A n additional word of c a u t i o n - this combination is not approved by the F D A and is considered experimental even though recent reports have not shown a higher incidence of morbidity or mortality associated with the concomitant use of both as compared to the individual drugs. 143,144The question t h a t really needs to be answered is : Are there any advantages to using the combination as compared to the individual drug and which patients should be on the combination? Of prime concern to the physician who is treating a patient on a MAOI should be the sudden, severe hypertensive crises t h a t usually occur in connection with tyraminecontaining foods such as aged cheese, Chianti wine, beer, chocolate candies, herring, chopped liver, etc. This is a medical emergency and should be treated accordingly. D. LITHIUM

L i t h i u m chloride or the carbonate has been used primarily in the t r e a t m e n t of mania. According to most studies, lithium has been shown to be an effective '~antimanic" agent 50

in approximately 75-85% of the patients and has been reported, when used prophylactically, to decrease the frequency and duration of attacks. 3~ 145 However, studies have found lithium also to be effective in the t r e a t m e n t of the depressed bipolar patient2 ~ 31 This drug does not act as an antidepressant like the TCA during the acute state, but instead decreases the total number of depressive episodes t h a t patients experience when maintained on lithium. More recently, lithium has been found to be effective as an antidepressant in the unipolar depressed p a t i e n t ) ~ These studies need to be validated, and, until then, lithium should be used in unipolar patients only if all other agents fail. Again, as with the TCA, the use of lithium should be weighed carefully. A confusional toxic state can occur very readily at lithium plasma levels above 1.5 mEq/1. However, this figure should not be considered as absolute, since some patients m a y become toxic at much lower plasma levels. Lithium levels, as well as the patient's mental status, must be monitored frequently. This is especially true for those who are concomitantly on other drugs, such as diuretics, which can very quickly lead to a toxic state.146 If a diuretic has to be prescribed, the lithium dosage must be reduced accordingly 147(Table 10). Hypothyroidism and nephrogenic diabetes insipidus have also been associated with the use of this drug. 14~ A common practice, which now may need re-evaluation, has been to m a i n t a i n patients on this agent for prolonged periods. A recent study has suggested t h a t indeed there m a y be nephrotoxic effects from the extended use of lithium. 148 These patients, who had impaired ability to concentrate urine, TABLE 10.-REDUCTION OF LITHIUM CLEARANCE IN THE PRESENCE OF CHLOROTHIAZIDE* DAILY CHLOROTHIAZIDE

REDUCTION OF LITHIUM CLEARANCE

(mg/day) (%) 500 mg 40% 750 mg 60% 1000 mg 70% *Adapted from Himmelhochet al.14T 51

underwent renal biopsy, which showed focal fibrosis, sclerotic glomeruli, severe tubular atrophy and microcysts. If these findings are validated, the use of lithium must be weighed very carefully in the bipolar patient b u t probably is unwarranted in the unipolar patient, who can be treated effectively, in most cases, with the available tricyclic antidepressants. E. ELECTROCONVULSIVETHERAPY (ECT) The modality of treatment known as electroconvulsive therapy (ECT) always arouses, especially in nonpsychiatric physicians, a great deal of controversy. Yet, it remains one of the safest, quickest methods of treating a psychotically depressed patient who is suicidal and/or cachectic. This t r e a t m e n t can be given on an ambulatory basis if the proper support systems and close supervision are available. However, the risks attached to this approach must be weighed very carefully, especially in the impulsive individual or in the patient who has made previous suicide attempts. The usual practice is to hospitalize the depressed, suicidal patient. Approximately 85% of the depressed patients treated with ECT recover completely from the episode without permanent effect on cognitive functions (Fig 6). This modality of t r e a t m e n t should not be recommended indiscriminately, and thus an accurate diagnosis is imperative. ECT is not indicated for the neurotically depressed patient and is absolutely contraindicated in the patient with an increased intracranial pressure. However, it should be added that even a myocardial infarction and pregnancy are n o t contraindications.150 Here, an accurate and detailed history is important. If the patient has been treated successfully in the past with ECT, this modality should be considered again, since the chances of a positive clinical response are great. 13~However, if antidepressants have never been used, this therapy might be entertained before going to ECT. Should suicide and/or a life-threatening situation be present, ECT treatment should be instituted immediately without awaiting the possible positive clinical response to a 2 - 3 - w e e k trial of antidepressant. Unfortunately, although the initial response rate to 52

100 o~ o

80

%)

~

60

~

40

~

2o

ECT

ANTI-

PLACEBO NO TREATMENT

Fig &-Effectiveness of different treatment modalities in depression. (Adapted from Lehmann2 49)

ECT is very high, some studies suggest t h a t the effects are not maintained beyond 6 months, at which point the relapse rate increases. 151,1~3 However, a review of the literature reveals this point to be equivocal.~4 VIII. DIAGNOSIS AND TREATMENT AND ADOLESCENTS

OF C H I L D R E N

It is beyond the scope of this monograph to describe in detail the diagnosis and t r e a t m e n t of child and adolescent depression, but we do wish to emphasize the existence of depression in these age groups and the importance of its recognition. In a recent review of the literature, Puig-Antich et al. 155 cited numerous studies describing depression and depressive equivalents in prepubertal children. Their own researches confirmed t h a t there is a group of children who meet standard Research Diagnostic Criteria (RDC) for depression and who responded to therapy with imipramine. They stated: 53

The presence of antisocial behavior in boys, losses, family malfunction, and the family history pattern suggest that prepubertal major depressive disorder might be a form of'~depressive spectrum disease," a type of unipolar depression (Winokur et al., 1971, 1973) in subjects with high genetic vulnerability and maladaptive home environments. It has been shown (D'Elia and Perris, 1972) that poor early home environment is associated with early age of onset i n unipolar depression, and not in bipolars. Therefore it appears plausible that, given high enough genetic vulnerability, the onset of unipolar depressive disorder could be lowered to prepuberty by an adverse early home environment. The high incidence of separation anxiety is also striking. Although not routinely assessed in adult depressions, it is not an infrequent finding, especially in geriatric depression (Beck, 1967). Not only did the subjects meet the Research Diagnostic Criteria for depression (dysphoric mood, poor appetite or weight loss, sleep difficulty, variation of mood, loss of energy, inappropriate guilt, poor concentration, thoughts of death or suicide, loss of pleasure, psychomotor agitation or retardation) but the majority of them also showed the presence of a conduct disorder following the onset of the depression. Although suicide is relatively rare in children, it is by no means unknown. In the 10-20-year-old age group, suicide is the fourth leading cause of death and apparently is continuing to rise rapidly. 45, ~5~,157It is, therefore, important for the physician to be alert to depression in the adolescent age group. The recognition of depression in the adolescent requires special efforts on the part of the physician because, as emphasized in a recent study, adolescents often do not appear sad until they begin to discuss their sad feelings. 158 They m a y initially seem bored, lonely, unable to concentrate, uninterested in the environment, but not specifically depressed. In the study cited, of 30 depressed adolescents, it required detailed and systematic inquiry to reveal the full extent of their depression and the fact t h a t three-fourths of t h e m had suicidal ideas and almost two-thirds had made some kind of suicidal gesture. Running away from home, insomnia, tiredness on awakening, feelings of loneliness, etc. were common in this group. 158 The physician who sees children and adolescents, particularly the latter, must take responsibility for recognizing the 54

s y n d r o m e of depression. The t r e a t m e n t is best c a r r i e d o u t b y a p s y c h i a t r i s t w h o h a s c o m p e t e n c e in d e a l i n g w i t h t h e s e age g r o u p s or at l e a s t in c o n s u l t a t i o n w i t h t h e specialist.

IX. SUMMARY D e p r e s s i o n is a w i d e s p r e a d illness in W e s t e r n society t h a t is u n d e r d i a g n o s e d a n d often i n a d e q u a t e l y treated. T h e diso r d e r is a m a j o r c a u s e of h u m a n suffering a n d social dysf u n c t i o n and a significant cause of death. Studies c o n d u c t e d d u r i n g the past two decades h a v e shed n e w l i g h t on a l m o s t e v e r y aspect of this d i s o r d e r - i t s biology, psychology, etiology, course a n d t r e a t m e n t . As a r e s u l t of t h e s e r e s e a r c h e s t h e r e are several effective t h e r a p i e s available, i n c l u d i n g p s y c h o t h e r a p y , specific a n t i d e p r e s s a n t m e d i c a t i o n s a n d electroconvulsive t h e r a p y . W i t h p r o p e r diagnosis a n d approp r i a t e t r e a t m e n t choice, up to 85% of p a t i e n t s will r e s p o n d f a v o r a b l y to t r e a t m e n t . This r e v i e w h a s a t t e m p t e d to pres e n t a n o v e r v i e w of depression t h a t will help t h e p h y s i c i a n to recognize t h e disorder, even in its m o r e obscure forms, a n d enable h i m to p l a n a n effective t r e a t m e n t . REFERENCES 1. Rubinstein, M.: Depression and Depressive States, in Simons, R. C., and Pardes, H. (eds.), Understanding Human Behavior in Health and Illness (Baltimore: Williams & Wilkins, 1977), pp. 598- 609. 2. Shapiro, A. K.: Psychochemotherapy, in Grenell, R. G., and Gabay, S. (eds.), Biological Foundations of Psychiatry, (New York: Raven Press, 1976), pp. 793 - 835. 3. Darwin, C.: The Expression of the Emotions of Man and Animals (Chicago: University of Chicago Press, 1965). 4. Bowlby,J.: Separation anxiety, Int. J. Psychoanal. 41:89, 1960. 5. Spitz, R.: Hospitalism. An enquiry into the genesis of psychiatric conditions in early childhood, Psychoanal. Study Child 1:53, 1945. 6. Harlow, H. F.: Learning to Love (New York: Jason Aronson, 1974). 7. Harlow, H. F., and Suomi, S. J.: Induced depression in monkeys, Behay. Biol. 12:273, 1974. 8. Brenner, C.: Psychoanalytic Technique and Psychic Conflict (New York: International Universities Press, 1976). 9. Engle, G., and Schmale, A. A.: Psychoanalytic theory of somatic disorders: Conversion, specificity, and the disease onset situation, J. Am. Psychoanal. Assoc. 15:344, 1967. 10. Strain, J. J., and Grossman, S.: Psychological Care of the Medically I l l - A Primer in Liaison Psychiatry (New York: Appleton-CenturyCrofts, 1975). 55

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SELF-ASSESSMENT ANSWERS 2. FaRe 3.1.~ 2.(~ 3.(~ 4.(~

64

4.(c) 5. (b) 6. (g) 7. (e)

8.(e) 9. (f) 10. (b)