Depression as seen by the internist

DEPRESSION AS SEEN BY THE INTERNIST MARK D. ALI"SCHULE

TABLE OF CONTENTS D E V E L O P M E N T O F - T H E P S Y C t t l A T R I C C O N C E P T OF DEPRESSION . . . . . . . . . . . . . . .

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ETIOLOGY; PRECIPITATING FACTORS

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BRAIN DISEASES . DRUGS

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E L E C T R O L Y T E DISORDERS . i

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HORMONAL DISORDERS MALNUTRITION

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CONCLUSION ON PRECIPITATING FACTORS . . . . . . .

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MURDEROUS ASSAULTS

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POSTPARTUM DEPRESSION OTItER SYMPTOMS

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PHYSICAL EXAMINATION

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CLINICAL LABORATORY FINDINGS .

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C L I N I C A L T Y P E S OF D E P R E S S I O N AND T H E I R T R E A T M E N T

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was Clinical Professor of Medicine at Harvard Medical School and has t a u g h t as Visiting Professor since his retirement. He received his medical degree from H a r v a r d Medical School and interned at H a r v a r d Hospitals. Doctor Altschule was Head of I n t e r n a l Medicine and Physiologic Research at McLean Hospital for 25 years. He is the author of a dozen books on pathophysiology and history and is a member of m a n y medical societies. Primarily a bedside teacher of i n t e r n a l medicine, he has done much patient-oriented research.

T H E CLINICAL SYNDROMES of depression are encountered by all medical practitioners. The syndromes usually are easily recognized, b u t in some cases the manifestations are subtle and misleading and can be diagnosed correctly only by perceptive and interested physicians. Depressed patients who are unable to care for themselves, or who are suicidal, or whose behavior threatens to disrupt a family or other group must be hospitalized.There is, however, little excuse for the depressed patients who do not need hospitalization to be treated by any but an internist or a general practitioner. The treating physician must assume a commitment to provide enough time for adequate and frequent patient visits until the patient is well. He must also assume the responsibility of informing himself with respect to the intricacies of medicinal treatment. The word depression is widely used in our language and has many meanings. To scientists, or those who use sciences, the word means a fall in the level of anything that m a y be measured. To economists, the word has similar b u t much broader meanings. None of these material concepts are under discussion here. For our purposes, the word will be used only to refer to a m o o d - a feeling of sadness or

unhappiness, a lowness of spirits. Although this definition might achieve widespread acceptance, it still is not precise enough for the present discussion, for in common usage it means any lowness of spirits. Despite a temptation to moralize, I shall omit discussing the so-called age of melancholy of the 1890s, invented by some journalist of the period in a manner that was followed some decades later by another journalist who invented the age of anxiety. It is interesting to muse on the fact that today's journalists call the 1890s the gay nineties, a period of universal happiness. If the term depression is to have a medical connotation, it must be separated from despondency. Despondency is, of course, caused by a loss or by a failure to attain some wanted object or condition. Depression is a disorder of unknown mechanism. It is disabling. The thought content always is more or less delusional in the sense that the morbid ideas are more or less unrealistic; the depression usually is accompanied by anxiety. (The latter fact is highly important, since ignorance of it may cause a variety of errors in diagnosis and hence in treatment.) Although. the etiology of depression is not known, many precipitating factors are recognized. These may seem to include despondency, but this is not accurate. It is the factor that may have caused despondency that may lead to depression, as will be discussed below. Despondency does not necessarily lead to depression in the medical sense, nor is every episode of medical depression preceded by despondency, and it is entirely useless to persist in looking for a factor that might have caused a despondency that was repressed but persisted in an unconscious form. As William J a m e s pointed out, this kind of reasoning can lead only to a total loss of meaning.

DEVELOPMENT OF THE PSYCHIATRIC CONCEPT OF DEPRESSION So striking and constant are its psychologic manifestations that the condition was one of the first psychiatric disorders d e s c r i b e d - i n fact, one of the first syndromes described that were recognized as such. The manic-depressive psychosis was clearly described, in writing, 18 centuries

ago, and a question naturally arises as to why this psychosis was recognized as a entity centuries before the other main psychiatric syndromes received clear recognition. This is easily answered: What is considered depression or elation may vary somewhat from time to time and place to place, but in the main these entities are easily recognized when they exceed the limits of normal day-to-day variations in mood. Disordered thinking, manifested by delusions, on the other hand, is much harder to recognize, unless extreme. This disorder, in its milder forms, manifests itself only by deviations from the norm as regards occupation, ambition, manners, attitude toward education, personal behavior, etc., and as such may be considered on the one hand as personal idiosyncrasy or, on the other, as an antisocial attitude. These diagnostic difficulties are especially likely to arise in a highly complex society where these behavior patterns may simply be manifestations of a considered unwillingness to respond to social stresses in a c c e p t e d - usually s t e r e o t y p e d - ways. Hence, simple observations of behavior often could not help to diagnose thinking disorders. In classical Greece, which gave us, fully formed, the concept of manic-depressive psychosis, hallucinations were considered objective phenomena .that happened to be seen or heard only by selected persons. In the Middle Ages, the dominance of soul-psychology and of demonology, both of which had the advantage of being able to explain anything, prevented any rational approach to the study of psychiatric phenomena. Fortunately, the manifestations of pathologic depression, and the related manic conditions, are so well defined as to make it impossible for any medical superstition, ancient, medieval or modern, to obscure the diagnosis. The very earliest medical writings, the Hippocratic corpus, contain the aphorism: "If a fright or despondency lasts a long time, it is a melancholic affection.''~ Galen, of course, repeated the established view that the disorder was caused by the accumulation (where?) of black bile, as the word melancholia indicates. Celsus, the Roman writer, was not a physician but his encyclopedic writings included much medical material. He wrote2:

"There is another form of madness which . . . goes no further t h a n a sadness . . . . The belly is to be kept as soft as possible; terrors are to be dispersed, and r a t h e r good hopes are to he given. E n t e r t a i n m e n t m u s t be sought in amusing stories and diversions, such as the person in health used to be most pleased with. If there are any works of his performing, they must be commended, and placed before his eyes. His groundless sorrow is to be mildly reprimanded. A r g u m e n t s must be offered now and then to persuade him, t h a t in those very things which disturb him, there is more m a t t e r for joy t h a n anxiety."

Today, Aretaeus is regarded as the creator of the best early descriptions of melancholia. However, it must be remembered that he had the benefit of material from earlier physicians, material that is lost to us. Like many good clinicians, he was skeptical of current theories of pathogenesis. He wroteZ: "It sends r u m b l i n g wind downwards a n d disturbs the understanding. On this account, in former days, these were called melancholies and flatulent persons. And yet, in certain of these cases, there is neither flatulence nor black bile, but mere" anger and grief, and sad dejection of mind; and these are called melancholies. The melancholies become such when they are overpowered by this evil. "It is a lowness of spirits from a single phantasy, without fever: and it appears to me t h a t melancholy is the commencement and a part of mania. For in those who are mad, the u n d e r s t a n d i n g is turned sometimes to anger and sometimes to joy, but in the melancholies to sorrow and despondency only. But they who are mad are so for the greater part of life, becoming silly, and doing dreadful and disgraceful things; but those affected with melancholy are not every one of t h e m affected according to one part i t u l a r form; b u t they are either suspicious of poisoning, or flee to the desert from misanthropy, or t u r n superstitious, or contract a hatred of life. Or if at any t i m e a relaxation takes place, in most cases hilarity supervenes, but these persons go mad . . . . "The characteristic appearances, then, are not obscure; for the patients are dull or stern, dejected or unreasonably torpid, without any manifest cause: such is the commencement of melancholy. And they also become peevish, dispirited, sleepless, and s t a r t up from li disturbed sleep. "Unreasonable fear also seizes them, if the disease tends to increase, when their dreams are true, terrifying, and clear: for whatever, when awake, they have an aversion to, as b e i n g an evil, rushes upon their visions in sleep. They are prone to change their minds readily; to become base, mean-spirited, illiberal, and in a little time, perhaps, simple, extravagant, munificent, not from any virtue of the soul, but from the changeableness of the disease. But if the illness become more urgent, hatred, avoidance of the h a u n t s of men, vain lamentations; they complain of life, and desire to die. In many, the u n d e r s t a n d i n g so leads to insensibility and fatuousness, t h a t they become ignorant of all things, or forgetful of themselves . . . . " 6

The rest of the important early literature has been reviewed elsewhere 4 and need not be gone into here. A few points might be mentioned, however. Caelius Aurelianus s reported t h a t Themison emphasized t h a t melancholia and m a nia were related. Caelius wrote: "The followers of Themison, as well as many others, consider melancholy a form of the disease of mania. . . . " Paulus Aegineta, who also wrote about melancholia in ancient times, is notable for appar e nt l y being the first to use the expression "crackpot," s t at i ng t ha t some patients believed themselves to be e a r t h e n vessels t hat might be cracked by ungentle handling, s This concept was repeated by man y writers, almost unchanged and always without attribution, well into the n i n e t e e n t h century. I, myself, have seen a similar symptom in a patient, formerly a prominent member of the faculty of a pr om i nent medical school, who thought he had to w.alk gingerly for fear of cracking his arse, which he believed had mysteriously t urned to glass.* Thomas Willis 7 made several notable contributions to our u n d er s tan d ing of the disorder. He called attention to the fact t h a t r u m i na t i on and the constriction of the field of interest occurred in the patients, t h a t melancholia might be the precursor of mania or of w hat we today call schizop h ren ia (it was then called stupidity or f o o l i s h n e s s f a t u i t a s ) and th a t a precipitating factor might be a loss. Today, this last idea is regarded as one of the great discoveries of the twen t i et h century. Another ancient idea t h a t is w or t hy of note held that, according to Wier and to Scott, ~ witches were merely women who were suffering from melancholia. This enlightened view led to the persecution of these authors. The early recognition t h a t m ani a and melancholia were related was main t a i ne d by all writers on the subject. It was inevitable t h a t a single t e r m would be invented to describe this relation. Although modern psychiatrists ascribe the *More than 400 years ago, Laevinus Lemnius described the identical delusion involving glass hind parts in a depressed patient. (See Lemnius, L., De habitu et conslitutione corporis [Antwerp: G. Simonen, 1561].) It seems that the stereotypy of human thought has no limits. 7

"discovery" of the manic-depressive psychosis to Kraepelin circa 1890, the fact is that the syndrome was known centuries earlier, and the term itself was created more than 300 years earlier. A hint of the formal connection between mania and melancholia is to be found in Theophile Bonet's work published in 1679. In his Sepulchretum sive Anatomia Practica ex Cadaveribus Morbo Donatis, Bonet used the term "melancholiac mania," i.e., the mania of melancholy. The words "melancholiac mania" are also found in the Edito Altera of 1700, revised by Johannes Jacobus Mangetus. Bonet's work Medicina Septentrionalis, published in 1686, contains the term "maniaco-melancholicus" in referring to the disorder discussed under the heading "Melancholic Anniversariae in Manium Degenerantis Admiranda Species." Bonet's use of the term "manic-depressive" is so casual that it implies common usage. Yet, I have not found the term in the sources his compilation mentions. Today's classification of depression divides the syndrome into psychotic and nonpsychotic varieties. It is interesting that a similar classification developed more 'than 1000 years ago out of some words of St. Paul. In his Second Epistle to the Corinthians, Chapter 7, verse 10, Paul wrote: "For godly sorrow worketh repentance to salvation not to be repented of, but the sorrow of the world worketh death." The word sorrow used in English translations of the Bible stood for the tristitia of Latin versions connoting sadness, sorrow, despondency, depression. Paul's distinction between the two kinds of tristitia, the one "from God" and the other "of the world," led medieval theologian s to enlarge on differences between the two kinds of depression. It was the perceptive psychologist John Cassian who began to give the discussion a modern psychiatric cast. His guide to the monastic life, De Institutis Coenobiorum, written around A.D. 420, included a discussion of how a monk could distinguish the two kinds of depression. The second kind, Cassian said, is rancorous, ineffective and irrational. His ideas were repeated two centuries later by Isidore of Seville, who contrasted the "disturbed irrational" second type with the beneficent "temperate and rational" first type. Similar comments were made by Bede a century after

Isidore. Thus, from the fifth to the eighth centuries, leaders of Christian thought recognized a distinction between rational and irrational depression. Some writers of that period included among the manifestations of irrational depression a desire to "un-be." In The Vices and Virtues, Alcuin stated that the despairing one "hateth himself and desireth his owne death." Another medieval belief that is particularly interesting today was that the irrational depression might be unconscious. A number of theologians of the era held that the various deadly sins might be the expression of an underlying, unsuspected depressive state. It is quite clear from the history of the development of the medical ideas about depression that we are dealing with a group of syndromes, related by their important features b u t differing in other important aspects. They are all combined under the term depression. In medicine, when we Kave a name for a disease, a name bestowed by some person of recognized authority, the attributes connected to that include: (1) the responsible specific etiologic factors, (2) the processes involved in pathogenesis, (3) the physiology and chemistry responsible for its signs and symptoms and (4) the signs and s y m p t o m s - i n c l u d i n g the societal c o n s e q u e n c e s - o f the disease. There may be disagreement about details, but all physicians know what the disease is recognized to be. The situation is different with respect to syndromes. We may recognize a number of widely different etiologic factors, or we may recognize none at all. We may recognize a common pathogenesis, or we may recognize none at all. We m a y recognize a common disturbance of physiology or chemistry, or we may recognize none at all. But in every case we recognize an identity of signs and symptoms, and this is what determines the clinical validity of the syndrome. Three centuries ago, the clinical syndrome of fever had no proved etiology, no established pathogenesis, no recognized disturbances of physiology or chemistry, yet nobody will deny that it was a valid syndrome. It had signs and symptoms that clinicians agreed on, even though they could not be measured objectively. The same is true today of the depressive syndrome.

If we all a g r e e - a s all the currently available evidence d e m a n d s - t h a t what we in medicine call depression is a syndrome made up of lesser syndromes, we must establish whether or not it is a figment of classification, that is to say, an artificial concept created by extreme and arbitrary selectivity, uninfluenced by the realities of clinical observation. We recognize that classification is, in the words of Lewis Carroll's writings on symbolic logic, a process whereby we imagine that certain things should be grouped together. This states correctly that the products of classification are the products of thinking. Does this mean that they have no r e a l i t y - a r e purely imaginary? We shall leave to one side the Platonic notion that the only reality is the idea of a thing. We must address ourselves to the problem of whether entities derived from classification can justify their existence. The depressive syndrome and its component syndromes are no figments of chissification. The history of medicine reveals the disappearance of many syndromes, not because their cure or prevention was discovered but only because classifications changed. Although future studies may tell us more about the pathophysiology of depression, it is unlikely that the disorder will disappear solely because of changes in classification. The disorder is a valid synd r o m e - not a figment of classification-and its component subsyndromes also have the reality that perceptive and honest clinical observation imparts. Since we are dealing with a syndrome and not a disease, we must recognize that we cannot expect to have at hand a single etiology and at best no more than a group of related pathophysiologic processes.

PATHOPHYSIOLOGY Understanding the mechanisms of the aspect of brain function we call perception and of the related errors of perception is based on a growing body of knowledge derived from clinical and experimental studies. Some understanding of the mechanisms of anxiety, fear and rage may be derived from studies of the limbic system and its seizure 10

disorders. A vague appreciation of the nature of logical thought, mathematical calculation, of memory and of related processes is possible. A current view is that since a man-made device can perform logical operations, make mathematical calculations and recall data, the brain must be some kind of computer. (This is hardly an advance in understanding, for when computers were first manufactured they were considered to be some kind of brain.) The mechanism of mood genesis is even more elusive. Nevertheless, methods are available for studying some aspects of brain function, and they naturally have been used. It obviously is not possible to study phenomena for which no observational methods have been developed. There is a corresponding tendency to try to explain clinical manifestations by whatever data come to hand and might reasonably be so used. The neurotransmitters have become cornerstones of neurophysiologic research and theory. A few decades ago, reserpine had been observed to cause depressions, and somewhat later found to deplete the brain of serotonin. A theory was formulated that stated that all depression was due to depletion of brain serotonin. This was a poor theory, because (1) in many cases, especially with large doses, it caused no depression but did cause parkinsonian symptoms; (2) reserpine depletes the brain not only of serotonin b u t also of histamine and catecholamines, (3) studies of brain or spinal fluid serotonin concentration show it to be low in other brain diseases not associated with depression, including hyperactive states, s and (4) there is no agreement that it actually is low in the brain in depressions. The situation with respect to catecholamines is even more persuasive. Amphetamine, known for 40 years as a potent mood elevator (but not in moderately or markedly depressed patients), resembles norepinephrine in chemical structure. It is also known more recently to change the distribution of catecholamines in tissues. Several decades ago, the first important series of compounds found to be effective against the manifestations of depressions were discovered. Studies showed that these compounds inhibited in one degree or another the enzyme catecholamine oxidase. (These 11

compounds are all hydrazines and, if anything, more regularly inhibit the formation of gamma-aminobutyric acid, the chief inhibitor of synaptic transmission, but this has not received much attention from the theory creators.) The introduction of a number of hydrazines for the treatment of depression was followed by withdrawal of some (because of toxic effects) and the loss of popularity of the others. Two of the still available compounds, Nardil and Niamid, are slow in action and not universally effective. Moreover, studies of parts of patients' brains or of fluids removed from patients have not yielded consistent data to show aberrations of catecholamine metabolism in depressions. Nevertheless, the theory creators have adhered to the catecholamine theory of mood. When clinical events made certain tricyclic drugs the choice of physicians treating depressions, a determined effort was made to show that these compounds do indeed affect catecholamine function. The changes are relx)rted, in diagrams as full of directional arrows as a roadway at the entrance of a large airport, to interfere with the movement of catecholamines across certain membranes. What has all this, whether true or otherwise, to do with mood? Nothing that is evident. In the meantime, Mother Nature has not been cooperative. The number of known neurotransmitters has proliferated. They are being studied, as they should be. What has all this to do with mood? Nothing that is evident. Actually, all these subcellular phenomena of u p t a k e , release, re-uptake, degradation, etc. of neurotransmitters observed in brain tissue are of dubious value in explaining psychiatric diseases and the effects of drugs that modify them. Although both the antidepressant drugs and lithium reach what are held to be therapeutic l e v e l s - l e v e l s that affect neurotransmitter s t a t u s - i n hours or a day or two, their effects may not become evident clinically for many days or weeks. Moreover, their effects, once achieved, may persist for weeks or months after the disappearance of the drug from the body. For practicing physicians, the normal and pathologic physiology of mood remains a m y s t e r y - a t any rate, not 12

explained by a n y data derived from current molecular biology.* T h e r e is a tendency today to ignore pathologic physiologic processes t h a t fail to involve subcellular constituents. Nevertheless, these coarser data should not be ignored. After all, physicians do not have to deal with any entities smaller th an a patient. A review of the earlier literature 9 revealed two physiologic abnormalities in patients with psychotic depressions. Patients with these depressions, at least those called e n d o g e n o u s - w i t h o u t any detectable e t i o l o g y - h a v e a very low rate of salivary secretion, both at rest and during chewing. This says something about autonomic function, b u t beyond this we cannot go. Attempts to t reat the psychiatric syndrome with eserine, which increases salivary secretion, were without benefit. Moreover, tricyclic drugs cause remission of the .psychiatric disorder and, if anything, dry the mouth even more. It appears t hat the data on salivary gland secretion, like the data on brain neurotransmitters, are irrelevant. Another finding, equally puzzling, is more interesting, although its meani ng still is elusive. Data obtained in patients with predictable manic-depressive cycles show t h a t they begin to r etai n salt and water 10 or 20 days before the beginning of a psychotic episode2 This is of great interest, because the remission induced by a few weeks of lithium t h e r a p y is ushered in by a salt and water diuresis. (Retention of salt and water occurs in at least one other type of psychosis, catatonia, a condition in which occasional patients swell up enough to look nephrotic.) No mecha*An excess of polyunsaturated fatty acids has been found in the blood of depressed patients. (See Ellis, F. R., and Sanders, T. A. B., Long chain polyunsaturated fatty acids in endogenous depressive, J. Neurol. Neurosurg. Psychiatry 40:168, 1977.) This finding is no more significant as regards the mechanism of depression than are any other biochemical data.. However, since the blood level of these fatty acids is affectedby diet, the role of diet, or of distorted removal of dietary constituents, must be considered in evaluating the possible meaning of the abnormality. It is perhaps interesting that elevated serum cholesterol levels are also common in depression. (See AItschule, M. D., Bodily Physiology in Mental and Emotional Disorders [New York: Grune & Stratton, Inc., 1953].) 13

nisms have been advanced to explain these changes. Depressed patients have diminished diuretic responses after drinking water. The occurrence of adrenocortical hyperactivity in patients with endogenous depressions has long been known. Recent studies have shown that the plasma ACTH level is much higher in such patients* than in other hospital patients. '~ Remission, whether spontaneous or induced by electroshock therapy, is accompanied by a return to normal of adrenocortical function" and of the plasma ACTH level. '~

ETIOLOGY; PRECIPITATING FACTORS The etiology of depressive states is not known. This statement is at variance with a considerable p o r t i o n - o r perhaps a l l - of psychodynamic writings. However, the history of medicine affords innumerable instances of mistakenly describing precipitating factors, or even initial symptoms, as etiologies. This applies to mental phenomena more strikingly than to any other aspect of medicine. The most marked examples of the lack of known etiology for depression are afforded by those patients who have predictable cycles. Patients like this may go to bed cheerful and wake up deeply depressed, to remain so for a period of weeks or months, and as suddenly become undepressed. I, myself, once saw a depression begin in mid-sentence during a conversation with me. (There is no reason to believe that my remarks were the cause.) These sudden onsets 9are the exception, not the rule, but they cannot be ignored. In many depressed patients, a psychologic precipitating factor seems to suggest itself. Such factors involve the initim production of despondency, and hence psychiatric theorists have claimed that an emotional loss is the cause of depression. Examination of the circumstances indicates that this line of reasoning is inaccurate. The seeming importance of a loss, of grief reactions and the like, recognized by writers of the past and rediscovered '":The hospitalized patients reported in this study were not given any diagnosis, but since they were receiving electroshock treatments, all or most of them may be presumed to have had depressions. 14

a few decades ago, becomes understandable if one appreciates the basic defect of the depressive personality, i.e., a constriction of the field of interest. This small field can be broadened, often greatly so, by association with a spouse, lover or parent and, in some instances, an employer or a child. Association with an institution or an occupation may have the same broadening effect. Loss of any of these cuts off most of the experience of the outside world the patient had, and the depressive state supervenes, or perhaps only becomes overt. Loss of the expectation of these as-yet-notacquired experiences can act similarly and, hence, disappointment can also be the forerunner of depressive states (as the authors of earlier days noted). It is not the loss but the inability to acquire new interests to replace those that no longer are available that leads to the development of overt depression. The basic h u m a n needs are held to be food, shelter and sex. Of these, the last ig most readily available today, and the other two only slightly less so. Another requirement, at least equal in importance to any of these three, is having work to do. Any society that fails to make it possible or actually makes it difficult for its members to have work to do is asking for trouble, and not solely because of low productivity. Having no work to do, with its requirement of a commitment to schedules, skill and integrity, certainly makes latent depressive states overt and perhaps actually may cause them in susceptible persons. Psychiatric theory requires that all patients with depressions blame themselves for their predicament and for having caused the events that led up to it. M a n y - p e r h a p s m o s t - d o not experience a feeling of guilt. Although psychiatric theory requires that depressed patients be full of self-recrimination, some patients, evidently unaware of this theory, are not full of self-blame but instead blame others, either collectively or as individuals, for their troubles. Most of this blaming of others is delusional and, hence, constitutes paranoia. Paranoid thinking may occur in depressions at any age but is somewhat more common in the older decades of life. One psychologic change that may precede a depression is a compulsive-obsessive neurosis. The compulsive-obsessive personality is one of the mys15

teries of psychiatry. (It is the chosen way of lift in some religions. The Talmud, for example, says, "He who washes his hands and does not clean his nails will later feel anxious and not know why.") A number of those who develop depressions exhibit compulsive-obsessive manifestations for years b e f o r e - a fact that has been taken to prove a direct causal relation. However, with the onset of a depression, the habitual complex structure of compulsive behavior begins to disintegrate. Instead of a person showing compulsiveness in personal hygiene, dress, occupation and residence, he begins to show disarray in one or another category of behavior, the remaining categories remaining compulsively stereotyped. As the depression deepens, other aspects of behavior sequentially become disarrayed. Finally, nothing is left of this behavior, the only residue being severely obsessive thinking. In cases such as these, the shrinking in the field of interest in one's own attributes is clearly a manifestation of the deepening depression and seemingly not the cause of it. The inverse relation between mood and degree of interest outside oneself needs to be studied more than it has. It is possible that a sounder view of the nature of depression is to be gained from observations on depressed patients outside mental hospitals than on those in one. Whether or not this idea can be validated is not evident now, but it is certainly clear that any view of the nature of depression must at least be incomplete if it ignores patients in whom nonpsychologic factors induce the illness. Hence, an i n t e r n i s t - a n d particularly one who frequently is called in consultation by other types of specialists-is likely to regard currently popular American psychiatric hypotheses about depression as no more t h a n mildly interesting. At any rate, such an internist's clinical experience can only persuade him of the unimportance of psychologic factors. Physicians in practice encounter patients in whom depression clearly is due to some nonpsychologic cause. It is entirely useless to search these patients' histories for the currently fashionable mention of an emotional loss preceding the depression because, even if such an occurrence is described by the patient, it is irrelevant. 16

BRAIN DISEASES Although many nutritional defiency states cause visible neural lesions, these diseases will be considered separately. The brain diseases considered at this point in the discussion all involve inflammation or neoplasia. TERTIARY SYPHILIS.-Although syphilis of the brain is far less common now than it was half a century ago, it still may present in the form of a psychologic disorder. Medical teaching always has emphasized the manic speech and behavior, the deterioration of intelligence and the neurologic changes that characterize general paresis. Nevertheless, general paresis may manifest itself as a depressive disorder accompanied by only minimally abnormal neurologic findings. The neurologic abnormalities increase in severity and in number but they may be overlooked early in the course of the illness. Although reports in the literature show that electroshock treatments benefit these p a t i e n t s at least with respect to their depressive s y m p t o m s - i t is obvious that energetic treatment of the syphilis should be started at once to cure the depression and to prevent permanent intellectual deterioration. MULTIPLE SCLEROSIS.- Most neurologic textbooks refer to the mental changes of patients with multiple sclerosis only b r i e f l y - a n d then only to mention the euphoria that is considered typical of the disease. Some textbooks of psychiatry do not mention multiple sclerosis at all. Nevertheless, this brain disease often causes mental symptoms. In its early stages it often leads to a diagnosis of hysteria. Later in its course it produces an affective disorder, either a euphoric or hypomanic state or a depressive syndrome. For reasons that are not apparent, the depression is characterized by irritable and fidgety behavior, not by apathy or retardation.

BRAIN TUMORS.-Although in most instances tumors of the brain cause symptoms that quickly suggest the diagnosis, in some cases the symptoms are quite different in that they are psychiatric in character. In some such instances, a depressive syndrome is the presenting disorder. The headaches and vague paresthesias and muscle weaknesses that 17

may also occur often are wrongly interpreted as supporting the diagnosis of a psychologic disorder. Some physicians believe that temporal lobe lesions are particularly likely to produce affective disorders. Occasionally the depressive syndrome presents as a postictal state after brief, forgotten seizures. ALZttEIMER'S DISEASE.--Although this disease is considered uncommon, it probably is not. Its true incidence will not become known until the number of carefully performed postmortem studies of so-called senile patients is greatly increased. The clinical picture of Alzheimer's disease as given in textbooks may be summarized in the words "a suddenly silly man of 50." Of course, some patients do present with this syndrome, but in others the picture is that of 'an agitated depression beginning at or after that age. This condition is difficult to distinguish from other agitated depressions that occur, at this age. The diagnostic feature, cerebral atrophy, can be detected only by means of pneumoencephalograms or CAT scans, which are not likely to be considered in the early stages of the illness. Nevertheless, the diagnosis should be thought of in patients of this type who fail to improve or who only briefly maintain their improvement after the usual treatment used in depression. Alzheimer's disease is, of course, incurable. STROKES.- Many patients who have strokes become paralyzed or lose their ability to speak. Despondency is not unexpected in such instances. In addition, some patients develop true affective disorders, occasionally manic but more commonly depressive in type. The development of this disorder has no constant relation to the severity or to the presence or absence of physical disability if that does develop. Physical rehabilitation (except for the nutritional, as will be mentioned later) has, at most, only a moderate effect on the depression, which should be treated with antidepressive drugs.

DRUGS In this day and age, with medical care readily obtainable by most Americans, drugs rank high as factors that pre18

cipitate depression. The list of drugs that can act in this manner is long. The drugs that most commonly cause depressions are among those that act on the central nervous system, e.g., tranquilizers, sedatives, antiemetics and antimigraine drugs. As regards these drugs as precipitating factors in depressions, there is good evidence that they are most likely to act in this manner in patients who have a strong family history or personal past history of depressive episodes. Some physicians do not prescribe reserpine or certain phenothiazines for such patients unless there are compelling reasons for using them. In any case, one of the most important questions to have answered is what medication is being taken and when it began. BARBITURATES.-They are notorious for causing deep depressions in occasional patients. RESERPINE.--Some internists have reported the deVelopment of depressions in more than 15% of patients who were given reserpine (or related drugs) in the treatment of hypertension. This statistic may be somewhat misleading, since headache, palpitation and elevation of blood pressure may be symptoms of depression in middle life. Accordingly, some of the patients who become severely depressed while taking reserpine actually may have been mildly depressed when the drug was first started. In any case, reserpine is likely to precipitate, aggravate or prolong depressions. These depression3 usually disappear quickly if the drug is stopped promptly. On the other hand, if the drug is not stopped when a depression commences, the syndrome becomes highly refractory to the ordinarily successful treatments. PttENOTtIIAZINES.--The phenothiazine drugs that contain no piperazine radical produce depressions. Promazine (Sparine) and izhlorpromazine (Thorazine) lack this radical and hence are common causes of depressive syndromes. As was pointed out previously, severe anxiety may occur in depression; it may be severe enough to cause the physician to overlook the depression with which it is associated. Giving promazine or chlorpromazine in such instances ameliorates the anxiety but aggravates the depression. When given to control the agitation that occurs in some depressed

19

CHLORPROMAZINE

I

HzCHzCHzN

(CH3) z

TRIFLUOPERAZINE

/--k

i

.=c.=c.=.\

/ NCH 3

patients, these drugs usually prolong the depression. These effects rapidly disappear when the drug is stopped. Attaching a piperazine radical to the phenothiazine molecule minimizes the latter's depression-producing effects (see accompanying formulas). DIAZEPIDES.--Today, these drugs are among the most frequently prescribed in the United States, being used in the treatment of anxiety or what is interpreted as anxiety. These drugs may cause or aggravate depression, diazepam (Valium) being much more likely than chlordiazepoxide (Librium) to do so. CoawmoIDs.--Adrenocortical steroids and related drugs commonly produce euphoria or even mild manic syndromes. However, depression may occur as a late development or, in occasional cases, early in the treatment. HORMONAL DISORDERS Hormonal disorders must be considered in the differentia] diagnosis of many psychiatric conditions because of the

20

similarity of many of the symptoms. This similarity has led some authors to conclude t h a t emotional upset causes a variety of endocrine diseases, a conclusion that hardly can be taken seriously on the basis of the data on hand. In any case, there are m a n y instances in which the reverse relationship can be demonstrated, i.e., a hormonal disorder produces a psychiatric syndrome. Only depression will be considered here. MENOPAUSE.-The menopause is the most common endocrine disorder in medicine, since more t h a n 50% of the individuals (i.e., all women) who survive into middle life have it. Although it is commonly regarded as a female disorder, some men clearly have it also. It is, of course, currently fashionable in the United States to ascribe all the symptoms of the menopause in women to the fear of the loss of femaleness, fear of the deterioration of skin texture and tissue turgor, etc., etc.; these might be a cause of despondency and hence might be one precipitating factor of depression in some instances. On the other hand, some women are relieved to have the menopause. Moreover, there is no constant relation between the onset of the menstrual irregularities and of that of the depression. In some cases, the latter occurs first. In any event, hormone therapy dissipates the psychiatric symptoms. (This must not be confused with the use of hormones to treat what is unfortunately called "involutional psychosis" or "involutional melancholia," a disorder that occurs 10 or 15 years after the menopause and is not benefited by hormonal therapy.) The diagnosis of climacteric depression in men is difficult; loss of libido and potency can be symptoms both of the climacteric and of primary depressions. However, some men have hot flashes, if only briefly, in association with the climacteric; this symptom is more likely to occur in men in their 50s than in older men. In any case, the simultaneous appearance of depression and hot flashes in a man of the appropriate age should be taken as an indication for replacement therapy with testosterone. PREGNANCY.-- Pregnancy is a common cause of mental disorder, not during but after it. (In Pinel's early statistics, 10% of all women in his mental hospital had recently had a 21

baby.) The features of postpartum depression are so distinctive as to require more extended discussion under the heading of Personal History. THYROID DYSFUNCTION.--Thyroid diseases commonly cause psychologic symptoms, the origin of which is easily recognized and treated. In some cases, however, there are diagnostic errors. Although elementary medical textbooks describe increased activity as a sign of hyperthyroidism, all experienced clinicians know that this thyroid disease commonly causes other manifestations when it develops after middle life. In such instances, the main symptoms are either cardiovascular complaints or, what is more pertinent here, depression. The patients may complain of palpitation and nervousness also, which usually are ascribed to anxiety when they actually are due to hyperthyroidism. Unfortunately, the diagnosis cannot be made conclusively without laboratory studies, but signs such as unusual brightness of the eyes, warm, sweaty hands (instead of the cold, clammy hands of emotional disorders) and a fine regular rapid tremor (instead of the coarser, irregular, somewhat slower tremor of anxious states) may suggest the correct diagnosis to a careful clinician. Hypothyroidism is easily recognized when it is severe enough to cause myxedema; the associated psychiatric disorders, i.e., myxedema coma and so-called myxedema madness, are also readily recognized. However, lesser degrees of thyroid deficiency may also cause psychiatric disorders, and these often are overlooked. The psychiatric syndromes in such cases most commonly are either anxiety states or depressions, with delusional-hallucinatory States of only infrequent occurrence. The hypothyroid symptoms that precede and accompany the depressions usually are considered specific only in retrospect, since they comprise a feeling of coldness, constipation and the tendency to gain w e i g h t - a l l common complaints in normal American women. Therefore, laboratory studies are necessary to establish the diagnosis. HYPERPARATHYROIDISM. - - W h e r e a s a majority of patients with hypoparathyroidism (except, of course, those with the

22

postoperative type) are given a diagnosis of psychoneurosis, schizoid personality or even schizophrenia when first seen, psychiatric disorders are less common in patients with hyperparathyroidism. A few patients have been described as having a cyclic mental illness with alternating mania and depression. Here, too, only laboratory studies tan establish the diagnosis. ADRENAL CORTEX DYSFUNCTION.-Although adrenal medullary tumors lead to a mistaken diagnosis of anxiety neurosis, they cause psychiatric illness much less frequently than do adrenal cortex disorders. The statistics on Addison's disease show that depression occurs in approximately 60% of the cases. Of course, in most instances, the other manifestations of the hypoadrenal state dominate the picture, but in occasional patients the depression appears first and the associated apathy, anorexia and weight loss are regarded as psychologic in origin. At this stage, the patients do not show definite pigmentation of the skin, but a few tiny pigmented mucosal areas in the mouth may suggest the diagnosis. To add to the difficulties of diagnosis, some chronically depressed patients show darkening of the skin, but, unlike patients with Addison's disease, they grow body hair in excess instead of losing it. The diagnosis of mild hypoadrenalism should be thought of in all patients who have stopped taking steroids after taking them for many months. In any case, the diagnosis of depression due to adrenal insufficiency requires careful laboratory studies. Cushing's syndrome is said to cause psychiatric disorders in approximately 85% of the cases. Some aspects of the problem were discussed previously under the heading of Drugs. In spontaneous hyperadrenocortical disease, hypomanic syndromes are less common and the diagnosis usually is anxiety neurosis, depressive psychosis or schizophrenia if the mental changes develop before the physical findings become marked. In such patients, the specific type of obesity, the striae and purpura may suggest the diagnosis. (It is interesting that the first case of Cushing's syndrome was described by Osler as a case of mania, diabetes and purpura.) The diagnosis of early Cushing's syndrome is difficult, even with careful laboratory studies.

23

HYPERINSULINISM. - - Hypoglycemia due to pancreatic overactivity is more likely to cause nervousness, dizzy spells, disorientation, unconsciousness or seizures than to cause depression. Nevertheless, occasional patients are encountered in whom depression is caused by the pancreatic disorder. The issue may be confused by" the overeating exhibited by some patients with primary depressions; however, these patients do all their overeating late at night and not all day long. On the other hand, it should not be concluded that eating all during the day and craving sweets is necessarily a symptom of hyperinsulinism. It is also seen in such diverse disorders as thiamine deficiency and anxiety states. Although the diagnosis of depression owing to hyperinsulinism cannot be made without laboratory studies, it should be suggested by a history of eating at normal times and of gaining weight uncontrollably.

MALNUTRITION Malnutrition is, of course, often a consequence of some mental disorder. Not only do these disorders sometimes decrease food intake but, at least in the United States, they more commonly cause the eating of a grossly unbalanced diet. As far back as 1798, Pinel stated that he cured what we now call schizophrenia by kind treatment plus a good diet; it is probable that the good diet acted by eliminating the effects of malnutrition commonly encountered in mental patients. On the other hand, the role of malnutrition in causing serious mental symptoms is not recognized. PELLAGRA.--The textbook description of "diarrhea, dermatitis and dementia" places pellagra among the psychiatric illnesses. However, patients with this triad of symptoms are encountered infrequently in America today. Nevertheless, pellagra still is a common disease in the United States even though no longer limited to Southern sharecroppers. It now occurs chiefly in elderly persons of any economic group who live alone, who have lost interest in eating meat and who do not take enough coffee to get enough nicotinic acid to prevent the symptoms. The syndrome usually seen initially is that of agitated depression 24

with the subsequent-sometimes the preceding-development of mild confusion. The diagnosis is suggested by a history of a low meat intake with a relatively high intake of processed carbohydrate foods, together with the finding of beginning signs of glossitis or stomatitis. Because vitamin B deficiencies usually a r e m u l t i p l e and also because they induce Changes in the ileum that impair absorption, the .patients should be treated with intramuscular injections of vitamin B complex. THIAMINE DEFICIENCY.--The neuropsychiatric disorders caused by severe thiamine deficiency include peripheral neuropathy, the Stokes-Adams syndrome, coma a n d ' t h e Wernicke-Korsakov psychosis. In addition, particularly when a mild chronic deficiency is present, the syndrome may be that of depression. (It should be noted that, according to one report, when patients diagnosed as schizophrenic were given a thiamine-poor diet, they became more hallucinated, more deluded and more withdrawn.) The diagnosis of depression due to thiamine deficiency is difficult to make because there are no peripheral neurologic manifestations except perhaps a history of paresthesias. The diagnosis should, however, be suggested by the dietary history. Ascoanic ACID DEFICIENCY.-- Clinical scurvy is not common in adults in the United States and hencethere are few opportunities to study it. However, clinical reports on scurvy from other places show that depression is a symptom of it. The metabolic derangements caused by ascorbic acid deficiency resemble those of phenylketonuria. It is interesting that giving ascorbic acid to chronically psychotic patients has been reported to cause improvement. PROTEIN DEFICIENC~/.-- Uncomplicated severe protein malnutrition is seen rarely in the United States. However, reports from other parts of the world indicate that depression is a manifestation of this disorder. The mechanism is not known but it is possible that there is a lack of tryptophan for the synthesis of nicotinic acid.

FOLIC ACID DEFICIENCY.--Folic acid deficiency may give rise to serious psychiatric disorders, manifested by delusion, confusion and hallucinations. It occasionally gives 25

rise to a depressive syndrome with little or no confusion or intellectual deterioration. Folie acid deficiency also causes anemia, b u t this may be only moderate and hence is not given its proper diagnostic importance. This deficiency state may arise in association with pregnancy, with the use of oral contraceptives, with alcoholism or simply w i t h a markedly abnormal diet. The symptoms disappear rapidly with specific treatment.

VITAMIN B~2 DEFICIENCY.- Some degree of mental change occurs in nearly all patients with pernicious anemia. The mental changes range from mere apathy through depression to hallucinatory psychoses. Although always accompanied by severe anemia, the apathy and depression are not hypoxic in origin; starting treatment rapidly alleviates the mental symptoms before the blood hemoglobin level begins to rise. PYRIDOXINEDEFICIENCY.--Depression has been described as part of the clinical picture of experimental pyridoxine deficiency in man. For reasons that are not evident, pyridoxine deficiency is common in alcoholics. IRON DEFICIENCY.-Although the clinical literature of 30 or 40 years ago on iron-deficiency anemias discussed their psychiatric manifestations, including depressions, the problem was never a simple one. In the first place, iron deficiency owing to malnutrition alone always has been rare in American adults; blood loss nearly always is a factor in the illness. In addition, the possible role of associated nutritional deficiency states often is difficult to clarify. In the second place, improvement in treatment and the development of blood banks have made severe chronic iron deficiency uncommon here. In the third place, the precise factor that produces mental changes in iron-deficiency states has never been identified. Iron is a constituent not only of hemoglobin but also of many other widely distributed enzymes; the possibility that many symptoms, including the psychiatric, are due to changes in some of these other enzymes must be borne in mind. Finally, the fact that all chronic iron-deficiency states are also zinc-deficiency states must not be overlooked. Zinc is a constituent of carbonic 26

anhydrase, an enzyme present in the brain in large amounts. In any case, the severity of depressions associated with iron-deficiency anemia does not parallel the blood hemoglobin concentration.

ELECTROLYTE DISORDERS Electrolyte disorders are seen more often in hospital practice than in ambulatory patients. This is true because these disorders are the result of serious illnesses that require hospital t r e a t m e n t or else they .are precipitated by the energetic t r e a t m e n t commonly used in hospitals. However, they are encountered in patients seen outside hospitals. SoDIUM.--Sodium depletion commonly occurs during the energetic t r e a t m e n t of cardiac decompensation. Clinicians of the past recognized that so-called cardiac psychosis was more common during the early phases of recovery than at the height of the symptoms of congestive heart failure. The psychiatric manifestations of sodium loss include apathy, severe depression, so-called schizophrenic syndromes and coma. These manifestations disappear rapidly w h e n - t h e patients are given salt. POTASSIUM.- Potassium deficiency is not uncommon during treatment with diuretics, during prolonged steroid therapy or during diarrheal diseases. Potassium depletion m a y cause severe depression, which is relieved when potassium salts are given. Some clinical studies indicate that the potassium depletion induced by the giving of large amounts of solutions of dextrose in water or in sodium chloride solution, without the addition of potassium, is one cause of postoperative psychosis. -Potassium excess in the body also may produce depression. This syndrome is not common; it may occur in uremia or in patients who receive aldosterone inhibitors for prolonged periods. The depression in the latter disorder may be accompanied by muscle spasms t h a t clearly differ from those of hypocalcemia. In any case, the cure of the hyperkalemic disorder relieves the depression.

27

MAGNES[UM.--Magnesium depletion occurs particularly after operations and in debilitated alcoholics. Although depressions occur in both these disorders, the role of the magnesium deficiency is not clear. CALcIUM.--Hypercalcemia from whatever cause may give rise to depression. This already has been discussed in relation to hyperparathyroidism. It may also occur during the course of steroid hormonal treatment of neoplasms. The hypercalcemia that occurs during excessive intake of milk and alkali in middle-aged or elderly patients with peptic ulcers commonly manifests itself in mental changes, including depression.* BICARBONATE.--Psychiatrie symptoms are prominent in several different disorders in which elevations of the plasma bicarbonate concentration are found. These include metabolic alkalosis produced by such diverse factors as the ingestion of excessive amounts of sodium bicarbonate and the vomiting of gastric acid. On the other hand, respiratory acidosis also causes a rise in plasma bicarbonate level. The psychiatric symptoms of these two opposite types of disease are similar, comprising anxiety, paranoid reactions, depression and, in extreme cases, stupor.

A CONCLUSION ON PRECIPITATING FACTORS The concept of so-called toxic-metabolic psychosis as a delirious state with hallucinations, delusion, confusion, intellectual disintegration, etc. has played an important and useful role in medical thinking, although the term "toxic-metabolic" is not always an accurate description of the etiology. It is evident that (1) either the concept should be expanded to include not only deliriums but affective disorders or (2) there should be an analogous concept of "toxicmetabolic depression," although here, too, "toxic-metabolic" is not a good descriptive term. What the syndrome is *For an illuminating general discussion of relations between calcium metabolism and depression, see Carman, J.D., Post, R. M., Goodwin, F. K., and Bunney, W. E., Jr., Calcium and electroconvulsive therapy of severe depressive illness, Biol. Psychiatry 12:5, 1977. 28

called is not important. What is important is that the differential diagnosis of depressions, and hence their treatment, can be carried out only by broadly informed practitioners.

THE HISTORY FAMILY HISTORY.-Patients with primary depressive disorders, i.e., depressive syndromes not clearly due to some definite disease, are likely to have a family history of depressive attacks (including suicide), of chronic alcoholism or of broken homes. Certainly patients with a family history of severe depressive disorders, especially those resulting in suicide, should not be given certain medications, e.g., reserpine, which are known to produce depressive states even m normal people.

PERSONAL HISWORY.--There are several things that always must be remembered as regards a patient's history. One is that if the depressive disorder is secondary to recognizable metabolic or brain diseases, the latter may be overlooked because their manifestations were submerged by the depressive manifestations. A serious diagnostic error. thus may be made. The patient may not only be denied effective specific medical treatment b u t m a y also be removed from medical (as opposed to psychiatric) supervision. Contrariwise, in cases of moderate depressive disorders, the somatic symptoms may divert attention from the true diagnosis of endogenous depression. In addition, it must never be forgotten that alcoholism may be the most striking manifestation of a manic-depressive disorder. The somatic symptoms and the alcoholism should not be considered part of the past history but rather part of the present illness. It is evident that the history should be taken by a perceptive, broadly informed medical practitioner. THE PRESENT ILLNESS.--The history of the present illness contains all the somatic manifestations that may afford a clue to the presence of an underlying recognizable metabolic or brain disease. In addition to these, if any are present, close attention must be paid to the psychologic manifestations. 29

It is a serious error to concentrate attention exclusively on the patient's feelings of sadness, unhappiness or self-deprecation. It is evident that at least equally important is the shrinking of the variety and extent of the patient's outside interests and exaggeration of his introspective interests. These manifestations become very marked in severe depressive states, but even in mild or early depressive disorders they may be so pronounced as to dominate the psychologic picture.

MURDEROUS ASSAULTS A high percentage of persons guilty of murderous assaults, usually against children and almost always not their own, are found to have been depressed before (and of course after) the event. These assaults are easily distinguished from assaults committed by persons with paranoid psychoses or with schizophrenic auditory hallucinations. One of the engaging aspects of psychodynamic psychiatry is that it can explain anything. Accordingly, explanations have been advanced to explain the assaultive behavior of depressed persons. Nevertheless, this behavior remains a mystery and, in addition, constitutes an important medicolegal problem.

POSTPARTUM DEPRESSION The postpartum period is one of drastic upheaval. There are great emotional changes, which have, of course, been discussed extensively in psychiatric writings and women's magazines. The fact that the postpartum period comprises a succession of extraordinarily varied and marked metabolic changes has not received much notice. The loss of placenta, a great factory for synthesis of anterior pituitary, adrenocortical and ovarian hormones, has been documented and to some extent studied. It should occasion no surprise that psychologic changes occur at a time of great metabolic flux and changes in gonadal and adrenocortical status. Nevertheless, these drastic physiologic changes cannot be used to explain the mood abnormalities that occur in the 30

postpartum period. Moreover, folate and vitamin B 6 deficiencies are common in pregnancy and probably persist. The weepiness of the sixth postpartum day comes on suddenly and mysteriously. It is noted with alarm by the husband and usually evokes an extra show of tenderness, additional flowers and a gift (perhaps a small piece of jewelry). On the other hand, the old experienced nurse regards the weepiness and spouse's response with equal disgust. The weepiness disappears as suddenly, and mysteriously, as it came. Its origin is not known. The true postpartum depression is another matter. It does not begin until a period of several weeks or more than a month has gone by. Its insidious onset and gradual progression prevent dating its beginning, but by the third month the depression is severe. Its treatment is that of severe depression in general, but there are special requirements with respect to the care of the baby. A remarkable aspect of the postpartum "depression is the fact that the baby is totally ignored and may not be mentioned at all by the mother. This is a good example of the marked contraction in interests that characterizes severe depression. In view of.the fact that both folate and vitamin B 6 deficiency may cause depression, the coexistence of these deficiency states must be explored.

OTHER SYMPTOMS The physical symptoms associated with depression c a n be trifling or, on the other hand, so extreme as to encourage the formation of phobic ideas about them. However, it must be remembered that phobic ideas of physical illness need not vary with the intensity of the symptoms or, indeed, with their occurrence at all. The most prominent symptom is extreme fatigability. This is related in part to the disordered intermediary metabolism that occurs in severely depressed patients TM b u t there must be other factors as well. A serious deficiency in motivation is also a factor, since, unable to commence vigorous exercise at all, these patients cannot achieve the benefit of a second wind, that is, they cannot achieve the 31

equilibrium state that develops when fatigue begins to set in during vigorous exertion. The extreme fatigability in neurosis can be overcome by a program of physical training. 9 There are, regrettably, no data in this regard in depressions. Another common complaint is weight change. This always is associated with anorexia, although interestingly enough, the weight change is a gain in as many as 10% of the cases. The anorexia lasts all day, but most patients take a moderate evening meal. Some depressed patients take a large meal rather late, and in some cases this meal is gargantuan and followed by nibbling until well after midnight. Despite the moderate number of calories taken over the 24-hour period, the fact that the entire caloric intake is taken over a short time may lead to puzzling obesity. Whatever the food intake, the diet is disproportionately high in boxed or canned carbohydrate and, hence, low in B vitamins. Almost all depressed patients have insomnia; many have terrifying nightmares. The ability to sleep is impaired even in the absence of bad dreams. If the patients do get to sleep, they are likely to awaken early, after only a little sleep. Palpitation and shortness of breath may be troublesome in some patients and may lead to the unnecessary use of cardiac drugs. Decreased libido, often with impotence or frigidity, is common in some depressions and is likely to cause marital discord. On the other hand, the lack of normal sexual satisfaction may lead to a vain search for. a more stimulating partner. Menstrual disturbances may occur in women. Indigestion, with gassiness, and stubborn constipation are very common and may occupy the major part of a depressed patient's interest. In addition to these common complaints there may be, less frequently, dizziness, paresthesia, neckaches spreading up the back of the head, urinary frequency and blurry vision.

PHYSICAL EXAMINATION The patient usually shows an abnormality of w e i g h t loss in about 90% of cases and gain in the remainder. 32

Women may exhibit excessive growth of facial hair. There may be evidences of poor personal hygiene, more marked in women over 20 years of age, because ordinarily these women are better groomed than men. Although the patients may not smell clean, they do not have the odor characteristic of schizophrenia. The facial expression is one of quiet sadness or active d e s p a i r - o r , in some cases, extreme disgust. The voice may be normal or low and hoarse. The oral responses may be very slow (so-called retardation) or they may be normal, or they may be made up of vigorous expression of a few reiterated thoughts derived from the depressed mood. The buccal mucous membranes are visibly dry and mucus is scant and thick. Poor dental hygiene may be evident. The heart and lungs are normal except for the frequent occurrence of a ringing exaggerated second aortic sound in patients past 50. The abdomen is likely to be distended and gassy. The hands and feet are cold and either pale or cyanotic, and may be moist, but less so than in patients with uncomplicated severe neurosis. The arterial pressure usually is normal, although in patients past 50 years of age, it is likely to be elevated. (The separation of psychiatry from medicine has had a number of unfortunate effects, one of which has been to remove from medicine awareness of the frequency of hypertension in depression and its almost regular remission with treatment of the depressive illness.) Roentgenographic studies are not remarkable except for the frequency and degree of osteoporosis in the patients older than 50, especially the women. (This complicates the effects of electroshock therapy.)

CLINICAL LABORATORY FINDINGS The hematocrit value, hemoglobin concentration and red blood cell count, all taken from finger or arm blood, although in the normal range, may be high for the specific patient, an effect of the cutaneous vasoconstriction that characterizes the disorder. These levels may fall slightly with effective treatment (unless the patient has had an anemia and is being treated for it). 33

The urine is not remarkable except for its high specific gravity and the occasional finding of glycosuria. Blood chemistry findings in a majority of cases reveal hyperglycemia after oral glucose administration and only occasionally during fasting. The rise in blood lactate and pyruvate and the fail in serum inorganic phosphate level after the glucose load are all excessive, clearly distinguishing this state from diabetes mellitus. The hyperglycemic state responds to insulin poorly or, more commonly, not at all. This disorder of carbohydrate metabolism is found in many types of stress and can be produced in normal persons by the administration of ACTH, adrenal corticoids or epinephrine. 13 Its mechanism seems to be a disorder of the tricarboxylic cycle (if that cycle really exists in intact man) or, at any rate, of intermediary carbohydrate metabolism. The defect is said to be in the altered function of the malate enzyme. The blood corticoid level usually is elevated in patients with endogenous depressions. The blood chemistry findings will, of course, manifest the effects of whatever metabolic disorder may be found to be the precipitating cause of the depressive illness. CLINICAL TYPES OF DEPRESSION AND THEIR TREATMENT The following clinical classifications are useful not only as diagnostic but also as therapeutic guides: ADYNAMIC DEPRESSIVE STATES.--There are patients in whom the predominant psychologic change is a marked lack of interest in what goes on in the world about them, or anywhere else. They get little pleasure, or the opposite, from anything. Their prevailing mood is not sadness or depression but rather a persistent boredom. (Years ago, Abraham Myerson described this syndrome as anhedonia, inability to enjoy or be entertained by anything.) Persons of this sort are boring and hence are not likely to be social successes unless they have high position. What is particularly distressing to their close associates is their inability to be dressed and ready for appointments, or to keep them at all. They cannot be counted on to carry out their obligations. Seeking escape from their persistent boredom, they

34

drift in and out of sexual affairs and are likely to experiment with technique. Their thought processes contain no delusional material. Many of them believe that they are inadequate, but this is no delusion. This type of depressive condition presents no dangers except for one-alcoholism. To blunt their feelings of boredom, and to make themselves seem less boring to others, they fall into the habit of drinking during the day and some of them become habituated to alcohol. Not only do they develop the physical and mental changes of alcoholic excess, but they have a high suicide rate after alcoholic debauches. It is difficult to break them of their habituation to alcohol, for they cannot develop the initiative to join Alcoholics Anonymous and they cannot be relied on to take disulfiram regularly. Aside from the chronic alcoholism that complicates the disorder, the adynamic depressive state may be successfully treated with analeptic drugs. In an earlier period before the use of amphetamines became restricted, many patients with this syndrome took amphetamines. They usually obtained relief but, when drug therapy was continued, they developed tachyphylaxis-the drug ceased to work. Some such patients learned to restrict the use of amphetamines (in 5-mg doses) to times when they had to keep an important appointment or make a social appearance. Much less troublesome is the use of medications based on piperazine. Piperazine is a normal constituent of mammalian brain. It has received little attention, and its function is: not known. However, when injected into animals, it produces hyperactivity. Its use in patients with adynamic depressive states usually is successful. The dose of the medication most commonly used, Ritalin, is 5 - 2 5 mg 3 times a day, starting with the low dose and increasing it as needed. Tachyphylaxis does not develop. It is interesting to observe that when the medication is effective and the patient is able to live a life of normal activity, many months must go by before he loses his feelings of inadequacy. Before this change in thinking occurs, the self-deprecation might be considered delusional and, hence, the only evidence of depression in these cases. It appears that this category of depression is a mild form 35

of, or is at least related to, the manic-depressive depressed state. REACTIVE DEPRESSION; NEUROTIC DEPRESSION.--Neurosis

is a common disorder. Its etiology is not known and in any case is not under consideration here. (It has been demonstrated that neurotic behavior can be genetic in animals; it can also be induced by conditioning, as that remarkable book by Munn '3 makes evident.) Depressive states are also common. Hence, one would expect that both neurosis and depressive states would occur together frequently. There is, however, one complicating fact, i.e., that the symptoms of neurosis and depressive states are similar in some respects. This by no means indicates, or even suggests, that the two are related. (One might as well conclude that brass-founders' ague and pyelonephritis are related because they both exhibit febrile manifestations.) The manifestdtions found in both anxiety states and most depressive states are those related to a n x i e t y - t h e feeling itself and, to some extent, the somatic and behavioral changes. A third factor that leads to the common occurrence together of neurosis and depression is the neurotic patient's low threshold for intolerance in all areas. For example, neurotic patients are intolerant of heat, of cold, of exertion, of pain, etc. They are also intolerant of a n x i e t y - d e g r e e s of anxiety that normal persons would recognize but ignore become very important to neurotic patients. The same probably is true of the feelings of despondency that arise from time to time in normal life. The normal feeling of responsibility that mature people have as a result of things they have done or not done becomes to the neurotic a feeling of guilt. (This is difficult to interpret today, for current educational theory, created by morbid central European Weltschmerz, teaches our children that to be normal they must feel guilty much of the time. This notion is curiously like one that was inculcated in American children of the past century. They were taught that they all participated in the guilt of Original Sin and would continue sinful for the rest of their lives, despite phenomenal efforts in the way of prayer and Good Works. Confession of this s i n - a n 36

ancient form of what today is called " i n s i g h t " - w a s essential for salvation.) The depressed neurotic patient feels good at irregular intervals and usually is at his worst late in the afternoon. This is completely different from the patient with the manic-depressive disorder, depressed stage, who feels very bad in the morning and suddenly seems to come to life in the late afternoon or evening (see below). The despondency usually is clearly situational but is exaggerated with respect to the circumstances. Thus, for example, a neurotic person may become markedly and persistently despondent if a son goes away to college or does not get accepted at a college; or if a daughter gets married or fails to get married. The despondency may be disabling, b u t then the other symptoms may also be disabling. The extreme egocentricity of neurotic persons is to be distinguished from the contraction of the interests of the patient with a depressive disorder. The egocentric neurotic patient is responsive to any idea of whatever nature that will encourage him to refer to his own feelings, either as such or as evoked by something that has been said by others, whereas the patient with a true depressive reaction is not responsive to what goes on about him and talks only about what has been in his mind concerning himself all along. The neurotic patient is also likely to have a variety of somatic complaints, changing from time to time and each lasting usually for a few weeks. In depressive states, the somatic complaints are fixed and often phobic and delusional. The treatment of neurosis is not satisfactory. The possible benefit of psychotherapy is difficult to evaluate in this condition, and in any case often does not persist after the end of the course of treatment. The medicinal treatment likewise is not sensationally successful. Although the symptom of anxiety is controllable with a variety of medications, e.g., phenobarbital, phenothiazines and diazepides, there are objections to all three. Phenobarbital may be addicting, and all three, especially the phenothiazines, are potentially depressing. (Fortunately, they usually are given in doses too small to be t r o u b l e s o m e - o r effective.) Moreover, controlling the anxiety in patients with this 37

chronic disorder seems to improve them little, if at all. Nevertheless, for some patients with the combination of severe neurotic anxiety and depression, drugs that contain both a phenothiazine moiety and an analeptic such as pipcridine are available. Of these, in my experience, trifluoperazine hydrochloride (Stelazine), in doses of 1 or 2 mg 3 times a day, is not only effective but most free from sideeffects. Unfortunately, the two m o i e t i e s - t h e antianxiety portion and the a n a l e p t i c - a r e present in a fixed ratio, which in perhaps 50% of the cases is not optimal for that patient. In some cases there is too much phenothiazine and in other cases too much analeptic. Diazepam is an antianxiety drug that is less likely to cause depression than some others. Patients with neurotic depressions are not likely to attempt suicide, although it is not rare to observe the dramatic taking of pills, followed by a call to some person who, in the j u d g m e n t of the patient, needs to be impressed. MANIC-DEPRESSIVE SYNDROME, DEPRESSED PHASE.--This

disorder was formerly, and still usually is, called manicdepressive psychosis, depressed phase. Since many, perhaps a majority, of the patients are not psychotic all the time, or in some cases at all, the word psychosis is out of place. The syndrome to be discussed in this section has welldefined features. Nevertheless, the diagnosis of this synd r o m e - a n d hence its correct and effective t r e a t m e n t - i s complicated by the fact that many of its manifestations are not specific. In fact, s o m e - n o t a l l - o f them are the same as s o m e - n o t a l l - o f the manifestations of s0-called reactive or neurotic depression. However, the total pictures of both are sufficiently different to permit distinguishing the two most of the time. For example, both may be accompanied by a n x i e t y - s o m e t i m e s so severe as to overshadow the depression, thereby leading to a false diagnosis of neurosis. However, the pattern of daily activity helps make the diagnosis of manic-depressive syndrome, depressed phase. In cases in which a manic phase anteceded the depression, the diagnosis is even clearer. It must be remembered that the volatile, on-and-off gaiety alternating quickly with depression in the neurotic is to be distinguished from the behav38

ior in m a n i a - w h i c h need not be happy at a l l - a n d which in any ease is protracted over weeks or months and not over hours or a few days. In another direction, a mild depressed phase of the manic-depressive syndrome may be missed, because the patient is not depressed to any recognizable degree; rather, he has a number of the somatic manifestations to an extent that is troublesome or a cause of alarm. In such eases, a search must be made for the diseases that might be responsible for the symptoms, and the search will prove fruitless. Here, again, the pattern of daily activity m a y be helpful, as is also true of a strong family history of depression, a history of a manic episode in the past or, in certain patients who insist on hiding psychologic symptoms, a persistent but tactful inquiry as regards his own estimate of any change in his feelings or in the extent of his interests. Nevertheless, a diagnosis with a satisfactory degree of certitude may not be possible in some such cases. Since depressions of the manic-depressive type almost always are self-limited (around 95% unless prolonged by the wrong kind of psychotherapy), it is appropriate to wait. It is also appropriate, after a suitable interval of observation, to consider a therapeutic test, i.e., the response to one of the milder quick-acting analepties, which may be manifested as a disappearance of the somatic complaints. In some cases, the chief symptom is one of explosive and persistent irritability, and this similarly m a y disappear, indicating that its cause was really a depressive state. The thought content of the patient with a moderate to marked depression of the type under discussion here is characterized by poverty of ideas, continuous rumination over one or a very few ideas. The most prominent ideas are delusional and associated with marked feelings of guilt. Anxiety, always present, may be severe, and this, combined with the prevailing despair, may give rise to agitated pacing and handwringing. The patient's response to questions or comments at this stage of the illness is characteristic. The descriptive term retardation is apt. The patient's responses are delayed and delivered slowly in a quiet, hoarse voice. Or he may start to talk, after an interval, and not finish his sentence. Such 39

responses as he does make are appropriate to the questions, making due allowances for his delusions. (After recovery, patients such as this one report that at the h e i g h t - o r perhaps d e p t h - o f their illness they hear and see things as through a thick, heavy fog or curtain.) The medicinal treatment of moderate or severe depressions of this type usually involves the use of tricyclics (of which imipramine and desipramine are faster-acting than amitryptiline) or hydrazines such as Nardil and Niamid (both slow-acting). The hydrazines and tricyclics never m a y be used together, and at least 10 days must be allowed between them if they are to be used consecutively. When tricyelics are given, they usually cause confusion for a few days, but this wears off. During this period, the patients should not drive. Sometimes a given dose works for a week or so and then seems to lose its effectiveness. If so, the dose should be incre.ased. This m a y happen several times before a lasting effect occurs. At this point, the patient is likely to be dry in the mouth. Patients with glaucoma or prostatism should not be given these drugs. Physicians should inform themselves of the effects. The hydrazines usually are called monoamine oxidase inhibitors, although this is only one of their actions and there is no proof that this effect is the mechanism of their action. They all interfere with the physiologic action of vitamin B e. These drugs have toxic effects. Suicide is a serious danger in moderately or severely depressed patients. A suicide attempt should result in immediate hospitalization and the start of a course of electroshock treatments. Electroshock treatments often are helpful in patients in whom the medications are ineffective. Some patients who have experienced remission after a course of electroshock treatments relapse a few weeks later. In some of these, daily injections of large amounts of testosterone for 10 days m a y restore the remission. 14 The use of male hormones in depression, suggested several decades ago, ~4 seems to be coming back into favor. Patients with moderate or marked depressions of the manic-depressive type m a y benefit markedly from treatment with lithium. Depressed patients who have had a manic attack do especially well, more than 90% showing 40

remissions. In the depressed patients who have never had a manic attack, the remission rate is about 60%. There are absolutely no data that explain the action of the drug. An effective response is heralded by a diuresis, which is interesting because the onset of cyclic depressions is preceded by a week or two of salt and water retention. 9 The plasma lithium level must be measured frequently if an effective dose is to be maintained and acute toxic effects avoided. Chronic lithium administration causes goiters, by mechanisms as yet unknown. '~ As far as is now known, this has nothing to do with its beneficial effects. When alcoholism accompanies the manic-depressive syndrome, the alcoholism m a y benefit greatly from the use of lithium. '6 Psychotherapy is a routine recommendation made by most American psychiatrists for any conscious patient about whom they are consulted. There is psychotherapy and psychotherapy. The so-called supportive type, tailored to each individual patient's situation, is part of the treatment of any disease (or what might be a disease) by any physician. Internists are likely to find this irksome in depressed patients but should persist nevertheless. So-called deep psychotherapy has been shown to prolong depressions and increase the risk of suicide. INVOLUTIONAL DEPRESSIONS. - - D e p r e s s i o n s may occur at any age, but those that occur in the later years of life m a y have a different quality from those that occur earlier. Some of the features that distinguish involutional depression (or, as it sometimes is called, involutional melancholia or involutional psychpsis melancholia) are the extreme degree of agitation and the occurrence, in many cases, of hallucinations. The occurrence together of severe depression and hallucinations is somewhat reminiscent of the beginning of schizophrenia, where these two groups of symptoms often occur together. The treatment of involutional depression is as above, but the results, especially of lithium therapy, are not as regularly effective as in depression at younger ages. The extreme degree of agitation requires treatment, and librium is the least depressing of the tranquilizers. In some cases, the degree of dehydration and wasting are so severe as to make electroshock therapy necessary to save life.

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DETERIORATION.--Deterioration is common in schizophrenia. It first reveals itself as a loss of reaction patterns that give the personality its individuality and its responsiveness, all appearing after recovery from an episode of delusions and hallucinations. American psychiatrists today call that stage '~recovery," although the patient still has a defective personality. American psychiatrists of the preWorld War II era, like European psychiatrists, called that loss of personality characteristics "deterioration." American psychiatrists today are wont to sneer at the earlier psychiatrists for reporting around 88% deterioration in schizophrenia. Today, these so-called schizophrenics in remission, who remain with markedly inadequate personalities, are forced into the community, where they constitute a markedly disruptive element in our urban society. A similar type of deterioration may result from drug abuse, including alcoholism. When deterioration due to schizophrenia or to ~lrug abuse progresses, roentgenographic s t u d i e s - e i t h e r air encephalograms or CAT s c a n s - r e v e a l brain atrophy in most cases. Deterioration in endogenous depression, as reported by psychiatrists of the early twentieth century, was uncommon, occurring in less than 5% of the cases. Today, a syndrome that resembles deterioration in terms of loss of salient personality features is more common. It almost always is accompanied by persistence of a moderate degree of the depression. The nature of this process is difficult to establish because contraction of the field of interest is a basic process in depression. Some of these patients recover quickly if the tranquilizer or sedative they have been taking is discohtinued. In other cases, the persistence of a socially inadequate, intellectually stultified and physically dilapidated state seems to be a sequel to prolonged so-called deep psychotherapy. This kind of psychotherapy encourages the patient to ruminate about his m i s e r i e s - r e a l or i m a g i n e d and his delusional feelings of unworthiness and deserved despair. These sad c r e a t u r e s - w o m e n for the most p a r t are to be found in upper middle class communities (the treatment is very expensive) made up largely of college graduates (who have had a course or two in social psychology and hence are up to the minute as regards the supersti42

tions that comprise much of these courses). Whether these persons are deteriorated or whether they have been conditioned to behave that way cannot be stated, although the latter seems more likely. The social value of Weltschmerz among the cognoscenti must not be overlooked, b u t w h a t we are discussing here goes far beyond the contrived dilapidation and despair of adolescent Weltschmerz. Among the cognoscenti there is a common belief, called the gewalt Gestalt, that middle class culture has created a world that is a terrible place for anybody who has ever had one or more parents. Consequently, the persistent depression is considered a normal and, perhaps, even a desirable state. ANOREXIA SERVOSA.-- Psychiatric nosology is a patchwork, insubstantial thing. It is based on clinical observation alone, and this is used to provide the distinctions necessary for making classifications. However, clinical observation sometimes may fail to appreciate similarities. It is possible that this situation has occurred with respect to anorexia nervosa, a condition in which the endocrine manifestations of extreme starvation (gonadal and thyroid hypofunction) have blunted our appreciation of the significance of the depressive mood and of the finding of adrenocortical hyperfunction. '7 It now appears that anorexia nervosa is ameliorated by lithium therapy. 18 It is possible that, at least in some adult patients with anorexia nervosa, the basic process is depression.

COMMENT It would be banal to point out that this clinical account has failed to present the subtleties of this most complicated syndrome. Certainly the majority of depressed patients exhibit many more, and much more varied, manifestations. The fact is that the diagnosis of depression and the recognition of its clinical types cannot be based on tests unless the depression is due to some recognized disease process. Under present conditions, the physician who wants to become expert in the diagnosis (and hence the treatment) of depressive disorders must be willing to spend the time necessary to do so. He must overcome the feeling of boredom or, 43

perhaps, of repugnance that depressed patients may evoke in him. Above all, he must learn that a feeling of hopelessness about these disorders is not warranted. However, he must know what he can and what he cannot do. He can diagnose the various types of depression and can prescribe their medicinal treatment, but he must know about the untoward effects of medicinals. He can and should give the psychologic support n e c e s s a r y d u r i n g the early period of medicinal treatment. He should be able to recognize suicidal patients and should insist on their immediate hospitalization and the immediate institution of electroshock therapy. Although electroshock therapy should be given or at least supervised by a physician experienced in that branch of treatment, the internist must know certain facts about the treatment that bear on the occurrence and prevention of complications. The.se facts and their implications were discussed previously. 19 1. The passage of the electric current through the brain stimulates hypothalamic centers and an autonomic discharge, m a i n l y vagal, occurs. Vasodilatation, lacrimation, salivation and mucus secretion all develop but are of little consequence. However, the vagal stimulation may cause heart block or cardiac standstill, both potentially fatal, b u t both absolutely preventable by the previous injection of atropine. 2. After a latent period of a few seconds, the seizure begins as a strong generalized tonic contraction of the whole body. There is a forced expiration. This sudden maximal contraction may cause small fractures of the vertebrae unless the seizure is modified by the use of muscle-relaxing drugs. A Valsalva state develops. Apnea persists for as much as half a minute. The rise in intrathoracic pressure diminishes the return of t h e blood to the heart, and the heart size decreases. The arterial blood pressure falls somewhat, and the work of the heart during this phase falls greatly. This is fortunate, for the apnea, combined with generalized muscular contractions that soon develop in the clonic phase, causes severe hypoxia. Accompanying this is an accumulation of carbon dioxide and a great amount of 44

lactate and pyruvate. The arterial blood pH usually falls below 7.0. The hypoxia and carbon dioxide acidosis are much less severe when the seizures are modified by musclerelaxing drugs. Cardiac electrical action during the seizure remains normal. 3. After the seizure, respiration returns, usually with severe hyperpnea, and there is also danger that the aspiration of buccal and tracheal secretions will occur. Small patches of temporary atelectasis develop but these are of no significance unless the aspirated secretions contain pathogenic organisms. Lung abscess may be a rare complication under the latter circumstances. The return of respiration is accompanied by the return to the heart of blood that had been trapped outside the thorax during the seizure. This greatly increases cardiac work unless the seizure had been modified by muscle-relaxing drugs. The returfi of blood to the heart distends its chambers, stimulating the vagus. The result is reflex heart Block or standstill, but this, too, is absolutely prevented by atropine. In addition, ventricular premature beats occur commonly. Occasionally there are brief runs of ventricular tachycardia. These vc.ntricular arrhythmias are owing perhaps to the effects of hypoxia at a time when circulating catecholamine levels are high. There are no limitations on physical activity after the treatment, although many patients are so confused for some hours as to be unable to drive a car. 4. The use of premedication with injectable barbiturates to allay apprehension and of muscle-relaxing drugs to minimize the possibility of fractures and to decrease the severity of the seizures creates problems as regards respiration. Hence, when such drugs are used, a person expert in establishing an airway and maintaining respiration by means of a bag should be in attendance. It is evident from all this that the internist plays an important role in ascertaining contraindications to electroshock treatment and in identifying and treating complications. In general, the internist must recognize that he is the only physician sufficiently broadly informed to be able to understand the problems of depressions in patients. As 45

such, he should be directly involved in all phases of the treatment, leaving only the actual carrying out of shock treatments to specialists. REFERENCES 1. Hippocrates. Trans. W. tl. S. Jones (Cambridge, Mass.: ttarvard University Press; London: William tteinemann, Ltd., 1948), Aphorisms V123. 2. Celsus, Aurelius Cornelius: Of Medicine. Trans. J. Grieve (London: tI. Renshaw and others, 1838), p. 133. 3. The Extant Works of Aretaeus, The Cappadocian. Trans. F. Adams (London: The Sydenham Society, 1856), pp. 298-300. 4. Altschule, M. D.: A Sourcebook in the History of Traditional Ps:)vho. pathology (Washington, D. C.: Hemisphere Press, 1976). 5. Caelius, Aurelianus: On Acute Diseases and On Chronic Diseases. Ed. and Trans. I. E. Drabkin (Chicago: The University of Chicago Press, N.D.), p. 563. 6. Paulus Aegineta: The Seven Books. Trans. F. Adams (London: The Sydenham Society, 1844), p. 383. 7. Willis, T.: Two Disco[~rses Concerning the Soul of Brutes, Which is That of the Vital and Sensitive of Man. Trans. S. Pordage (London: Thomas Dring, 1683), p. 788. 8. Shaywitz, B. A., Cohen, D. J., and Bowers, hi. B.: CSF monoamine metabolites in children with minimal brain dysfunction: Evidence for alteration of brain dopamine, J. Pediatr. 9~.67, 1977. 9. Altschule, M. D.: Bodily Physiology in Mental and Emotional Disorders (New York: Grune & Stratton, Inc., 1953). 10. Berson, S. A., and Yalow, R. S.: Radioimmunoassay of ACTH in plasma, J. Clin. Invest. 47:2725, 1968. 11. Altschule, M. D., Parkhurst, B. It., and Promisel, E.: Effect of treatment on the excretion of 17-ketosteroids in patients with mental disease, Arch. Neurol. Psychiatry 64:516, 1950. 12. Altschule, M. D.: Carbohydrate Metabolism in Mental Disease; Associated Changes in Phosphate Metabolism, in Himwich, It. E. (Ed.), Biochemistry, Schizophrenia and Affective Illnesses (Baltimore: The Williams & Wilkins Company, 1971). 13. Munn, N. L.: Handbook of Psychological Research on the Rat (Boston: Houghton Mifflin Company, 1950). 14. Altschule, M. D., and Tillotson, K. J.: The use of testosterone in the treatment of depressions, N. Engi. J. Med. 239:1036, 1948. 15. Child, C., Nolan, G., and Jubiz, W.: Changes in serum thyroxine, triiodothyronine, and thyrotropin induced by lithium in normal subjects and in rats, Clin. Pharmacol. Ther. 2~.715, 1976. 16. Merry, J., Reynolds, C. M., Bailey, J., and Coppen, A.: Prophylactic treatment of alcoholism by lithium carbonate, Lancet 2:481, 1976. 17. Altschule, M. D.: Adrenocortical function in anorexia nervosa before and after lobotomy, N. Engl. J. Med. 248:808, 1953. 46

18. Barcai, A.: Lithium in adult anorexia nervosa, Acta Psychiatr. Scand. 55:97, 1977. 19. Altschule, M. D., and Tillotson, K. J.: Mechanisms underlying pulmonary and cardiac complications of electrically induced convulsions, N. Engl. J. Med. 238:113, 1948.

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