-tion through the other pathway. This work not only tells us something about chlorpromazine but can tell us something about the differences between these two pathways. Such basic research can, therefore, tell us both about drugs and about the way the brain works. It can also provide methods for the selection of better new drugs. For example, it has been indicated above that the drug iproniazid is sometimes helpful in the treatment of depression. This drug has no specific effect on the behavior of laboratory animals when given by ordinary injection. However, if a very small tube is placed in the animal's brain and the tube connected with a solution of iproniazid, the animal will learn rapidly to press a lever energetically which causes iproniazid to be injected into his hypothalamus. This is a clear and striking effect which resembles the effect produced by electrical stimulation in the same area. This finding tells us something about the drug iproniazid, but also may provide a method for finding other chemical compounds which may produce effects similar to iproniazid and may be either more effective or have fewer unpleasant side effects. As we learn more about the way drugs act in the brain and the way the brain acts to affect behavior, it may become possible to set up screening procedures with which to search for drugs with specific effects useful in treating psychiatric symptoms or syndromes. To this end the National Institute of Mental Health is actively promoting a program of support for studies aimed at evaluating the assets and liabilities of drugs in current use in psychiatry. This is combined with a broad program of basic research on the ways in which drugs affect brain function and brain function affects behavior. III. PSYCHOPHARMACOLOGY PROGRAM OF THE NIMH It is clear from the foregoing account that psychopharmacology has become of major importance to the field of mental health. The Psychopharmacology Service Center was organized within the National Institute of Mental Health in the fall of 1956 to stimulate needed research in this field. This program was substantially furthered by the 83d Congress, which appropriated the sum of $2 million for the support of research on the assets, liabilities, and mechanisms of action of these drugs. An additional sum was appropriated for the support of the Psychopharmacology Service Center's staff activities. A. THE PSYCHOPHARMACOLOGY SERVICE CENTER The objectives of the Psychopharmacology Service Center are as follows: 1. To stimulate and support a broad program of clinical research. a. To establish the clinical efficacy of psychiatric drugs. (1) To obtain precise and definitive knowledge about the effectiveness of drugs in the treatment of psychiatric patients. (2) To establish the indications and contraindications for the use of particular drugs for specific types of patients. (3) To develop new methods and techniques for use in clinical drug research. (4) To delineate and analyze the nondrug factors, such as environmental influences or staff attitudes, that seriously affect the responses of patients to drug therapy. b. To gain the most complete knowledge possible of the toxic and other undesirable side effects of the drugs. (1) To obtain full-range knowledge about the somatic side effects, and their relation to amelioration of symptoms, dosage, route of administration, and duration of treatment. (2) To obtain information about adverse effects of drugs on psychological functions, such as learning, psychomotor performance, and efficiency. 2. To promote the development of better drugs. a. To encourage and support the synthesis of new compounds. b. To stimulate the development of efficient screening methods for selecting potentially useful compounds. 3. To promote fundamental research on the modes of action of psychopharmacological drugs. a. To stimulate and support research leading to an understanding of the psychological and physiological variables (including autonomic functioning) basic to modes of action of chemical compounds in normal human beings and in mentally ill patients. b. To promote studies of the effects of drugs on animal behavior. c. To stimulate and support research on neurophysiological and electrophysiological correlates of drug action in men and animals, and to establish the relationship of these correlates to overt behavior. d. To promote studies of the effects of drugs at the cellular and biochemical level. In the last year and a half the Psychopharmacology Service Center has been actively engaged in stimulating a variety of research projects designed to carry out the objectives described above. 1. Clinical studies A considerable number of clinical drug studies are now underway. To date the major emphasis has been upon the stimulation of clinical studies of the effectiveness of various drugs with schizophrenic patients, since this group constitutes the largest segment of the hospitalized psychiatric patient population. Work now underway should provide detailed knowledge concerning the effectiveness of reserpine and the phenothiazine derivates with this patient population. In addition it should reveal differential effects of any of these drugs in specific patient subgroups or symptom complexes within the broad diagnostic category of schizophrenia. Additional studies focus on the effectiveness of these drugs in the treatment of nonhospitalized schizophrenic patients and in maintaining in the community patients released from the hospital on maintenance drug therapy. Several of the studies now underway will also develop new approaches to the measurement and analysis of drug effects in psychiatric patients. One project is determining whether chronic schizophrenic patients respond better to drug therapy if they are treated in a specialized active treatment center than if they are treated in a State hospital. 2. Side effects Other current studies are investigating the relationship between the Parkinsonian side effects produced by chlorpromazine and reserpine and the clinical improvement produced by these drugs. Still others are concerned with the effects of these drugs on a variety of psychological functions, including reasoning, performance under stress, reaction time, perception, and complex psychomotor activities. 3. Drug synthesis and screening Although the drug industry is actively synthesizing and testing a wide variety of chemical compounds for tranquilizing or energizing activity, a few drug synthesis projects are being supported in academic institutions to enable investigators there to pursue fresh ideas and concepts, and to develop new methods for the synthesis of potentially useful psychiatric drugs. A number of the projects now being supported which deal with the effects of drugs on animal behavior will provide information useful to the pharmaceutical industry in improving their methods for detecting better psychiatric drugs. 4. Basic research A considerable number of research projects now underway deal directly with the way these drugs act on the central nervous system, at the biochemical or neurophysiological levels. Other studies attempt to define and clarify the ways in which these drugs modify behavior of animals or the psychological and physiological functioning of normal human subjects. 5. Relationship of the Psychopharmacology Service Center research program to the total drug research activity of the country The American drug industry has been and is working intensively at synthesizing and testing drugs potentially useful in the treatment of psychiatric patients. While present methods used to identify such drugs with experimental animals are probably not ideal, the information on clinical effectiveness of these compounds is often inadequate to enable the real usefulness of the current screening methods to be determined. In attempting to improve our identifying and screening techniques, the Psychopharmacology Service Center program interacts with the work of the industry in several ways. First, the Psychopharmacology Service Center is able to support more complex and definitive clinical drug studies which will provide the necessary information for the evaluation of current animal screening methods. Second, through grant support and interaction with potential investigators, the staff of the Psychopharmacology Service Center can both assist the expansion of existing centers for the clinical study of psychiatric drugs and enable new research units to be formed, thereby increasing the total national effort in this direction. In addition the Psycho pharmacology Service Center keeps in close contact with ongoing research in those areas which it is not supporting. Consultative services on problems of research planning have been made available both to clinical investigators connected with the drug industry and to investigators working independently or under grants from private foundations. The Institute is now supporting, through its research grants program, a total of 79 investigations in psychopharmacology for a total of $1,685,219. Since the Psychopharmacology Service Center's program has been in existence for only a year and a half, results are not available from many of the studies now under support. In addition, the Psychopharmacology Service Center has established a technical information unit to serve as a clearinghouse for data and scientific reports. The unit has collected approximately 3,500 articles on the use of drugs in psychiatry and the effect of drugs on human psychological functioning and animal behavior, plus a variety of articles on their side effects and mechanisms of action. This material is made available to interested investigators and is used in the preparation of review articles on various aspects of the field. In the above ways the Psychopharmacology Service Center acts to supplement and complement the considerable amount of ongoing research in psychopharmacology. B. OTHER INSTITUTE ACTIVITIES A number of research studies on the psychoactive drugs are also being conducted in the Institute's own laboratories. These include electrophysiological and other studies which attempt to determine the parts of the brain on which these drugs act, as well as detailed studies of the behavioral effects of psychopharmacologic agents. In addition the Addiction Research Center at Lexington, Ky., is studying these compounds for addictive properties. Clinical investigators at the Institute are comparing the effects of psychoactive drugs on intellectual, perceptual, and motor skills in the schizophrenic patients and normal individuals. Other studies are concentrating on the extent to which a patient's life history affects his response to these compounds. The Institute is also planning to conduct controlled large-scale trials of the psychoactive drugs in a new research facility that is being activated this year. This facility will also provide a setting for studying the impact of drug therapy on mental hospital services and evaluating the need for increased hospitalcommunity cooperation to promote rehabilitation of mental patients. IV. CONCLUSION We have seen that each of the major categories of new, or recently used, drugs which influence psychological function has potential therapeutic value. A few carefully controlled clinical studies have been made, and other such studies are now in progress. But much additional clinical research needs to be done. In addition to their therapeutic potential, these drugs are also proving to be useful in basic laboratory investigations of the functioning of the nervous system. It is to be anticipated that the use of these drugs will continue, both in therapy and in research. New drugs and other derivatives of present drugs will undoubtedly appear, and be given trials. Scientific evaluation will continue. The interplay between research and clinical application should make it possible for these drugs to be appropriately used as a part of the total treatment program for many persons suffering from mental and emotional disorders. APPENDIX (REPRESENTATIVE LIST OF PSYCHOACTIVE DRUGS NOW AVAILABLE FOR PRESCRIPTION USE BY PHYSICIANS) 2. Rauwolfia alkaloids: (psychomotor agitation): Reserpine Rescinnamine Deserpidine 3. Chemically heterogeneous tranquilizers (anxiety-tension states): (a) Diphenylmethane derivatives: EXHIBIT 11. SUPPLEMENTARY MATERIAL BY DR. IAN STEVENSON 1. Examples of failure to emphasize adequate harmful side effects of drugs Journal, American Medical Asociation, 162: 628, 1956. Drug B: Advertising represents the drug as having negligible side effects and complications, yet a report by a reliable investigator in the New York State Journal of Medicine, 57: 1742, 1957 (see also American Journal of Psychiatry 114: 656, 1958), describes important and potentially dangerous side effects. Subsequent advertising of both these drugs had continued to neglect or minimize side effects. 2. Use in advertising of uncontrolled investigations with neglect of negative studies and controlled experiments Drug A. Marketed after only two published clinical reports of its effectiveness. Advertising has continued to quote from uncontrolled and impressionistic observations and to neglect mention of two controlled studies of this drug which show that it is not more effective than a blank placebo or a much cheaper barbiturate. (Editorial: British Medical Journal, Nov. 24, 1956, 1227) "TOXIC EFFECTS OF MEPROBAMATE "The sedative drug meprobamate (Miltown, Equanil) is beginning to be widely prescribed in Britain. It is a drug which has been accepted everywhere in the United States both by doctors and by the public, to whom surprisingly enough it is advertised. Last March a drugstore in Los Angeles displayed a large advertisement, 'Yes, we have miltown.' It has been praised almost daily in the press, on the wireless, and on television, the particular claim being that it is specially suited for the relief of tension, anxiety, and insomnia, since it is almost free from side effects. What is happening now is that the side effects and undesirable actions are being discovered and recorded. Meprobamate has caused severe and widespread skin reactions. H. T. Friedman and W. L. Marmelzat1 describe five cases in which mainly purpurtic rashes were seen. These were accompanied by severe itching, and appeared first in the area of the pelvic girdle, the genitalia, and groin. They say that one 400-milligram tablet of 1 Friedman, H. T., and Marmelzat, W. L., J. Amer. Med. Assoc., 1956, 162, 628. 3 2 meprobamate may produce the skin lesions in less than 4 hours. In addition they report 3 cases in which the drug produced not sedation but excitement, 1 case of excessive peristalsis and diarrhea, and 1 case of palsy of the extraocular muscles with diplopia. W. J. Carmel and T. Dannenberg also describe 3 cases of purpura, oedema, and erythema observed within 3 months. A patient after taking two tablets suffered from generalized pruritus with petechial dermatitis over the thighs and inguinal region, later affecting arms, hands, and feet. The thighs and buttocks were diffusely swollen and erythematous. This record is characteristic of the others. F. I. Gottlieb has also described a case of a woman of 42 who, after a third tablet, developed a widespread hemorrhagic rash on the axillae, breast, abdomen, thighs, and legs. She had a rise of temperature together with chills and some oedema. After 4 days she had widespread purpura. These results strongly suggest that meprobamate belongs to the class of compounds which can release histamine in the body. F. Lemere ‘ considers that meprobamate is habit forming, since patients become dependent on it and cannot continue without it. Six patients who had been formerly addicts to alcohol and barbiturates refused to continue taking meprobamate because they did not want to become addicted to it also. "In the journal this week Drs. E. D. West and A. F. da Fonseca report some controlled trials with meprobamate. In one of them they compared it with sodium amylobarbitone in the treatment of 51 patients with psychoneurosis and found the results were almost the same. But the authors add that some few patients did benefit from meprobamate only and others from sodium amylobarbitone only. Transient urticarial rashes occurred in five of their patients. Meprobamate has the disadvantage of costing the hospital dispensary 24 times considerations suggest that claims made for meprobamate that it is the ideal as much as an equivalent therapeutic dose of a short-acting barbiturate. These drug for the treatment of insomnia, tension, and anxiety should be accepted with great reserve." Disagree with Dr. Kline as to (a) Capacity of physicians to evaluate drugs. Many examples show their failure to do this: Bleeding, purging, blistering; diet for ulcer, recently studied; many surgical operations. (b) That the market place is the best place for the test of a drug. Alcohol, tobacco, different brands of aspirin, at least one well-known tranquilizer, spa treatments. Advertising will not be continued unless it is valuable, but medical treatments may be. 3. Examples of use of dramatic, pictorial, and symbolic techniques of advertising. (1) Symbolic techniques. Snow in the woods, alpine mountains and lakes to suggest serenity and link this with the tranquilizer named. Many such advertisements contain almost no expository verbal content. (2) Pictures of patients disturbed, depressed, anxious, and subsequently radiantly cheerful with implication that they have been transformed by the drug advertised. Word pictures similarly drawn ; brief cases histories. (3) Phrases of dramatic impact, torn out of context and run as leads to and advertisement. Now "care of the man rather than merely his stomach" in ad for a tranquilizer combined with anticholinergic drug quoted from a book, the authors of which have spent years studying the influence of suggestion and who have protested the uncritical widespread use of many drugs having no value. Drug B: Marketed with wide advertising as having "normalizing" effects. A recent article in American Journal of Psychiatry, 111:656, 1958, reported a study in which this drug was found relatively ineffective compared to other preparations in its group. 3. Use of dramatic, pictorial, and symbolic techniques of advertising Examples provided of drugs C, D, E. 4. Use of quasi-scientific manner of presenting advertising material Example of drug F. 2 Carmel, W. J., and Dannenberg, T., New England J. Med., 1956, 255, 770. Gottlieb, F. I., J. Amer. Med. Assoc., 1956, 161, 96. * Lemere, F., ibid., 1956, 160, 1431. |