The symptoms we now use for classification may be end products not suitable as the basis for etiological groupings. This was true with miasmal fever and numerous other "syndromes" in the past.

LEADS AS TO ETIOLOGY

It would be almost unnatural if responsivity to drugs did not provide valuable leads as to mechanisms of action and etiological factors. This is true not only in respect to biochemical and neurophysiological but also psychological and social factors. The social and psychological circumstances under which these medications lead to favorable (or unfavorable) outcome must necessarily provide information about psychodynamics and physiodynamics. To cite only one instance: the incidence of depression among reserpine treated patients who are given the drug for hypertension is markedly higher than the incidence of such depression in psychiatric cases. This helps to clarify and substantiate a hypothesis about the psychodynamics of the hypertensive individual which has long been suspected but never before been so subject to experimental validation, i. e., a large number of these individuals must constantly be proving to themselves and to everyone else that they are remarkably active and potent since there exists a great underlying fear of not being able to cope with the world. When such an individual is immobilized and his energy level reduced (as occurs with reserpine) he can no longer utilize this ego defense and ergo there follows the depression.

The use of iproniazid is suggestive of both psychodiagnostic and biochemical mechanisms. It is not infrequent that the neurotic patient will present symptoms of both anxiety and depression. Many times in the treatment of such a case it is extremely valuable to know whether the depression is subsequent upon the anxiety or whether the anxiety is basic and eventually leads to depression as a sequelae. In our own clinical experience to date it would appear that if depression were basic the individual has a good therapeutic response to iproniazid whereas if the anxiety is basic the secondary depression does not respond to the same degree. Similarly, in the biochemical area there is at least tentative evidence that the inhibition of monamine oxidase is one mechanism which will provide relief for such conditions. This is naturally highly suggestive of the chemicopathology of this condition and leads to some verifiable (or disconfirmable) hypotheses.

PHILOSOPHIC IMPORT

The so-called mind-body problem has been a perennial one in both philosophy and psychology. Although at the moment it may seem rather a fantasy and somewhat farfetched, there is reason to have hope that the defining of relationships between the two may eventually lead to either an isomorphism or the development of a conceptual system capable of encompassing both.

SPECIFIC PSYCHIATRIC SYNDROMES

There are also a sizable number of specific areas in which it probably would be well worth while exploring whether pharmaceuticals can be developed which have useful application.

Obsessive compulsive neurosis

Of all the psychiatric conditions this is among the least amenable to presently available forms of therapy. In occasional cases psychotherapy and in other cases presently available pharmacotherapy or a combination have proved effective but these tend to be the exception rather than the rule. As implied above, it may be that obsessive compulsive behavior itself is a defense against a number of quite different underlying pathologies but this has not yet been established. A further point is that in my opinion the lumping together of obsessive thinking and compulsive behavior may be erroneous and misleading. Certainly the two types do have something in common insofar as they are repetitive and apparently "beyond the control" of the patient but there are certain other clinical elements which suggest that in reality these may be separate disease entities. In the usual obsessional patient there is frequently a spread of the obsessions from their starting point to other areas of thought and as a rule the general patterns of thinking are of the "obsessional" variety even in areas where there is not overt pathology. With the exception to be mentioned shortly it is unusual in the very extreme for an obsessional patient to become compulsive. Similarly, the compulsive patient rarely has an "obsession" about any area other than the one involved with the compulsion itself. Frequently these patients appear to be quite "free" in other

The

areas without the obsessional type thinking in uncontaminated areas. exception to the above rule is when a patient is placed under extreme danger in which case any or all of the ego defense mechanisms may be called into play. One example of this was seen during the last World War and in the Korean conflict when the soldier's life was directly endangered. Some of these individuals in attempting to ward off the threatened destruction of integrity utilized both obsessive and compulsive (as well as other mechanisms) of defense. The other example is when the destructive threat arises internally as seems to be the case in many instances of schizophrenia. Such individuals will again call into play panneurotic defenses which may include both obsessions and compulsions in addition to psychosomatic conversions, etc.

By the use of such mechanisms it is sometimes possible for the patient to achieve compensatory stability which may persist over many years. The regularity with which a certain percentage of incipient schizophrenias utilize the obsessivecompulsive defenses to achieve such stability has led some clinicians to the conclusion (erroneous in my opinion) that this syndrome is a precursor of schizophrenia or falls in a category between the neuroses and the psychoses. In contrast most obsessives and most compulsives give no evidence whatsoever of underlying schizophrenic or other psychotic processes.

In the search for pharmaceuticals which may favorably influence the outcome of such behavior I believe the distinction should be made in searching for agents with which to treat obsessions and those with which to treat compulsions. The development of animal screening techniques for drugs in this area present some interesting challenges. Evidences of compulsive behavior are far from unknown in veterinary practice and such animals might be used directly or a determination made of the circumstances under which such pathology arose in an effort to replicate it. (Mettler, incidentally, holds that animals become neurotic only as a result of association with humans-which is certainly some sort of social commentary.) I believe it would be also possible to determine the presence of "obsessional" thinking by the utilization of certain discrimination choices.

The usefulness and validity of inducing such behavior by neurological lesions will be discussed subsequently.

Arteriosclerosis

Even the most ardent advocates of the presently available pharmaceuticals which are purported to be of use in the treatment of arteriosclerosis are not satisfied with the relatively minor changes which they feel can be evoked. Metrazol, L-Glutavite, etc., produced, if anything, only mild symptomatic changes. Considering the increasing importance of this group of patients it probably constitutes the most neglected area in psychiatric research in terms of its importance. Twenty years ago only 11 percent of the admissions in New York State were over the age of 70, whereas in recent years this group has constituted approximately 30 percent of the admissions. In a special sense this group is the particular responsibility of the pharmaceutical industry since in no small manner it is drugs that are responsible for this influx of arteriosclerotics and seniles: Without the antibiotics the great majority of these patients would have not lived into this age group and hence would not have had the opportunity of becoming mentally ill. As the Hoover Commission report commented, there is little point in prolonging life if it is to end an ignominious hospitalization in a mental institution. In many respects the problem is even broader than has generally been recognized since unquestionably a very large segment of the population develop lesser degrees of cerebral arteriosclerosis not severe enough to require hospitalization but of sufficient seriousness to impair their intellectual, emotional, and behavioral functioning. Pharmaceuticals useful in the handling of both the hospitalized and the subclinical cases in this area would contribute not only to a more productive and healthy society but would probably have a market exceeding that of any drug now available. A number of possible approaches to this problem are either contemplated or already underway. To indicate only a few of these: Pharmacological agents which induced peripheral vasodilation may act to increase cerebral circulation. Although it is doubtful if brain tissue which has been without oxygen for any sustained period can be revived there invariably exists a borderline area in which the changes are still reversible and an increase in blood flow may make these again functional.

Another slightly different approach to the problem would be by the use of anticoagulants which also to some degree might permit the rehabilitation of brain tissue which was only functionally inactivated and, perhaps, more importantly, prevent extension of the vascular shutdown. The brain possesses a remarkable

capacity to reutilize available tissue so that it is not unreasonable to expect that if extension of the damage can be prevented at least a percentage of these patients could achieve some degree of social recovery. A third approach would be through the use of certain hormones which, on the basis of preliminary evidence, may act to stimulate revascularization and promote extension of capillaries and other vascular elements. This, too, would serve to bring back into function marginal tissue and prevent extension of the damage.

Once agents of this type have been identified, the need for early detection and treatment will assume extremely significantly proportions. Instead of waiting until the process has extended to a degree that the individual is incapacitated or the deficit grossly obvious it would be of great importance to look for early signs of such pathology both by physical examination (possibly utilizing the retinal artery) and by psychological test devices since this is one area in which they have a high degree of both reliability and validity. In addition to the prevention of mental disease such a program would go far to promote successful enterprise in all walks of life-the academic, the industrial, or what have you. At the present time major policy decisions and direction are frequently made by individuals who have achieved seniority and there appears to be a correlation between seniority and arteriosclerosis. Fortunately the correlation is not 100 percent and obviously any senior individual hearing or reading this constitutes one of the exceptions.

Intelligence

The need for some effective means of treating mental deficiency is obvious from the great excitement occasioned by even the remotest claims of some new method of treatment. Available agents which are claimed to have some effect are not felt to be very effective even by their strongest protagonist. The generous financial support given to Linus Pauling for his plan to undertake biochemical investigations in this area is another reflection of the immensity and importance of the problem. Presumptive evidence that at least some types of mental disease are due to biochemical idiosyncrasies is demonstrated by the oligophrenia accompanying phenylketonuria which at long last appears to be under control. Once again early detection and prophylaxis against extended damage present an alluring prospect.

The potentialities of dealing with intelligence by pharmaceutical techniques can also be dealt with in a positive sense. In other words it may be possible not only to correct the deficits of nature but to extend and intensify the intellectual functions of the average individual. Certainly the amount of gray matter with which we are endowed would indicate that the human mind is capable of much more intensive and extensive use. The occasional individual who for at least short periods of time is capable of truly creative and intensive thinking would demonstrate that the failure of the majority of us to perform this way is a result of inadequate function rather than of capacity. The tentative gestures in the direction of augmenting this function as indicated by the use of psychomotor stimulants and similar preparations argue strongly for the case that with intensive research the availability of such drugs is probably really not beyond our grasp. Let us contemplate with a tiny bit of satisfaction the fact that we at least have enough intelligence to recogsize that we do not have enough intelligence and should try to do something about the situation.

Sexual potency

The sampling of persons whom a psychiatrist gets to see are necessarily biased and selected but certainly in this group the problem of sexual potency is by no means a minor one. According to the unquestionably reliable reports of a majority of patients this the same problem is no less frequent among the spouses and friends who supposedly are normal. On the basis of the few field studies that have been done there is confirmation of the widely endemic nature of this problem. The real difficulty is that the deficiency is not limited to loss of adequate sexual satisfaction but that the frustration of the female and the feelings of impotence of the male extend themselves into other life relationships, often with disastrous effects. The female frustrated between the sheets will find outlets for her frustration and irritability in life situations which may prove socially disruptive. The male, having failed to demonstrate his potency in bed will attempt to compensate by proving his prowess in ordering about his employees and barking at his children or he may take the diametrically opposite attack, feeling that since he does not function as a male in one area that he has no right to try in other sectors. These are only a few among a multitude of the possible reactions against such a situation. There exists no question that 98 percent of impotence is on an emotional basis. Psychotherapy, where it is successful, is available in any case to only a fraction

of a fraction of a percent which places the major medical responsibility in the hands of medical research which in this case unquestionably involves the pharmaceutical industry.

Homosexuality

Although there is no firm agreement as to the etiology of homosexuality it is the opinion of some of us that there are basically two quite different conditions involved although the outward manifestations may appear highly similar. One might postulate that there is a genetic type of homosexuality with which the individual is born and that the second type is that imposed by the emotional reaction to a particular environment. If one were to hold that the individual born with a predisposition in this direction were the true homosexual the other would then appropriately be labeled as a pseudohomosexual. The basis for this dichotomy is still largely on clinical therapeutic grounds since with some patients the recognition and acceptance of the fact that homosexuality may for them be the most appropriate means of sexual outlet provides complete relief of secondary symptoms such as anxiety, depression, etc. They are, in fact, quite joyful that their sexual expression need not necessarily foredoom them to feelings of guilt and the like. On the other hand with the pseudohomosexual there is no willingness to accept a homosexual role but much more a desire to be heterosexual at the same time accompanied by an unwillingness to assume the emotional and practical responsibilities of the heterosexual condition.

It is sometimes felt that genetic conditions are per se untreatable and therefore the greatest therapeutic effort should be devoted to those whose illness arises as a result of environmental circumstances. This I believe to be a false conception since genetic deficits or idiosyncrasies can frequently be successfully managed and eventually when knowledge becomes adequate may even be rectified pre- or immediately post-natally and may ultimately be preventable. There exists some evidence that there are biological differences in "genetic" homosexuals but this work needs further substantiation. It is however not inconceivable that the

defect may turn out to be an alterable one.

On the other hand homosexuality, particularly if it is reinforced by years of living, regardless of whether it be genetic or environmental in its origin is a difficult problem to treat and would probably be much less amenable to pharmacologic influence. There have been numerous attempts to alter such behavior by the use of hormones and various chemicals, none of which have stood the test of time. A more fruitful therapy would probably begin before there were overt manifestations of the condition since, as indicated, reinforcement in the form of repeated experience complicates the problem. Thus, in this speculative instance, the correction of a genetic condition is easier than one arising environmentally (at least on paper).

Sleep

The problem of an adequate hypnotic has by no means been successfully solved and unquestionably the work will continue along these lines until more appropriate preparations are available. As in other therapies, e. g., the phenothiazines, the aim of some people is to obtain "the perfect sedative" or "the perfect hypnotic" whereas such an animal would be a contradiction in term. By this I mean that there are individuals whose major problem is falling asleep and who are fine once that condition has been achieved. There are other individuals who experience no difficulty in dropping into the arms of Morpheus but who find the proximity of such a type that they remain for only an hour or two. In other cases there is the problem of early rising. It appears extremely unlikely that a single hypnotic would be capable of rectifying all these pathologies. The newer hypnotics appear to have certain advantages over traditional ones but they have not been time tested long enough for such conclusions to be fully substantiated. Actually the older hypnotics such as chloral hydrate and paraldehyde have among the largest margins of safety and were it not for the fact that they presently are not available in the convenient tablet form, that paraldehyde has an all too recognizable odor, and that chloral hydrate is not always fully predictable in its action because the first step in its breakdown depends upon the gastric state-they would be among the very best.

In the opposite direction there are individuals who are obsessed by sleep, devoting a disproportionate amount of time to this activity. Along with these in terms of correcting such a condition one cannot but speculate as to why sleep is necessary at all since no one as yet has demonstrated a biochemical or physiological explanation that can be substantiated in terms of such requirements. Certainly there are individuals who spontaneously sleep only a few hours a night but whose perform

ance is in every respect equal to the usual 8-hour addict. An interesting side effect of psychic energizers appears to be that in most cases the sleep requirements are reduced to 4 or 5 hours a night without any development of fatigue. Patients on an ambulatory, extremely functional basis, have in my own practice been able to go for a year now with 3 to 5 hours a night sleep with no evidence of undesirable side effects. For a period I also experimented with iproniazid on myself and found the same condition resulting. The psychomotor stimulants will also act this way for short periods of time but present a disadvantage in that there tends to be a subsequent letdown and that in substantial doses they frequency induce euphoria. On the other hand they act much more quickly than the presently available psychic energizers so perhaps the combination of the two (as originated by Spiegel) is the most valuable way of using them both in depression or prevention of fatigue. It is an interesting speculation as to what the world would do with a daily increase of 6 or 8 billion extra man-hours of time which would result if the 2 billion people in the universe were to save 3 or 4 hours of sleep every night. If used responsibly and profitably it might be a significant contribution and at least permit some of us who find a continual time deficit move toward that ideal of a 48-hour day. Memory

Not only in arteriosclerosis is there loss of memory but almost all of us at times find that information which we had once learned has "disappeared" although on occasions when we do not need it, it sometimes intrudes itself. On the basis of hypnosis it appears fairly evident that almost everything that has happened to us is actually still present but is not always available. Under proper conditions of hypnotic regression it is possible to return an individual to earlier periods of his life during which memory of events transpiring appears to be almost complete. Occasionally one hears, or sees or meets individuals whose conscious recall is very much of this type. Not only do these individuals have so-called photographic memories but they are able to reproduce at will almost everything they have seen or read. Recently on a quiz program, the $64,000 Question, there appeared an individual of this type whose intelligence level did not appear extraordinary but whose capacity to reproduce from memory was quite phenomenal in terms of the capacities of the average person. The fact that engrams are probably present gives rise to the provocative notion that these, somehow or other, might be facilitated selectively to be made available when needed. In part, this is involved with the stimulation of certain areas of the brain as is evident by stimulation of various areas of the brain noted by Penfield and others during surgery. Selective ablation in animals or stimulation in humans and animals might give a lead as to their loci. Even at the present time with the use of barbiturates and certain other compounds it is possible to facilitate re-creation of situations in which an individual is able to bring to active recall events which were not available otherwise. It certainly does not seem beyond the realm of possibility to find pharmaceuticals which would not only facilitate hypnosis but might act to allow memory to be selectively used in the completely waking state.

At the other extreme is the desirability on certain occasions of having memories repressed or obliterated and this again presents challenging areas for investigation to determine whether pharmaceuticals alone or in combination with other techniques might be useful in temporarily at least repressing memories which are interfering with the emotional or mental health of the individual.

Addiction

Our own work would seem to indicate that at least in a fair number of cases of addiction iproniazid might prove useful. Nunnberg had advanced the hypothesis that underlying most addiction is depression and by rectifying the depressive state the drive toward addiction is relieved. This would apply to not only narcotic addiction but also to the much more common problem of alcoholism, of which there are roughly some 4 million individuals in the United States at the present time who are regarded as "problem drinkers." The usefulness of the psychomotor stimulants in the area of emotionally determined obesity is already known. It is not at all unlikely that these pharmaceuticals work not simply because they reduce appetite per se but to some degree serve to relieve underlying depression. Our knowledge of the mechanism is still extremely limited in this respect.

Pain asymbolia

Despite a history dating back to the earliest records of mankind the mechanism by which opiates reduce pain is still not known. Recent neurosurgical and neurophysiological evidence would indicate that not only are there specific areas of the brain which mediate this function but that these may be localized to some